MH_dev_281

Synergistic effect of interleukin 1 alpha on nontypeable Haemophilus influenzae-induced up-regulation of human beta-defensin 2 in middle ear epithelial cells . BACKGROUND : We recently showed that beta-defensins have antimicrobial activity against nontypeable Haemophilus influenzae ( NTHi ) and that interleukin 1 alpha ( P01583 REA ) up-regulates the transcription of beta-defensin 2 ( DEFB 4 according to new nomenclature of the Human Genome Organization ) in human middle ear epithelial cells via a Src-dependent Raf - Q02750 REA / 2 - P29323 REA signaling pathway . Based on these observations , we investigated if human middle ear epithelial cells could release P01583 REA upon exposure to a lysate of NTHi and if this cytokine could have a synergistic effect on beta-defensin 2 up-regulation by the bacterial components . METHODS : The studies described herein were carried out using epithelial cell lines as well as a murine model of acute otitis media ( OM ) . Human cytokine macroarray analysis was performed to detect the released cytokines in response to NTHi exposure . Real time quantitative PCR was done to compare the induction of P01583 REA or beta-defensin 2 mRNAs and to identify the signaling pathways involved . Direct activation of the beta-defensin 2 promoter was monitored using a beta-defensin 2 promoter-Luciferase construct . An P01583 REA blocking antibody was used to demonstrate the direct involvement of this cytokine on DEFB 4 induction . RESULTS : Middle ear epithelial cells released P01583 REA when stimulated by NTHi components and this cytokine acted in an autocrine / paracrine synergistic manner with NTHi to up-regulate beta-defensin 2 . This synergistic effect of P01583 REA on NTHi-induced beta-defensin 2 up-regulation appeared to be mediated by the p38 Q96HU1 kinase pathway . CONCLUSION : We demonstrate that P01583 REA is secreted by middle ear epithelial cells upon exposure to NTHi components and that it can synergistically act with certain of these molecules to up-regulate beta-defensin 2 via the p38 Q96HU1 kinase pathway .

Dopamine-related genes and spontaneous smoking cessation in ever-heavy smokers . Several studies have provided evidence for associations of polymorphisms located in and near dopamine-related genes and nicotine dependence and other smoking-related phenotypes , including pharmacogenetic interactions . AIM : The purpose of the present work was to examine the association of SNPs in the P20711 REA ( DDC ) , dopamine receptor D2 ( P14416 REA ) and dopamine transporter ( Q01959 REA ) genes with smoking cessation in a large retrospective study featuring approximately 900 cessation events . MATERIALS & METHODS : Data originated from the enrollment questionnaire of the epidemiological ESTHER study of community-dwelling adults aged 50-74 years , conducted in the German state of Saarland between July 2000 and December 2002 . Restricting the analyses to subjects who reported to have regularly smoked > 20 cigarettes per day at some point in their life , we used survival analysis methods to model the time from initiation of regular smoking to cessation ( defined as quitting with abstinence lasting until enrollment ) and its relation with eight polymorphisms in the aforementioned genes ( five in DDC , two in P14416 REA and one in Q01959 REA ) in 1446 participants . RESULTS : Neither individual variants nor DDC haplotypes were associated with the probability of overcoming nicotine dependence in this cohort . CONCLUSION : The repeated suggestion of associations between the variants examined and nicotine dependence in previous reports seems to contrast the negative results in the present study . This would appear consistent with the hypothesis that the establishment of regular heavy smoking might abolish associations between genetic determinants of nicotine dependence and nicotine dependence-related phenotypes , in particular the probability of successful smoking cessation .

Phosphodiesterase - 4 inhibitors as a novel approach for the treatment of respiratory disease : cilomilast . Phosphodiesterase - 4 ( DB05876 ) is an important DB02527 - metabolising enzyme in immune and inflammatory cells , airway smooth muscle and pulmonary nerves . The phosphodiesterase 4 ( DB05876 ) enzyme plays a significant role in modulating the activity of DB02527 , an important second messenger that mediates the relaxation of airway smooth muscle and suppresses inflammatory cell function , thereby attenuating the inflammatory response . Selective inhibitors of this enzyme show a broad spectrum of activity in animal models of P48444 REA and asthma . These drugs block the hydrolysis of DB02527 via inhibition of DB05876 and are attractive candidates for novel anti-inflammatory drugs . At present , two second-generation DB05876 inhibitors for the treatment of P48444 REA and asthma patients are being tested in clinical Phase III trials . The most advanced compound is the orally active , selective DB05876 inhibitor cilomilast ( DB03849 MEN , SB - 207499 , cis - 4 - cyano - 4 - [ 3 - cyclopentyloxy - 4 - methoxyphenyl ] - cyclohexanecarboxylic acid ; GlaxoSmithKline ) . DB03849 MEN shows high selectivity for DB02527 - specific DB05876 , an isoenzyme that predominates in pro-inflammatory and immune cells and that is 10 - fold more selective for Q08499 REA than for P27815 REA , - B or - C . In vitro , cilomilast suppresses the activity of several pro-inflammatory and immune cells that have been implicated in the pathogenesis of asthma and P48444 REA . Moreover , it is highly active in animal models of these diseases . DB03849 MEN has been shown to exert potent anti-inflammatory effects both in vitro and in vivo . It is orally active and may be effective in the treatment of asthma and P48444 REA ; however , complete assessment of the therapeutic value of this novel compound class must await the outcome of longer-term clinical trials . This review presents a summary of the preclinical and clinical profile of cilomilast in patients with P48444 REA .

Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages . 2,3 , 7,8- Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 REA ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 REA protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up-regulation of an important inflammation marker , P35354 REA mRNA expression within 1h , and by 3h , several other markers become up-regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 + ) , and activation of P47712 REA and P35354 REA . A comparative study among three different human cell lines showed that activation of P35354 REA within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 REA and P10145 REA mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 REA . Based on the rapidity of activation of P47712 REA and P35354 REA , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 REA has been observed , it is apparent that this unique action of TCDD is carried out through a distinct " nongenomic " pathway which , is clearly discernable from the classical , " genomic " action pathway of the P35869 REA by not requiring the participation of P27540 REA .

Gene profiling in Pap-cell smears of high-risk human papillomavirus-positive squamous cervical carcinoma . OBJECTIVE : The purpose of the study was to investigate benign and malignant squamous cervical cells obtained by cervical swabs with regard to differentially expressed genes and gene expression profiling , in order to evaluate the biological behavior and clinical outcome of cervical malignancies . METHODS : Cervical squamous cells from six women with high-risk human papillomavirus positive [ HR-HPV ( + ) ] cervical carcinoma and from six HPV-negative women with normal ectocervical cells were analyzed by cDNA array . RESULTS : cDNA over-expression of several genes such as MET ( c-met ) , Nm23 - H1 ( P15531 REA ) , P00533 REA , P21802 REA , Nm23 - H2 ( P22392 REA ) , P04626 REA ( c-erbB - 2 ) , cyclin-dependent kinase inhibitor 4 ( CDKN 2A , P42771 REA ) , cytokeratin 8 ( P05787 REA ) , P01116 REA ( K-ras ) , P17948 REA , KGF ( P21781 REA ) , P10415 REA - like 2 protein ( Q92843 ) , Q15303 REA , P04198 ( N-myc ) , cyclin D1 ( P24385 REA ) , P10721 REA ( c-kit ) , secreted phosphoprotein 1 ( P10451 REA ) and P42224 REA , was significant in cervical squamous cell carcinoma ( CSCC ) . Gene expression was downregulated for 13 genes in CSCC , such as interleukin 1 alpha ( P01583 REA ) , the transforming growth factor receptor beta superfamily ( TGFbeta ; P01137 REA ) , some members of the insulin-like growth factor binding proteins ( IGFBPs ) and the integrin family ( P23229 REA , P05556 REA ) . CONCLUSION : This study was focused on the gene expression profiling of HR-HPV ( - ) and ( + ) cervical squamous cells and CSCC obtained by cytobrush . We observed gene expression patterns and signaling pathways that permit the investigator to distinguish between benign squamous cervical cells and CSCC with and without HPV infection .

TNP - 470 blockage of P15692 REA synthesis is dependent on MAPK / P35354 REA signaling pathway in DB00102 - activated hepatic stellate cells . Angiogenesis is a key pathogenic event in hepatic fibrogenesis , which is mediated by activated hepatic stellate cells ( HSCs ) . TNP - 470 is a known anti-angiogenic agent in cancer , and in this study , we investigated the regulatory mechanisms of TNP - 470 blockage of vascular endothelial growth factor ( P15692 REA ) synthesis in activated HSCs . Primary HSCs were isolated from rat liver , cultured in vitro , and activated with platelet-derived growth factor-BB ( DB00102 ) . After treatment with TNP - 470 , DB04743 MEN , PD98059 , SB203580 or SP600125 , activated HSCs were analyzed by immunoblotting , quantitative RT-PCR , and ELISA for mitogen-activated protein kinase ( MAPK ) family [ ERKs , JNK , and p38 ] , cyclooxygenase - 2 ( P35354 REA ) , and P15692 REA levels . Phosphorylation of Q8TCB0 / 42 MAPK , which was followed by increased expressions of P35354 REA and P15692 REA , was observed in DB00102 - activated HSCs ; these events could be ameliorated by addition with TNP - 470 in time - and dose-dependent manners . TNP - 470 also inhibited the secretion of P15692 REA from activated HSCs into culture supernatant . Furthermore , TNP - 470 blockage of P15692 REA production in activated HSCs could be nullified by exogenous inoculation with prostaglandin E ( 2 ) . In summary , our findings suggest that TNP - 470 exhibits the observed anti-angiogenic properties in activated HSCs by targeting the P35354 REA / phospho - Q8TCB0 / 42 MAPK pathway to inhibit P15692 REA production .

Interaction between serotonin 5 - Q13049 REA receptor gene and dopamine transporter ( Q01959 REA ) gene polymorphisms influences personality trait of persistence in Austrian Caucasians . We examined 89 normal volunteers using Cloninger ' s Temperament and Character Inventory ( TCI ) . Genotyping the 102T / C polymorphism of the serotonin 5HT2A receptor gene and the ser 9gly polymorphism in exon 1 of the dopamine D3 receptor ( P35462 REA ) gene was performed using PCR-RFLP , whereas the dopamine transporter ( Q01959 REA ) gene variable number of tandem repeats ( VNTR ) polymorphism was investigated using PCR amplification followed by electrophoresis in an 8 % acrylamide gel with a set of size markers . We found a nominally significant association between gender and harm avoidance ( P= 0.017 ; women showing higher scores ) . There was no association of either Q01959 REA , P35462 REA or 5HT2A alleles or genotypes with any dimension of the TCI applying Kruskal-Wallis rank-sum tests . Comparing homozygote and heterozygote Q01959 REA genotypes , we found higher novelty seeking scores in homozygotes ( P= 0.054 ) . We further found a nominally significant interaction between Q01959 REA and 5HT2A homo - / heterozygous gene variants ( P= 0.0071 ; Q01959 REA and 5HT2A genotypes P value of 0.05 ) , performing multivariate analysis of variance ( MANOVA ) . Examining the temperamental TCI subscales , this interaction was associated with persistence ( genotypes : P= 0.004 ; homo - / heterozygous gene variants : P= 0.0004 ) . We conclude that an interaction between Q01959 REA and 5HT2A genes might influence the temperamental personality trait persistence .

Association of dopamine-related gene alleles , smoking behavior and decline in FEV 1 in subjects with P48444 REA : findings from the lung health study . Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease ( P48444 REA ) . Specific dopamine related gene alleles have previously been found to be associated with smoking initiation , maintenance and cessation . We investigated the association between specific dopamine related gene alleles and both change in smoking behavior and lung function change over time in individuals with mild-to-moderate P48444 REA . Subjects included a subset of participants in the Lung Health Study ( LHS ) , a smoking intervention study in smokers with mild to moderate P48444 REA . Smoking status was determined and lung function performed at baseline and annually for 5 years . In post-hoc analyses , we assessed the association of the dopamine receptor ( P14416 REA ) TaqI A1 ( + ) allele ( A1A1 , A1A2 genotypes ) and A1 ( - ) allele ( A2A2 genotype ) , and the dopamine transporter ( Q01959 REA ) 9R ( + ) allele ( 9R9R and 9R10R genotypes ) and 9R ( - ) allele ( 10R10R genotype ) with both changes in smoking status and lung function in a subset of LHS subjects . No significant associations were noted between variants in these genes and success in smoking cessation . However , in exploratory analyses that did not adjust for multiple comparisons , sustained male ( but not female ) quitters with the P14416 REA A1 ( - ) allele and / or the Q01959 REA 9R ( + ) allele showed an accelerated decline in Q99581 ( 1 ) similar to that of continuing smokers over 5 years after quitting smoking . These preliminary findings suggest that dopamine-related genes may play a role in the progression of P48444 REA , at least in the subset of male ex-smokers whose disease continues to progress despite sustained quitting , and warrants additional confirmatory and mechanistic studies .

Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A , contributing to tumor necrosis factor-induced lethal hepatitis . DB00118 MEN ( DB00118 MEN ) is synthesized by methionine adenosyltransferases ( MATs ) . Ablation of the liver-specific Q00266 REA gene results in liver neoplasia and sensitivity to oxidant injury . Here we show that acidic sphingomyelinase ( ASMase ) mediates the downregulation of Q00266 REA by P01375 REA . The levels of Q00266 REA mRNA as well as P24752 REA I / III protein decreased in cultured rat hepatocytes by in situ generation of ceramide from exogenous human placenta ASMase . Hepatocytes lacking the ASMase gene ( ASMase - / - ) were insensitive to P01375 REA but were responsive to exogenous ASMase-induced downregulation of Q00266 REA . In an in vivo model of lethal hepatitis by P01375 REA , depletion of DB00118 MEN preceded activation of caspases 8 and 3 , massive liver damage , and death of the mice . In contrast , minimal hepatic DB00118 MEN depletion , caspase activation , and liver damage were seen in ASMase - / - mice . Moreover , therapeutic treatment with DB00118 MEN abrogated caspase activation and liver injury , thus rescuing ASMase + / + mice from P01375 REA - induced lethality . Thus , we have demonstrated a new role for ASMase in P01375 REA - induced liver failure through downregulation of Q00266 REA , and maintenance of DB00118 MEN may be useful in the treatment of acute and chronic liver diseases .

MEK inhibition in non-small cell lung cancer . P01116 REA mutations are the most common mutations in non-small cell lung cancer ( NSCLC ) with adenocarcinoma histology . P01116 REA mutations result in the activation of the RAF-MEK - P29323 REA pathway , and agents that target RAF-MEK - P29323 REA pathways have been investigated in P01116 REA mutant NSCLC . The two agents furthest in development are selumetinib and trametinib . DB08911 MEN has greater binding for the Q02750 REA / 2 allosteric site , and generally has superior pharmacokinetics . A randomized phase II trial of docetaxel with and without selumetinib revealed that the combination resulted numerically superior overall survival , and a statistically significant improvement in progression-free survival and objective response rate . However , a concerning rate of hospital admission , grade 3 or 4 neutropenia , and febrile neutropenia was observed with the combination . Trials have investigated MEK inhibitors as single agents and in combination with erlotinib , and the data do not support the further development . The activity of MEK inhibitors appears to be similar in patients with P01116 REA mutant and wild-type NSCLC suggesting P01116 REA mutation status is not a reliable biomarker for efficacy . It is possible that mutations of genes in addition to P01116 REA mutations impact the activity of MEK inhibitors , or specific subsets of P01116 REA mutations may be resistant or susceptible to MEK inhibition . Other potential explanations are gene amplifications , alternative RNA splicing of genes resulting in activation of their protein products , and deregulation of noncoding RNAs and consequent altered protein expression .

Peroxisomal and mitochondrial targeting of serine :p yruvate / alanine : glyoxylate aminotransferase in rat liver . DB00133 MEN :p yruvate / alanine : glyoxylate aminotransferase ( P21549 REA or P21549 REA / AGT ) of rat liver is a unique enzyme of dual subcellular localization , and exists in both mitochondria and peroxisomes . To characterize a peroxisomal targeting signal of rat liver P21549 REA , a number of C-terminal mutants were constructed and their subcellular localization in transfected COS - 1 cells was examined . Deletion of C-terminal Q9BZE0 , and point mutation of K2 ( the second Lys from the C-terminus ) , P19013 REA and E15 caused accumulation of translated products in the cytoplasm . This suggests that the Q03393 REA of P21549 REA is not identical to PTS 1 ( the C-terminal SKL motif ) in that it is not restricted to the C-terminal tripeptide . In vitro synthesized precursor for mitochondrial P21549 REA was highly sensitive to the proteinase K digestion , whereas peroxisomal P21549 REA ( SPTp ) was fairly resistant to the protease . In in vitro import experiment with purified peroxisomes , however , SPTp recovered in the peroxisomal fraction was very sensitive to the protease . These results suggest that the mitochondrial precursor is synthesized as an unfolded form and is translocated into the mitochondrial matrix , whereas SPTp is synthesized as a folded form and its conformation changes to an unfolded form just before translocation into peroxisomes .

DB01628 MEN : a highly selective P35354 REA inhibitor . OBJECTIVE : To review the available literature evaluating the pharmacology , pharmacokinetics , clinical efficacy , and adverse effects of etoricoxib , a highly selective cyclooxygenase - 2 ( P35354 REA ) inhibitor that is not currently approved for use in the US . DATA SOURCES : Literature retrieval was accessed through MEDLINE ( 1966 - December 2004 ) , Current Contents ( 1998 - December 2004 ) , and Cochrane Library ( 4th quarter 2004 ) . References from retrieved articles , information from the manufacturer , and abstracts from the American College of Rheumatology and Annual European Congress of Rheumatology meetings were searched . STUDY SELECTION AND DATA EXTRACTION : All clinical trials published in English evaluating etoricoxib were included in this review . An abstract was excluded if it presented preliminary data from trials that are now published , analyzed data previously reported in a published clinical trial , or compared etoricoxib with placebo for an indication with published active-comparator controlled trials . DATA SYNTHESIS : Twelve clinical trials evaluating efficacy were reviewed . Efficacy for acute pain has been evaluated in acute gout , primary dysmenorrhea , and dental surgery and for chronic pain in rheumatoid arthritis , osteoarthritis , and chronic lower back pain . For safety , 3 clinical trials and 6 retrospective analyses of gastrointestinal , renovascular , or cardiovascular adverse effects were reviewed . CONCLUSIONS : Available studies demonstrate the efficacy of etoricoxib compared with nonsteroidal antiinflammatory drugs , but no published studies to date have compared etoricoxib with other selective P35354 REA inhibitors . While these agents have demonstrated a significant reduction in gastrointestinal adverse effects , the cardiovascular adverse effects of selective P35354 REA inhibition are not well defined . Further study is necessary to delineate the benefits and risks of etoricoxib compared with alternative treatment regimens .

Glucocorticoid-induced S-adenosylmethionine enhances the interferon signaling pathway by restoring P42224 REA protein methylation in hepatitis B virus-infected cells . Patients with chronic hepatitis B usually exhibit a low response to treatment with interferon α ( IFN-α ) . An alternative approach to increase the response rate of IFN-α might be to immunologically stimulate the host with glucocorticoids ( GCs ) before treatment with IFN-α , but the underlying mechanism remains unclear . We hypothesized that the GCs enhance IFN signaling by inducing S-adenosylmethionine ( DB00118 MEN ) when hepatitis B virus ( HBV ) replication was effectively suppressed by IFN-α . Here , we investigated the effect of GCs and IFN-α on DB00118 MEN production and methionine adenosyltransferase 1A ( Q00266 REA ) expression in vitro . Furthermore , we determined whether post-transcriptional regulation is involved in HBV-repressed Q00266 REA expression and DB00118 MEN production induced by dexamethasone ( DB00514 ) . We found that DB00118 MEN homeostasis was disrupted by DB00514 and that DB00514 directly regulated Q00266 REA expression by enhancing the binding of the glucocorticoid receptor ( GR ) to the glucocorticoid-response element ( GRE ) of the Q00266 REA promoter . HBV reduced DB00118 MEN production by increasing methylation at GRE sites within the Q00266 REA promoter . The X protein of hepatitis B virus led to hypermethylation in the Q00266 REA promoter by recruiting DNA methyltransferase 1 , and it inhibited GR binding to the GRE in the Q00266 REA promoter . DB00514 could increase an antiviral effect by inducing DB00118 MEN production via a positive feedback loop when HBV is effectively suppressed by IFN-α , and the mechanism that involves DB00514 - induced DB00118 MEN could increase P42224 REA methylation rather than P42224 REA phosphorylation . These findings provide a possible mechanism by which GC-induced DB00118 MEN enhances the antiviral activity of IFN-α by restoring P42224 REA methylation in HBV-infected cells .

Safety of etoricoxib , a new cyclooxygenase 2 inhibitor , in patients with nonsteroidal anti-inflammatory drug-induced urticaria and angioedema . BACKGROUND : The use of selective inhibitors of cyclooxygenase 2 ( P35354 REA ) has been shown to be safe in patients with aspirin-induced asthma . However , a few individuals with cutaneous reactions to nonsteroidal anti-inflammatory drugs ( NSAIDs ) experience urticaria or angioedema when challenged with various coxibs . OBJECTIVE : To investigate the clinical tolerance of NSAID-sensitive individuals to the selective P35354 REA inhibitors etoricoxib and celecoxib . METHODS : Patients with NSAID-induced urticaria or angioedema were challenged in a double-masked , placebo-controlled design protocol with etoricoxib ( 120 mg ) and celecoxib ( 200 mg ) . Cutaneous , respiratory , and general symptoms ; vital signs ; and pulmonary function were monitored hourly for 3 hours . RESULTS : Fifty-eight patients ( 46 females and 12 males ) with a mean + / - SD age of 31.7 + / - 14.1 years ( range , 13-66 years ) who showed urticaria or angioedema when challenged with NSAIDs were included in this study . A cutaneous clinical pattern was observed in 34 patients ( 59 % ) , and a mixed pattern ( cutaneous and respiratory ) was seen in 24 ( 41 % ) . Celecoxib provocation of 54 patients induced urticaria in 3 , urticaria and angioedema in 2 , and urticaria , rhinorrhea , and conjunctival erythema in 1 ( reaction rate , 11.1 % ) . DB01628 MEN challenges performed in 56 patients induced urticaria in 3 and angioedema in 1 ( reaction rate , 7.1 % ) . CONCLUSIONS : These results confirm that most NSAID-sensitive individuals with cutaneous reactions to classic NSAIDs will tolerate specific P35354 REA inhibitors , supporting the use of thesedrugs after careful oral provocation in such patients .

Soluble epoxide hydrolase inhibitor , TUPS , protects against isoprenaline-induced cardiac hypertrophy . BACKGROUND AND PURPOSE : We have previously shown that isoprenaline-induced cardiac hypertrophy causes significant changes in the expression of cytochromes P450 ( CYP ) and soluble epoxide hydrolase ( sEH ) genes . Therefore , it is important to examine whether the inhibition of sEH by 1 - ( 1 - methanesulfonyl-piperidin - 4 - yl ) - 3 - ( 4 - trifluoromethoxy-phenyl ) - urea ( TUPS ) will protect against isoprenaline-induced cardiac hypertrophy . EXPERIMENTAL APPROACH : Male Sprague-Dawley rats were treated with TUPS ( 0.65 mg kg ( - 1 ) day ( - 1 ) , p . o . ) , isoprenaline ( 5 mg kg ( - 1 ) day ( - 1 ) , i . p . ) or the combination of both . In vitro H9c2 cells were treated with isoprenaline ( 100 μM ) in the presence and absence of either TUPS ( 1 μM ) or 11,12 EET ( 1 μM ) . The expression of hypertrophic , fibrotic markers and different CYP genes were determined by real-time PCR . KEY RESULTS : Isoprenaline significantly induced the hypertrophic , fibrotic markers as well as the heart to body weight ratio , which was significantly reversed by TUPS . Isoprenaline also caused an induction of P04798 REA , Q16678 REA , CYP 2B1 , CYP 2B2 , CYP 4A3 and CYP 4F4 gene expression and TUPS significantly inhibited this isoprenaline-mediated effect . Moreover , isoprenaline significantly reduced 5,6- , 8,9- , 11,12- and 14,15- EET and increased their corresponding 8,9- , 11,12- and 14,15- dihydroxyeicosatrienoic acid ( DHET ) and the 20 - HETE metabolites . TUPS abolished these isoprenaline-mediated changes in arachidonic acid ( AA ) metabolites . In H9c2 cells , isoprenaline caused a significant induction of P01160 REA , DB04899 and P34913 REA mRNA levels . Both TUPS and 11,12- EET significantly decreased this isoprenaline-mediated induction of P01160 REA , DB04899 and P34913 REA . CONCLUSIONS AND IMPLICATIONS : TUPS partially protects against isoprenaline-induced cardiac hypertrophy , which confirms the role of sEH and CYP enzymes in the development of cardiac hypertrophy .

BIMG 80 , a novel potential antipsychotic drug : evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex . In radioligand binding studies , BIMG 80 , a new putative antipsychotic , displayed good affinity at certain serotonin ( P08908 REA , 5 - Q13049 REA , P50406 REA ) , dopamine ( D1 , D2L , D4 ) , and noradrenergic ( alpha 1 ) receptors . The effect of acute subcutaneous BIMG 80 , clozapine , haloperidol , risperidone , amperozide , olanzapine , and Seroquel was then investigated on dopamine release in medial prefrontal cortex , nucleus accumbens , and striatum in freely moving rats using the microdialysis technique . Four different neurochemical profiles resulted from the studies : ( a ) Systemic administration of BIMG 80 , clozapine , and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens . ( b ) DB00502 induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex . ( c ) DB00734 MEN and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated . ( d ) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum . Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects , BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects .

Dabrafenib and trametinib , alone and in combination for P15056 REA - mutant metastatic melanoma . Dabrafenib and trametinib were approved for use as monotherapies in P15056 REA - mutant metastatic melanoma by the U . S . Food and Drug Administration ( FDA ) in 2013 , and most recently , their use in combination has received accelerated FDA approval . Both drugs target the mitogen-activated protein kinase ( MAPK ) pathway : dabrafenib selectively inhibits mutant P15056 REA that constitutively activates the pathway , and trametinib selectively inhibits Q02750 REA and P36507 REA proteins activated by RAF kinases . The phase III study of dabrafenib in P15056 REA ( V600E ) metastatic melanoma reported rapid tumor regression in most patients and a 59 % objective RECIST response rate . The median progression-free survival ( PFS ) and overall survival ( OS ) were improved compared with dacarbazine . Toxicities were well tolerated and different from those reported for vemurafenib , the first FDA-approved P15056 REA inhibitor . Efficacy has been demonstrated in other P15056 REA - mutant genotypes . The phase III study of trametinib in P15056 REA inhibitor-naïve patients with P15056 REA ( V600E ) or P15056 REA ( V600K ) also showed benefit with a prolonged median PFS and OS compared with chemotherapy . DB08911 MEN is ineffective in patients who have progressed on P15056 REA inhibitors . A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy , with less cutaneous toxicity . Here , we review the clinical development of both drugs as monotherapies and in combination , and discuss their role in the management of P15056 REA - mutant melanoma .

Activation of MAPKs influences the expression of drug-metabolizing enzymes in primary human hepatocytes . We examined the effects of model activators of mitogen-activated protein kinases ( MAPKs ) on basal and rifampicin - , phenobarbital - and dioxin-inducible expression of phase I and phase II biotransformation enzymes in primary human hepatocytes . Cells were treated for 24 h with sorbitol ( SOR ) , anisomycin ( ANI ) and epidermal growth factor ( P01133 REA ) in the presence or absence of inducers . The levels of P04798 REA , P05177 REA , P20813 REA , P08684 REA , P22309 REA , O75795 REA , P50225 REA , Q06520 REA , O43704 REA , P08263 REA , P09210 REA mRNAs were determined . SOR and P01133 REA inhibited the expression of the tested genes , while ANI had no effect . We conclude that MAPKs play important role in the transcriptional regulation of drug-metabolizing enzymes .

P35354 REA derived DB00917 and DB01240 play an important role via EP2 and PPARdelta receptors in early steps of oil induced decidualization in mice . Differentiation of endometrial stromal cells into decidual cells ( decidualization ) is prerequisite for blastocyst implantation . Different prostanoids are shown to be involved in the cascade of events found in implantation and decidualization . Previous reports described that cyclooxygenase - 2 ( P35354 REA ) derived prostacyclin ( DB01240 ) plays an important role via peroxisome proliferator activated receptor ( PPARdelta ) nuclear receptor in implantation and decidualization . Herein , we investigated the role of P35354 REA derived DB00917 and DB01240 and examined the protein expression and regulation of P23219 REA , P35354 REA , membrane-bound prostaglandin E synthase ( mPGES - 1 ) , prostaglandin I synthase ( PGIS ) , DB00917 receptor ( EP2 ) and PPARdelta in hormone primed oil infused uterine horn as well as in non-infused uterine horn ( control horn ) . Our results show that selective P35354 REA inhibitor ( DB04743 MEN ) inhibits decidualization while P23219 REA inhibitor ( SC560 ) does not affect decidualization . P35354 REA , mPGES - 1 , PGIS , EP2 and PPARdelta immunostaining are strongly observed at 24 h and 48 h in oil-induced horn and than significantly reduced at 72 h and 120 h and absent in non-infused horn . However P23219 REA immunostaining is observed in infused as well as in non-infused horn . Our immunohistochemical studies corroborated well with follow up western blotting of the same proteins . DB00917 and DB01240 products were also elevated at 24h and 48 h after oil induction in infused horn in comparison to control horn . Our data suggest that P35354 REA derived both DB00917 and DB01240 mediate its function via EP2 and PPARdelta receptors in early steps of decidualization in mice .

Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 MENMAX DB00734 MEN is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 REA , P05177 REA , P10632 REA , P11712 REA - arg 144 , P11712 REA - cys 144 , P33261 REA , P10635 REA , P08684 REA and P20815 REA supplemented with an NADPH-generating system . DB01267 SUB was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7.5 , 0.4 and 0.2 pmol pmol ( - 1 ) CYP min ( - 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 REA and 3A activities . Thus , both P10635 REA and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 REA ) and ketoconazole ( inhibitor of P08684 REA ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP 3A contributes significantly to the metabolism of risperidone in rat .

PDE 4B5 , a novel , super-short , brain-specific DB02527 phosphodiesterase - 4 variant whose isoform-specifying N-terminal region is identical to that of DB02527 phosphodiesterase - 4D6 ( PDE 4D6 ) . The DB02527 - specific phosphodiesterase - 4 ( DB05876 ) gene family is the target of several potential selective therapeutic inhibitors . The four DB05876 genes generate several distinct protein-coding isoforms through the use of alternative promoters and 5 ' - coding exons . Using mouse transcripts , we identified a novel , super-short isoform of human Q07343 REA encoding a novel 5 ' terminus , which we label PDE 4B5 . The protein-coding region of the novel 5 ' exon is conserved across vertebrates , chicken , zebrafish , and fugu . Reverse-transcription-polymerase chain reaction ( PCR ) and quantitative ( PCR ) measurements show that this isoform is brain-specific . The novel protein is 58 + / - 2 kDa ; it has DB02527 hydrolyzing enzymatic activity and is inhibited by DB05876 - selective inhibitors rolipram and cilomilast ( DB03849 MEN ) . Confocal and subcellular fractionation analyses show that it is distributed predominantly and unevenly within the cytosol . The 16 novel N-terminal residues of PDE 4B5 are identical to the 16 N-terminal residues of the super-short isoform of Q08499 REA ( PDE 4D6 ) , which is also brain-specific . PDE 4B5 is able to bind the scaffold protein Q9NRI5 , whose gene has been linked to schizophrenia . Microarray expression profiling of the DB05876 gene family shows that specific DB05876 genes are enriched in muscle and blood fractions ; however , only by monitoring the individual isoforms is the brain specificity of the super-short Q08499 REA and Q07343 REA isoforms revealed . Understanding the distinct tissue specificity of DB05876 isoforms will be important for understanding phosphodiesterase biology and opportunities for therapeutic intervention .

Association of P35462 REA and Q13224 REA with impulse control and related behaviors in Parkinson ' s disease . We aimed to assess whether allelic variants of dopamine receptor , glutamate receptor , and serotonin transporter genes are associated with the appearance of impulse control and related behaviors ( ICRB ) in Parkinson ' s disease ( PD ) with dopamine replacement therapy ( P29323 REA ) . We surveyed ICRB in consecutive Korean patients with PD who were treated with stable P29323 REA using modified Minnesota Impulsive Disorders Interview over a period of 4 months . In the 404 patients who completed the interview and the 559 Korean healthy normal controls , genotyping was performed for variants of the P35462 REA p . S9G , P14416 REA Taq 1A , Q13224 REA c . 366C > G , c . 2664C > T and c . - 200T > G , and the promoter region of the serotonin transporter gene ( 5 - HTTLPR ) . Behavioral abnormalities suggestive of ICRB including compulsive buying , gambling , sexual behavior and eating , and punding , were present in 14.4 % of the patients . Variants of P14416 REA and 5 - HTTLPR were not associated with the risk of developing ICRB . However , the AA genotype of P35462 REA p . S9G and the CC genotype of Q13224 REA c . 366C > G were more frequent in patients with ICRB than in nonaffected patients ( odds ratio [ OR ] = 2.21 , P = 0.0094 ; and 2.14 , P = 0.0087 , after adjusting for age and sex ) . After controlling for clinical variables in the multivariate analysis , carriage of either AA genotype of P35462 REA or CC genotype of Q13224 REA was identified as an independent risk factor for ICRB ( adjusted OR : 2.57 , P = 0.0087 ) . Variants of P35462 REA p . S9G and Q13224 REA c . 366C > G may be associated with the appearance of ICRB in PD .

ZNF 804a regulates expression of the schizophrenia-associated genes Q9NQE7 , P21964 REA , Q07343 REA , and P14416 REA . ZNF 804a was identified by a genome-wide association study ( GWAS ) in which a single nucleotide polymorphism ( SNP rs1344706 ) in ZNF 804a reached genome-wide statistical significance for association with a combined diagnosis of schizophrenia ( SZ ) and bipolar disorder . Although the molecular function of ZNF 804a is unknown , the amino acid sequence is predicted to contain a C2H2 - type zinc-finger domain and suggests ZNF 804a plays a role in DNA binding and transcription . Here , we confirm that ZNF 804a 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 REA , the two genes we find upregulated by ZNF 804a . Using immunochemistry we establish that ZNF 804a is localized to the nucleus of rat neural progenitor cells in culture and in vivo . We demonstrate that expression of ZNF 804a results in a significant increase in transcript levels of Q9NQE7 and P21964 REA , relative to GFP transfected controls , and a statistically significant decrease in transcript levels of Q07343 REA and P14416 REA . Furthermore , we show using chromatin immunoprecipitation assays ( ChIP ) that both epitope-tagged and endogenous ZNF 804a directly interacts with the promoter regions of Q9NQE7 and P21964 REA , suggesting a direct upregulation of transcription by ZNF 804a on the expression of these genes . These results are the first to confirm that ZNF 804a 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 ZNF 804a may modulate a transcriptional network of SZ associated genes .

[ ( 11 ) C ] 5 - HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain . The PET tracer [ ( 11 ) C ] 5 - hydroxytryptophan ( [ ( 11 ) C ] 5 - HTP ) , which is converted to [ ( 11 ) C ] 5 - hydroxytryptamine ( [ ( 11 ) C ] 5 - HT ) by aromatic amino acid decarboxylase ( P20711 REA ) , is thought to measure 5 - HT synthesis rates . But can we measure these synthesis rates by kinetic modeling of [ ( 11 ) C ] 5 - HTP in rat ? Male rats were scanned with [ ( 11 ) C ] 5 - HTP ( 60 minutes ) after different treatments . Scans included arterial blood sampling and metabolite analysis . 5 - HT synthesis rates were calculated by a two-tissue compartment model ( 2TCM ) with irreversible tracer trapping or Patlak analysis . DB00190 MEN ( inhibitor peripheral P20711 REA ) dose-dependently increased [ ( 11 ) C ] 5 - HTP brain uptake , but did not influence 2TCM parameters . Therefore , 10 mg / kg carbidopa was applied in all subsequent study groups . These groups included treatment with NSD 1015 ( general P20711 REA inhibitor ) or p-chlorophenylalanine ( PCPA , inhibitor of tryptophan hydroxylase , P17752 REA ) . In addition , the effect of a low-tryptophan ( DB00150 ) diet was investigated . NSD 1015 or DB00150 depletion did not affect any model parameters , but PCPA reduced [ ( 11 ) C ] 5 - HTP uptake , and the k3 . This was unexpected as NSD 1015 directly inhibits the enzyme converting [ ( 11 ) C ] 5 - HTP to [ ( 11 ) C ] 5 - HT , suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites . As different results have been acquired in monkeys and humans , [ ( 11 ) C ] 5 - HTP-PET may be suitable for measuring 5 - HT synthesis in primates , but not in rodents .

Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 REA ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 REA ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 REA ) at 3 and 12 months . P10632 REA * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 REA levels ( P= 0.003 and P= 0.007 ) and were 2.2- and 2.5- fold more likely to develop P42126 REA and CND ( P= 0.039 and P= 0.041 ) , respectively . P34913 REA 55Arg , P51589 REA * 7 , P10632 REA * 1B , and P10632 REA g . 36785A allele carriers had lower EET and DHET P04141 REA levels . P10632 REA g . 25369T and P10632 REA g . 36755A allele carriers had higher EET levels . Patients with P10632 REA * 2C and P34913 REA 404del variants had worse long-term outcomes while those with P34913 REA 287Gln , P51589 REA * 7 , and P11712 REA g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .

The effect of chronic antipsychotic drug on hypothalamic expression of neural nitric oxide synthase and dopamine D2 receptor in the male rat . Antipsychotic-induced sexual dysfunction is a common and serious clinical side effect . It has been demonstrated that both neuronal nitric oxide ( P29475 REA ) and dopamine D2 receptor ( P14416 REA ) in the medial preoptic area ( MPOA ) and the paraventricular nucleus ( PVN ) of the hypothalamus have important roles in the regulation of sexual behaviour . We investigated the influences of 21 days ' antipsychotic drug administration on expression of P29475 REA and P14416 REA in the rat hypothalamus . DB00502 ( 0.5 mg / kg / day i . p . ) significantly decreased P29475 REA integrated optical density in a sub-nucleus of the MPOA , medial preoptic nucleus ( Q9BQR3 ) , and decreased the P29475 REA integrated optical density and cell density in another sub-nucleus of the MPOA , anterodorsal preoptic nucleus ( ADP ) . DB00734 MEN ( 0.25 mg / kg ) inhibited the P29475 REA integrated optical density in the ADP . P29475 REA mRNA and protein in the MPOA but not the PVN was also significantly decreased by haloperidol . DB00502 and risperidone increased P14416 REA mRNA and protein expression in both the MPOA and the PVN . Quetiapine ( 20 mg / kg / day i . p . ) did not influence the expression of P29475 REA and P14416 REA in either the MPOA or the PVN . These findings indicate that hypothalamic P29475 REA and P14416 REA are affected to different extents by chronic administration of risperidone and haloperidol , but are unaffected by quetiapine . These central effects might play a role in sexual dysfunction induced by certain antipsychotic drugs .

Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in lung cancers . P00533 REA mutations identify patients who are more likely to respond to treatment with epidermal growth factor receptor ( P00533 REA ) tyrosine kinase inhibitors ( TKIs ) than cytotoxic chemotherapy . The distinct success of the first-generation P00533 REA TKIs erlotinib and gefitinib has been accompanied by the observation that acquired resistance to these treatments develops after a median of 1 year of treatment . Newer , second-generation P00533 REA TKIs have been developed with the intent to delay or overcome acquired resistance by the broader inhibition of kinases ( eg , P04626 REA and vascular endothelial growth factor receptor ) and / or altering the interactions with P00533 REA through irreversibly binding to the kinase domain . This article discusses many of these agents ( including afatinib , dacomitinib , DB05007 MEN , AP26113 , and CO - 1686 ) which have the potential for greater efficacy compared with first-generation P00533 REA TKIs , and may also have clinical activity against other oncogenic mutations within the P00533 REA family , including P04626 REA .

Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population-based twin studies demonstrate that approximately 40-50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 REA Val 158Met , P21397 REA 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 REA , Q01959 REA 3 ' VNTR and P14416 REA exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38.51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five-Factor Inventory , Spielberger ' s State-Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 REA ) were lowest in the entire group . The effects of gender , age and the Q13049 REA gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 REA gene on the 9/9 Q01959 REA genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 REA gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 REA ) NEO-FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .

Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL - 7647 . PURPOSE : Agents inhibiting the epidermal growth factor receptor ( P00533 REA ) have shown clinical benefit in a subset of non-small cell lung cancer patients expressing amplified or mutationally activated P00533 REA . However , responsive patients can relapse as a result of selection for P00533 REA gene mutations that confer resistance to DB00171 competitive P00533 REA inhibitors , such as erlotinib and gefitinib . We describe here the activity of EXEL - 7647 ( DB05007 MEN ) , a novel spectrum-selective kinase inhibitor with potent activity against the P01133 REA and vascular endothelial growth factor receptor tyrosine kinase families , against both wild-type ( WT ) and mutant P00533 REA in vitro and in vivo . EXPERIMENTAL DESIGN : The activity of P00533 REA inhibitors against WT and mutant EGFRs and their effect on downstream signal transduction was examined in cellular assays and in vivo using A431 and MDA-MB - 231 ( WT P00533 REA ) and H1975 ( L858R and T790M mutant P00533 REA ) xenograft tumors . RESULTS : EXEL - 7647 shows potent and long-lived inhibition of the WT P00533 REA in vivo . In addition , EXEL - 7647 inhibits cellular proliferation and P00533 REA pathway activation in the erlotinib-resistant H1975 cell line that harbors a double mutation ( L858R and T790M ) in the P00533 REA gene . In vivo efficacy studies show that EXEL - 7647 substantially inhibited the growth of H1975 xenograft tumors and reduced both tumor P00533 REA signaling and tumor vessel density . Additionally , EXEL - 7647 , in contrast to erlotinib , substantially inhibited the growth and vascularization of MDA-MB - 231 xenografts , a model which is more reliant on signaling through vascular endothelial growth factor receptors . CONCLUSIONS : These studies provide a preclinical basis for clinical trials of DB05007 MEN in solid tumors and in patients bearing tumors that are resistant to existing P00533 REA - targeted therapies .

P20711 REA inhibition does not influence the diuretic and natriuretic response to exogenous alpha-atrial natriuretic peptide in man . The role of dopamine synthesis in the renal actions of human alpha-atrial natriuretic peptide ( alpha P01160 REA ) was investigated in six dehydrated volunteers using the P20711 REA inhibitor carbidopa . Each subject received oral placebo or carbidopa ( 100 mg ) followed by an infusion of alpha P01160 REA 10 pmol.kg-1.min - 1 for 1 h . The responses to placebo alone and to carbidopa alone were investigated on separate occasions . alpha P01160 REA produced a similar increase in plasma immunoreactive alpha P01160 REA whether placebo or carbidopa pretreatment had been given . Urinary dopamine excretion was increased by alpha P01160 REA . DB00190 MEN pretreatment substantially attenuated this increase without affecting the natriuretic or water-diuretic response to alpha P01160 REA . DB00190 MEN also failed to alter the change in filtration fraction produced by alpha P01160 REA . The results suggest that increased synthesis of intrarenal dopamine is not required for the renal effects of alpha P01160 REA in man .

MicroRNA -137/181 c regulates serine palmitoyltransferase and in turn amyloid β , novel targets in sporadic Alzheimer ' s disease . The contribution of mutations in amyloid precursor protein ( P05067 REA ) and presenilin ( PSEN ) to familial Alzheimer ' s disease ( AD ) is well established . However , little is known about the molecular mechanisms leading to amyloid β ( Aβ ) generation in sporadic AD . Increased brain ceramide levels have been associated with sporadic AD , and are a suggested risk factor . DB00133 MEN palmitoyltransferase ( P21549 REA ) is the first rate-limiting enzyme in the de novo ceramide synthesis . However , the regulation of P21549 REA is not yet understood . Evidence suggests that it may be posttranscriptionally regulated . Therefore , we investigated the role of miRNAs in the regulation of P21549 REA and amyloid β ( Aβ ) generation . We show that P21549 REA is upregulated in a subgroup of sporadic AD patient brains . This is further confirmed in mouse model studies of risk factors associated with AD . We identified that the loss of miR - 137 , - 181c , - 9 , and 29a / b - 1 increases P21549 REA and in turn Aβ levels , and provides a mechanism for the elevated risk of AD associated with age , high-saturated-fat diet , and gender . Finally , these results suggest P21549 REA and the respective miRNAs may be potential therapeutic targets for sporadic AD .

Painless burn injury caused by post-traumatic syringomyelia . BACKGROUND : Syringomyelia , which is generally related to congenital malformations and tumors , may lead to paresthesia and dysfunctions in thermo-algesic perception . Post-traumatic syringomyelia ( Q03393 REA ) is a rare type of this disease characterised by the development of a cystic formation containing cerebrospinal fluid ( P04141 REA ) , which develops inside the spinal cord after spinal trauma . AIM : The description of a case diagnosed as painless burn injury caused by Q03393 REA . METHOD : One case report . CONCLUSION : Although there are a number of reports regarding the formation of neuropathic ulcers related to syringomyelia , painless burn injury descriptions are very rare . Despite available limited data related to this subject , it is important to warn patients about traumas-especially burns-after a diagnosis of Q03393 REA .

Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid-beta deposition ( P05067 REA ; P49768 REA ; PS2 ; P02649 REA ; P01034 REA ; ubiquilin - 1 ) , oxidative stress ( NOS 2 ; NOS 3 ) and inflammatory response ( P01583 REA ; P01584 REA ; P05231 REA ; P01375 REA ) . Genome-wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 REA ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 REA ; P35462 REA ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 REA gene ; P02649 REA ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene-environment interactions in AD , that are still poorly understood , is essential to predict disease-risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti-AD drugs .

Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 REA , Q16678 REA , P11712 REA , P33261 REA , P05181 REA , P05093 REA , P11511 REA , P35869 REA , P03372 REA , Q92731 REA , ERRRG , P06401 REA , P07099 REA , P34913 REA , P37059 REA , P37058 REA , P28161 REA , P21266 REA , GSTT 2 , P09211 REA , NAT 1 , NAT 2 , P21964 REA , P07327 REA , P00325 REA , P00326 REA , P05091 REA , P35228 REA , NOS 3 , P01583 REA , P01584 REA , O15527 REA , P36639 REA [ P36639 REA ] , P14416 REA , P35462 REA , P21917 REA , P31645 REA , P04150 REA [ GCCR ] , P42898 REA , and P15559 REA . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .