interacts_with DB00159?
ω-3 fatty acid eicosapentaenoic acid attenuates P25189 +-induced neurodegeneration in fully differentiated human SH-SY5Y and primary mesencephalic cells . DB00159 ( EPA ) , a neuroactive omega-3 fatty acid , has been demonstrated to exert neuroprotective effects in experimental models of Parkinson 's disease ( PD ) , but the cellular mechanisms of protection are unknown . Here , we studied the effects of EPA in fully differentiated human SH-SY5Y cells and primary mesencephalic neurons treated with P25189 (+) . In both in-vitro models of PD , EPA attenuated an P25189 (+) -induced reduction in cell viability . EPA also prevented the presence of electron-dense cytoplasmic inclusions in SH-SY5Y cells . Then , possible mechanisms of the neuroprotection were studied . In primary neurons , EPA attenuated an P25189 (+) -induced increase in Tyrosine-related kinase B ( TrkB ) receptors . In SH-SY5Y cells , EPA down-regulated reactive oxygen species and nitric oxide . This antioxidant effect of EPA may have been mediated by its inhibition of neuronal NADPH oxidase and cyclo-oxygenase-2 ( P35354 ) , as P25189 (+) increased the expression of these enzymes . Furthermore , EPA prevented an increase in cytosolic phospholipase A2 ( P47712 ) , an enzyme linked with P35354 in the potentially pro-inflammatory arachidonic acid cascade . Lastly , EPA attenuated an increase in the bax:bcl-2 ratio , and cytochrome c release . However , EPA did not prevent mitochondrial enlargement or a decrease in mitochondrial membrane potential . This study demonstrated cellular mechanisms by which EPA provided neuroprotective effects in experimental PD . The P28335 receptor agonist lorcaserin reduces nicotine self-administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . DB04871 ( ( 1R ) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl ) is a selective 5-HT(2C) receptor agonist with clinical efficacy in phase-III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0.3-3 mg/kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22-h food deprivation or palatability . Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation . DB04871 ( 0.6-1 mg/kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self-administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . DB04871 also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . DB04871 did not reinstate nicotine-seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0.3-1 mg/kg ) reduced nicotine-induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five-choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5-HT(2C) receptor agonists , similarly affect both food- and nicotine-motivated behaviors , and nicotine-induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5-HT(2C) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence . Influence of cystic fibrosis transmembrane conductance regulator on gene expression in response to Pseudomonas aeruginosa infection of human bronchial epithelial cells . Chronic lung infection by Pseudomonas aeruginosa causes significant morbidity in cystic fibrosis patients initiated by the failure of innate immune responses . We used microarray analysis and real-time PCR to detect transcriptional changes associated with cytokine production in isogenic bronchial epithelial cell lines with either wild-type ( WT ) or mutant cystic fibrosis transmembrane conductance regulator ( P13569 ) in response to P. aeruginosa infection . The transcription of four NF-kappaB-regulated cytokine genes was maximal in the presence of WT P13569 : the interleukin-8 ( P10145 ) , P05231 , P09341 , and intracellular adhesion molecule 1 ( P05362 ) genes . Analysis of protein expression in two cell lines paired for wild-type and mutant P13569 with three P. aeruginosa strains showed P05231 and P10145 expressions were consistently enhanced by the presence of WT P13569 in both cell lines with all three strains of P. aeruginosa , although some strains gave small P10145 increases in cells with mutant P13569 . P09341 production showed consistent enhancement in cells with WT P13569 using all three bacterial strains in one cell line , whereas in the other cell line , P09341 showed a significant increase in cells with either WT or mutant P13569 . P05362 was unchanged at the protein level in one of the cell lines but did show mild enhancement with WT P13569 in the other cell pair . Inhibitions of NF-kappaB prior to infection indicated differing degrees of dependence on NF-kappaB for production of the cytokines , contingent on the cell line . Cytokine effectors of innate immunity to P. aeruginosa were found to be positively influenced by the presence of WT P13569 , indicating a role in resistance to P. aeruginosa infection . Potential effects of peroxisome proliferator-activated receptor activator on LPS-induced lung injury in rats . Multiple factors contribute to the pathogenesis and prognosis of chronic obstructive pulmonary disease( P48444 ) , still requiring new therapeutic strategies and medications for the disease . The aim of the present study is to investigate the model of lipopolysaccharide ( LPS ) -induced chronic lung injury and hyperinflation and test therapeutic effects of peroxisome proliferator-activated receptor ( Q07869 ) -gamma agonist . Wister rats were challenged with intra-tracheal instillation of LPS at concentrations of 0.006 , 0.060 , 0.600 , and 6.000 mg/ml per kg , twice a week , for 1 , 2 , 4 and 6 weeks . Q07869 activator , 15-deoxy-Delta12,14-prostaglandin J2 ( 15D-PGJ2 ) , or vehicle ( PBS ) was administered orally and daily at the dose of 1 and 10 mg/ml per kg in animals challenged with LPS or PBS at the dose of 0.060 mg/ml per kg body weight twice a week for 4 weeks . We found that intra-tracheal exposure of LPS resulted in a dose-dependent pattern of chronic lung hyperinflation and hypertrophy , increased alveolar enlargement , reduced vascular endothelial growth factor ( P15692 ) and elevated tissue inhibitor of metalloproteinases ( P01033 ) -1 levels in bronchoalveolar lavage ( BAL ) fluid , and early changes of leukocyte influx and interferon ( IFN ) -gamma levels in bronchoalveolar lavage ( BAL ) fluid . P37231 agonist ameliorated these changes related with the dose used.LPS-induced lung disease model shows some similarities with human disease , and P37231 agonist maybe an alternative for P48444 therapy . DB00159 inhibits prostaglandin D2 generation by inhibiting cyclo-oxygenase-2 in cultured human mast cells . BACKGROUND : DB00159 ( EPA ) is catalysed by cyclo-oxygenase ( P36551 ) , as is arachidonic acid , and is a competitive inhibitor of arachidonate metabolism . OBJECTIVES : We examined the effect of EPA on prostaglandin ( PG ) D2 generation in the cultured human mast cells with IgE-anti-IgE challenge incubation . METHODS : Cultured human mast cells were incubated with EPA ( 1 micromol/L ) for 20 h , then challenged with anti-IgE incubation after treatment with IgE . At the same time , P36551 inhibitors were tested to identify P23219 and P35354 activity . PGD2 synthetic activity was also assayed in a cell-free homogenate of cultured mast cells with P36551 inhibitors and EPA . DB11320 in the culture medium and in cells was assayed with the HPLC-fluorescent method . PGD2 and PGD3 were assayed with gas chromatography-mass spectrometry and the stable isotope dilution method . RESULTS : Although EPA incubation did not affect histamine release by cultured human mast cells in response to IgE-anti-IgE challenge incubation , it did decrease PGD2 generation by inhibiting the P35354 pathway . In contrast , in the cell-free homogenate of cultured human mast cells , EPA inhibited both P23219 and P35354 activities . CONCLUSION : Pre-incubation with EPA primarily affects the P35354 pathway in cultured human mast cells and reduces PGD2 generation in response to IgE-anti-IgE challenge incubation . These findings suggest that P23219 and P35354 have different substrate flow systems in mast cells . They also suggest that endogenous EPA diet supplementation would reduce PGD2 production and could serve as an anti-inflammatory substrate in human mast cells . Omega-3 polyunsaturated fatty acids and inflammatory processes : nutrition or pharmacology ? DB00159 ( EPA ) and docosahexaenoic acid ( DB01708 ) are n-3 fatty acids found in oily fish and fish oil supplements . These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis , adhesion molecule expression and leucocyte-endothelial adhesive interactions , production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid , production of inflammatory cytokines and T cell reactivity . In parallel , EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DB01708 give rise to anti-inflammatory and inflammation resolving resolvins and protectins . Mechanisms underlying the anti-inflammatory actions of n-3 fatty acids include altered cell membrane phospholipid fatty acid composition , disruption of lipid rafts , inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes , activation of the anti-inflammatory transcription factor P37231 ( i.e. peroxisome proliferator activated receptor γ ) and binding to the G protein coupled receptor Q5NUL3 . These mechanisms are interlinked . In adult humans , an EPA plus DB01708 intake greater than 2 g day⁻¹ seems to be required to elicit anti-inflammatory actions , but few dose finding studies have been performed . Animal models demonstrate benefit from n-3 fatty acids in rheumatoid arthritis ( RA ) , inflammatory bowel disease ( Q9UKU7 ) and asthma . Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta-analyses of the data . Clinical trails of fish oil in patients with Q9UKU7 and asthma are inconsistent with no overall clear evidence of efficacy . Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment-refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand-independent activation . With regard to the latter mechanism , interleukin-6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 -related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long-term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies . Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre-RT ) , at the fourth week of RT ( mid-RT ) , and 1 month after RT completion ( post-RT ) . Two serial punch biopsies were performed at pre- and mid-RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) -2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre-RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid-RT ( P30518 ) was greater than 0.5 , seven ( 100 % , p=0.0515 ) and five ( 71.4 % , p=0.3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre-RT were associated with P30518 ( p=0.0782 ) . For the mid-RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0.5 ( p=0.2222 ) . CONCLUSION : The poor mid-RT tumor response was associated with the coexpression of P35354 and P00533 . DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5-HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase-2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX-gavage ( 30mgkg(-1) ) and , a single dose of 1,2 dimethylhydrazine ( Q03001 ; i.p. , 125mgkg(-1) ) . After 6 weeks of FLX-treatment , our results revealed that FLX and nor-fluoxetine ( N-FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5-HT ) levels ( P < 0.05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0.05 ) resulting in lower 5-hydroxyindoleacetic acid ( 5-HIAA ) levels ( P < 0.01 ) and , P28335 receptor mRNA expressions . FLX-treatment decreased dysplastic Q9NQ94 development ( P < 0.01 ) and proliferative process ( P < 0.001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0.05 ) , P15692 ( P < 0.001 ) , and P35354 expression ( P < 0.01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events . DB00159 modulates DB00091 -induced proinflammatory cytokine over-expression in osteoblastic cells in vitro . Several adverse outcomes are reported in subjects undergoing long term DB00091 ( DB00091 ) treatment . Severe osteopenia has been described in clinical and experimental reports , while beneficial effects of n-3 polyunsaturated fatty acids ( PUFAs ) on bone metabolism are recognized . In the present study we investigated the effects of n-3 versus n-6 PUFAs on osteoblastic cells treated with DB00091 , evaluating the expression of interleukin ( IL ) -1 & #223 ; , interleukin-6 ( P05231 ) , inducible nitric oxide synthase ( P35228 ) , and cyclooxygenase-2 ( P35354 ) in two different experimental protocols and the production of P05231 , IL-1 & #223 ; , and tumor necrosis factor alpha ( TNFalpha ) in cells challenged simultaneously with DB00091 and eicosapentaenoic acid ( EPA ) for 48h . IL-1 & #223 ; and P05231 up-regulation , induced by DB00091 , was counteracted by the addition of EPA in both protocols ; on the contrary , arachidonic acid ( AA ) magnified DB00091 the effects . P35354 and P35228 levels were not modified by DB00091 treatment . These in vitro results , that substantiate clinical reports of DB00091 -induced osteopenia , demonstrate a beneficial effect of EPA on DB00091 -altered cytokine profile , opening new perspectives in the non-pharmacological management of adverse outcomes in DB00091 -treated patients . The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor/nuclear receptor interaction . As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus . Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed " correctors " such as DB09280 ( VX-809 ) that improve P13569 maturation and trafficking and " potentiators " such as ivacaftor ( VX-770 ) that enhance channel activity may provide important advances in CF therapy . Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX-770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX-770 , markedly increasing its turnover rate . Chronic VX-770 treatment also reduced mature wild-type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short-term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and/or development of new potentiator compounds that do not interfere with P13569 stability . Immunohistochemical analysis of carcinomatous and sarcomatous components in the uterine carcinosarcoma : a case report . Uterine carcinosarcoma ( malignant mixed Mullerian tumor ) is an uncommon female genital tract neoplasm characterized by an admixture of epithelial and stromal malignant cells . We report a case of 50-year-old peri-menopausal woman diagnosed to have early-stage ( IB due to FIGO ) uterine carcinosarcoma of the homologous type with superficial ( 3mm ) myo-invasion . The patient showed no clinical symptoms of the disease and had no family history of female genital tract malignancies . Positive immunostaining for steroid receptors ( estrogen-alpha and progesterone receptors ) , cytokeratin , and P00533 was detected only in the carcinomatous area , whereas beta-catenin , BCL-2 , P35354 , p16(INK4a) , P60484 , Q8IUH3 , and vimentin were immunoreactive in both components . P10275 , CD10 , desmin , HER-2/neu , and P04637 were found to be negative either in the carcinomatous or in the sarcomatous area . Tumor proliferative activity was higher in the carcinomatous ( 25 % ) than in the sarcomatous ( 2 % ) component . Based on these findings , immunohistochemical evaluation of multiple receptor status in the carcinomatous and sarcomatous areas of carcinosarcoma may provide a clue to the pathogenesis and hormonal receptor status of this uncommon uterine malignancy . DB00991 : kinetic and dynamic profile in the treatment of pain . DB00991 ( 4,5-diphenyl-2-oxazolepropionic acid ) is a non-steroidal anti-inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . DB00991 has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . DB00991 's strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF-kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . DB00991 and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF-36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti-rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc. in several different painful musculoskeletal conditions . P28335 receptor involvement in female rat lordosis behavior . Adult , hormone-primed , ovariectomized rats ( P05231 -344 ) with bilateral implants within the ventromedial nucleus of the hypothalamus ( VMN ) , were injected with 0.5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone . This priming produced rats with 2 different levels of sexual receptivity . Rats with a lordosis to mount ratio ( L/M ) >/= 0.5 were used to examine the potential lordosis-inhibiting effects of the 5- Q13049 receptor antagonist , R(+)-a- ( 2 , 3-dimethoxyphenyl ) -1-[2(4-fluoro-phenylethyl)]-4-piperidine-methanol ( MDL 100,907 ) , and the P28335 receptor antagonist , 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo [ 2 , 3-f ] indole ( SB 206553 ) . Rats with low sexual receptivity ( L/M < 0.5 ) were bilaterally infused with the 5- Q13049 /2C receptor agonist , (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl ( DOI ) , or DOI plus either MDL 100,907 or SB 206553 to determine if either drug would attenuate the lordosis-facilitating effects of DOI . The P28335 receptor antagonist , but not the 5- Q13049 receptor antagonist , effectively inhibited lordosis behavior . Similarly , SB 206553 was more effective than MDL 100,907 in reducing the DOI-induced increase in lordosis responding . However , both drugs limited the duration of lordosis responding initiated by DOI . These results are consistent with prior suggestions that 5- Q13049 /2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that P28335 , rather than 5- Q13049 , receptors are primarily responsible for the effects of 5-HT2 receptor-active drugs on lordosis behavior . The role of serotonin receptor subtypes in the behavioural effects of neuroleptic drugs . A paw test study in rats . The present study was designed to evaluate the roles of serotonin P08908 and 5-HT2 receptors in the effects of neuroleptic drugs in the paw test . This behavioural test has been shown to model both the antipsychotic efficacy as well as the extrapyramidal side-effect liability of neuroleptic drugs . Whereas the P08908 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin ( 8-OHDPAT ) reduced the effects of the classical neuroleptic haloperidol , it increased the effects of the atypical neuroleptic clozapine . The 5-HT2 receptor antagonist ketanserin as well as the P28335 /5-HT2 receptor antagonist ritanserin , on the other hand reduced the effects of haloperidol , whereas the P28335 /5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ( DOI ) reduced the effects of clozapine . The most important finding , however , was that the behavioural effects of different ( putative ) neuroleptics ( fluphenazine , P35240 -39166 , remoxipride , prothipendyl , thioridazine and risperidone ) were differentially influenced by both 8-OHDPAT and DOI , suggesting that there are important differences between the neuronal mechanisms underlying the behavioural effects of these neuroleptic drugs , even within the subclasses of classical and atypical neuroleptics . A 9-year-old male with a duplication of chromosome 3p25.3p26.2 : clinical report and gene expression analysis . We describe a 9-year-old male referred for genetic evaluation for Prader-Willi syndrome ( PWS ) . PWS is the most common genetically defined cause of life-threatening obesity and results from a functional loss of paternally expressed genes from the chromosome 15q11-q13 region . The patient presented with pervasive developmental disorder , delayed speech , and rapid onset of obesity at age 4 years , all features similar to PWS . However , chromosome 15q11-q13 methylation testing and fragile X studies were normal . GTG-banding and fluorescence in situ hybridization ( Q5TCZ1 ) with whole chromosome 3 paint probe ( WCP3 ) and a chromosome 3p subtelomeric probe suggested a duplication of 3p25.3p26.2 , a finding supported by comparative genomic hybridization ( CGH ) . This region of chromosome 3p contains genes which contribute to obesity and behavioral problems , most notably , ghrelin ( Q9UBU3 ) , an oxytocin receptor ( P30559 ) , solute carrier family six members ( gamma-aminobutyric acid ( GABA ) neurotransmitter transporters , P30531 and P48066 ) , and peroxisome proliferator-activated receptor gamma ( P37231 ) . To characterize these obesity and behavior related genes in our subject , we performed quantitative RT-PCR and compared expression levels with similarly aged male subjects ( four non-obese males , four obese males , and four PWS males-two with 15q11-q13 deletions and two with maternal disomy 15 ) . Our studies suggest increased expression of several genes in the 3p duplication region , including Q9UBU3 and P37231 , which may contribute to the phenotypic features in our 3p duplication subject . DB06212 , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) -induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan-treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte-associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan-treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan-treated rats . CONCLUSIONS : DB06212 is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . DB06212 is a promising pharmacological tool in the treatment of renal edema . Reduced P25874 -1 content in in vitro differentiated beige/brite adipocytes derived from preadipocytes of human subcutaneous white adipose tissues in obesity . INTRODUCTION : Brown adipose tissue ( Q14032 ) is a potential therapeutic target to reverse obesity . The purpose of this study was to determine whether primary precursor cells isolated from human adult subcutaneous white adipose tissue ( WAT ) can be induced to differentiate in-vitro into adipocytes that express key markers of brown or beige adipose , and whether the expression level of such markers differs between lean and obese young adult males . METHODS : Adipogenic precursor cells were isolated from lean and obese individuals from subcutaneous abdominal WAT biopsies . Cells were grown to confluence , differentiated for 2.5 weeks then harvested for measurement of gene expression and P25874 protein . RESULTS : There was no difference between groups with respect to differentiation into adipocytes , as indicated by oil red-O staining , rates of lipolysis , and expression of adipogenic genes ( P15090 , P37231 ) . WAT genes ( P31274 , P06400 ) were expressed equally in the two groups . Post differentiation , the beige adipose specific genes Q99966 and Q07011 were significantly increased in both groups , but classic Q14032 markers Q15915 and Q68G74 decreased significantly . Cell lines from both groups also equally increased post-differentiation expression of the thermogenic-responsive gene Q9UBK2 ( P20142 -1α ) . P25874 gene expression was undetectable prior to differentiation , however after differentiation both gene expression and protein content were increased in both groups and were significantly greater in cultures from lean compared with obese individuals ( p < 0.05 ) . CONCLUSION : Human subcutaneous WAT cells can be induced to attain Q14032 characteristics , but this capacity is reduced in WAT cells from obese individuals . P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state . Genetics of idiopathic disseminated bronchiectasis . Bronchiectasis is an abnormal dilation of bronchi , consequent to the destruction of their walls . It is included in the category of obstructive pulmonary diseases , along with chronic obstructive pulmonary disease ( P48444 ) , asthma , and cystic fibrosis . In approximately 50 % of cases , bronchiectasis is associated with underlying conditions ; in the remainder , known causes are not ascertainable ( idiopathic bronchiectasis ) . A search for genetic determinants of this phenotype , with the cystic fibrosis gene as a candidate , has been performed by three independent groups . The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms . The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis . A few other genes have been investigated in idiopathic bronchiectasis , with negative results . Idiopathic bronchiectasis is , therefore , to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases ( or P13569 -opathies ) , whose pathogenesis is influenced by environmental factors and other undetermined genes . Cyclooxygenase-independent inhibition of H2O2-induced cell death by S-ketoprofen in renal cells . The stress response of the distal tubule to oxidative attack may be relevant to recovery from acute renal failure . In distal tubular Madin-Darby cells ( MDCK ) , H(2)O(2) induced up-regulation of cyclooxygenases ( P23219 and P35354 ) , prostaglandin-E(2) production and caspase-independent cell death . Cell death was inhibited by S-ketoprofen , but not by the much weaker P36551 inhibitor R-ketoprofen . Interestingly , we identified 15-deoxy-Delta(12,14)-prostaglandin-J(2) ( 15d-PGJ(2) ) , a peroxisome-proliferator activated receptor-gamma agonist , as a lethal prostaglandin whose effect was reproduced by the P37231 agonist ciglitazone . Nevertheless , H(2)O(2)-induced cell death was unaffected by other non-steroidal anti-inflammatory drugs ( NSAIDs ) or all-trans-retinoic acid . Moreover , c-Jun-N-terminal kinase inhibitor SP600125 prevented 15-deoxy-Delta(12,14)-PGJ(2)-induced cell death , but not H(2)O(2)-induced cell death . P37231 antagonist GW9662 showed no affect on the cell death . These results indicated that protection by S-ketoprofen was P36551 -independent and PPARgamma independent . Moreover , the IC(50) value of the action of S-ketoprofen for the inhibition of H(2)O(2)-induced MDCK cell death ( approximately equal 140microM ) was much higher than the IC(50) value for the inhibition of P23219 and P35354 activities ( approximately equal 1microM ) . Further design of S-ketoprofen derivatives devoid of P36551 inhibitory activity will give opportunity to protect the kidney against oxidative attack while avoiding unwanted effects of NSAID . Molecular evolution of the oxytocin-oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine-amino-acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre- P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature . 2(3H)-benzoxazolone and bioisosters as " privileged scaffold " in the design of pharmacological probes . The 2(3H)-benzoxazolone heterocycle and its bioisosteric surrogates ( such as 2(3H)-benzothiazolinone , benzoxazinone , etc. ) have received considerable attention from the medicinal chemists owing to their capacity to mimic a phenol or a catechol moiety in a metabolically stable template . These heterocycles and pyrocatechol have indeed similar pKa 's , electronic charge distribution , and chemical reactivity . Therapeutic applications of this template are very broad , and range from analgesic anti-inflammatory compounds ( including P37231 antagonists ) to antipsychotic and neuroprotective anticonvulsant compounds . High affinity ligands have been obtained also for dopaminergic ( D2 and D4 ) , serotoninergic ( P08908 and P28223 ) , sigma-1 and sigma-2 receptors . Owing to the high number of positive hits encountered with this heterocycle and its congeners , 2(3H)-benzoxazolone template certainly deserves the title of " privileged scaffold " in medicinal chemistry . Regulation of male fertility by P13569 and implications in male infertility . BACKGROUND : The cystic fibrosis transmembrane conductance regulator ( P13569 ) is a DB02527 -activated Cl(-) and HCO(3)(-) conducting channel , mutations of which are known to be associated with male infertility . However , the underlying mechanisms remain elusive . METHODS : Literature databases were searched for papers on the topics related to P13569 and male fertility and infertility with relevant keywords . Unpublished data from authors ' laboratory were also included for analysis . RESULTS : Clinical evidence shows increased mutation frequency or reduced P13569 expression in men with congenital bilateral absence of vas deferens ( CBAVD ) or sperm abnormalities , such as azoospermia teratospermia and oligoasthenospermia . Studies on primary rodent Sertoli cells and germ cells , as well as testes from P13569 knockout mice or a cryptorchidism model , yield findings indicating the involvement of P13569 in spermatogensis through the HCO(3)(-)/ Q96PN6 / DB02527 /CREB( Q03060 ) pathway and the NF-κB/ P35354 /PGE(2) pathway . Evidence also reveals a critical role of P13569 in sperm capacitation by directly or indirectly mediating HCO(3)(-) entry that is essential for capacitation . P13569 is emerging as a versatile player with roles in mediating different signaling pathways pertinent to various reproductive processes , in addition to its long-recognized role in electrolyte and fluid transport that regulates the luminal microenvironment of the male reproductive tract . CONCLUSIONS : P13569 is a key regulator of male fertility , a defect of which may result in different forms of male infertility other than CBAVD . It would be worthwhile to further investigate the potential of developing novel diagnostic and contraceptive methods targeting P13569 .