interacts_with DB01241?
Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : DB08907 is a sodium glucose co-transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : (14)C-alpha-methylglucoside uptake in Chinese hamster ovary-K cells expressing human , rat , or mouse SGLT2 or P13866 ; (3)H-2-deoxy-d-glucose uptake in Q9BTT4 myoblasts ; and 2-electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT(G) ) in vehicle or canagliflozin-treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg/kg lowered RT(G) from 415±12 mg/dl to 94±10 mg/dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT(G) . DB08907 dose-dependently decreased BG concentrations in db/db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : DB08907 lowered RT(G) and increased UGE , improved glycemic control and beta-cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity . LG839 : anti-obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA-customized nutraceutical , LG839 ( LifeGen , Inc. , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D.I.E.T. study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self-identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi-square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0.01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0.05 ) , and increased energy ( P < 0.001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 -gamma2 , P42898 , 5- Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r=0.42 , P=0.045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA-directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity . DB00278 -coupled Affi-Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . DB00278 has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba(2+) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan-snake ( Oxyuranus scutellatus ) venom and bound to the argatroban-coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days . Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at DB00988 D2- and Serotonin- P08908 -receptors as well as an antagonism at Serotonin-5- Q13049 -receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein . P50591 -deficiency accelerates vascular calcification in atherosclerosis via modulation of O14788 . The osteoprotegerin ( O00300 ) and receptor activator of nuclear factor-κB ligand ( O14788 ) cytokine system , not only controls bone homeostasis , but has been implicated in regulating vascular calcification . P50591 ( P50591 ) is a second ligand for O00300 , and although its effect in vascular calcification in vitro is controversial , its role in vivo is not yet established . This study aimed to investigate the role of P50591 in vascular calcification in vitro using vascular smooth muscle cells ( VSMCs ) isolated from P50591 (-/-) and wild-type mice , as well as in vivo , in advanced atherosclerotic lesions of P50591 (-/-)ApoE(-/-) mice . The involvement of O00300 and O14788 in this process was also examined . P50591 dose-dependently inhibited calcium-induced calcification of human VSMCs , while P50591 (-/-) VSMCs demonstrated accelerated calcification induced by multiple concentrations of calcium compared to wild-type cells . Consistent with this , O14788 mRNA was significantly elevated with 24 h calcium treatment , while O00300 and P50591 expression in human VSMCs was inhibited . Brachiocephalic arteries from P50591 (-/-)ApoE(-/-) and ApoE(-/-) mice fed a high fat diet for 12 w demonstrated increased chondrocyte-like cells in atherosclerotic plaque , as well as increased aortic collagen II mRNA expression in P50591 (-/-)ApoE(-/-) mice , with significant increases in calcification observed at 20 w . P50591 (-/-)ApoE(-/-) aortas also had significantly elevated O14788 , P12643 , IL-1β , and Q07869 -γ expression at 12 w . Our data provides the first evidence that P50591 deficiency results in accelerated cartilaginous metaplasia and calcification in atherosclerosis , and that P50591 plays an important role in the regulation of O14788 and inflammatory markers mediating bone turn over in the vasculature . Peroxisome proliferator-activated receptor-gamma activation inhibits tumor metastasis by antagonizing P84022 -mediated epithelial-mesenchymal transition . Epithelial-mesenchymal transition ( EMT ) was shown to confer tumor cells with abilities essential for metastasis , including migratory phenotype , invasiveness , resistance to apoptosis , evading immune surveillance , and tumor stem cell traits . Therefore , inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis . Here , we show that activation of peroxisome proliferator-activated receptor γ ( Q07869 -γ ) inhibits transforming growth factor β ( TGF-β ) -induced EMT in lung cancer cells and prevents metastasis by antagonizing P84022 function . Activation of Q07869 -γ by synthetic ligands ( troglitazone and rosiglitazone ) or by a constitutively active form of Q07869 -γ prevents TGF-β-induced loss of P12830 expression and inhibits the induction of mesenchymal markers ( vimentin , P19022 , fibronectin ) and matrix metalloproteases . Consistently , activation of Q07869 -γ also inhibited EMT-induced migration and invasion of lung cancer cells . Furthermore , effects of Q07869 -γ ligands were attenuated by siRNA-mediated knockdown of Q07869 -γ , indicating that the ligand-induced responses are Q07869 -γ dependent . Selective knockdown of Q15796 and P84022 by siRNA showed that TGF-β-induced EMT is P84022 dependent in lung cancer cells . Activation of Q07869 -γ inhibits TGF-β-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads . Consistently , Q07869 -γ activation prevented TGF-β-induced transcriptional repression of P12830 promoter and inhibited transcriptional activation of P19022 promoter . Finally , treatment of mice with troglitazone or knockdown of P84022 in tumor cells significantly inhibited TGF-β-induced experimental metastasis in SCID-Beige mice . Together , with the low toxicity profile of Q07869 -γ ligands , our data show that these ligands may serve as potential therapeutic agents to inhibit metastasis . P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 " normal " control patients and 4 patients with relapsing-remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross-reactivity with thrombin ) and sensitive ( detection limit -- 0.7 ng/ml ) with an imprecision of CV = 8.3 % ( intraseries ) and 7.0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0.55 mg/l ( CV +/- 33 % , range : 0.28-0.93 mg/l ) , in normal plasma 121.8 mg/l +/- 21 % , resulting in a mean P04141 /plasma concentration quotient ( Q(Proth) -- 4.5 x 10(-3) ( CV +/- 35 % , range : 2.1-8.3 x 10(-3) ) corresponding to a mean albumin quotient in this group of subjects of Q(Alb) = 5.8 x 10(-3) . Due to the Q(Proth) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood- P04141 barrier function is normal . DB06643 for joints and bones . DB06643 is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . DB06643 suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . DB06643 reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo . [ Hyperlipidemia and peroxisome proliferator-activated receptor ( Q07869 ) -- regulation of the PPARalpha gene by O15516 : O00327 ] . The main pathological findings in atherosclerosis include abnormal reactions of neutrophils , lymphocytes and monocytes/macrophages , vascular smooth muscle cells and vascular endothelial cells , and the accumulation of cholesterol ester in the arterial wall . Therefore , investigating the effects of these abnormal reactions on the arterial wall may improve understanding of the mechanisms underlying atherosclerosis . Three types of peroxisome proliferator-activated receptors ( PPARs ) : PPARalpha , PPARbeta/delta , and PPARgamma are expressed in endothelial cells . In endothelial cells , the ligands/activators for PPARalpha and PPARgamma increase Cu2+ , DB01593 -superoxide dismutase . In addition , the phorbol myristate acetate ( PMA ) -stimulated 22 kDa-subunit ( P13498 ) protein levels and 47 kDa-subunit ( p47phox ) protein levels in NADPH ( superoxide generating enzyme nicotinamide adenine dinucleotide phosphate ( reduced form ) ) oxidase were decreased by treatment with PPARalpha and PPARgamma ligands/activators . Recently , we showed that the O15516 : O00327 heterodimer regulates the PPARalpha gene via promoter of PPARalpha . Moreover , we report a patient with severe hypertriglyceridemia associated with anemia and hypoalbuminemia , in which the former may have caused the latter two conditions . This is the first reported case of abrupt onset of severe hypertriglyceridemia resulting in suppression of bone marrow and liver function . Here , based on recent studies including our own , we describe the relationships between risk factors for atherosclerosis , especially hyperlipidemia and PPARs and the molecular mechanisms that govern lipid metabolism in the arteries . Atheroprotective effect of oleoylethanolamide ( OEA ) targeting oxidized LDL . Dietary fat-derived lipid oleoylethanolamide ( OEA ) has shown to modulate lipid metabolism through a peroxisome proliferator-activated receptor-alpha ( Q07869 -α ) -mediated mechanism . In our study , we further demonstrated that OEA , as an atheroprotective agent , modulated the atherosclerotic plaques development . In vitro studies showed that OEA antagonized oxidized LDL ( ox-LDL ) -induced vascular endothelial cell proliferation and vascular smooth muscle cell migration , and suppressed lipopolysaccharide ( LPS ) -induced LDL modification and inflammation . In vivo studies , atherosclerosis animals were established using balloon-aortic denudation ( Q92934 ) rats and ApoE(-/-) mice fed with high-caloric diet ( HCD ) for 17 or 14 weeks respectively , and atherosclerotic plaques were evaluated by oil red staining . The administration of OEA ( 5 mg/kg/day , intraperitoneal injection , i.p. ) prevented or attenuated the formation of atherosclerotic plaques in HCD- Q92934 rats or HCD-ApoE(-/-) mice . Gene expression analysis of vessel tissues from these animals showed that OEA induced the mRNA expressions of Q07869 -α and downregulated the expression of M-CFS , an atherosclerotic marker , and genes involved in oxidation and inflammation , including P35228 , P35354 , P01375 -α and P05231 . Collectively , our results suggested that OEA exerted a pharmacological effect on modulating atherosclerotic plaque formation through the inhibition of LDL modification in vascular system and therefore be a potential candidate for anti-atherosclerosis drug . Q07869 gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease . BACKGROUND : Q07869 ( PPARalpha ) regulates the expression of genes involved in lipid metabolism and inflammation , making it a candidate gene for atherosclerosis and ischemic heart disease ( IHD ) . METHODS AND RESULTS : We investigated the association between the leucine 162 to valine ( L162V ) polymorphism and a G to C transversion in intron 7 of the PPARalpha gene and progression of atherosclerosis in the DB01241 Coronary Angiography Trial ( LOCAT ) , a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study ( Q9NP85 ) , a prospective study of healthy middle-aged men in the United Kingdom . There was no association with plasma lipid concentrations in either study . Both polymorphisms influenced progression of atherosclerosis and risk of IHD . V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis . Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes . The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele . Homozygotes for the intron 7 C allele had increased risk of IHD , an effect modulated by the L162V polymorphism CONCLUSIONS : The PPARalpha gene affects progression of atherosclerosis and risk of IHD . Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall . GM- P04141 priming drives bone marrow-derived macrophages to a pro-inflammatory pattern and downmodulates DB00917 in response to O60603 ligands . In response to pathogen recognition by Toll-like receptors ( TLRs ) on their cell surface , macrophages release lipid mediators and cytokines that are widely distributed throughout the body and play essential roles in host responses . Granulocyte macrophage colony-stimulating factor ( GM- P04141 ) is important for the immune response during infections to improve the clearance of microorganisms . In this study , we examined the release of mediators in response to O60603 ligands by bone marrow-derived macrophages ( BMDMs ) primed with GM- P04141 . We demonstrated that when stimulated with O60603 ligands , non-primed BMDMs preferentially produced PGE(2) in greater amounts than Q06643 (4) . However , GM- P04141 priming shifted the release of lipid mediators by BMDMs , resulting in a significant decrease of PGE(2) production in response to the same stimuli . The decrease of PGE(2) production from primed BMDMs was accompanied by a decrease in PGE-synthase mRNA expression and an increase in P01375 -α and nitric oxide ( NO ) production . Moreover , some GM- P04141 effects were potentiated by the addition of IFN-γ . Using a variety of O60603 ligands , we established that PGE(2) release by GM- P04141 -primed BMDMs was dependent on O60603 co-receptors ( Q15399 , Q9Y2C9 ) , P08571 , MyD88 and the nuclear translocation of NFκB but was not dependent on peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) activation . Indeed , GM- P04141 priming enhanced O60603 , O00206 and MyD88 mRNA expression and phospho-IκBα formation . These findings demonstrate that GM- P04141 drives BMDMs to present a profile relevant to the host during infections . DB00741 is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . DB00741 ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta-hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 -induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells . P12004 D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment . The cyclin D1 gene encodes the labile serum-inducible regulatory subunit of a holoenzyme that phosphorylates and inactivates the retinoblastoma protein . Overexpression of cyclin D1 promotes cellular proliferation and normal physiological levels of cyclin D1 function to inhibit adipocyte differentiation in vivo . We have previously shown that cyclin D1 inhibits peroxisome proliferator-activated receptor ( Q07869 )gamma-dependent activity through a cyclin-dependent kinase- and retinoblastoma protein-binding-independent mechanism . In this study , we determined the molecular mechanism by which cyclin D1 regulated PPARgamma function . Herein , murine embryonic fibroblast ( MEF ) differentiation by PPARgamma ligand was associated with a reduction in histone deacetylase ( Q13547 ) activity . P12004 D1-/- MEFs showed an increased propensity to undergo differentiation into adipocytes . Genetic deletion of cyclin D1 reduced Q13547 activity . Reconstitution of cyclin D1 into the cyclin D1-/- MEFs increased Q13547 activity and blocked PPARgamma-mediated adipogenesis . PPARgamma activity was enhanced in cyclin D1-/- cells . Reintroduction of cyclin D1 inhibited basal and ligand-induced PPARgamma activity and enhanced HDAC repression of PPARgamma activity . P12004 D1 bound HDAC in vivo and preferentially physically associated with Q13547 , Q92769 , O15379 , and Q9UQL6 . Chromatin immunoprecipitation assay demonstrated that cyclin D1 enhanced recruitment of Q13547 and O15379 and histone methyltransferase O43463 to the Q07869 response element of the lipoprotein lipase promoter and decreased acetylation of total histone H3 and histone H3 lysine 9 . Collectively , these studies suggest an important role of cyclin D1 in regulation of PPARgamma-mediated adipocyte differentiation through recruitment of HDACs to regulate Q07869 response element local chromatin structure and PPARgamma function . DB01095 enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type-1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein-1 , and intercellular adhesion molecule-1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects . Targeting Q01196 / Q06455 -histone deacetylase repressor complex : a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in Q01196 / Q06455 -positive acute myeloid leukemia cells . In t(8;21) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) -containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( DB00313 ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . DB00313 causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i.e. , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that DB00313 treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i.e. , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase-dependent apoptosis . Taken together , these data support the notion that DB00313 might effectively target Q01196 / Q06455 -driven leukemogenesis through disruption of aberrant Q13547 function and that DB00313 should be integrated in novel therapeutic approaches for Q01196 / Q06455 -positive AML . Coactivators for the orphan nuclear receptor RORalpha . A mutation in the nuclear orphan receptor RORalpha results in a severe impairment of cerebellar development by unknown mechanisms . We have shown previously that RORalpha contains a strong constitutive activation domain in its C terminus . We therefore searched for mammalian RORalpha coactivators using the minimal activation domain as bait in a two-hybrid screen . Several known and putative coactivators were isolated , including glucocorticoid receptor-interacting protein-1 ( Q9Y3R0 ) and peroxisome proliferator-activated receptor ( Q07869 ) -binding protein ( PBP/ Q15648 / Q15648 ) . These interactions were confirmed in vitro and require the intact activation domain of RORalpha although different requirements for interaction with Q9Y3R0 and PBP were detected . Even in the absence of exogenous ligand , RORalpha interacts with a complex or complexes of endogenous proteins , similar to those that bind to ligand-occupied thyroid hormone and vitamin D receptors . Both PBP and Q9Y3R0 were shown to be present in these complexes . Thus we have identified several potential RORalpha coactivators that , in contrast to the interactions with hormone receptors , interact with RORalpha in yeast , in bacterial extracts , and in mammalian cells in vivo and in vitro in the absence of exogenous ligand . Q9Y3R0 functioned as a coactivator for the RORalpha both in yeast and in mammalian cells . Thus , Q9Y3R0 is the first proven coactivator for RORalpha . Identification of Reverb(alpha) as a novel ROR(alpha) target gene . The nuclear receptor superfamily comprises a large number of ligand-activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR(alpha) ( P35398 ) and Reverb(alpha) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR(alpha) and Reverb(alpha) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR(alpha)1 in Q9BTT4 cells significantly induces Reverb(alpha) expression as demonstrated by Northern blot analysis . Using reverse transcription-PCR to analyze Reverb(alpha) gene expression from staggerer mice , we found that there was a significant reduction of Reverb(alpha) mRNA in the skeletal muscle comparing it with the wild-type mice , which suggests that ROR(alpha) is involved in the regulation of Reverb(alpha) gene expression . Transient transfection assays using the Reverb(alpha) promoter demonstrate that ROR(alpha) regulates the Reverb(alpha) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR(alpha) regulates Reverb(alpha) transcription via a monomeric ROR response element located in the Reverb(alpha) gene promoter . Electrophoretic mobility shift assays show that ROR(alpha) binds strongly to this site in a specific-manner . Finally , overexpression of Q9Y3R0 / Q06418 -2 , but not Q15788 , potentiates ROR(alpha)-stimulated Reverb(alpha) promoter activity in transient transfection experiments . Together , our results identify Reverb(alpha) as a novel target gene for ROR(alpha) . DB01281 inhibits effector T cells through regulatory T cells and TGF-β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune-mediated diseases . DB01281 , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , DB01281 suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 -independent mechanism by which DB01281 inhibits activated T cells . We show that in vitro , DB01281 synergizes with NO from bone marrow-derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF-β signaling abrogated the inhibitory effect of DB01281 . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , DB01281 was ineffective in P84022 -deficient mice , supporting a requirement for TGF-β signaling . Thus , in addition to preventing naive T cells from being fully activated , DB01281 can turn off already activated effector T cells by an NO/regulatory T cell/TGF-β-dependent pathway . This mechanism is similar to cell-extrinsic effects of endogenous P16410 and may be particularly important in the ability of DB01281 to treat chronic inflammatory disease .