interacts_with DB00898?
DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side-effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side-effects from domperidone may be influenced by patient-related factors including polymorphisms in genes encoding drug-metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side-effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single-nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single-nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty-eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p=0.0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p=0.041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p=0.0277 ) . The side-effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side-effects . P32297 variant for lung cancer is associated with chronic obstructive pulmonary disease in Korea . BACKGROUND : Genome-wide association studies have identified P32297 as a lung cancer and chronic obstructive pulmonary disease ( P48444 ) candidate gene in non-Hispanic Caucasian cohorts . However , there are differences in minor allele frequencies among ethnic groups , and limited data exists for Asian populations . OBJECTIVES : The aim of this case-control study was to determine whether there is an association between P48444 and genetic variation in P32297 in the Korean population . In addition , we investigated the association of P32297 with intermediate disease phenotypes including emphysema and lung function in P48444 subjects . METHODS : Two single-nucleotide polymorphisms ( SNPs ) in P32297 ( rs660652 and rs12910984 ) were genotyped in 219 P48444 subjects registered in the Korean Obstructive Lung Disease cohort study and in 305 control subjects . Volumetric computed tomography was performed in all P48444 subjects . Emphysema severity was measured quantitatively by determining the volume fraction of the lung below -950 Hounsfield units . Logistic regression analysis for case-control analysis and linear regression modeling for quantitative analysis were performed using SAS . RESULTS : This case-control analysis of 219 P48444 patients and 305 control participants identified a significant association between an SNP of P32297 ( rs12910984 ) and P48444 ( p = 0.049 ) . Analysis in P48444 subjects revealed that genetic variations were not associated with FEV1 . There was no association between SNPs and emphysema severity . However , both SNPs were significantly associated with DLCO . CONCLUSION : Genetic variations in P32297 are associated with P48444 in the Korean population . Differential gene expression in relation to the clinical characteristics of human brain arteriovenous malformations . Arteriovenous malformations ( AVMs ) of the central nervous system are considered as congenital disorders . They are composed of abnormally developed dilated arteries and veins and are characterized microscopically by the absence of a capillary network . We previously reported DNA fragmentation and increased expression of apoptosis-related factors in AVM lesions . In this article , we used microarray analysis to examine differential gene expression in relation to clinical manifestations in 11 AVM samples from Japanese patients . We categorized the genes with altered expression into four groups : death-related , neuron-related , inflammation-related , and other . The death-related differentially expressed genes were P14780 , P15018 , P04179 , Q16548 , P39900 , and P17066 . The neuron-related genes were P01303 , P06702 , Q15784 , S100Abeta , Q9UQM7 , Q8TBG9 , P08172 , and Q8NCB2 . The inflammation-related genes were PTX3 , P10145 , P05231 , P02778 , P32455 , P20309 , P09341 , P27930 , P55774 , and Q99616 . In addition , we compared gene expression in those with or without clinical characteristics including deep drainer , embolization , and high-flow nidus . We identified a small number of genes . Using these microarray data we are able to generate and test new hypotheses to explore AVM pathophysiology . Microarray analysis is a useful technique to study clinical specimens from patients with brain vascular malformations . Association study of 45 candidate genes in nicotine dependence in Han Chinese . Numerous genetic linkages , association studies have been performed in different ethnic groups and revealed many susceptibility loci and genes for nicotine dependence . However , limited similar researches were performed in Han Chinese . This study was designed to investigate the association of candidate genes with nicotine dependence in Han Chinese . We genotyped 384 SNPs within 45 candidate genes with nicotine dependence in a Han Chinese population consisting 223 high nicotine dependent subjects and 257 low nicotine dependent subjects by employing GoldenGate genotyping assay ( Illumina ) . Following association analysis was performed using PLINK software . Individual SNP-based association analysis revealed that nine SNPs located in P35462 ( rs2630351 ) , P21918 ( rs1967550 ) , Q9Y6R4 ( rs2314378 ) , DDC ( rs11575461 ) , Q05901 ( rs4954 ) , O75899 ( rs2779562 ) , P14416 ( rs11214613 and rs6589377 ) and P43681 ( rs2236196 ) were significantly associated with FTND after correction for multiple testing with the p values from 2.59×10(-7) to 9.99×10(-5) . Haplotype-based association analysis revealed haplotype G-A-A formed by rs2630351 , rs167771 and rs324032 and haplotype G-G-G-A formed by rs3773678 , rs2630349 , rs2630351 and rs167771 in P35462 ; haplotype of G-A formed by rs2779562 and rs2808566 in O75899 and haplotype of T-T-A-G-A formed by rs6832644 , rs4057797 , rs9764 , rs4552421 and rs10033119 in P25929 are associated with FTND ( p=3.61×10(-7)-8.78×10(-6) ) . Our results provided confirmation of the previous findings that P14416 , P35462 , DDC , Q05901 , O75899 and P43681 are associated with nicotine dependence . Furthermore , we for the first time report a significant association between nicotine dependence and P21918 , Q9Y6R4 and P25929 . These findings need independent replication in the future studies . Chromosome 8p as a potential hub for developmental neuropsychiatric disorders : implications for schizophrenia , autism and cancer . Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia . Presumably , owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult . However , the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established . There are 484 annotated genes located on 8p ; many are most likely oncogenes and tumor-suppressor genes . Molecular genetics and developmental studies have identified 21 genes in this region ( ADRA1A , O15013 , Q15822 , Q15825 , Q05901 , Q9UBT3 , Q16555 , Q06889 , O60258 , Q9NP95 , P11362 , FZD3 , LDL , NAT2 , P07197 , Q02297 , PCM1 , P00750 , P48454 , Q8N474 and P54219 / P54219 ) that are most likely to contribute to neuropsychiatric disorders ( schizophrenia , autism , bipolar disorder and depression ) , neurodegenerative disorders ( Parkinson 's and Alzheimer 's disease ) and cancer . Furthermore , at least seven nonprotein-coding RNAs ( microRNAs ) are located at 8p . Structural variants on 8p , such as copy number variants , microdeletions or microduplications , might also contribute to autism , schizophrenia and other human diseases including cancer . In this review , we consider the current state of evidence from cytogenetic , linkage , association , gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease . We also describe how a mutation in an 8p gene ( Fgf17 ) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex . We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer , despite the shortcomings of this evidence . Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17-1A and interleukin-2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co-medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin-2 ( P60568 ) induced cytotoxicity and P60568 -induced-ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 -induced-ADCC . DB00904 , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type-2 receptor antagonist augmented the P60568 -induced-ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type-2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC . Immunotoxicity of aminocarb . III . Exposure route-dependent immunomodulation by aminocarb in mice . Aminocarb , a phenylsubstituted methylcarbamate pesticide ( 4-dimethylamino-3-methyl-N-carbamate ; matacil ) , previously suspected of a relatively low immunotoxic potential , was administered by four different exposure routes to C57BL/6 mice . A single sublethal exposure by oral and dermal routes stimulated humoral immune response at a relatively low dose ; 1/256 LD50 of aminocarb . Intraperitoneal ( i.p. ) injection decreased the humoral P27918 response , whereas inhalation of aminocarb had no marked effect on peripheral immune status in exposed animals . Thus , i.p. exposure resulted in higher immunotoxicity over oral administration of aminocarb . Similarly , marked route-related exposure differences in immunomodulatory effects of aminocarb were noted for mitogenic stimulation of spleen lymphocytes and mixed lymphocyte response . Other indices , such as delayed type hypersensitivity ( DTH ) and production of interleukin-2 ( P60568 ) were unchanged . Interestingly , expression of major histocompatibility complex ( MHC ) class II by purified , lipopolysaccharide ( LPS ) -stimulated B cells increased equally after i.p. and oral exposures to aminocarb . Overall , a weak immunosuppressive potential of aminocarb was concluded , which was possibly due to indirect interaction of the pesticide with the immune system . However , aminocarb may represent an autoimmunity-inducing toxic . Effects of ethanol on the properties of platelets and endothelial cells in model experiments . AIM : To investigate effects of ethanol on activity markers of atherosclerosis in an in vitro endothelial cell model . METHODS : After 24 h incubation with ethanol ( 0.0095 % ) , human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide , and were then incubated in direct contact with activated platelets . Following this incubation , the expression of P29965 and CD62P on platelets , and the expression of intercellular adhesion molecule-1 ( P05362 ) , vascular cell adhesion molecule-1 ( P19320 ) , urokinase plasminogen activator receptor ( Q03405 ) , and membrane-type 1 matrix metalloproteinase ( P50281 ) on endothelial cells were measured by flow cytometry . RESULTS : The increased expression of P19320 and Q03405 on endothelial cells by proinflammatory stimulation with activated platelets was significantly reduced through pre-incubation with ethanol ( P < 0.05 ) . Furthermore , platelets in direct contact with ethanol and with endothelial cells pre-incubated in ethanol showed a significant reduction in their P29965 expression ( P < 0.05 ) . DB00898 had no significant effect on P05362 and P50281 expression on endothelial cells . CONCLUSION : DB00898 directly attenuates platelet activation and has significant endothelial cell-mediated effects on selected markers of atherosclerosis in vitro . These findings underline possible protective effects of ethanol on atherosclerosis . GABA Receptors Genes Polymorphisms and DB00898 Dependence : No Evidence of an Association in an Italian Male Population . OBJECTIVE : The genes encoding for gamma-aminobutyric acid ( GABA ) A and B receptors may be considered as candidates for alcoholism ; genetic alterations at this level may produce structural and functional diversity and thus play a role in the response to alcohol addiction treatment . To investigate these aspects further , we conducted a preliminary genetic association study on a population of Italian male alcohol addicts , focusing on GABA A and B receptors . METHODS : A total of 186 alcohol-dependent subjects ( in the first phase 139 , then 47 more samples ) and 182 controls were genotyped for 25 single nucleotide polymorphisms ( SNPs ) of genes encoding the alpha-1 subunit of GABA A receptor ( P14867 ) and subunits 1 and 2 of GABA B receptor ( Q9UBS5 and O75899 ) . The chi-squared test for allele and genotype distributions and Hardy-Weinberg equilibrium analysis of both subjects and controls were performed . Bonferroni 's correction for multiple comparisons was applied . RESULTS : Preliminary results comparing 139 alcohol-dependent subjects and 182 controls showed differences in genotype distribution in the former for SNP rs29253 , located in the intron region of the Q9UBS5 gene . In order to clarify the meaning of this association , 47 more samples from alcohol-dependent subjects were tested for this SNP only : the previously found association was not confirmed . CONCLUSION : The lack of significant differences between the two groups does not provide evidence that GABRA 1 and Q9UBS5 and 2 genes are candidates for alcoholism in this population . Further studies with larger samples are needed , together with investigation of other components of the GABA pathway . Growth factor-induced transcription of GluR1 increases functional AMPA receptor density in glial progenitor cells . We analyzed the effects of two growth factors that regulate oligodendrocyte progenitor ( O-2A ) development on the expression of glutamate receptor ( GluR ) subunits in cortical O-2A cells . In the absence of growth factors , GluR1 was the AMPA subunit mRNA expressed at the lowest relative level . P09038 ( P09038 ) caused an increase in GluR1 and GluR3 steady-state mRNA levels . Platelet-derived growth factor ( PDGF ) did not modify the mRNA levels for any of the AMPA subunits but selectively potentiated the effects of P09038 on GluR1 mRNA ( 4.5-fold increase ) . The kainate-preferring subunits Q13003 , Q16099 , and Q16478 mRNAs were increased by P09038 , but these effects were not modified by cotreatment with PDGF . Nuclear run-on assays demonstrated that PDGF+ P09038 selectively increased the rate of GluR1 gene transcription ( 2.5-fold over control ) . Western blot analysis showed that GluR1 protein levels were increased selectively ( sixfold over control ) by PDGF+ P09038 . Functional expression was assessed by rapid application of AMPA to cultured cells . AMPA receptor current densities ( pA/pF ) were increased nearly fivefold in cells treated with PDGF+ P09038 , as compared with untreated cells . Further , AMPA receptor channels in cells treated with PDGF+ P09038 were more sensitive to voltage-dependent block by intracellular polyamines , as expected from the robust and selective enhancement of GluR1 expression . Our combined molecular and electrophysiological findings indicate that AMPA receptor function can be regulated by growth factor-induced changes in the rate of gene transcription . Altered decorin leads to disrupted endothelial cell function : a possible mechanism in the pathogenesis of fetal growth restriction ? OBJECTIVE : Fetal growth restriction ( P09769 ) is a key cause of adverse pregnancy outcome where maternal and fetal factors are identified as contributing to this condition . Idiopathic P09769 is associated with altered vascular endothelial cell functions . P07585 ( P07585 ) has important roles in the regulation of endothelial cell functions in vascular environments . P07585 expression is reduced in P09769 . The objectives were to determine the functional consequences of reduced P07585 in a human microvascular endothelial cell line model ( HMVEC ) , and to determine downstream targets of P07585 and their expression in primary placental microvascular endothelial cells ( PLECs ) from control and P09769 -affected placentae . APPROACH : Short-interference RNA was used to reduce P07585 expression in HMVECs and the effect on proliferation , angiogenesis and thrombin generation was determined . A Growth Factor PCR Array was used to identify downstream targets of P07585 . The expression of target genes in control and P09769 PLECs was performed . RESULTS : P07585 reduction decreased proliferation and angiogenesis but increased thrombin generation with no effect on apoptosis . The array identified three targets of P07585 : O60258 , Q14116 and O14793 . Validation of target genes confirmed decreased expression of P15692 , P14780 , EGFR1 , P12314 and P49763 in HMVECs and PLECs from control and P09769 pregnancies . CONCLUSIONS : Reduction of P07585 in vascular endothelial cells leads to disrupted cell functions . The targets of P07585 include genes that play important roles in angiogenesis and cellular growth . Therefore , differential expression of these may contribute to the pathogenesis of P09769 and disease states in other microvascular circulations . Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism (PE). tPA has not been replaced by third generation plasminogen activators , e.g. DB00015 ( Ret ) and DB00031 ( TNK ) that circulate with longer life-spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor-1 ( e.g. P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility . Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators . DB00659 and naltrexone are effective medications in the treatment of alcoholism . However , effect sizes are modest . Pharmacogenomics may improve patient-treatment-matching and effect sizes . It is hypothesized that naltrexone exerts its effect through genetic characteristics associated with the dopaminergic/opioidergic positive reinforcement system , whereas acamprosate works through the glutamatergic/GABAergic negative reinforcement system . DB00898 -dependent subjects were randomly assigned to either acamprosate or naltrexone . Subjects participated in a cue-exposure experiment at the day before and at the last day of medication . Reductions in cue-induced craving and physiological cue reactivity were measured . Differential effects of naltrexone and acamprosate on these outcomes were tested for different polymorphisms of the opioid , dopamine , glutamate and GABA-receptors . Significant matching effects were found for polymorphisms at the P14416 , Q16445 and P47870 gene . In addition , a trend was found for the P35372 polymorphism . This provides evidence for the matching potential of genotypes . It is expected that more effective treatments can be offered when genetic information is used in patient-treatment-matching . Altered gene expression in the spleen of adolescent rats following high ethanol concentration binge drinking . Binge drinking of alcoholic beverages among adolescents is a common practice that can have serious health consequences . DB00898 is a potent immunomodulator that alters a wide range of immune responses . However , it is unclear whether there is a differential immune response to alcoholic beverages with a high versus low concentration of ethanol . In this study , we used a PCR array containing 46 primer pairs of selected genes to compare mRNA expression in the spleen , an immune system organ , of adolescent rats following binge drinking of alcohol solutions containing either 20 % or 52 % ethanol ( v/v , 4.8 g/kg daily dosage ) , or water ( control ) for 3 d . We found that , expression of IL-1β , P05231 , P13500 , and GABA(A) receptor α2 subunit in the spleen were decreased , and P41594 and P46098 receptor expression were increased after administration of an ethanol solution containing 52 % ethanol , but not one with 20 % ethanol . Our data suggest that alcohol-mediated immunomodulatory effects are , in part , dependent on the ethanol by volume concentration . This is the first study to show that exposure to a high ethanol percentage beverage can have more profound effects on immune responses than one with a low percentage of ethanol . Genetics and alcoholism . DB00898 is widely consumed ; however , excessive use creates serious physical , psychological and social problems and contributes to the pathogenesis of many diseases . DB00898 use disorders ( that is , alcohol dependence and alcohol abuse ) are maladaptive patterns of excessive drinking that lead to serious problems . Abundant evidence indicates that alcohol dependence ( alcoholism ) is a complex genetic disease , with variations in a large number of genes affecting a person 's risk of alcoholism . Some of these genes have been identified , including two genes involved in the metabolism of alcohol ( P00325 and P05091 ) that have the strongest known affects on the risk of alcoholism . Studies continue to reveal other genes in which variants affect the risk of alcoholism or related traits , including P47869 , P08172 , P48051 and Q8WXX7 . As more variants are analysed and studies are combined for meta-analysis to achieve increased sample sizes , an improved picture of the many genes and pathways that affect the risk of alcoholism will be possible . Genetic basis of delay discounting in frequent gamblers : examination of a priori candidates and exploration of a panel of dopamine-related loci . INTRODUCTION : Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards . It has been consistently linked to pathological gambling and other forms of addictive behavior , and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders ( i.e. , an endophenotype ) . Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission . The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine-related variants in a sample of frequent gamblers . METHODS : Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva . RESULTS : In a priori tests , two loci previously associated with delayed reward discounting ( rs1800497 and rs4680 ) were not replicated , however , the long form of P21917 VNTR was significantly associated with lower discounting of delayed rewards . Exploratory analysis of the dopamine-related panel revealed 11 additional significant associations in genes associated with dopamine synthesis , breakdown , reuptake , and receptor function ( P35462 , Q01959 , DDC , P09172 , and Q05940 ) . An aggregate genetic risk score from the nominally significant loci accounted for 17 % of the variance in discounting . Mediational analyses largely supported the presence of indirect effects between the associated loci , delay discounting , and pathological gambling severity . CONCLUSIONS : These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting . Development of peptidomimetic ligands of Pro- DB00149 - DB00145 -NH(2) as allosteric modulators of the dopamine D(2) receptor . A variety of stable , small-molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro- DB00149 - DB00145 -NH(2) ( P00747 ) modulates dopaminergic neurotransmission . Photoaffinity labeling ligands based upon P00747 peptidomimetics have been used to establish that P00747 binds to the P14416 at a site that is different from the orthosteric site , thus making P00747 and its peptidomimetics allosteric modulators of the dopamine receptor . Through the design , synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam , bicyclic , and spiro-bicyclic scaffolds , support was provided for the hypothesis that the bioactive conformation of P00747 is a type II β-turn . In addition , studies with peptidomimetics designed to mimic either a type VI β-turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH(2) pharmacophore in the same topological space as that seen in the type II β-turn . Extensive studies with the spiro-bicyclic P00747 peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold . This information was used to transform existing positive modulators into negative modulators , which demonstrated that small structural changes in the spiro-bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of P00747 peptidomimetics . Clinical trials in thrombolytic therapy , Part 2 : The open-artery hypothesis and RAPID-1 and RAPID-2 . The open-artery hypothesis as supported by thrombolytic study results is discussed . The open-artery hypothesis states that survival after acute myocardial infarction ( AMI ) is maximized by achieving early and sustained patency of the infarct-related artery . However , two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase , despite previous evidence that alteplase led to earlier recanalization of infarct-related arteries . The Global Utilization of DB00086 and Tissue P00747 Activator for Occluded Coronary Arteries ( GUSTO-1 ) trial suggested that early and complete patency is essential for short-term survival after AMI . Subsequent observations indicated that an open infarct-related artery at the time of hospital discharge is associated with improved long-term survival . In the DB00015 Angiographic Phase II International Dose-Finding ( RAPID-1 ) trial , complete patency was more frequent in patients who received a double-bolus regimen of reteplase than in patients who received standard-dose alteplase . Similar results were obtained in the DB00015 versus DB00009 Patency Investigation during Myocardial Infarction ( RAPID-2 ) trial , which compared the same double-bolus reteplase regimen with an accelerated regimen of alteplase . In both RAPID studies , mortality was lower and other outcomes were more favorable in reteplase recipients . DB00015 seems more likely to produce normal blood flow soon after AMI than either standard-dose or accelerated alteplase and may be associated with a lower mortality rate . This lends further support to the open-artery hypothesis . Identification of genes associated with enhanced metastasis of a large cell lung carcinoma cell line . We have compared the transcriptional profile of large cell lung tumor cell lines NIH-H460 and H460-M making use of the Affymetrix GeneChip system . H460-M is derived from NIH-H460 and displays enhanced experimental and spontaneous metastasis in nude mice . Out of the 12,600 genes investigated , 73 ( 0.6 % ) were up-regulated and 114 ( 0.9 % ) were down-regulated on the basis of the scoring criteria . We have classified the de-regulated genes according to the following categories : immune response , enzymes , modulation of transcription , signal transduction , cytoskeleton/adhesion and extracellular matrix associated proteins , cell-cycle/apoptosis , transporters and ' others ' . Among the remarkable features of this system are the up-regulation of the steady-state mRNA levels of neuroendocrine markers such as neurotensin ( P30990 ) , neuroendocrine-specific protein ( NSP ) , neural cell adhesion molecule 1 ( P13591 ) and gamma-aminobutyric acid B-type receptor ( O75899 ) in cell line H460-M . Semaphorin 3B ( Q13214 ) was dramatically down-regulated in cell line H460-M and emerged as the most interesting gene for target validation . DB00898 -related expectancies are associated with the D2 dopamine receptor and GABAA receptor beta3 subunit genes . Molecular genetic research has identified promising markers of alcohol dependence , including alleles of the D2 dopamine receptor ( P14416 ) and the GABAA receptor beta3 subunit ( P28472 ) genes . Whether such genetic risk manifests itself in stronger alcohol-related outcome expectancies , or in difficulty resisting alcohol , is unknown . In the present study , A1+ ( A1A1 and A1A2 genotypes ) and A1- ( A2A2 genotype ) alleles of the P14416 and P55008 + ( G1G1 and P55008 non- P55008 genotypes ) and P55008 - ( non- P55008 non- P55008 genotype ) alleles of the P28472 gene were determined in a group of 56 medically ill patients diagnosed with alcohol dependence . Mood-related alcohol expectancy ( AE ) and drinking refusal self-efficacy ( DRSE ) were assessed using the Drinking Expectancy Profile ( Manual for the Drinking Expectancy Profile , Behaviour Research and Therapy Centre , Brisbane , 1996 ) . Patients with the P14416 A1+ allele , compared with those with the P14416 A1- allele , reported significantly lower DRSE in situations of social pressure . Similarly , lower DRSE was reported under social pressure by patients with the P28472 P55008 + allele when compared to those with the P28472 P55008 - alleles . Patients with the P28472 P55008 + allele also revealed reduced DRSE in situations characterized by negative affect than those with the P28472 P55008 - alleles . Patients carrying the P28472 P55008 + allele showed stronger AE relating to negative affective change ( for example , increased depression ) than their P28472 P55008 - counterparts . Biological influence in the development of some classes of cognitions is hypothesized . The clinical implications , particularly with regard to patient-treatment matching and the development of an integrated psychological and pharmacogenetic approach , are discussed . Partial agonists of the α3β4* neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats . DB00898 use disorders ( AUDs ) impact millions of individuals and there remain few effective treatment strategies . Despite evidence that neuronal nicotinic acetylcholine receptors ( nAChRs ) have a role in AUDs , it has not been established which subtypes of the nAChR are involved . Recent human genetic association studies have implicated the gene cluster P32297 - P30532 - P30926 encoding the α3 , α5 , and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence ; however , their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools . To determine the role of the α3 , and β4 subunits of the nAChR in ethanol self-administration , we developed and characterized high-affinity partial agonists at α3β4 nAChRs , CP-601932 , and PF-4575180 . Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure . We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations , suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs . Also varenicline , an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice , reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs . Furthermore , the selective α4β2(*) nAChR antagonist , DHβE , did not reduce ethanol intake . Together , these data provide further support for the human genetic association studies , implicating P32297 and P30926 genes in ethanol-mediated behaviors . CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs . An in vitro model of human acute ethanol exposure that incorporates P49682 - and P61073 -dependent recruitment of immune cells . Alcoholic liver disease ( P33897 ) is one of the commonest causes of cirrhosis and liver failure in the developed world . Hepatic inflammation is the critical stage in progression of both P33897 and non- P33897 , but it remains difficult to study the underlying mechanisms in a human system , and current animal models do not fully recapitulate human liver disease . We developed a human tissue-based system to study lymphocyte recruitment in response to ethanol challenge . Precision-cut liver slices ( PCLS ) from human livers were incubated in culture , and hepatic function was determined by albumin production , 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide assay , glucose uptake responses , and morphometric assessment . Responses of tissue and lymphocytes to ethanol exposure were determined by PCR , flow cytometry , histology , and lymphocyte infiltration assays . Human PCLS demonstrated appropriate upregulation of P05181 , ADH1α , and P00326 in response to ethanol treatment . DB00898 also induced expression of endothelial P19320 and P05362 , production of sICAM-1 and P10145 , and the chemokine receptors P49682 and P61073 on P01730 and CD8 lymphocytes . P49682 - and P61073 -dependent migration of lymphocytes into the tissue increased significantly in response to treatment with ethanol . We have demonstrated that ethanol increases chemokine receptor expression and lymphocyte recruitment into human liver tissue , suggesting that it may operate directly to promote hepatitis in P33897 . The physiological and pathophysiological responses of the PCLS to ethanol in vitro highlight the potential of this assay for dissecting the molecular mechanisms underlying human liver inflammation and as a screening tool for novel therapeutics . DNA binding-independent induction of P25963 gene transcription by PPARalpha . PPARs are ligand-activated transcription factors that regulate energy homeostasis . In addition , PPARs furthermore control the inflammatory response by antagonizing the nuclear factor-kappaB ( NF-kappaB ) signaling pathway . We recently demonstrated that PPARalpha activators increase P25963 mRNA and protein levels in human aortic smooth muscle cells . Here , we studied the molecular mechanisms by which PPARalpha controls P25963 expression . Using transient transfection assays , it is demonstrated that PPARalpha potentiates p65-stimulated P25963 transcription in a ligand-dependent manner . Site-directed mutagenesis experiments revealed that PPARalpha activation of P25963 transcription requires the NF-kappaB and Sp1 sites within P25963 promoter . Chromatin immunoprecipitation assays demonstrate that PPARalpha activation enhances the occupancy of the NF-kappaB response element in P25963 promoter in vivo . Overexpression of the oncoprotein E1A failed to inhibit PPARalpha-mediated P25963 promoter induction , suggesting that DB02527 response element binding protein-binding protein/p300 is not involved in this mechanism . By contrast , a dominant-negative form of P11473 -interacting protein 205 ( Q15648 ) comprising its two LXXLL motifs completely abolished PPARalpha ligand-mediated activation . Furthermore , cotransfection of increasing amounts of Q15648 relieved this inhibition , suggesting that PPARalpha requires Q15648 to regulate P25963 promoter activity . By contrast , Q15648 is not involved in PPARalpha-mediated NF-kappaB transcriptional repression . Taken together , these data provide a molecular basis for PPARalpha-mediated induction of P25963 and demonstrate , for the first time , that PPARalpha may positively regulate gene transcription in the absence of functional Q07869 response elements . Gene expression studies provide clues to the pathogenesis of uterine leiomyoma : new evidence and a systematic review . BACKGROUND : Uterine leiomyomas are extremely common and a major cause of pelvic pain , bleeding , infertility , and the leading indication for hysterectomy . Familial and epidemiological studies provide compelling evidence that genetic alterations play an important role in leiomyoma development . METHODS : Using Affymetrix U133A GeneChip we analysed expression profiles of 22,283 genes in paired samples of leiomyoma and adjacent normal myometrium . We compared our results with previously published data on gene expression in uterine leiomyoma and identified the overlapping gene alterations . RESULTS : We detected 80 genes with average differences of > or = 2-fold and false discovery rates of < 5 % ( 14 overexpressed and 66 underexpressed ) . A comparative analysis including eight previous gene expression studies revealed eight prominent genes ( P07327 , P18847 , P29373 , O00622 , Q07507 , P42262 , P01344 , Q5EB52 ) identified by at least five different studies , eleven genes ( P00352 , P25063 , P29279 , O43602 , P28562 , P01100 , O60829 , P24592 , P41222 , P43115 , P04818 ) reported by four studies , twelve genes ( ABCA , P04083 , Q15847 , O00585 , P38936 , Q14194 , P54849 , P03372 , FY , Q99683 , P37173 , P35625 ) identified by three studies , and 40 genes reported by two different studies . CONCLUSIONS : Review of gene expression data revealed concordant changes in genes regulating retinoid synthesis , IGF metabolism , TGF-beta signaling and extracellular matrix formation . Gene expression studies provide clues to the relevant pathways of leiomyoma development . P00747 activator inhibitor-1 supports P10145 -mediated neutrophil transendothelial migration by inhibition of the constitutive shedding of endothelial P10145 /heparan sulfate/syndecan-1 complexes . The endothelium is the primary barrier to leukocyte recruitment at sites of inflammation . Neutrophil recruitment is directed by transendothelial gradients of P10145 that , in vivo , are bound to the endothelial cell surface . We have investigated the identity and function of the binding site(s) in an in vitro model of neutrophil transendothelial migration . In endothelial culture supernatants , P10145 was detected in a trimolecular complex with heparan sulfate and syndecan-1 . Constitutive shedding of P10145 in this form was increased in the presence of a neutralizing Ab to plasminogen activator inhibitor-1 ( P05121 ) , indicating a role for endothelial plasminogen activator in the shedding of P10145 . Increased shedding of P10145 /heparan sulfate/syndecan-1 complexes was accompanied by inhibition of neutrophil transendothelial migration , and aprotinin , a potent plasmin inhibitor , reversed this inhibition . Platelets , added as an exogenous source of P05121 , had no effect on shedding of the complexes or neutrophil migration . Our results indicate that P10145 is immobilized on the endothelial cell surface through binding to syndecan-1 ectodomains , and that plasmin , generated by endothelial plasminogen activator , induces the shedding of this form of P10145 . P05121 appears to stabilize the chemoattractant form of P10145 at the cell surface and may represent a therapeutic target for novel anti-inflammatory strategies . DB00898 blocks leukocyte recruitment and endothelial cell activation in vivo and in vitro . Immune system impairment and increased susceptibility to infection among alcohol abusers is a significant but not well-understood problem . We hypothesized that acute ethanol administration would inhibit leukocyte recruitment and endothelial cell activation during inflammation and infection . Using LPS and carrageenan air pouch models in mice , we found that physiological concentrations of ethanol ( 1-5 g/kg ) significantly blocked leukocyte recruitment ( 50-90 % ) . Because endothelial cell activation and immune cell-endothelial cell interactions are critical regulators of leukocyte recruitment , we analyzed the effect of acute ethanol exposure on endothelial cell activation in vivo using the localized Shwartzman reaction model . In this model , ethanol markedly suppressed leukocyte accumulation and endothelial cell adhesion molecule expression in a dose-dependent manner . Finally , we examined the direct effects of ethanol on endothelial cell activation and leukocyte-endothelial cell interactions in vitro . DB00898 , at concentrations within the range found in human blood after acute exposure and below the levels that induce cytotoxicity ( 0.1-0.5 % ) , did not induce endothelial cell activation , but significantly inhibited P01375 -mediated endothelial cell activation , as measured by adhesion molecule ( P16581 , P05362 , P19320 ) expression and chemokine ( P10145 , P13500 , RANTES ) production and leukocyte adhesion in vitro . Studies exploring the potential mechanism by which ethanol suppresses endothelial cell activation revealed that ethanol blocked NF-kappaB nuclear entry in an P25963 -dependent manner . These findings support the hypothesis that acute ethanol overexposure may increase the risk of infection and inhibit the host inflammatory response , in part , by blocking endothelial cell activation and subsequent immune cell-endothelial cell interactions required for efficient immune cell recruitment . Selective increases of AMPA , DB01221 , and kainate receptor subunit mRNAs in the hippocampus and orbitofrontal cortex but not in prefrontal cortex of human alcoholics . Glutamate is the main excitatory transmitter in the human brain . Drugs that affect the glutamatergic signaling will alter neuronal excitability . DB00898 inhibits glutamate receptors . We examined the expression level of glutamate receptor subunit mRNAs in human post-mortem samples from alcoholics and compared the results to brain samples from control subjects . RNA from hippocampal dentate gyrus ( HP-DG ) , orbitofrontal cortex ( OFC ) , and dorso-lateral prefrontal cortex ( DL- P27918 ) samples from 21 controls and 19 individuals with chronic alcohol dependence were included in the study . Total RNA was assayed using quantitative RT-PCR . Out of the 16 glutamate receptor subunits , mRNAs encoding two AMPA [ 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid ] receptor subunits P42262 and P42263 ; three kainate receptor subunits Q13002 , Q13003 and Q16478 and five DB01221 ( N-methyl-D-aspartate ) receptor subunits Q05586 , Q12879 , Q14957 , O15399 , and Q8TCU5 were significantly increased in the HP-DG region in alcoholics . In the OFC , mRNA encoding the DB01221 receptor subunit Q8TCU5 was increased , whereas in the DL- P27918 , no differences in mRNA levels were observed . Our laboratory has previously shown that the expression of genes encoding inhibitory GABA-A receptors is altered in the HP-DG and OFC of alcoholics ( Jin et al. , 2011 ) . Whether the changes in one neurotransmitter system drives changes in the other or if they change independently is currently not known . The results demonstrate that excessive long-term alcohol consumption is associated with altered expression of genes encoding glutamate receptors in a brain region-specific manner . It is an intriguing possibility that genetic predisposition to alcoholism may contribute to these gene expression changes . Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor . Studies with P29320 -293 cells and neurons . We co-immunoprecipitated the Ca(2+)-sensing receptor ( CaR ) and type B gamma-aminobutyric acid receptor ( GABA-B-R ) from human embryonic kidney ( P29320 ) -293 cells expressing these receptors and from brain lysates where both receptors are present . CaRs extensively co-localized with the two subunits of the GABA-B-R ( Q96GN5 and R2 ) in P29320 -293 cell membranes and intracellular organelles . Coexpressing CaRs and GABA-B-R1s in P29320 -293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [ Ca(2+) ] ( [Ca(2+)](e) ) . In contrast , coexpressing CaRs and GABA-B-R2s enhanced CaR expression and signaling responses to raising [Ca(2+)](e) . The latter effects of the O75899 on the CaR were blunted by coexpressing the Q9UBS5 . Coexpressing the CaR with Q9UBS5 or R2 enhanced the total cellular and cell surface expression of the Q9UBS5 or R2 , respectively . Studies with truncated CaRs indicated that the N-terminal extracellular domain of the CaR participated in the interaction of the CaR with the Q9UBS5 and R2 . In cultured mouse hippocampal neurons , CaRs co-localized with the Q9UBS5 and R2 . CaRs and GABA-B-R1s also co-immunoprecipitated from brain lysates . The expression of the CaR was increased in lysates from Q9UBS5 knock-out mouse brains and in cultured hippocampal neurons with their Q9UBS5 genes deleted in vitro . Thus , CaRs and GABA-B-R subunits can form heteromeric complexes in cells , and their interactions affect cell surface expression and signaling of CaR , which may contribute to extracellular Ca(2+)-dependent receptor activation in target tissues . All-trans retinoic acid downregulates P00352 -mediated stemness and inhibits tumour formation in ovarian cancer cells . Aldehyde dehydrogenase 1 ( P00352 ) is a cancer stem-like cell ( CSC ) marker in human cancers ; however , the specific P00352 -regulated function and its underlying signalling pathways have not been fully demonstrated . Here , we investigated the P00352 -regulated function and its underlying signalling and tested whether all-trans retinoic acid ( DB00755 ) can suppress P00352 -regulated tumour behaviour in ovarian cancer cells . By modulating P00352 expression using flow cytometry enrichment and exogenous overexpression or knockdown , we showed that the P00352 activity is positively correlated with stemness in ovarian cancer cells according to measures such as sphere formation and CSC marker expression as well as tumourigenesis in a mouse xenograft model . The findings indicate that the P00352 directly regulates the functions of ovarian cancer cells . We also showed that P00352 can regulate the expression of FoxM1 and P46531 , which are involved in the downstream signalling of P00352 -mediated biofunctions . Inhibition of FoxM1 by Thiostrepton and of Notch1 by DAPT downregulated the sphere formation ability of cells . DB00755 reduced P00352 expression , suppressed tumour formation and inhibited sphere formation , cell migration and invasion in P00352 -abundant ovarian cancer cells . We conclude that DB00755 downregulates P00352 /FoxM1/Notch1 signalling and suppresses tumour formation in ovarian cancer cells . ZNF804a regulates expression of the schizophrenia-associated genes Q9NQE7 , P21964 , Q07343 , and P14416 . ZNF804a was identified by a genome-wide association study ( GWAS ) in which a single nucleotide polymorphism ( SNP rs1344706 ) in ZNF804a reached genome-wide statistical significance for association with a combined diagnosis of schizophrenia ( SZ ) and bipolar disorder . Although the molecular function of ZNF804a is unknown , the amino acid sequence is predicted to contain a C2H2-type zinc-finger domain and suggests ZNF804a plays a role in DNA binding and transcription . Here , we confirm that ZNF804a directly contributes to transcriptional control by regulating the expression of several SZ associated genes and directly interacts with chromatin proximal to the promoter regions of Q9NQE7 and P21964 , the two genes we find upregulated by ZNF804a . Using immunochemistry we establish that ZNF804a is localized to the nucleus of rat neural progenitor cells in culture and in vivo . We demonstrate that expression of ZNF804a results in a significant increase in transcript levels of Q9NQE7 and P21964 , relative to GFP transfected controls , and a statistically significant decrease in transcript levels of Q07343 and P14416 . Furthermore , we show using chromatin immunoprecipitation assays ( ChIP ) that both epitope-tagged and endogenous ZNF804a directly interacts with the promoter regions of Q9NQE7 and P21964 , suggesting a direct upregulation of transcription by ZNF804a on the expression of these genes . These results are the first to confirm that ZNF804a regulates transcription levels of four SZ associated genes , and binds to chromatin proximal to promoters of two SZ genes . These results suggest a model where ZNF804a may modulate a transcriptional network of SZ associated genes . Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng/ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs. P09038 ( 10 ng/ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease . Association of Q05940 gene polymorphisms with alcohol dependence . DB00898 -related diseases cause significant harm in the western world . Up to 65 % of the phenotypic variance is genetically determined . Few candidate genes have been identified , comprising P08319 , P05091 , P21964 , P34998 , Q01959 ( Q01959 ) , P47869 and P21397 . While abnormalities in the dopaminergic mesolimbic reward system are considered important mediators of alcoholism , studies analyzing variants of dopamine receptors showed conflicting results . Other modulators of the reward system are synaptosomal genes . Among candidate genes , polygenic variants of the Vesicular Monamine Transporter 2 ( Q05940 ) gene locus associated with alterations of drinking behavior were published . These variants comprise single nucleotide polymorphisms ( SNPs ) within the promoter region and the open reading frame . In this study , we confirm the association of Q05940 SNP rs363387 ( allelic association : p = 0.015 ) with alcohol dependence . This SNP defines several haplotypes including up to four SNPs ( minimal p = 0.0045 ) . In addition , numeric effects in the subgroups of males and patients with positive family history were found . We suggest that several rs363387 T-allele containing haplotypes increase the risk of alcohol dependence ( OR 1.53 ) , whereas G-allele containing haplotypes confer protection against alcohol dependence . Taken together , there is supporting evidence for a contribution of Q05940 gene variants to phenotypes of alcohol dependence . Changes of several brain receptor complexes in the cerebral cortex of patients with Alzheimer disease : probable new potential pharmaceutical targets . Although Alzheimer disease ( AD ) has been linked to defects in major brain receptors , studies thus far have been limited to the determination of receptor subunits or specific ligand binding studies . However , the availability of current technology enables the determination and quantification of brain receptor complexes . Thus , we examined levels of native receptor complexes in the brains of patients with AD . Cortical tissue was obtained from control subjects ( n = 12 females and 12 males ) and patients with AD ( n = 12 females and 12 males ) within a 3-h postmortem time period . The tissues were kept frozen until further biochemical analyses . Membrane proteins were extracted and subsequently enriched by ultracentrifugation using a sucrose gradient . Membrane proteins were then electrophoresed onto native gels and immunoblotted using antibodies against individual brain receptors . We found that the levels were comparable for complexes containing GluR2 , GluR3 and P48058 as well as P08908 . Moreover , the levels of complexes containing muscarinic AChR M1 , Q9UHB4 and GluR1 were significantly increased in male patients with AD . Nicotinic AChRs 4 and 7 as well as dopaminergic receptors D1 and D2 were also increased in males and females with AD . These findings reveal a pattern of altered receptor complex levels that may contribute to the deterioration of the concerted activity of these receptors and thus result in cognitive deficits observed in patients with AD . It should be emphasised that receptor complexes function as working units rather than individual subunits . Thus , the receptor deficits identified may be relevant for the design of experimental therapies . Therefore , specific pharmacological modulation of these receptors is within the pharmaceutical repertoire . Nicotinic acetylcholine receptors containing the α6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons . DB00184 and alcohol are often co-abused suggesting a common mechanism of action may underlie their reinforcing properties . Both drugs acutely increase activity of ventral tegmental area ( VTA ) dopaminergic ( DAergic ) neurons , a phenomenon associated with reward behavior . Recent evidence indicates that nicotinic acetylcholine receptors ( nAChRs ) , ligand-gated cation channels activated by ACh and nicotine , may contribute to ethanol-mediated activation of VTA DAergic neurons although the nAChR subtype(s) involved has not been fully elucidated . Here we show that expression and activation of nAChRs containing the α6 subunit contribute to ethanol-induced activation of VTA DAergic neurons . In wild-type ( WT ) mouse midbrain sections that contain the VTA , ethanol ( 50 or 100 mM ) significantly increased firing frequency of DAergic neurons . In contrast , ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express Q15825 , the gene encoding the α6 nAChR subunit ( α6 knock-out ( KO ) mice ) . DB00898 -induced activity in WT slices was also reduced by pre-application of the α6 subtype-selective nAChR antagonist , α-conotoxin MII[E11A] . When co-applied , ethanol potentiated the response to ACh in WT DAergic neurons ; whereas co-application of ACh and ethanol failed to significantly increase activity of DAergic neurons in α6 KO slices . Finally , pre-application of α-conotoxin MII[E11A] in WT slices reduced ethanol potentiation of ACh responses . Together our data indicate that α6-subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons . These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement , providing a potential common therapeutic molecular target to reduce nicotine and alcohol co-abuse . Differential expression of retinoic acid receptor-beta isoforms during chick limb ontogeny . Retinoids influence both morphogenetic events and differentiation during development of the vertebrate limb . These effects are mediated through nuclear retinoid receptors , which modulate target gene expression . We report here the cloning and characterization of three promoter- and splicing-variants of the retinoic acid receptor-beta ( P10826 ) from chick . These receptor isoforms are independently expressed during limb development . RAR beta 2 but not RAR beta 1 transcripts are enriched three-fold in the posterior limb bud , reflecting the increased RA concentrations in this region . RAR beta 1 transcripts are initially present throughout the limb bud mesenchyme and ectoderm , then become restricted within perichondrial regions and loose connective tissue of the limb . RAR beta 1 expression closely overlaps that of P13591 ( neural cell adhesion molecule ) and tenascin in non-neuronal tissues . RAR beta 2 transcripts are present within a subset of those limb tissues which express RAR beta 1 . In the early limb bud RAR beta 2 transcripts are detected in proximal limb mesenchyme and in the initial mesenchymal condensate . In older limbs RAR beta 2 mRNAs are abundant in cells lateral to the digit cartilage . Neither RAR beta 1 nor RAR beta 2 transcripts are associated specifically with regions of limb cell death . The differential expression and regulation of RAR beta isoforms suggests these variants may have different roles in limb development . DB00898 dose-dependently elicits opposing regulatory effects on hippocampal AMPA receptor P42262 subunits through a zeta inhibitory peptide-sensitive kinase in adolescent and adult Sprague-Dawley rats . AMPA receptor P42262 subunits are strongly implicated in cognition , and prior work suggests that these subunits may be regulated by atypical protein kinase C ( aPKC ) isoforms . The present study assessed whether hippocampal and cortical AMPA receptor P42262 subunit regulation may be an underlying factor in known age-related differences to cognitive-impairing doses of ethanol , and if aPKC isoforms modulate such responses . Hippocampal AMPA receptor P42262 subunit , protein kinase Mζ ( PKMζ ) , and PKCι/λ expression were elevated during adolescence compared to adults . 1 h following a low-dose ( 1.0-g/kg ) ethanol exposure , hippocampal AMPA receptor P42262 subunit serine 880 phosphorylation was decreased in adolescents , but was increased in adults . Age-dependent changes in P42262 subunit phosphorylation were paralleled by alterations in aPKC isoforms , and zeta inhibitory peptide ( Q8N5A5 ) administration prevented ethanol-induced increases in both in adults . DB00898 -induced changes in P42262 subunit phosphorylation were associated with delayed regulation in synaptosomal P42262 subunit expression 24 h later . A higher ethanol dose ( 3.5-g/kg ) failed to elicit changes in most measures in the hippocampus at either age . Similar to the hippocampus , analysis of cerebral cortical tissue also revealed age-related declines . However , no demonstrable effects were found following a low-dose ethanol exposure at either age . High-dose ethanol exposure reduced adolescent P42262 subunit phosphorylation and aPKC isoform expression that were again accompanied by delayed reductions in synaptosomal P42262 subunit expression . Together , these results suggest that P42262 -containing AMPA receptor modulation by aPKC isoforms is age- , region- and dose-dependently regulated , and may potentially be involved in developmentally regulated ethanol-induced cognitive impairment and other ethanol behaviors . Role of P30532 -A3 genetic Locus variants and developing drug for chronic obstructive pulmonary disease . Cigarette smoking is one of the major risk factors for P48444 and P48444 severity . In turn P48444 is a major independent risk factor for lung cancer . Genome-wide association ( GWA ) studies both in lung cancer and P48444 highlighted the same variants ( SNPs ) on chromosome 15q25 marking the gene cluster P32297 - P30926 - P30532 for these smoking related diseases , showing a stimulating connection between this common genetic region and smoking behavior and smoking related illnesses . Different authors identified two candidate regions associated with age at smoking initiation in patients with P48444 . The nicotinic acetylcholine receptor polymorphism ( rs1051730 ) on chromosome 15q25 is associated with major tobacco-related diseases in the general population with additional increased risk of P48444 as well as lung cancer . Moreover variants on the gene cluster P32297 - P30926 - P30532 are associated with nicotine addiction antismoking therapy and antismoking therapy side-effects . These findings not only support the notion that variants can influence any therapy for smoking cessation , but offer rational bases to develop new drugs and new therapeutic strategies . Scope of Proposed Topic ( 50 words ) : Genome-wide association ( GWA ) studies both in lung cancer and P48444 highlighted the same variants ( SNPs ) on the gene cluster P32297 - P30926 - P30532 . These data not only support the notion that variants can influence any therapy for smoking cessation , but offer rational bases to develop new drugs and new therapeutic strategies . [ DB00988 -beta-hydroxylaseaktivität im Plasma von Dialysepatienten ( author 's transl ) ] . Plasma dopamin-b-hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50.0 +/- 29.3 IU . There was was no significant difference between males ( 53.9 +/1 33.8 IU ) and females ( 47.4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0.01 ) decreased ( 32.5 % /- 17.6 IU ) , suggesting lowered sympathetic activity and/or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients . Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post-prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post-prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and DB00222 are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 -sensitive potassium ( K+ DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti-carcinogen , anti-mutagen , and anticancer initiator , for its anti-diabetic activity in comparison to the two commercial drugs ( DB00731 and DB00222 ) . The drugs and the compounds were docked to the DB00171 -dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME/Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule . Domain organization of the DB00171 -sensitive potassium channel complex examined by fluorescence resonance energy transfer . K( DB00171 ) channels link cell metabolism to excitability in many cells . They are formed as tetramers of Kir6.2 subunits , each associated with a Q09428 subunit . We used mutant GFP-based FRET to assess domain organization in channel complexes . Q8N1N2 -length Kir6.2 subunits were linked to YFP or cyan fluorescent protein ( P27918 ) at N or C termini , and all such constructs , including double-tagged YFP-Kir6.2- P27918 ( Y6.2C ) , formed functional K( DB00171 ) channels . In intact COSm6 cells , background emission of YFP excited by 430-nm light was ∼6 % , but the Y6.2C construct expressed alone exhibited an apparent FRET efficiency of ∼25 % , confirmed by trypsin digestion , with or without Q09428 co-expression . Similar FRET efficiency was detected in mixtures of P27918 - and YFP-tagged full-length Kir6.2 subunits and transmembrane domain only constructs , when tagged at the C termini but not at the N termini . The FRET-reported Kir6.2 tetramer domain organization was qualitatively consistent with Kir channel crystal structures : C termini and M2 domains are centrally located relative to N termini and M1 domains , respectively . Additional FRET analyses were performed on cells in which tagged full-length Kir6.2 and tagged Q09428 constructs were co-expressed . These analyses further revealed that 1 ) NBD1 of Q09428 is closer to the C terminus of Kir6.2 than to the N terminus ; 2 ) the Kir6.2 cytoplasmic domain is not essential for complexation with Q09428 ; and 3 ) the N-terminal half of Q09428 can complex with itself in the absence of either the C-terminal half or Kir6.2 . Altered gene expression by low-dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real-time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT-PCR TaqMan low-density array ( TLDA ) . We found that expression of tumor necrosis factor-α ( P01375 -α ) , which activates both inflammation and NF-κB-dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion-channel genes CACNA1 , Q12809 , P51787 and P15382 were down-regulated by 1-μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion-channel function , may underlay the seemingly disparate array of arsenic-associated diseases , such as cancer , cardiovascular disease , and diabetes . Multiple single-nucleotide polymorphisms ( SNPs ) in the Japanese population in six candidate genes for long QT syndrome . We report here 20 single-nucleotide polymorphisms ( SNPs ) , including 15 novel ones , in six genes that are considered to be candidates for long QT syndrome ( LQTS ) : 2 SNPs in Q14721 , 3 in Q9UK17 , 3 in Q14654 , 7 in O60706 , 3 in P08588 , and 2 in Q05940 . We also examined their allelic frequencies in a Japanese sample population of LQTS-affected and nonaffected individuals . These data will be useful for genetic association studies designed to investigate acquired arrhythmias . Innovative approaches for the development of antidepressant drugs : current and future strategies . Depression is a highly debilitating disorder that has been estimated to affect up to 21 % of the world population . Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors ( SSRIs ) and serotonin and norepinephrine reuptake inhibitors ( SNRIs ) , there continue to be many unmet clinical needs with respect to both efficacy and side effects . These needs range from efficacy in treatment resistant patients , to improved onset , to reductions in side effects such as emesis or sexual dysfunction . To address these needs , there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas . There is tremendous diversity in the types of targets and approaches being taken . At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms ( P08908 , P28222 , P28221 , P28335 , alpha-2A ) . At the other end of the spectrum are more novel targets , such as neurotrophins ( P23560 , IGF ) , based on recent findings that antidepressants induce neurogenesis . In between , there are many approaches that range from directly targeting serotonin receptors ( P28335 , P50406 ) to targeting the multiplicity of potential mechanisms associated with excitatory ( glutamate , DB01221 , Q14416 , P41594 ) or inhibitory amino acid systems ( GABA ) or peptidergic systems ( neurokinin 1 , DB05394 1 , melanin-concentrating hormone 1 , V1b ) . The present review addresses the most exciting approaches and reviews the localization , neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations . P13569 in a lipid raft- P19438 complex modulates gap junctional intercellular communication and P10145 secretion . Mutations in the cystic fibrosis transmembrane conductance regulator ( P13569 ) cause a chronic inflammatory response in the lung of patients with Cystic Fibrosis ( CF ) . We have showed that P01375 signaling through the Src family tyrosine kinases ( SFKs ) was defective as determined by an inability of P01375 to regulate gap junctional communication ( GJIC ) in CF cells . Here , we sought to elucidate the mechanisms linking P01375 signaling to the functions of P13569 at the molecular level . In a MDCKI epithelial cell model expressing wild-type ( WtCFTR ) or mutant P13569 lacking its PDZ-interacting motif ( P13569 -DeltaTRL ) , P01375 increased the amount of WtCFTR but not P13569 -DeltaTRL in detergent-resistant membrane microdomains ( DRMs ) . This recruitment was modulated by SFK activity and associated with O60565 localization of P19438 and c-Src . Activation of P19438 signaling also decreased GJIC and markedly stimulated P10145 production in WtCFTR cells . In contrast , the absence of P13569 in DRMs was associated with abnormal P19438 signaling as revealed by no recruitment of P19438 and c-Src to lipid rafts in P13569 -DeltaTRL cells and loss of regulation of GJIC and P10145 secretion . These results suggest that localization of P13569 in lipid rafts in association with c-Src and P19438 provides a responsive signaling complex to regulate GJIC and cytokine signaling . Interplay between inhibitory ferric and stimulatory curcumin regulates phosphorylation-dependent human cystic fibrosis transmembrane conductance regulator and ΔF508 activity . Curcumin potentiates cystic fibrosis transmembrane conductance regulator ( P13569 ) activation in an DB00171 -independent but phosphorylation-dependent manner . The underlying molecular mechanisms are unclear . Here , P29320 -293T cells cultured in an Fe(3+)-containing medium were transiently transfected with P13569 constructs , and the role of the inhibitory Fe(3+) bridge between intracellular loop 3 and the regulatory domain of P13569 in this pathway was investigated . The results showed that ethylenediaminetetraacetic acid ( DB00974 ) stimulated phosphorylation-dependent P13569 activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe(3+)-binding interface . Furthermore , curcumin potentiation of P13569 was significantly weakened not only by Fe(3+)-insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N-ethylmaleimide or DB00974 pretreatment that removes Fe(3+) . More importantly , potentiation of P13569 was completely suppressed by sufficient Fe(3+) . Finally , the insertion of Fe(3+)-insensitive H950R/S768R increased the curcumin-independent activity of ΔF508 but weakened its curcumin potentiation . Thus , Fe(3+) homeostasis in epithelia may play a critical role in regulating P13569 activity , and targeting Fe(3+)-chelating potentiators may direct new therapies for cystic fibrosis . The human interleukin 18 gene Q14116 maps to 11q22.2-q22.3 , closely linked to the P14416 gene locus and distinct from mapped IDDM loci . Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all-trans-retinoic acid ( DB00755 ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR-alpha , RXR-beta and RXR-gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and DB00755 . Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K( DB00171 ) channels in pancreatic beta-cells and are used to stimulate insulin release in type 2 diabetes , whereas the K( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta-cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . DB01120 and tolbutamide are beta-cell selective and reversible . DB00222 , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K( DB00171 ) channels in addition to those in beta-cells and are only slowly reversible . Similar properties have been observed by recording K( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K( DB00171 ) channel subunits . While K( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2-type K( DB00171 ) channels ( e.g. , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K( DB00171 ) channels are to be avoided . [ Genetic aspects of occupational chronic obstructive lung disease under exposure to various risk factors ] . The article deals with data on association of SNP rs1828591 of Q96QV1 gene with COLD development under exposure to dust and chemical factors . SNP rs1800470 of TGFbeta1 gene is associated with occupational COLD under exposure to dust and did not show connection with COLD under exposure to chemical aerosols . No association was seen between SNP rs4129267 of IL-6R gene and SNP rs1051730 of P32297 gene with occupational COLD under exposure to the studied factors . SNP rs1828591 of Q96QV1 gene is associated with occupational COLD development under exposure to dust and chemical factors . Study of association of genotype and phenotypic features of COLD revealed the following trends : " dust " COLD patients with genotype AA SNP rs1800470 of TGFbeta1 gene show lower level of P02741 and P01375 , if compared with other genotypes . DB00898 increases desensitization of recombinant P48058 AMPA receptor and TARP combinations . Glutamate receptors are important target molecules of the acute effect of ethanol . We studied ethanol sensitivity of homomeric P48058 receptors expressed in human embryonic kidney 293 cells and examined whether recently discovered transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( AMPA ) receptor regulatory proteins ( TARPs ) affect ethanol sensitivity . Coexpression of the TARPs , stargazin , and gamma4 increased the time constant ( tau-value ) of current decay in the presence of agonist , thus slowing the onset of desensitization and increasing the steady-state current . DB00898 produced less inhibition of the peak current than the steady-state current for all types of the P48058 receptors . In addition , ethanol concentration-dependently accelerated the rate of desensitization , measured as the tau-value of fast decay of peak current . This effect was enhanced with coexpression of TARPs . The recovery from desensitization was slowed down by coexpression of gamma4 but ethanol did not affect this process in any P48058 combination . The results support the idea that increased desensitization is an important mechanism in the ethanol inhibition of AMPA receptors and indicate that coexpression of TARPs can alter this effect of ethanol . HepG2 human hepatoma cells express multiple cytokine genes . Although cytokines are known to be involved in the regulation of a variety of hepatocellular functions , hepatocytes themselves are generally considered only targets but not producers of these important mediators . In order to investigate whether cells of hepatocellular linages are a potential source of various regulatory cytokines we have estimated the multiple cytokine gene expression in the culture of well differentiated human HepG2 hepatoma cells using RT-PCR . Our findings demonstrate that HepG2 cells express mRNAs for interferon gamma ( P01579 ) , tumour necrosis factor alpha ( P01375 ) , transforming growth factor beta ( TGF-beta ) , macrophage colony-stimulating factor ( P09603 ) , oncostatin-M ( P13725 ) , intercellular adhesion molecule ( P05362 ) , interleukin 4 ( P05112 ) , P05113 , P13232 , P22301 , IL-11 , IL-12 and P05231 receptor ( IL-6R ) . At the same time the expression of IL-1 , P60568 , P08700 , P05231 , P29965 and IL-2R genes was not detected . It was concluded that hepatocytes are potential producers of a variety of cytokines , some of them being able to regulate hepatocellular functions directly , while others are important regulators of leukocyte activity . Thus , on the one hand , hepatocytes may express autoregulatory cytokines and on the other hand , influence the functions of other liver cells like Kupffer , Ito or endothelial cells . Due to their large amount , liver parenchymal cells could be an important source of sytemically acting pro- and anti-inflammatory and other regulatory cytokines . Genetics of alcoholism . DB00898 use and alcohol use disorders are substantially heritable . Variants in genes coding for alcohol metabolic enzymes have long been known to influence consumption . More recent studies in family-based samples have implicated P47869 , nicotinic receptor genes such as Q05901 , and a number of other specific single genes as associated with alcohol use disorders . The growing use of genetic analyses , in particular studies using polygenic risk scores ; neurobiologic pathways ; and methods for quantifying gene × gene and gene × environment interactions have also contributed to an evolving understanding of the genetic architecture of alcohol use disorders . Additionally , the study of behavioral traits associated with alcohol dependence such as impulsivity and sensation seeking , and the influences of demographic factors ( i.e. , sex and ethnicity ) have significantly enhanced the genetics of alcoholism literature . This article provides a brief overview of the current topically relevant findings in the field to date and includes areas of research still requiring attention . Low ethanol concentration alters P30532 RNA levels during early human development . DB00898 use is common and consumption during pregnancy has been shown to lead to a myriad of physical and neurologic abnormalities commonly referred to as fetal alcohol spectrum disorder . Substance addiction , which includes alcohol , has been shown to involve the major nicotinic acetylcholine receptor subunit P30532 . Using human embryonic stem cells as a model of early human development , we show that low concentrations of ethanol ( 20mM ) can alter the expression of P30532 . Changes in P30532 expression is linked to altered GABA and DB01221 receptor expression , as well as abnormal development of the frontal cortex . These results suggest that alcohol exposure can alter early neurologic development , which may favor addiction and other developmental abnormalities in unborn children . Association of indices of liver and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 diabetes in 6,733 non-diabetic Finnish men . AIMS/HYPOTHESIS : Of the confirmed type 2 diabetes susceptibility loci only a few are known to affect insulin sensitivity . We examined the association of indices of hepatic and adipocyte insulin resistance ( IR ) with 19 confirmed type 2 diabetes risk loci in a large population-based study . METHODS : Non-diabetic participants ( n = 8,460 , age 57.3 ± 7.0 years , BMI 26.8 ± 3.8 kg/m(2) ; mean ± SD ) from a population-based cohort underwent an OGTT . Of them , 6,733 non-diabetic men were genotyped for single nucleotide polymorphisms ( SNPs ) in or near PPARG2 ( also known as P37231 ) , Q14654 , Q9NQB0 , Q8IWU4 , Q03014 , P42772 , Q9Y6M1 , Q5VV42 , P35680 , O76024 , Q86VZ6 , O75794 , P19075 , Q6YHU6 , Q9P2N4 , Q04721 , P51787 , P49286 and SNP rs7480010 . We investigated hepatic IR with a new index of liver IR . The adipocyte IR index was defined as a product of fasting P80303 and plasma insulin levels . RESULTS : Type 2 diabetes risk SNPs in or near Q14654 and Q03014 were significantly ( p < 0.0013 ) , and those in or near P42772 , Q04721 and P49286 were nominally ( p < 0.05 ) , associated with decreased liver IR index . The Pro12 allele of PPARG2 was significantly associated with a high adipocyte IR index and nominally associated with high liver IR . CONCLUSIONS/INTERPRETATION : The Pro12 allele of PPARG2 seems to impair insulin 's antilipolytic effect , leading to high P80303 release in the fasting state and IR . In addition , the type 2 diabetes risk alleles of Q14654 and Q03014 , which are known to impair insulin secretion , were associated with increased hepatic insulin sensitivity . Cross-talk between PKA-Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . DB01656 , a phosphodiesterase (PDE)4-selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up-regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up-regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners . We also found that protein kinase A catalytic subunit β ( PKA-Cβ ) and nuclear factor-κB ( NF-κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA-Cβ phosphorylates p65 in a DB02527 -dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA-Cβ-induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor . DB09280 - DB08820 in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 . DB00501 induces interleukin-18 production through H2-agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) -18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine-induced Q14116 production . DB00501 induced the activation of caspase-1 , which is reported to modify immature Q14116 to mature/active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild-type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers . Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at DB00988 D2- and Serotonin- P08908 -receptors as well as an antagonism at Serotonin-5- Q13049 -receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein . DB00501 enhances antigen-specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti-ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB/c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG(1) , IgG(2a) and/or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE , IgG(1) and IgG(2a) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies . FcεRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages . BACKGROUND : Monocyte differentiation into dendritic cells or macrophages and recruitment to peripheral organs in chronic inflammatory diseases are directed by allergen challenge via FcεRI as well as the nature of soluble factors in the microenvironment . High-affinity receptor for IgE stimulation of effector cells results in the release of histamine , which acts on various histamine receptors ( HR ) 1-4 , expressed by immune cells . METHODS : We examined the effect of FcεRI stimulation of human monocytes on P35367 expression and function of differentiating cells . The mRNA levels of P35367 , P25021 and histidine decarboxylase of differentiating cells were detected by quantitative real-time PCR . Expression of CD1c , CD11c , P34810 and Q86VB7 was detected by flow cytometry . Amount of histamine , P05231 and IL-12p70 in the cell culture was measured with the help of cytometric bead arrays or ELISA assays . Numbers of P35367 -expressing macrophages were evaluated by immunofluorescence double staining of P34810 and P35367 on human skin sections . RESULTS : We demonstrated that FcεRI stimulation promotes the generation of P35367 -expressing macrophage-like cells with enhanced histamine biosynthesis and P35367 -mediated proinflammatory properties . Supporting our in vitro findings , high numbers of P35367 -expressing P34810 (pos) macrophages were detected in the dermis of atopic dermatitis ( AD ) skin lesions . CONCLUSION : Our observations point to a close histamine-/HR-mediated activation of dermal macrophages , leading to modified cell differentiation and responsiveness via P35367 , which might contribute to the aggravation of allergic skin inflammation in AD . The low-potency , voltage-dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high-affinity human ether-a-go-go-related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower-affinity Q12809 blockers may be different . In this study , alanine-substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . DB01182 's blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open-channel model ) . These findings are supported by very slow recovery of wild-type Q12809 channels from block at -120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open-state propafenone binding-site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi-stacking interactions with two or more Phe656 side-chains ) is either perturbed or becomes less accessible because of closed-channel gating . This provides further evidence for the existence of gating-induced changes in the spatial location of Phe656 side chains .