interacts_with DB00583?
Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large-scale Genome-Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2,047 subjects of European descent ( 1,062 cases and 985 controls ) . DB00184 dependence was assessed with multiple smoking measures , including the Fagerström Test for DB00184 Dependence , the Diagnostic and Statistical Manual for Mental Disorders-IV ( DSM-IV ) nicotine dependence , the DB00184 Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single-item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM-V . P10275 -dependent activation of endothelial nitric oxide synthase in vascular endothelial cells : role of phosphatidylinositol 3-kinase/akt pathway . The mechanisms of testosterone-induced vasodilatation are not fully understood . This study investigated the effect of testosterone on nitric oxide ( NO ) synthesis and its molecular mechanism using human aortic endothelial cells ( HAEC ) . DB00624 at physiological concentrations ( 1-100 nm ) induced a rapid ( 15-30 min ) increase in NO production , which was associated with phosphorylation and activation of endothelial NO synthase ( P29474 ) . Then , the involvement of the androgen receptor ( AR ) , which is abundantly expressed in HAEC , was examined . The effect of testosterone on P29474 activation and NO production were abolished by pretreatment with an AR antagonist nilutamide and by transfection with AR small interference RNA . In contrast , testosterone-induced P29474 phosphorylation was unchanged by pretreatment with an aromatase inhibitor or by transfection with ERalpha small interference RNA . DB02901 , a nonaromatizable androgen , also stimulated P29474 phosphorylation . Next , the signaling cascade that leads to P29474 phosphorylation was explored . DB00624 stimulated rapid phosphorylation of Akt in a time- and dose-dependent manner , with maximal response at 15-60 min . The rapid phosphorylation of P29474 or NO production induced by testosterone was inhibited by Akt inhibitor SH-5 or by phosphatidylinositol ( PI ) 3-kinase inhibitor wortmannin . Co-immunoprecipitation assays revealed a testosterone-dependent interaction between AR and the p85alpha subunit of P19957 -kinase . In conclusion , testosterone rapidly induces NO production via AR-dependent activation of P29474 in HAEC . Activation of P19957 -kinase/Akt signaling and the direct interaction of AR with p85alpha are involved , at least in part , in P29474 phosphorylation . Dietary L-carnitine supplementation increases lipid deposition in the liver and muscle of yellow catfish ( Pelteobagrus fulvidraco ) through changes in lipid metabolism . DB00583 has been reported to improve growth performance and reduce body lipid content in fish . Thus , we hypothesised that carnitine supplementation can improve growth performance and reduce lipid content in the liver and muscle of yellow catfish ( Pelteobagrus fulvidraco ) , a commonly cultured freshwater fish in inland China , and tested this hypothesis in the present study . Diets containing l-carnitine at three different concentrations of 47 mg/kg ( control , without extra carnitine addition ) , 331 mg/kg ( low carnitine ) and 3495 mg/kg ( high carnitine ) diet were fed to yellow catfish for 8 weeks . The low-carnitine diet significantly improved weight gain ( WG ) and reduced the feed conversion ratio ( FCR ) . In contrast , the high-carnitine diet did not affect WG and FCR . Compared with the control diet , the low-carnitine and high-carnitine diets increased lipid and carnitine contents in the liver and muscle . The increased lipid content in the liver could be attributed to the up-regulation of the mRNA levels of SREBP , PPARγ , fatty acid synthase ( FAS ) and ACCa and the increased activities of lipogenic enzymes ( such as FAS , glucose-6-phosphate dehydrogenase , 6-phosphogluconate dehydrogenase and malic enzyme ) and to the down-regulation of the mRNA levels of the lipolytic gene P50416 . The increased lipid content in muscle could be attributed to the down-regulation of the mRNA levels of the lipolytic genes P50416 and Q96AD5 and the increased activity of lipoprotein lipase . In conclusion , in contrast to our hypothesis , dietary carnitine supplementation increased body lipid content in yellow catfish . Incorporating age at onset of smoking into genetic models for nicotine dependence : evidence for interaction with multiple genes . DB00184 dependence is moderately heritable , but identified genetic associations explain only modest portions of this heritability . We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence . Specifically , we incorporated the interaction between allele count and age at onset of regular smoking ( AOS ) into association analyses of nicotine dependence . Subjects were from the Collaborative Genetic Study of DB00184 Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non-nicotine-dependent smokers as controls , all of European descent . Compared with main effect models , SNP x AOS interaction models resulted in higher numbers of nominally significant tests , increased predictive utility at individual SNPs and higher predictive utility in a multi-locus model . Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis , including rs16969968 from P30532 and rs2314379 from Q9Y6R4 . P30532 exhibited larger effects in later-onset smokers , in contrast with a previous report that suggested the opposite interaction ( Weiss et al. 2008 ) . However , a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses . These include SNPs located in Q13224 ( P = 1.5 x 10(-5) ) , which encodes a subunit of the N-methyl-D-aspartate receptor channel , a key molecule in mediating age-dependent synaptic plasticity . Incorporation of logically chosen interaction parameters , such as AOS , into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery . Coordination complexes with the redox active tetrathiafulvalene based imino-pyrazine ligand : syntheses , a radical cation salt , crystal structures and electrochemistry . The tetrathiafulvalene based 2-immino-pyrazine derivative ( Q15669 -CHN-2-pyz ) ( ) was synthesized and characterized . Its radical cation salt ( (+)PF(6)(-) ) was prepared as single crystals by electrocrystallisation . (+)PF(6)(-) crystallizes in the triclinic P1 space group . Four 1 : 2 bis(hexafluoroacetylacetonate)M(ii) complexes coordinated with were prepared ( M = Mn for , M = Co for , M = Cu for and M = DB01593 for ) . Complex crystallizes in the monoclinic P06681 /c space group , complexes and crystallize in the triclinic space group P1 . Two pyrazine N atoms from two different donors are coordinated in cis configuration for and trans configuration for and to the metallic ion of M(hfac)(2) ( hfac(-)=hexafluoroacetylacetonate anion ) . The manganese atom adopts a pseudo-compressed octahedral geometry while the copper and the zinc ions adopt axially elongated octahedral geometries . Both crystal packing structures and electrochemical properties are appropriate for their potential use as starting molecular bricks for conducting and magnetic materials . P10275 -induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53/p73-mediated apoptosis in breast carcinomas . P10275 ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR 's anti-tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 and O15350 , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 are AR-target genes , mediating androgen-induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas . Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with DB01098 , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20-week-old Zucker obese and 16-week-old ZDF rats were treated with DB01098 ( 25 mg/kg/day ) or Enalapril ( 20 mg/kg/day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75-175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with DB01098 or Enalapril . Three novel mutations in the carnitine-acylcarnitine translocase ( O43772 ) gene in patients with O43772 deficiency and in healthy individuals . DB00583 -acylcarnitine translocase ( O43772 ) and carnitine palmitoyltransferase II ( P23786 ) are key enzymes for transporting long-chain fatty acids into mitochondria . Deficiencies of these enzymes , which are clinically characterized by life-threatening non-ketotic hypoglycemia and rhabdomyolysis , can not be distinguished by acylcarnitine analysis performed using tandem mass spectrometry . We had previously reported the P23786 genetic structure and its role in P23786 deficiency . Here , we analyzed the O43772 gene in 2 patients diagnosed clinically with O43772 deficiency , 18 patients with non-traumatic rhabdomyolysis and 58 healthy individuals , all of whom were confirmed to have normal P23786 genotypes . To facilitate O43772 genotyping , we used heat-denaturing high-performance liquid chromatography ( DHPLC ) , which helped identify five distinct patterns . The abnormal heteroduplex fragments were subjected to O43772 -specific DNA sequencing . We found that one patient with O43772 deficiency , Case 1 , carried c.576G > A and c.199-10t > g mutations , whereas Case 2 was heterozygous for c.106-2a > t and c.576G > A . We also found that one patient with non-traumatic rhabdomyolysis and one healthy individual were heterozygous for c.804delG and the synonymous mutation c.516T > C , respectively . In summary , c.576G > A , c.106-2a > t and c.516T > C are novel O43772 gene mutations . Among the five mutations identified , three were responsible for O43772 deficiency . We have also demonstrated the successful screening of O43772 mutations by DHPLC . P10275 mediates non-genomic activation of phosphatidylinositol 3-OH kinase in androgen-sensitive epithelial cells . Androgens are known to modulate many cellular processes such as cell growth and survival by binding to the androgen receptor ( AR ) and activating the transcription of target genes . Recent data suggested that AR can also mediate non-transcriptional actions outside the nucleus in addition to its ligand-inducible transcription factor function . Here , we describe a transcription-independent activation of the phosphatidylinositol 3-OH kinase ( P19957 -K ) signaling pathway by androgens . Using non-transformed androgen-sensitive epithelial cells , we show that androgens enhance the P19957 -K activity by promoting accumulation of phosphoinositide-3-P phospholipids in vitro . This activation is found in conjunction with an increased time-dependent phosphorylation of the downstream kinase AKT/protein kinase B on both DB00133 (473) and DB00156 (308) residues . Hormone-stimulated phosphorylation of AKT requires AR since incubation with the anti-androgen bicalutamide completely abolishes the androgen-stimulated AKT phosphorylation . Accordingly , we show that androgens increase AKT phosphorylation level in prostatic carcinoma PC3 cells only once they have been transfected with AR . Downstream , androgens enhance phosphorylation of transcription factor Q12778 ( Q12778 ) - Q9NUQ9 and proapoptotic Bad protein and promote cell survival as they can counteract an apoptotic process . We also report that non-genomic effects of androgens are based on direct interaction between AR and the p85alpha regulatory subunit of class I(A) P19957 -K . Together , these novel findings point out an important and physiologically relevant link between androgens and the P19957 -K/AKT signaling pathway in governing cell survival . Bovine viral diarrhea viruses differentially alter the expression of the protein kinases and related proteins affecting the development of infection and anti-viral mechanisms in bovine monocytes . Using a proteomics approach , we evaluated the effect of cytopathic ( cp ) , and non-cytopathic ( ncp ) bovine viral diarrhea viruses ( BVDV ) on the expression of protein kinases and related proteins in bovine monocytes . Proteins were isolated from membrane and cytosolic fractions with the differential detergent fractionation ( DDF ) method and identified with 2D-LC P19957 P78325 . Of approximately 10,000 proteins identified , 378 proteins had homology with known protein kinases or related proteins . Eighteen proteins involved in cell differentiation and activation , migration , anti-viral mechanisms ( interferon/apoptosis ) , biosynthesis , sugar metabolism and oncogenic transformation were significantly altered in BVDV-infected monocytes compared to the uninfected controls . Six proteins , mostly related to cell migration , anti-viral mechanisms , sugar metabolism and possibly tumor resistance were differentially expressed between the ncp and cp BVDV-infected monocytes . Particularly , the expression of the receptor of activated C kinase ( RACK ) , of pyridoxal kinase ( PK ) , diacyglycerol kinase ( Q16854 ) and Brutons tyrosine kinase ( Q06187 ) was decreased in monocytes infected with cp BVDV compared to ncp BVDV , possibly contributing to the cytopathic effect of the virus . This and other findings are discussed in view of the possible role the identified proteins play in the development of viral infection and oncogenic transformation of cells . Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein-Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy/hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 -32765 , recently renamed DB09053 , has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors . Reduction of airway anion secretion via P13569 in sphingomyelin pathway . The present study concerns the involvement of the ceramide produced through sphingomyelinase ( SMase ) -mediated catalysis in airway anion secretion of Calu-3 cells . Short-circuit current ( Isc ) measurement revealed that isoproterenol ( ISO , 0.1 microM ) -induced anion secretion was prevented by pretreatment with SMase ( 0.3 U/ml , for 30 min ) from the basolateral but not the apical side , although basal and 1-ethyl-2-benzimidazolinone ( 1-EBIO , a Ca2+-activated K+ channel opener ) -induced Isc were unaffected . The effects of SMase were reproduced in responses to forskolin ( 20 microM ) or 8-bromo- DB02527 ( 2 mM ) . P06681 -ceramide , a cell-permeable analog , also repressed the 8-bromo- DB02527 -induced responses . Nystatin permeabilization studies confirmed that the SMase- and P06681 -ceramide-induced repressions were due to hindrance of augmentation of cystic fibrosis transmembrane conductance regulator ( P13569 ) -mediated conductance across the apical membrane . Further , SMase failed to influence K+ conductance across the basolateral membrane . These results suggest that the ceramide originating from basolateral sphingomyelin acts on activated P13569 from the cytosolic side , hindering anion secretion . [ DB09053 : A new drug of B-cell malignancies ] . DB09053 ( Imbruvica® ) is a first-in-class , orally administered once-daily , that inhibits B-cell antigen receptor signaling downstream of Bruton 's tyrosine kinase ( Q06187 ) . DB09053 has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed/refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed/refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression-free survival , response rate and overall survival in patients with relapsed/refractory CLL , including in those with del 17p . DB09053 had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B-cell malignancies . The sulphydryl containing P12821 inhibitor Zofenoprilat protects coronary endothelium from Doxorubicin-induced apoptosis . Pediatric and adult cancer patients , following the use of the antitumor drug Doxorubicin develop cardiotoxicity . Pharmacological protection of microvascular endothelium might produce a double benefit : ( i ) reduction of myocardial toxicity ( the primary target of Doxorubicin action ) and ( ii ) maintenance of the vascular functionality for the adequate delivery of chemotherapeutics to tumor cells . This study was aimed to evaluate the mechanisms responsible of the protective effects of the angiotensin converting enzyme inhibitor ( ACEI ) Zofenoprilat against the toxic effects exerted by Doxorubicin on coronary microvascular endothelium . We found that exposure of endothelial cells to Doxorubicin ( 0.1-1μM range ) impaired cell survival by promoting their apoptosis . P27361 /2 related p53 activation , but not reactive oxygen species , was responsible for Doxorubicin induced caspase-3 cleavage . P04637 mediated-apoptosis and impairment of survival were reverted by treatment with Zofenoprilat . The previously described PI-3K/ P29474 /endogenous fibroblast growth factor signaling was not involved in the protective effect , which , instead , could be ascribed to cystathionine gamma lyase dependent availability of H2S from Zofenoprilat . Furthermore , considering the tumor environment , the treatment of endothelial/tumor co-cultures with Zofenoprilat did not affect the antitumor efficacy of Doxorubicin . In conclusion the ACEI Zofenoprilat exerts a protective effect on Doxorubicin induced endothelial damage , without affecting its antitumor efficacy . Thus , sulfhydryl containing ACEI may be a useful therapy for Doxorubicin-induced cardiotoxicity . Association between apolipoprotein E4 and rehabilitation outcome in hospitalized ischemic stroke patients . OBJECTIVE : To determine the value of apolipoprotein E4 ( P02649 *E4 ) allele in predicting discharge impairment and disability in ischemic stroke patients after acute rehabilitation . DESIGN : Prospective study comparing results of rehabilitation in patients with different P02649 genotypes . SETTING : Acute neurologic rehabilitation department in Israel . PARTICIPANTS : One hundred one consecutive patients 75 years old or less with a first ischemic stroke . INTERVENTIONS : Not applicable . MAIN OUTCOME MEASURE : Impairment , as measured by the National Institutes of Health Stroke Scale ( NIHSS ) , and disability , as assessed with the Q9UBW7 trade mark instrument . RESULTS : On admission , there was no significant difference in the Q9UBW7 or NIHSS measurements between the apo E4 group and other patients , but the prevalence of aphasia was 2.07 times more frequent in those with the P02649 *E4 genotype ( 95 % confidence interval , 0.98-4.4 ) . A logistic regression model demonstrated that score measurements on admission were highly predictive of the NIHSS score at discharge ( receiver operator curve=96.1 % ) , whereas the presence of the P02649 *E4 genotype did not add significantly to the model in predicting poorer rehabilitation treatment outcome as measured by the Q9UBW7 or the NIHSS . CONCLUSIONS : The presence of the apo E4 allele did not predict a poorer outcome of rehabilitation treatment after ischemic stroke , but it was associated with an increased prevalence of aphasia . Further studies are warranted to confirm this association . Decreased mitochondrial carnitine translocase in skeletal muscles impairs utilization of fatty acids in insulin-resistant patients . P01308 resistance ( IR ) and its health consequences ( diabetes , hypertension , cardiovascular disease , obesity etc. ) affect between 25 and 35 % of Westernized populations . Decreased fatty acid ( FA ) oxidation in skeletal muscle is implicated in obesity-related IR . DB00583 -acylcarnitine translocase ( O43772 ) transports long-chain FAs both into mitochondria ( as carnitine esters for energy-generating processes ) and out of mitochondria . To determine whether O43772 activity correlates with decreased FA oxidation we measured O43772 concentrations in cellular and mitochondrial extracts from the skeletal muscle of 19 obese IR individuals and of 19 lean controls . We also evaluated carnitine transport in skeletal muscle mitochondria in both groups . Mitochondrial O43772 was decreased at translational and transductional level , and carnitine-carnitine and acylcarnitine-carnitine exchange rates were significantly lower in IR subjects . Aberrant acylcarnitine flux into mitochondria was not correlated with decreased activity of other components of the mitochondrial carnitine system ( i.e. , carnitine palmitoyl transferase-I and II ) . Our data suggest that by restraining entry of FA-coenzyme A into mitochondria , low O43772 levels increase cytosolic FA levels and their incorporation into glycerolipids . The low level of O43772 in IR muscle may contribute to the elevated muscle concentrations of triglycerides , diacylglycerol , and FA-coenzyme A characteristic of IR muscle . Broadening of transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model to represent late stage androgen depletion independent cancer . BACKGROUND : The transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model closely mimics PC-progression as it occurs in humans . However , the timing of disease incidence and progression ( especially late stage ) makes it logistically difficult to conduct experiments synchronously and economically . The development and characterization of androgen depletion independent ( ADI ) TRAMP sublines are reported . METHODS : Sublines were derived from androgen-sensitive TRAMP-C1 and TRAMP- P06681 cell lines by androgen deprivation in vitro and in vivo . Epithelial origin ( cytokeratin ) and expression of late stage biomarkers ( P12830 and KAI-1 ) were evaluated using immunohistochemistry . P10275 ( AR ) status was assessed through quantitative real time PCR , Western blotting , and immunohistochemistry . Coexpression of AR and P12830 was also evaluated . Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays . Proliferation/survival of sublines in response to androgen was assessed by WST-1 assay . In vivo growth of subcutaneous tumors was assessed in castrated and sham-castrated C57BL/6 mice . RESULTS : The sublines were epithelial and displayed ADI in vitro and in vivo . Compared to the parental lines , these showed ( 1 ) significantly faster growth rates in vitro and in vivo independent of androgen depletion , ( 2 ) greater tumorigenic , and invasive potential in vitro . All showed substantial downregulation in expression levels of tumor suppressor , P12830 , and metastatis suppressor , KAI-1 . Interestingly , the percentage of cells expressing AR with downregulated P12830 was higher in ADI cells , suggesting a possible interaction between the two pathways . CONCLUSIONS : The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness . DB08816 reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 receptor antagonists have been reported to exert anti-inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild-type C57BL/6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg/kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet-neutrophil aggregates , neutrophil activation and P29965 expression on platelets . CLP-induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor-treated animals . Moreover , ticagrelor abolished CLP-provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet-neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 in septic mice . Our data indicate that ticagrelor can reduce CLP-induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis . Neem leaf glycoprotein suppresses regulatory T cell mediated suppression of monocyte/macrophage functions . We have shown that neem leaf glycoprotein ( NLGP ) inhibits the regulatory T cell ( Tregs ) induced suppression of tumoricidal functions of P08571 (+) P34810 (+) monocyte/macrophages ( MO/Mφ ) from human peripheral blood . Cytotoxic efficacy of MO/Mφ toward macrophage sensitive cells , U937 , is decreased in presence of Tregs ( induced ) , however , it was increased further by supplementation of NLGP in culture . Associated Treg mediated inhibition of perforin/granzyme B expression and nitric oxide release from MO/Mφ was normalized by NLGP . Altered status of signature cytokines , like , IL-12 , P22301 , P05231 , TNFα from MO/Mφ under influence of Tregs is also rectified by NLGP . Tregs significantly enhanced the expression of altered marker , mannose receptor ( CD206 ) on P34810 (+) cells that was downregulated upon NLGP exposure . In addition to tumoricidal functions , antigen presenting ability of MO/Mφ is hampered by Treg induced downregulation of P33681 , P42081 and HLA- DB01048 . NLGP upregulated these molecules in MO/Mφ even in the presence of Tregs . Treg mediated inhibition of MO/Mφ chemotaxis in contact dependent manner was also normalized partially by NLGP , where participation of P51681 was documented . Overall results suggest that Treg influenced pro-tumor MO/Mφ functions are rectified in a significant extent by NLGP to create an anti-tumor immune environment . First report of warfarin dose requirements in patients possessing the P11712 *12 allele . BACKGROUND : DB00682 is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S-warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin . Numerous variant alleles of P11712 have been identified . The P11712 *12 ( rs9332239 ) allele harbors a P489S substitution in P11712 which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 , Q9BQB6 and P02649 variant alleles . None of the four patients carried the common P11712 variant alleles ( *2 , *3 , *5 , *6 , *7 , *8 , *9 , *11 , *13 ) despite a relatively low MWWD ( 23.4±7.94 mg ) compared to 208 patients carrying the CYP29C9*1 genotype ( 32.2±12.65 mg ) . Given that P11712 *12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 *12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 genotypes also demonstrated lower dose requirements in the patients that possessed P11712 *12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 substrates . This is the first report of patients with the rare P11712 *12 genotype and lower warfarin dose requirements . DB00583 -palmitoyltransferase 2 deficiency : novel mutations and relevance of newborn screening . We report on a newborn male , born at term after an uneventful pregnancy presenting with a pathological acylcarnitine profile in routine newborn screening on the third day of life . The profile showed characteristic elevations of C14:0- , C16:0- , C16:1- and C18:1-acylcarnitines , while the ratio of ( C16 + C18:1 ) / P06681 was increased , suggesting P23786 - or carnitine-acylcarnitine-translocase- deficiency . The acylcarnitine profile in blood taken on day 9 was normal with breast milk feeding . No dicarboxylic aciduria was found . In fibroblasts , the activity of P23786 was decreased to 25 % , overall oxidation of the long-chain fatty acids was reduced to 10 % of control values . Sequence analysis of the P23786 gene showed heterozygosity for two previously undescribed mutations in exon 4 : c.748-749delAA ( truncating ) , and c.1436A > G ( p.Tyr479Cys ; missense ) mutations . The asymptomatic parents were found to be heterozygous , the mother carries the c.748-749delAA and the father the c.1436A > G mutation . The boy is now 2.5 years old ; no clinical symptoms associated with the marked impairment of long-chain fatty acid oxidation have occurred . Confirmation of mitochondrial fatty acid oxidation defects from an initial abnormal newborn-screening by tandem mass spectrometry should include enzyme and , if possible , molecular genetic analysis despite a normal 2nd screening . Biochemical testing of urine ( organic acids ) may be unrevealing . DB00184 activates P46937 through nAChRs mediated signaling in esophageal squamous cell cancer ( ESCC ) . Cigarette smoking is an established risk factor for esophageal cancers . P46937 ( P46937 ) , the key transcription factor of the mammalian Hippo pathway , has been reported to be an oncogenic factor for many cancers . In this study , we find nicotine administration can induce nuclear translocation and activation of P46937 in ESCC . Consistently , we observed nuclear translocation and activation of P46937 by knockdown of P32297 , which is a negative regulator of nicotine signaling in bronchial and esophageal cancer cells . DB00184 administration or P32297 depletion substantially increased proliferation and migration in esophageal cancer cells . Interestingly , we find that P46937 physically interacts with nAChRs , and nAChRs-signaling dissociates P46937 from its negative regulatory complex composed with α-catenin , β-catenin and 14-3-3 in the cytoplasm , leading to upregulation and nuclear translocation of P46937 . This process likely requires PKC activation , as PKC specific inhibitor Enzastaurin can block nicotine induced P46937 activation . In addition , we find nicotine signaling also inhibits the interaction of P46937 with Q9H3D4 , which contributes to the inhibitory effect of nicotine on apoptosis . Using immunohistochemistry analysis we observed upregulation of P46937 in a significant portion of esophageal cancer samples . Consistently , we have found a significant association between P46937 upregulation and cigarette smoking in the clinical esophageal cancer samples . Together , these findings suggest that the nicotine activated nAChRs signaling pathway which further activates P46937 plays an important role in the development of esophageal cancer , and this mechanism may be of a general significance for the carcinogenesis of smoking related cancers . Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts . DB00583 palmitoyl transferase 2 ( P23786 ) and very-long-chain Acyl- DB01992 dehydrogenase ( P49748 ) deficiencies are among the most common inborn mitochondrial fatty acid β-oxidation ( FAO ) disorders . Despite advances in their clinical and molecular characterizations , few therapeutic approaches exist for these diseases . DB02709 ( RSV ) is a natural polyphenol extensively studied for its potential health benefits . Indeed , it is presently thought that RSV could delay the onset of some cancers , and have protective effects against common aging disorders such as type II diabetes , cardiovascular or neurodegenerative diseases . Here , we show that exposure to RSV induces a dose- and time-dependant increase in FAO flux in human fibroblasts , and can restore normal FAO capacities in a panel of patients ' fibroblasts with the mild forms ( harboring various genotypes ) of P23786 or P49748 deficiency . The correction of FAO flux correlated with a marked increase in mutant P23786 or P49748 protein level , in cells treated by RSV . Inhibition of sirtuin 1 ( Q96EB6 ) by Sirtinol and the use of peroxisome proliferator-activated receptor gamma co-activator-1-alpha ( P20142 -1α ) small interfering RNAs demonstrate that the RSV-induced stimulation of FAO requires the presence of P20142 -1α and Q96EB6 . These results show , for the first time , that RSV markedly induces mitochondrial FAO capacities in human fibroblasts , and provides the initial proof-of-concept that RSV might be efficient for correction of inherited FAO disorders . DB00142 reverses Pb2+-induced reductions of DB01221 receptor subunits in vitro . The objective of this study is to determine the effects of Pb2+ on N-methyl-d-aspartate receptor ( NMDAR ) subunits -- Q07869 , Q12879 and Q13224 in primary cultured neuronal cells . We hypothesize that L-glutamic acid ( GA ) reverses Pb2+-induced NMDAR damage . Neuronal cells were isolated from the fetus brain at 18-20th day of gestation of pregnant Sprague Dawley ( SD ) rats . All experiments were included three independent cell preparations ( N=3 ) . The neuronal cells were exposed to Pb2+ ( 10(-10) , 10(-9) , 10(-8) and 10(-7)M ) for 24 h . Neurons were pretreated with NMDAR agonist -- L-glutamic acid ( GA ) ( 200 microM ) and antagonists dizocipine ( MK-801 , 50 nM ) for 1h and then exposed to 10(-7)M of Pb2+ for 24 h . Finally , GA at 2 , 0.2 and 0.02 mM was incubated with neurons prior to Pb2+ exposure . Aliquots of Q9UHB4 , Q12879 and Q13224 proteins from cell homogenate were immunoprecipitated with protein A agarose and detected by Western blotting . The addition of GA unconventionally reversed the reductions of NMDAR by Pb at protein levels , whereas MK-801 exacerbated Pb2+-induced damage . The protection by GA against Pb2+-induced reduction of NMDAR was dose-dependent . These findings suggest that the administration of GA may be a potential approach to intervene the Pb2+-induced NMDAR alterations . Practical identifiability of HIV dynamics models . We study the practical identifiability of parameters , i.e. , the accuracy of the estimation that can be hoped , in a model of HIV dynamics based on a system of non-linear Ordinary Differential Equations ( ODE ) . This depends on the available information such as the schedule of the measurements , the observed components , and the measurement precision . The number of patients is another way to increase it by introducing an appropriate statistical " population " framework . The impact of each improvement of the experimental condition is not known in advance but it can be evaluated via the Fisher Information Matrix ( Q9UBW7 ) . If the non-linearity of the biological model , as well as the complex statistical framework makes computation of the Q9UBW7 challenging , we show that the particular structure of these models enables to compute it as precisely as wanted . In the HIV model , measuring HIV viral load and total P01730 + count were not enough to achieve identifiability of all the parameters involved . However , we show that an appropriate statistical approach together with the availability of additional markers such as infected cells or activated cells should considerably improve the identifiability and thus the usefulness of dynamical models of HIV . [ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non-lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) DB08816 is especially more effective in intermediate-and high-risk non-ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non-invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy . DB00583 palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases . The high incidence of acute encephalopathy in East Asia suggests the role of genetic factors in its pathogenesis . It has recently been reported that variations of the P23786 ( carnitine palmitoyl transferase II ) gene may be associated with fatal or severe cases of influenza-associated encephalopathy . In the present study , we examined the genotype of P23786 in cases of acute encephalopathy associated with various preceding infections . Twenty-nine Japanese patients with acute encephalopathy with biphasic seizures and late reduced diffusion ( AESD ) or acute necrotizing encephalopathy ( ANE ) were studied . The frequency of F352C of P23786 exon 4 was significantly higher in patients than in controls . All patients who had allele C in F352C had allele I in V368I and allele M in M647V ( CIM haplotype ) , which reportedly decreases P23786 activity to one third of that with Q9UBW7 or FVM haplotype . The frequency of CIM haplotype was significantly different between patients and controls , but not between AESD and ANE . Our results revealed that having at least one CIM allele is a risk factor for the onset of acute encephalopathy , regardless of its antecedent infections . Both the ADP receptors P47900 and Q9H244 , play a role in controlling shape change in human platelets . Two types of ADP receptors , P2Y(1) and P2Y(12) are involved in platelet aggregation . The P2X(1) receptor is also present but its role , in terms of platelet function , is not yet defined . The aim of this study was to establish if the ADP receptors , P2Y ( 1 , ) P2Y(12) and P2X(1) play a role in controlling platelet shape change ( PSC ) in human platelets . PSC is an early phase of platelet activation that precedes aggregation . Using a high-resolution channelyzer , PSC was assessed by measuring the median platelet volume ( MPV ) . The P2Y(1) receptor antagonist P59665 2179 ( 1.06 - 10.25 micro mol/l ) blocked ADP-induced PSC ( by 100 % ) . The median IC(50) was 3.16 micro mol/l . P59665 2179 also significantly ( P = 0.01 ) inhibited PSC induced by the combination of ADP + serotonin ( 5HT ) . The P2Y(12) receptor antagonist AR-C69931MX significantly inhibited ( at 10s , P = 0.009 ; 15 s , P = 0.001 and 30 s , P = 0.015 ) ADP-induced PSC . The P2X(1) receptor antagonist TNP- DB00171 had no significant effect on ADP- or ADP + 5HT-induced PSC . We conclude that the IC(50) of a P2Y(1)-blocker can be derived because of the high-resolution and reproducibility of the channelyzer technique . In addition to the P2Y(1) purinoceptor , the P2Y(12)receptor appears to be involved in ADP-induced PSC since this process was significantly inhibited by AR-C69931MX . The channelyzer technique may be more reliable than optical aggregometry to assess PSC . DB09280 - DB08820 in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 . [ Recent advances in the study of AMPK and inflammatory pulmonary disease ] . AMP-activated protein kinase ( AMPK ) is an important regulator of cellular energy homeostasis . Recent studies demonstrated that AMPK is a novel signaling molecule modulating inflammatory responses and oxidative stress which are involved in inflammatory pulmonary diseases , such as asthma , chronic obstructive pulmonary disease ( P48444 ) , pulmonary infectious diseases and pulmonary fibrosis . AMPK attenuates inflammatory lung injury by phosphorylating its downstream targets , such as sirtuin1 ( Q96EB6 ) , peroxisome proliferator-activated receptor gamma coactivator-1alpha ( P20142 -1alpha ) , p53 and forkhead box O3a ( FoxO3a ) . This review summarized the relationship between AMPK and the development of inflammatory pulmonary diseases . Epigenetic regulation of angiotensin-converting enzyme 2 ( Q9BYF1 ) by Q96EB6 under conditions of cell energy stress . Q9BYF1 ( angiotensin-converting enzyme 2 ) counterbalances the actions of P12821 ( angiotensin-converting enzyme ) by metabolizing its catalytic product , the vasoactive and fibrogenic peptide AngII ( angiotensin II ) , into Ang-(1-7) [ angiotensin-(1-7) ] . Enhanced Q9BYF1 expression may be protective in diabetes , cardiovascular disease and cancer . However , relatively little is known about the specific physiological factors regulating Q9BYF1 expression . In the present paper , we show , by Western blotting and qPCR ( quantitative real-time PCR ) , that Q9BYF1 expression is increased under conditions of cell stress , including hypoxic conditions , IL (interleukin)-1β treatment and treatment with the AMP mimic AICAR ( 5-amino-4-imidazolecarboxamide riboside ) . The NAD+-dependent deacetylase Q96EB6 ( silent information regulator T1 ) was found to be up-regulated after AICAR treatment but , conversely , was down-regulated after IL-1β treatment . ChIP analysis demonstrated that Q96EB6 bound to the Q9BYF1 promoter and that binding was increased after AICAR treatment , but decreased after IL-1β treatment . Inhibition of Q96EB6 activity ablated the AICAR-induced increase in Q9BYF1 . In conclusion , we have established that the expression of the Q9BYF1 transcript is controlled by the activity of Q96EB6 under conditions of energy stress . 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 . Alterations of the X-linked lymphoproliferative disease gene O60880 in common variable immunodeficiency syndrome . X-linked lymphoproliferative ( XLP ) disease is a primary immunodeficiency caused by a defect in the O60880 gene . At least 3 major manifestations characterize its clinical presentation : fatal infectious mononucleosis ( Q9UBW7 ) , lymphomas , and immunoglobulin deficiencies . Common variable immunodeficiency ( CVID ) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to infection . In some patients with CVID , a defective btk or P29965 gene has been found , but most often there is no clearly identified etiology . Here , 2 unrelated families in whom male members were affected by CVID were examined for a defect in the XLP gene . In one family previously reported in the literature as having progressive immunoglobulin deficiencies , 3 brothers were examined for recurrent respiratory infections , whereas female family members showed only elevated serum immunoglobulin A levels . A grandson of one of the brothers died of a severe Aspergillus infection secondary to progressive immunoglobulin deficiency , Q9UBW7 , aplastic anemia , and B-cell lymphoma . In the second family , 2 brothers had B lymphocytopenia and immunoglobulin deficiencies . X-linked agammaglobulinemia syndrome was excluded genetically , and they were classified as having CVID . The occurrence of Q9UBW7 in a male cousin of the brothers led to the XLP diagnosis . Because the O60880 gene was found altered in both families , these findings indicate that XLP must be considered when more than one male patient with CVID is encountered in the same family , and O60880 must be analyzed in all male patients with CVID . Moreover , these data link defects in the O60880 gene to abnormal B-lymphocyte development and to dysgammaglobulinemia in female members of families with XLP disease . 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 . L-carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow . BACKGROUND : In our model of a congenital heart defect ( Q8NE62 ) with increased pulmonary blood flow ( PBF ; shunt ) , we have recently shown a disruption in carnitine homeostasis , associated with mitochondrial dysfunction and decreased endothelial nitric oxide synthase ( P29474 ) /heat shock protein (Hsp)90 interactions that contribute to P29474 uncoupling , increased superoxide levels , and decreased bioavailable nitric oxide ( NO ) . Therefore , we undertook this study to test the hypothesis that L-carnitine therapy would maintain mitochondrial function and NO signaling . METHODS : Thirteen fetal lambs underwent in utero placement of an aortopulmonary graft . Immediately after delivery , lambs received daily treatment with oral L-carnitine or its vehicle . RESULTS : L- DB00583 -treated lambs had decreased levels of acylcarnitine and a reduced acylcarnitine:free carnitine ratio as compared with vehicle-treated shunt lambs . These changes correlated with increased carnitine acetyl transferase ( P43155 ) protein and enzyme activity and decreased levels of nitrated P43155 . The lactate:pyruvate ratio was also decreased in L-carnitine-treated lambs . Hsp70 protein levels were significantly decreased , and this correlated with increases in P29474 /Hsp90 interactions , NOS activity , and NOx levels , and a significant decrease in P29474 -derived superoxide . Furthermore , acetylcholine significantly decreased left pulmonary vascular resistance only in L-carnitine-treated lambs . CONCLUSION : L- DB00583 therapy may improve the endothelial dysfunction noted in children with CHDs and has important clinical implications that warrant further investigation . SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation . Cystic fibrosis ( CF ) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator ( P13569 ) gene . CF is characterized by chronic bacterial lung infections and inflammation , and we have previously reported that tissue transglutaminase ( TG2 ) , a multifunctional enzyme critical to several diseases , is constitutively up-regulated in CF airways and drives chronic inflammation . Here , we demonstrate that the generation of an oxidative stress induced by P13569 -defective function leads to protein inhibitor of activated P35610 (PIAS)y-mediated TG2 SUMOylation and inhibits TG2 ubiquitination and proteasome degradation , leading to sustained TG2 activation . This prevents peroxisome proliferator-activated receptor ( Q07869 )gamma and IkBalpha SUMOylation , leading to NF-kappaB activation and to an uncontrolled inflammatory response . Cellular homeostasis can be restored by small ubiquitin-like modifier ( SUMO ) -1 or Q8N2W9 gene silencing , which induce TG2 ubiquitination and proteasome degradation , restore PPARgamma SUMOylation , and prevent IkBalpha cross-linking and degradation , thus switching off inflammation . DB06757 superoxide dismutase overexpression as well as the treatment with the synthetic superoxide dismutase mimetic EUK-134 control Q8N2W9 -TG2 interaction and TG2 SUMOylation . TG2 inhibition switches off inflammation in vitro as well as in vivo in a homozygous F508del- P13569 mouse model . Thus , TG2 may function as a link between oxidative stress and inflammation by driving the decision as to whether a protein should undergo SUMO-mediated regulation or degradation . Targeting TG2-SUMO interactions might represent a new option to control disease evolution in CF patients as well as in other chronic inflammatory diseases , neurodegenerative pathologies , and cancer . Laboratory selection of Haemonchus contortus for resistance to ivermectin . The eighth generation of adult Haemonchus contortus , selected by subjecting infected pairs of sheep to suboptimal ivermectin treatment once per generation from parent ( P ; O75936 isolate ) through P08709 ( IV-A ; selected isolate ) , required an approximate 4-fold increase in the ivermectin dose to produce 95 % efficacy compared with its contemporary parent isolate . In a dose titration experiment the dose-response curve of the drug pressure-derived isolate , IV-A , was significantly ( 0.02 less than P less than 0.05 ) less steep than was the response curve of the parent , O75936 , isolate . Potency estimates based upon these nonparallel dose-response curves would not remain constant over a range of efficacy levels but would decrease rapidly at efficacies greater than 95 % . Passage of a closed population of the P00451 generation of IV-A sequentially through pairs of sheep for an additional 11 generations ( P23610 -F8K ) without additional drug pressure being applied produced no reversion to sensitivity to ivermectin relative to the P08709 generation , thus suggesting that the selected " resistance " was stable . Effect of the IkBα mutant gene delivery to DB05914 on rat chronic pancreatitis . This study aimed to investigate the effect of inhibitors of the NF-kΒ alpha mutant gene ( IkBaM ) delivery to mensenchymal stem cells ( MSCs ) on rat chronic pancreatitis ( CP ) . A total of 120 Sprague-Dawley rats were randomly divided into 6 groups of 20 : Group A was injected with sterile saline solution , Group B was injected with allogenic MSCs , Group C1 was injected with allogenic IkBαM-MSCs cultured in vitro 4 h before CP modeling , Group P06681 was injected with allogenic IkBαM-MSCs cultured in vitro during CP modeling , Group P01024 was cultured with allogenic IkBαM-MSCs cultured in vitro 4 h after CP modeling , and Group D was injected with rAAV2-MSCs . Cytokine levels of P05362 , P29279 , IL-1 , P05231 , P10145 , P01375 -α , P01033 , P16035 , P22301 , FN , P03956 , P08253 , P08254 , and P14780 were examined . The results indicated that allogenic IκBαM-MSCs could reduce pro-inflammatory cytokine levels and increase anti-inflammatory cytokine levels in CP . The allogenic IkBαM-MSCs reduced the activation and promoted the apoptosis of pancreatic stellate cells in the rat model of CP . IkBαM-MSCs influenced the proliferation and apoptosis of pancreatic stellate cells by regulating the activation of the Q07869 , MAPK , P42345 , TGF-β , NOD-like receptor , Notch , WNT , TGF-β1-SMAD-2/3 , and P04637 signal transduction pathways . Immunogenicity of the Brucella melitensis recombinant ribosome recycling factor-homologous protein and its cDNA . A study was conducted to evaluate the immunogenicity of the Brucella melitensis ribosome recycling factor ( Q96E11 ) -homologous protein ( CP24 ) . The CP24 gene was cloned , expressed in Escherichia coli and purified . The resulting purified recombinant protein ( rCP24 ) produced delayed-type hypersensitivity ( DTH ) reactions in B. melitensis-infected mice but not in naive controls . Thus , we decided to characterise the immune responses generated with DNA vaccination ( pcDNACP24 ) or immunisation with the rCP24 in adjuvant . Animals injected with pcDNACP24 exhibited a dominance of IgG2a to IgG1 while mice injected with rCP24 developed a higher response of IgG1 than IgG2a . Both immunisation protocols were capable of eliciting CP24-specific gamma interferon ( P01579 ) producing cells . Spleen cells from pcDNACP24-immunised mice did not produce interleukin ( IL ) -4 , P22301 or up-regulation of P60568 mRNA . Cells from rCP24-immunised mice produced P22301 , up-regulated P60568 mRNA but did not produce P05112 . Neither immunisation with purified CP24 nor injection of pcDNACP24 protected mice against challenge with live smooth B. melitensis . However , the potential of CP24 for a Brucella diagnostic test based on an in vitro antigen ( Ag ) -specific P01579 production or DTH test would be worth testing . Chemokine production and leukocyte recruitment to the lungs of Paracoccidioides brasiliensis-infected mice is modulated by interferon-gamma . Chemokines and chemokine receptors play a role in cell recruitment during granulomatous inflammatory reactions . Here , we evaluated the expression of chemokines and chemokine receptors and their regulation by P01579 in the course of Paracoccidioides brasiliensis ( Pb ) infection in mice . We found an association between KC and MIP-1alpha ( P10147 ) production and neutrophil infiltration in the lungs of Pb-infected mice during the early acute phase of infection . High levels of RANTES/ P13501 , P13500 / P13500 , P02778 / P02778 , and Mig/ Q07325 simultaneously with mononuclear cell infiltration in the lungs was found . In the absence of P01579 ( GKO mice ) we observed increased production of KC and MIP-1alpha and chronic neutrophilia . Moreover , we found a change in the chemokine receptor profiles expressed by wild-type ( WT ) versus GKO animals . Increased expression of P49682 and P51681 , and low levels of P51677 and CCR4 were observed in the lungs of Pb-infected WT mice , whereas the opposite effect was observed in the lungs of GKO mice . Consistent with these results , infected cells from WT mice preferentially migrated in response to P02778 ( P49682 ligand ) , while those from GKO mice migrated in response to eotaxin/ P51671 ( P51677 ligand ) . These results suggest that P01579 modulates the expression of chemokines and chemokine receptors as well as the kind of cells that infiltrate the lungs of Pb-infected mice . Disorders of carnitine transport and the carnitine cycle . DB00583 plays an essential role in the transfer of long-chain fatty acids across the inner mitochondrial membrane . This transfer requires enzymes and transporters that accumulate carnitine within the cell ( O76082 carnitine transporter ) , conjugate it with long chain fatty acids ( carnitine palmitoyl transferase 1 , CPT1 ) , transfer the acylcarnitine across the inner plasma membrane ( carnitine-acylcarnitine translocase , O43772 ) , and conjugate the fatty acid back to DB01992 for subsequent beta oxidation ( carnitine palmitoyl transferase 2 , P23786 ) . Deficiency of the O76082 carnitine transporter causes primary carnitine deficiency , characterized by increased losses of carnitine in the urine and decreased carnitine accumulation in tissues . Patients can present with hypoketotic hypoglycemia and hepatic encephalopathy , or with skeletal and cardiac myopathy . This disease responds to carnitine supplementation . Defects in the liver isoform of CPT1 present with recurrent attacks of fasting hypoketotic hypoglycemia . The heart and the muscle , which express a genetically distinct form of CPT1 , are usually unaffected . These patients can have elevated levels of plasma carnitine . O43772 deficiency presents in most cases in the neonatal period with hypoglycemia , hyperammonemia , and cardiomyopathy with arrhythmia leading to cardiac arrest . Plasma carnitine levels are extremely low . Deficiency of P23786 present more frequently in adults with rhabdomyolysis triggered by prolonged exercise . More severe variants of P23786 deficiency present in the neonatal period similarly to O43772 deficiency associated or not with multiple congenital anomalies . Treatment for deficiency of CPT1 , P23786 , and O43772 consists in a low-fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from carnitine , carnitine supplements , and avoidance of fasting and sustained exercise . A novel O43772 splicing mutation in patients of different ethnic origin with neonatally lethal carnitine-acylcarnitine translocase ( O43772 ) deficiency . DB00583 -acylcarnitine translocase ( O43772 ) deficiency is a rare disorder of fatty acid oxidation associated with high mortality . Two female newborns of different ethnic origin ( the first Anglo-Celtic and the second Palestinian Arab ) both died after sudden collapse on day 2 of life . Both had elevated bloodspot long-chain acylcarnitines consistent with either O43772 or carnitine palmitoyltransferase II ( P23786 ) deficiency ; the latter was excluded by demonstrating normal P23786 activity in fibroblasts . Direct sequencing of all O43772 ( O43772 ) gene exons and exon-intron boundaries revealed that Patient 1 was compound heterozygous for a novel c.609-3c > g ( IVS6-3c > g ) mutation on the paternal allele and a previously described c.326delG mutation on the maternal allele . Patient 2 was homozygous for the same , novel c.609-3c > g mutation . Previously reported O43772 mutations have been almost exclusively confined to a single family or ethnic group . Analysis of fibroblast cDNA by RT-PCR , agarose gel electrophoresis and sequencing of extracted bands showed that both mutations produce aberrant splicing . c.609-3C > G results in exon 7 skipping leading to a frameshift with premature termination seven amino acids downstream . c.326delG was confirmed to produce skipping of exons 3 or 3 plus 4 . O43772 activity in both patients ' fibroblasts was near-zero . For both families , prenatal diagnosis of an unaffected fetus was performed by mutation analysis on CVS tissue in a subsequent pregnancy . Due to the urgency of prenatal diagnosis in the second family , molecular diagnosis was performed prior to demonstration of O43772 enzyme deficiency , illustrating that mutation analysis is a rapid and reliable approach to first-line diagnosis of O43772 deficiency . [ Exploration of exercise intolerance by 31P NMR spectroscopy of calf muscles coupled with Q9BWK5 and ergometry ] . One hundred patients presenting with exercise intolerance or rhabdomyolysis episodes have been examined successively by 31P Nuclear Magnetic Resonance Spectroscopy ( P59665 ) of leg plantar flexor muscles with exercise test . In all cases a muscle biopsy was performed . At the end of investigations , diagnosis of a metabolic myopathy was made in 33 patients : glycogenolysis or glycolysis deficiency in 8 cases , mitochondrial myopathy in 24 cases and P23786 deficiency in one case . Muscular dystrophy or congenital myopathy were diagnosed in 6 cases . No precise etiology could be found in 30 patients with either high CK levels or muscle biopsy abnormalities . Seven patients had rhabdomyolysis related to excessive physical activities . Twenty-four patients had functional symptoms . The principal P59665 parameters used for diagnosis were the values of intracellular pH at the end of exercise and the time constant of phosphocreatine resynthesis during recovery . Lack of acidosis after exercise was observed in all patients with blockade of glycogenolysis or glycolysis . A slowing in phosphocreatine resynthesis was found in 66 p.cent of patients with definite mitochondrial myopathy . The specificity of these parameters were respectively 92.4 p.cent and 85.5 p.cent for the two groups . In conclusion (31)P P59665 allows the detection of muscular glycogenoses with a sensitivity close to 100 p.cent . However , its sensitivity was lower for the detection of mitochondrial myopathies , as is also known for the other in vivo metabolic investigations , reflecting the heterogeneity of expression of mitochondrial abnormalities in a given muscle . The integration of imaging in the examination protocol may help to orientate towards the diagnostic of a dystrophy in some patients . Mechanism of purinergic activation of endothelial nitric oxide synthase in endothelial cells . BACKGROUND : Decreased endothelial nitric oxide ( NO ) synthase ( P29474 ) activity and NO production are critical contributors to the endothelial dysfunction and vascular complications observed in many diseases , including diabetes mellitus . Extracellular nucleotides activate P29474 and increase NO generation ; however , the mechanism of this observation is not fully clarified . METHODS AND RESULTS : To elucidate the signaling pathway(s) leading to nucleotide-mediated P29474 phosphorylation at DB00133 -1177 , human umbilical vein endothelial cells were treated with several nucleotides , including DB00171 , UTP , and ADP , in the presence or absence of selective inhibitors . These experiments identified P47900 , P41231 , and possibly P51582 as the purinergic receptors involved in P29474 phosphorylation and demonstrated that this process was adenosine independent . Nucleotide-induced P29474 phosphorylation and activity were inhibited by BAPTA-AM ( an intracellular free calcium chelator ) , rottlerin ( a protein kinase Cdelta inhibitor ) , and protein kinase Cdelta siRNA . In contrast , blockade of AMP-activated protein kinase , calcium/calmodulin-dependent kinase II , calcium/calmodulin-dependent kinase kinase , serine/threonine protein kinase B , protein kinase A , extracellular signal-regulated kinase 1/2 , and p38 mitogen-activated protein kinase did not affect nucleotide-mediated P29474 phosphorylation . CONCLUSIONS : The present study indicates that extracellular nucleotide-mediated P29474 phosphorylation is calcium and protein kinase Cdelta dependent . This newly identified signaling pathway opens new therapeutic avenues for the treatment of endothelial dysfunction . Genomics and the prospects of existing and emerging therapeutics for cardiovascular diseases . The growing knowledge about genetic influence on cardiovascular diseases ( CVD ) combined with the recently generated amounts of genomic data hold promise to the identification of new markers for atherosclerotic CVD . Cardiovascular pharmacogenomics and pharmacogenetics have now the potential for leading to identification of genetic contributors and therefore to the development of predictive genetic tests that could optimize drugs efficacy and minimize toxicity . Clinical studies have shown that genetic variations within cytochromes P450 ( CYPs ) , 3-Hydroxyl-3-Methylglutaryl DB01992 Reductase ( P04035 ) and apolipoprotein E ( P02649 ) genes influence individual 's response to lipid lowering statins . Furthermore , development of antagonists or inhibitors of molecules such as peroxisome proliferator-activated receptors ( PPARs ) , lipoprotein-associated phospholipase A(2) ( Lp-PLA(2) ) , angiotensin-converting enzyme ( P12821 ) , angiotensin receptors and tumor necrosis factor ( P01375 ) -alpha could be another alternative to prevent atherosclerosis . In addition , novel molecules under the name of biologics including family of peptides such as atrial natriuretic peptide ( P01160 ) and brain natriuretic peptide ( DB04899 ) , urocortin , apelin and antimicrobial peptides ( AMPs ) could be considered as new targets for the prevention and treatment of CVD . In this article , we will focus mainly on recent genomic advances in the development of new markers and therapeutic agents for CVD . We present an array of molecules that could have pharmacological benefit for the treatment of heart disease . We also discuss in details new strategies including biologics , which are actually the focus of companies for clinical development of therapeutic drugs . All these efforts provide optimism and attractive promise to cure CVD . DB01098 , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium-induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB/c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) -alpha were determined by immunoassay and real time-PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real-time PCR . Disease activity scores in DSS-induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin-treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . DB01098 also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS-induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription . Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in-vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . DB00682 derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K-2,3-epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription-regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild-caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque-Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super-warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28.3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain . DB00583 palmitoyltransferase 2 : New insights on the substrate specificity and implications for acylcarnitine profiling . Over the last years acylcarnitines have emerged as important biomarkers for the diagnosis of mitochondrial fatty acid beta-oxidation ( mFAO ) and branched-chain amino acid oxidation disorders assuming they reflect the potentially toxic acyl- DB01992 species , accumulating intramitochondrially upstream of the enzyme block . However , the origin of these intermediates still remains poorly understood . A possibility exists that carnitine palmitoyltransferase 2 ( P23786 ) , member of the carnitine shuttle , is involved in the intramitochondrial synthesis of acylcarnitines from accumulated acyl- DB01992 metabolites . To address this issue , the substrate specificity profile of P23786 was herein investigated . Saccharomyces cerevisiae homogenates expressing human P23786 were incubated with saturated and unsaturated P06681 -C26 acyl-CoAs and branched-chain amino acid oxidation intermediates . The produced acylcarnitines were quantified by P19957 -MS/MS . We show that P23786 is active with medium ( Q99618 -C12 ) and long-chain ( C14-C18 ) acyl- DB01992 esters , whereas virtually no activity was found with short- and very long-chain acyl-CoAs or with branched-chain amino acid oxidation intermediates . Trans-2-enoyl- DB01992 intermediates were also found to be poor substrates for P23786 . Inhibition studies performed revealed that trans-2-C16:1- DB01992 may act as a competitive inhibitor of P23786 ( K(i) of 18.8 microM ) . The results obtained clearly demonstrate that P23786 is able to reverse its physiological mechanism for medium and long-chain acyl-CoAs contributing to the abnormal acylcarnitines profiles characteristic of most mFAO disorders . The finding that trans-2-enoyl-CoAs are poorly handled by P23786 may explain the absence of trans-2-enoyl-carnitines in the profiles of mitochondrial trifunctional protein deficient patients , the only defect where they accumulate , and the discrepancy between the clinical features of this and other long-chain mFAO disorders such as very long-chain acyl- DB01992 dehydrogenase deficiency . Substrate specificity of human carnitine acetyltransferase : Implications for fatty acid and branched-chain amino acid metabolism . DB00583 acyltransferases catalyze the reversible conversion of acyl-CoAs into acylcarnitine esters . This family includes the mitochondrial enzymes carnitine palmitoyltransferase 2 ( P23786 ) and carnitine acetyltransferase ( P43155 ) . P23786 is part of the carnitine shuttle that is necessary to import fatty acids into mitochondria and catalyzes the conversion of acylcarnitines into acyl-CoAs . In addition , when mitochondrial fatty acid β-oxidation is impaired , P23786 is able to catalyze the reverse reaction and converts accumulating long- and medium-chain acyl-CoAs into acylcarnitines for export from the matrix to the cytosol . However , P23786 is inactive with short-chain acyl-CoAs and intermediates of the branched-chain amino acid oxidation pathway ( BCAAO ) . In order to explore the origin of short-chain and branched-chain acylcarnitines that may accumulate in various organic acidemias , we performed substrate specificity studies using purified recombinant human P43155 . Various saturated , unsaturated and branched-chain acyl- DB01992 esters were tested and the synthesized acylcarnitines were quantified by P19957 -MS/MS . We show that P43155 converts short- and medium-chain acyl-CoAs ( P06681 to Q99622 - DB01992 ) , whereas no activity was observed with long-chain species . Trans-2-enoyl- DB01992 intermediates were found to be poor substrates for this enzyme . Furthermore , P43155 turned out to be active towards some but not all the BCAAO intermediates tested and no activity was found with dicarboxylic acyl- DB01992 esters . This suggests the existence of another enzyme able to handle the acyl-CoAs that are not substrates for P43155 and P23786 , but for which the corresponding acylcarnitines are well recognized as diagnostic markers in inborn errors of metabolism . Prenatal diagnosis of carnitine palmitoyltransferase 2 deficiency in chorionic villi : a novel approach . DB00583 palmitoyltransferase 2 ( P23786 ) deficiency , the most common autosomal recessive inherited disease of the mitochondrial long-chain fatty acid ( LCFA ) beta-oxidation , may result in three distinct clinical phenotypes , namely , a mild adult muscular form , a severe infantile hepatocardiomuscular disease , and a neonatal form , which includes dysmorphic features in addition to hepatocardiomuscular symptoms . Both the latter forms are life-threatening diseases , and prenatal diagnosis ( P01160 ) can be offered to couples at a one-fourth risk of having an affected child . P01160 of P23786 deficiency hitherto relied mostly on mutation detection from fresh chorionic villi ( 10 weeks ' gestation ) , since P23786 activity could be assayed on cultured amniocytes only ( 16-17 weeks ' gestation ) .We devised a P23786 activity assay from 10 mg of chorionic villi sampling ( CVS ) . Combining this enzymatic assay to haplotype study using polymorphic markers linked to the P23786 gene , we were able to carry out within 2 days , P23786 deficiency P01160 , in two unrelated families , using a CVS performed at the 11th week of gestation . Vasorelaxant activity of some structurally related triterpenic acids from Phoradendron reichenbachianum ( Viscaceae ) mainly by NO production : ex vivo and in silico studies . The aim of the current study was to investigate the vasorelaxant activity of five structurally-related triterpenic acids namely ursolic ( 1 ) , moronic ( 2 ) , morolic ( 3 ) , betulinic ( 4 ) and 3,4-seco-olean-18-ene-3,28-dioic ( 5 ) acids . The vasorelaxant effect of compounds 1-5 were determined on endothelium-denuded and endothelium-intact rat aortic rings pre-contracted with noradrenaline ( 0.1 μM ) . All compounds showed significant relaxant effect on endothelium-intact vessels in a concentration-dependent manner ( p < 0.05 ) . Ursolic , moronic and betulinic acids were the most potent vasorelaxant agents with 11.7 , 16.11 and 58.46 μM , respectively . Since vasorelaxation was blocked by L-NAME , while indomethacin did not inhibit the effect , endothelium-derived nitric oxide seems to be involved in triterpenic 2 and 3 mode of action . Compounds 1-5 were docked with a crystal structure of P29474 . Triterpenes 1-5 showed calculated affinity with P29474 in the C1 and P06681 binding pockets , near the catalytic site ; Ser248 and Asp480 are the residues that make hydrogen bonds with the triterpene compounds . Relative contribution of adipose triglyceride lipase and hormone-sensitive lipase to tumor necrosis factor-α ( P01375 -α ) -induced lipolysis in adipocytes . P01375 -α potently stimulates basal lipolysis in adipocytes , which may contribute to hyperlipidemia and peripheral insulin resistance in obesity . Recent studies show that adipose triglyceride lipase ( Q96AD5 ) and hormone-sensitive lipase ( Q05469 ) act sequentially in catalyzing the first two steps of adipose lipolysis in response to β-adrenergic stimulation . Here , we sought to determine their functional roles in P01375 -α-induced lipolysis . Silencing of Q96AD5 expression in adipocytes almost completely abolished basal and P01375 -α-induced glycerol release . In comparison , the glycerol release under the same conditions was only partially decreased upon reduction in expression of either Q05469 or the Q96AD5 coactivator Q8WTS1 . Interestingly , overexpression of Q96AD5 restored the lipolytic rates in cells with silenced Q05469 or Q8WTS1 , indicating a predominant role for Q96AD5 . While expression of Q96AD5 , Q05469 and Q8WTS1 remains mostly unaffected , P01375 -α treatment caused a rapid abrogation of the Q96AD5 inhibitory protein P27469 . P01375 -α drastically decreased the level of P27469 mRNA , and the level of P27469 protein could be maintained by inhibiting proteasomal protein degradation using MG-132 . Furthermore , coexpression of P27469 was able to significantly decrease P01375 -α-stimulated lipolysis mediated by overexpressed Q96AD5 or Q8WTS1 . We propose that the early reduction in P27469 content is permissive for P01375 -α-induced lipolysis . Phospho-ΔNp63α/ P36956 protein interactions : bridging cell metabolism and cisplatin chemoresistance . Tumor protein ( TP ) -p53 family members ( Q9H3D4 , Q9H3D4 and O15350 ) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment . DB00515 -induced phosphorylation of ΔNp63α was shown to have a role in regulating intracellular ΔNp63α protein levels . We previously found that squamous cell carcinoma ( SCC ) cells exposed to cisplatin displayed the Q13315 -dependent phosphorylation of ΔNp63α ( p-ΔNp63α ) , which is critical for the transcriptional regulation of specific downstream mRNAs and microRNAs and is likely to underlie the chemoresistance of SCC cells . However , SCC cells expressing non-p-ΔNp63α became more cisplatin-resistant . We also found that p-ΔNp63α forms complexes with a number of proteins involved in cell death response through regulation of cell cycle arrest , apoptosis , autophagy , RNA splicing and chromatin modifications . Here , we showed that p-ΔNp63α induced P05089 , P04406 , and P23786 gene transcription in cisplatin-sensitive SCC cells , while non-p-ΔNp63α increased a transcription of CAD , P11413 and P49327 genes in cisplatin-resistant SCC cells . We report that the p-ΔNp63α-dependent regulatory mechanisms implicated in the modulation of plethora of pathways , including amino acid , carbohydrate , lipid and nucleotide metabolisms , thereby affect tumor cell response to cisplatin-induced cell death , suggesting that the Q13315 -dependent ΔNp63α pathway plays a role in the resistance of tumor cells to platinum therapy . A case of CPT deficiency , homoplasmic mtDNA mutation and ragged red fibers at muscle biopsy . A 45-year-old male patient had an episode of acute renal failure with myoglobinuria , myalgias , weakness , and markedly increased serum CK levels . Similar episodes had occurred in the past . DB00583 palmitoyl-transferase II ( P23786 ) deficiency was documented both biochemically and genetically . Interestingly , muscle biopsy also showed some ragged red fibers ( Q96E11 ) and complete mitochondrial DNA ( mtDNA ) sequence disclosed a homoplasmic T3394C point mutation . This mutation is described in Leber 's hereditary optic neuropathy ( LHON ) or in patients with diabetes mellitus . Genes involved in carnitine synthesis and carnitine uptake are up-regulated in the liver of sows during lactation . BACKGROUND : Convincing evidence exist that carnitine synthesis and uptake of carnitine into cells is regulated by peroxisome proliferator-activated receptor α ( Q07869 ) , a transcription factor which is physiologically activated during fasting or energy deprivation . Sows are typically in a negative energy balance during peak lactation . We investigated the hypothesis that genes involved in carnitine synthesis and uptake in the liver of sows are up-regulated during peak lactation . FINDINGS : Transcript levels of several PPARα target genes involved in fatty acid uptake ( P15090 , O43772 ) , fatty acid oxidation ( Q15067 , CYP4A24 ) and ketogenesis ( P54868 , Q9NSA1 ) were elevated in the liver of lactating compared to non-lactating sows ( P < 0.05 ) . In addition , transcript levels of genes involved in carnitine synthesis ( P49189 , Q9NVH6 , O75936 ) and carnitine uptake ( O76082 ) in the liver were greater in lactating than in non-lactating sows ( P < 0.05 ) . DB00583 concentrations in liver and plasma were about 20 % and 50 % , respectively , lower in lactating than in non-lactating sows ( P < 0.05 ) , which is likely due to an increased loss of carnitine via the milk . CONCLUSIONS : The results of the present study show that PPARα is activated in the liver of sows during lactation which leads to an up-regulation of genes involved in carnitine synthesis and carnitine uptake . The PPARα mediated up-regulation of genes involved in carnitine synthesis and uptake in the liver of lactating sows may be regarded as an adaptive mechanism to maintain hepatic carnitine levels at a level sufficient to transport excessive amounts of fatty acids into the mitochondrion . Supplementation of Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 in diet-induced obese mice is associated with gut microbial changes and reduction in obesity . OBJECTIVE : To investigate the functional effects of probiotic treatment on the gut microbiota , as well as liver and adipose gene expression in diet-induced obese mice . DESIGN : Male C57BL/6J mice were fed a high-fat diet ( HFD ) for 8 weeks to induce obesity , and then randomized to receive HFD+probiotic ( Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 , n = 9 ) or HFD+placebo ( n = 9 ) for another 10 weeks . Normal diet ( ND ) fed mice ( n = 9 ) served as non-obese controls . RESULTS : Diet-induced obese mice treated with probiotics showed reduced body weight gain and fat accumulation as well as lowered plasma insulin , leptin , total-cholesterol and liver toxicity biomarkers . A total of 151,061 pyrosequencing reads for fecal microbiota were analyzed with a mean of 6,564 , 5,274 and 4,464 reads for the ND , HFD+placebo and HFD+probiotic groups , respectively . Gut microbiota species were shared among the experimental groups despite the different diets and treatments . The diversity of the gut microbiota and its composition were significantly altered in the diet-induced obese mice and after probiotic treatment . We observed concurrent transcriptional changes in adipose tissue and the liver . In adipose tissue , pro-inflammatory genes ( TNFα , P05231 , IL1β and MCP1 ) were down-regulated in mice receiving probiotic treatment . In the liver , fatty acid oxidation-related genes ( PGC1α , CPT1 , P23786 and Q15067 ) were up-regulated in mice receiving probiotic treatment . CONCLUSIONS : The gut microbiota of diet-induced obese mice appears to be modulated in mice receiving probiotic treatment . Probiotic treatment might reduce diet-induced obesity and modulate genes associated with metabolism and inflammation in the liver and adipose tissue . Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon-rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 -R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid-like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . DB04839 did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet-related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event . Q07869 -γ regulates carnitine homeostasis and mitochondrial function in a lamb model of increased pulmonary blood flow . OBJECTIVE : DB00583 homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow ( Shunt ) . Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in Q07869 -γ expression in Shunt lambs . Thus , this study was carried out to determine if there is a causal link between loss of Q07869 -γ signaling and carnitine dysfunction , and whether the Q07869 -γ agonist , rosiglitazone preserves carnitine homeostasis in Shunt lambs . METHODS AND RESULTS : siRNA-mediated Q07869 -γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 ( CPT1 and 2 ) and carnitine acetyltransferase ( P43155 ) protein levels . This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction , as determined by a reduction in cellular DB00171 levels . In turn , the decrease in cellular DB00171 attenuated NO signaling through a reduction in P29474 /Hsp90 interactions and enhanced P29474 uncoupling . In vivo , rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining DB00171 levels . This in turn preserved P29474 /Hsp90 interactions and NO signaling . CONCLUSION : Our study indicates that Q07869 -γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo . Further , it identifies a new mechanism by which Q07869 -γ regulates NO signaling through Hsp90 . Thus , Q07869 -γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow . Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV-1 , we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV-1 , immortalized oral keratinocytes ( OKF6/ O14746 -2 ; O14746 -2 cells ) were characterized for the fate of HIV-specific RNA and DNA . At 6 h post inoculation with X4 or R5-tropic HIV-1 , HIV-1gag RNA was detected maximally within O14746 -2 cells . Reverse transcriptase activity in O14746 -2 cells was confirmed by VSV-G-mediated infection with HIV-NL4-3Deltaenv-EGFP . DB00495 inhibited EGFP expression in a dose-dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV-1 DNA was detected in O14746 -2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non-productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 -2 cells trans infected co-cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell-to-cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non-replicative integration , while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h . P10275 antagonism and an insulin sensitizer block the advancement of vaginal opening by high-fat diet in mice . Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty . In high fat-fed rodents , the timing of vaginal opening ( VO ) is advanced , suggesting that puberty begins earlier . Because obesity can increase androgens , which interfere with normal steroid feedback in adult females , we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat-fed mice . Age at VO was examined in mice fed high-fat or low-fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle ( controls ) . VO was advanced in high-fat vs. low-fat controls , and flutamide blocked this advancement . VO was also delayed in low fat-fed flutamide-treated females , suggesting involvement of androgens in the timing of normal puberty . We next investigated if high-fat diet-induced insulin resistance contributes to early VO , as elevated insulin can stimulate androgen production . VO was examined in mice on either diet treated with the insulin sensitizer metformin . Metformin blocked high-fat advancement of VO but did not alter the timing of VO in low fat-fed mice . P01308 was elevated in high fat-fed females that had undergone VO compared with age-matched low fat-fed or metformin-treated animals on either diet that had not undergone VO . Together , these data suggest a model in which metabolic changes induced by high-fat diet , including transient increased circulating insulin , act in part by increasing androgen action to influence the timing of puberty in females . P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , DB08816 and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas DB08816 is in clinical development as an orally active agent .