interacts_with DB00215?
Expression of Th2-skewed pathology mediators in monocyte-derived type 2 of dendritic cells ( DC2 ) . The information conveyed from dendritic cells ( DCs ) to naïve P01730 (+) T cells has crucial influence on their differentiation toward effector T cells . In an effort to identify DC-derived molecules directly contributing to T cell differentiation , we searched for molecules distinctively expressed between two DC subtypes , which were differentiated from peripheral monocytes by cultivation with GM- P04141 ( for Q9NPG8 ) or P08700 ( for DC2 ) in the presence of P05112 and had the ability to induce naïve T cells to differentiate into Th1 or Th2 cells , respectively . As the first step to address this issue , we subtracted Q9NPG8 transcripts from those of DC2 and compiled the gene profile dominantly expressed in DC2 , whose products are known to reside in other than the nucleus . Intriguingly , many of them were molecules involved in Th2-skewed disease pathologies , such as P02751 , P38570 , Q14956 , Q03405 , P25089 , Q8NHJ6 , P05121 , P16050 , P24557 , P19878 , P10147 , P18510 , P09486 , and Q9NY15 , suggesting that DCs function not only as antigen presenting cells but also as producers of Th2 pathology specific milieus leading to disease deteriorations . We also found that expressions of Q02318 , O14495 , Q8WXG1 , and O15438 were up-regulated in DC2 , implying their significant function in Th2-deviated states . The identification of differentially expressed genes between DC subtypes provides new insights into their functions and our comparative gene expression profile will be highly useful for the identification of DC-derived key molecules for T cell differentiation . DB00996 prevents oxaliplatin-induced central sensitization in the dorsal horn neurons in rats . OBJECTIVES : The present study aims to study the alteration of glutamatergic transmission in the dorsal horn neurons and the effect of gabapentin on oxaliplatin-induced neuropathic pain in rats . MATERIALS AND METHODS : DB00526 ( 5 mg/kg ) or saline was administered to adult male Sprague-Dawley rats . DB00996 ( 60 mg/kg , IP ) or vehicle was injected daily . Mechanical allodynia was assessed using a series of von Frey filaments . The expression of glutamate receptor subunits ( Q13224 and GluR1 ) and brain-derived neurotrophic factor ( P23560 ) was measured in the dorsal horn . The glutamatergic strength was recorded in the spinal cord slices . RESULTS : Administration of oxaliplatin induced significant hyperreactivity to mechanical stimuli in rats , which was attenuated by gabapentin . Significant increase in the expression of P23560 was found in the dorsal horn in rats receiving oxaliplatin , which was prevented by gabapentin . Further studies also observed a significant increase in the expression of GluR1 and Q13224 , as well as enhanced glutamatergic transmission in the dorsal horn neurons in rats treated with oxaliplatin . The upregulation of glutamatergic transmission was significantly reversed by gabapentin . CONCLUSION : These results illustrated an increased expression of P23560 and enhanced glutamatergic transmission in rats with oxaliplatin-induced neuropathic pain , which was markedly attenuated by gabapentin . In vivo effects of a combined P28222 receptor/ P31645 antagonist in experimental pulmonary hypertension . AIMS : A mechanism for co-operation between the serotonin ( 5-hydroxytryptamine , 5-HT ) transporter and P28222 receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated in vitro . Here we determine , for the first time , the in vivo effects of a combined P28222 receptor/serotonin transporter antagonist ( LY393558 ) with respect to the development of pulmonary arterial hypertension ( PAH ) and its in vitro effects in human pulmonary artery smooth muscle cells ( hPASMCs ) derived from idiopathic PAH ( IPAH ) patients . METHODS AND RESULTS : We determined the effects of LY393558 as well as a selective serotonin transporter inhibitor , citalopram , on right ventricular pressure , right ventricular hypertrophy , and pulmonary vascular remodelling in wildtype mice and mice over-expressing serotonin transporter ( P31645 + mice ) before and after hypoxic exposure . We also compared their effectiveness at reversing PAH in P31645 + mice and hypoxic mice . Further , we examined the proliferative response to serotonin in IPAH hPASMCs . We also clarified the pharmacology of serotonin-induced vasoconstriction and P28222 receptor/serotonin transporter interactions in mouse isolated pulmonary artery . DB00215 had a moderate effect at preventing and reversing experimental PAH in vivo whereas LY393558 was more effective . LY393558 was more effective than citalopram at reversing serotonin-induced proliferation in IPAH hPASMCs . There is synergy between P28222 receptor and serotonin transporter inhibitors against serotonin-induced vasoconstriction in mouse pulmonary arteries . CONCLUSION : P28222 receptor and serotonin transporter inhibition are effective at preventing and reversing experimental PAH and serotonin-induced proliferation of PASMCs derived from IPAH patients . Targeting both the serotonin transporter and P28222 receptor may be a novel therapeutic approach to PAH . Purification and characterization of mouse O15528 overproduced by an Escherichia coli system coexpressing molecular chaperonins GroEL/ES . The expression of mouse O15528 in Escherichia coli has been dramatically enhanced by coexpression of GroEL/ES . To reveal the enzymatic properties of O15528 , we measured its hydroxylation activity toward vitamin D3 and DB01436 ( 1alpha(OH)D3 ) in addition to the physiological substrate DB00146 . Surprisingly , O15528 converted vitamin D3 to 1alpha, DB00146 . Both 1alpha-hydroxylation activity toward vitamin D3 , and 25-hydroxylation activity toward 1alpha(OH)D3 were observed . The Km and Vmax values for 25-hydroxylation activity toward 1alpha(OH)D3 were estimated to be 1.7 microM and 0.51 mol/min/mol P450 , respectively , while those for 1alpha-hydroxylation activity toward DB00146 were 0.050 microM and 2.73 mol/min/mol P450 , respectively . Note that the substrate must be fixed in the opposite direction in the substrate-binding pocket of O15528 between 1alpha-hydroxylation and 25-hydroxylation . Based on these results and the fact that human Q02318 and Streptomyces CYP105A1 also convert vitamin D3 to 1alpha, DB00146 , 1alpha-hydroxylation , and 25-hydroxylation of vitamin D3 appear to be closely linked together . DB00877 selectively blocks interleukin-2-induced proliferating cell nuclear antigen gene expression in T lymphocyte . Evidence for inhibition of CREB/ P39905 binding activities . The macrolide rapamycin arrests T lymphocytes stimulated by interleukin-2 ( P60568 ) at P55008 /S . We have recently found that P60568 induced an increase in the binding of discrete transcription factors of the P39905 / DB02527 -responsive element binding factor ( CREB ) family at P55008 /S , and that this effect was inhibited by rapamycin ( Feuerstein , N. , Huang , D. , Hinrichs , S. H. , Orten , D. J. , Aiyar , N. , and Prystowsky , M. B. ( 1995 ) J. Immunol. 154 , 68-79 ) . We now show , by using high resolution two-dimensional gel electrophoresis , that rapamycin inhibited selectively the synthesis of three discrete P60568 -induced soluble proteins ( 35 kDa/pI approximately 5 , 68 kDa/pI approximately 4 , 110 kDa/pI approximately 4.3 ) . Analysis of nuclear proteins demonstrated that rapamycin selectively blocked the expression of proliferating cell nuclear antigen ( P12004 ) , an obligate cofactor of DNA polymerase-delta , an important component for DNA replication . DB00877 inhibited the P60568 -induced P12004 mRNA , and the murine P12004 promoter activity in P60568 -stimulated cells . Inducible CRE-binding proteins were shown previously to be required for P12004 promoter activity in P60568 -stimulated T lymphocytes . Using DNA binding gel mobility shift assay we demonstrated that rapamycin potently inhibited the binding of CREB/ P39905 transcription factors to CRE elements in the murine proximal P12004 promoter . These results suggest that P12004 is a preferred target in a rapamycin-sensitive transduction pathway , and that the mechanism by which rampamycin inhibits P12004 gene expression may involve the inhibition of the interaction of CREB/ P39905 transcription factors with CRE elements in the proximal P12004 promoter . A transcriptional block in the P60568 promoter at the -150 AP-1 site in effector CD8+ T cells . Both P01730 + and CD8+ T cells that produce P60568 in response to Ag recognition have been isolated . However , most effector CD8+ T cells recovered after exposure to Ag do not produce sufficient P60568 to sustain growth , and depend on P01730 + T helper cells for this obligate growth factor . P60568 expression in P01730 + T cells is primarily controlled at the level of transcription , but mechanisms restricting P60568 production in CD8+ T cells have not been elucidated . To evaluate transcriptional regulation of the P60568 gene in CD8+ T cells , we stably transfected reporter genes into Ag-specific CD8+ T cell clones . P10747 + CD8(+) T cells unable to transcribe the P60568 gene in response to antigenic stimulation had a block in transactivation of the -150 P10747 response element ( CD28RE ) /AP-1 site of the P60568 promoter , but did transactivate the composite NFAT/AP-1 and O75051 /AP-1 sites , and a consensus AP-1 motif . Mutation of the nonconsensus -150 AP-1 site to a consensus AP-1 site , or insertion of a CD28RE/AP-1 consensus site upstream of the native -150 CD28RE/AP-1 site restored transactivation of the altered promoter . These results suggest that the defect at the -150 site may reflect the absence or inactivity of a required factor rather than repression of the P60568 promoter . Multiple messenger ribonucleic acid transcripts and revised gene organization of the human DB00024 receptor . Northern blot analysis of human DB00024 receptor ( hTSHR ) messenger ribonucleic acid ( mRNA ) expression has previously demonstrated multiple species of transcripts in the thyroid gland , suggesting the presence of multiple transcription initiation sites , alternatively spliced forms or alternate polyadenylation ( poly(A) ) sites . The first two have already been reported elsewhere . To clarify alternate poly(A) sites in the hTSHR gene , the present study was designed to characterize three full-length hTSHR cDNAs with distinct poly(A) signals that we have previously cloned . The comparison of the nucleotide sequencing data on the 3'UTR of these three clones to the Draft Human Genome in NCBI database revealed that the 3' segment of exon 10 of hTSHR gene contains three tandem repeats of the poly(A) sites , from which are expressed three full-length P16473 mRNAs with distinct 3'UTR length . The longest one appears to be a predominant transcript . From these data , together with ( i ) the previously reported organization of hTSHR genome and ( ii ) use of the Draft Human Genome to localize the unidentified sequence in the alternatively spliced form of truncated hTSHR , we propose the complete structure of hTSHR gene . Rather than 10 exons , our analysis suggests that hTSHR gene seems to contain 13 exons and 12 introns . At least three full-length P16473 mRNAs with distinct poly(A) sites and five alternatively spliced forms of P16473 mRNAs are expressed from the single hTSHR gene . Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5-hydroxytryptamine ; 5-HT ) , 5-HT receptors 1A ( 5-HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel-allergic patients , at 72 h post-challenge with the antigen . In addition , the effects of 5-HT2AR agonist 2,5-dimethoxy-4-iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel-stimulated peripheral blood mononuclear cells from nickel-allergic patients , regarding their proliferation and interleukin ( IL ) -2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell-like line ( XS52 ) , regarding its IL-1beta production . Serotonin-positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0.01 ) in 5-HT1AR-positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5-HT2AR- and P31645 -positive cells were increased ( p < 0.001 for both ) in the eczematous skin . Treatment of nickel-stimulated peripheral blood mononuclear cells with 5x10(-5) mol/l of DOI inhibited ( p < 0.01 ) the proliferation of nickel-stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . DB00215 at 10(-6) mol/l tended to inhibit the production of IL-1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction . P60568 inhibits DB01221 receptor-mediated currents directly and may differentially affect subtypes . Using whole-cell patch-clamp recordings , this study investigated the effects of interleukin-2 ( P60568 ) on N-methyl-d-aspartate ( DB01221 ) receptor-mediated currents ( I( DB01221 ) ) in rat cultured hippocampal neurons and human embryonic kidney ( P29320 ) 293 cells expressing recombinant DB01221 receptors . We found that P60568 ( 0.01-1ng/ml ) immediately and significantly decreased peak I( DB01221 ) in cultured neurons . Interestingly , the peak I( DB01221 ) induced in P29320 293 cells was also inhibited by P60568 . We also found that P60568 differentially decreased the peak amplitudes of Q12879 - and Q13224 -containing DB01221 receptor-mediated currents ( I( Q12879 ) and I( Q13224 ) ) by 54+/-5 % and 30+/-4 % , respectively . These results provide new evidence that P60568 induces rapid inhibition of peak currents of DB01221 receptor-mediated responses with possible Q9UHB4 / Q12879 and Q9UHB4 / Q13224 subtype-differentiation , and suggest that the inhibition is mediated by direct interaction between P60568 and DB01221 receptors . Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors . P12004 -dependent kinases ( CDKs ) are essential in the control of cell cycle progression . Inhibition of CDKs represents a new approach for pharmacological intervention in the treatment of a variety of proliferative diseases , especially cancer . Based on the crystal structure of P24941 in complex with an imidazole indolinone compound 1 ( DB03428 ) , lead optimization through modeling , synthesis , and SAR studies has led to the discovery of a novel series of pyrrolyllactone and pyrrolyllactam indolinones as potent P24941 inhibitors . Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents . The risk of developing pancreatitis is elevated in type 2 diabetes and obesity . Cases of pancreatitis have been reported in type 2 diabetes patients treated with P0C6A0 ( P43220 ) receptor agonists . To examine whether the P43220 agonist exenatide potentially induces or modulates pancreatitis , the effect of exenatide was evaluated in normal or diabetic rodents . Normal and diabetic rats received a single exenatide dose ( 0.072 , 0.24 , and 0.72 nmol/kg ) or vehicle . Diabetic ob/ob or HF- Q11206 mice were infused with exenatide ( 1.2 and 7.2 nmol·kg(-1)·day(-1) ) or vehicle for 4 wk . Post-exenatide treatment , pancreatitis was induced with caerulein ( CRN ) or sodium taurocholate ( ST ) , and changes in plasma amylase and lipase were measured . In ob/ob mice , plasma cytokines ( IL-1β , P60568 , P05231 , P13500 , IFNγ , and TNFα ) and pancreatitis-associated genes were assessed . Pancreata were weighed and examined histologically . Exenatide treatment alone did not modify plasma amylase or lipase in any models tested . Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion . Plasma cytokines and pancreatic weight were unaffected by exenatide . Exenatide upregulated Reg3b but not Il6 , Ccl2 , Nfkb1 , or Vamp8 expression . Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation , vacuolation , and acinar single cell necrosis in mice and rats , respectively . Ductal cell proliferation rates were low and similar across all groups of ob/ob mice . In conclusion , exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents . DB09045 for the treatment of type 2 diabetes . DB09045 is a novel glucagon-like peptide 1 ( P0C6A0 ) receptor agonist with a unique structure that supports once-weekly dosing in patients with type 2 diabetes ( T2DM ) , most of whom have a big pill burden . It appears to be efficacious in reducing hemoglobin A1c ( HbA1c ) up to 1.59 % and promotes modest weight loss up to 3 kg with a low incidence of hypoglycemia and mild to moderate gastrointestinal adverse events . Convenient weekly dosing could improve compliance and help attain sustained glycemic goals . Addressing obesity is an integral part of T2DM management and weight loss may contribute to better glycemic and cardiovascular benefits . Results of ongoing clinical trials on cardiovascular safety are important to determine the risk-to-benefit ratio . As with any drug , patient selection and ongoing monitoring will be important . If approved , dulaglutide will be one of the first weekly P43220 agonist to be available in a ready-to-use pen device with an automatic injector . Effect of lipoteichoic acid on P60568 and P05113 release from T lymphocytes in asthma and P48444 . Susceptibility to infections with gram-positive bacteria , which are an important trigger of exacerbations , is increased in P48444 and asthma . Unraveling the underlying mechanisms may help developing therapeutic strategies to reduce exacerbation rates . The aim of this study was to evaluate the effects of lipoteichoic acid ( P01374 ) , a danger signal from gram-positive bacteria , on T cell cytokines related to bacterial infection defense in P48444 and asthma . T cell populations within peripheral blood mononuclear cells ( PBMCs ) were ex-vivo activated towards T(H)2/T(C)2 subtypes and subsequently stimulated with P01374 . P60568 and P05113 concentrations in cell culture supernatants were measured by ELISA comparative between non-smokers ( NS ) , current smokers without airflow limitation ( S ) , smokers with moderate to severe P48444 and mild to moderate asthmatics ( A ) ( each n=10 ) . P60568 and P05113 baseline levels were without differences between the cohorts . After T cell activation , P60568 and P05113 releases were increased in all cohorts , however , for P60568 this increase was significantly higher in S and by trend in P48444 compared to the other groups . P01374 time-dependently suppressed P60568 release in NS , S and P48444 but not in A . P01374 reduced P05113 release in P48444 and A but not in NS and S. Summarized , P01374 reduces T(H)2/T(C)2 cytokines indicating immunosuppressive effects , which are dysregulated in P48444 and asthma . This implies a misguided response to gram-positive bacterial infections , which might help to explain the increased susceptibility to bacterial infections in P48444 and asthma . Down-regulation of cholesterol 7alpha-hydroxylase ( P22680 ) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway . DB04540 7alpha-hydroxylase ( P22680 ) , the rate-limiting enzyme in the neutral pathway of bile acid biosynthesis , is feedback-inhibited at the transcriptional level by hydrophobic bile acids . Recent studies show that bile acids are physiological ligands for farnesoid X receptor ( Q96RI1 ) . Activated Q96RI1 indirectly represses P22680 transcription through induction of small heterodimer protein ( Q15466 -1 ) . In this study , we provide evidence that bile acids rapidly down-regulate P22680 transcription via activation of the JNK/c-Jun pathway . Furthermore , we demonstrate that Q15466 -1 is also a direct target of activated c-Jun . In primary rat hepatocyte cultures , taurocholate ( TCA ) strongly activated JNK in a time- and concentration-dependent manner . P01375 -alpha , a potent activator of JNK , also rapidly activated JNK and down-regulated P22680 mRNA levels . Overexpression of dominant-negative P45983 or a transactivating domain mutant of c-Jun significantly blocked the ability of TCA to down-regulate P22680 mRNA . In contrast , overexpression of wild-type c-Jun ( c-Jun(wt) ) enhanced the repression of P22680 by TCA . Moreover , overexpression of c-Jun(wt) resulted in increased Q15466 -1 promoter activity . Mutation of a putative AP-1 ( c-Jun ) element suppressed c-Jun-mediated activation of the Q15466 -1 promoter construct . These results indicate that the bile acid-activated JNK pathway plays a pivotal role in regulating P22680 levels in primary rat hepatocytes . Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 *4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P=0.003 and P=0.007 ) and were 2.2- and 2.5-fold more likely to develop P42126 and CND ( P=0.039 and P=0.041 ) , respectively . P34913 55Arg , P51589 *7 , P10632 *1B , and P10632 g.36785A allele carriers had lower EET and DHET P04141 levels . P10632 g.25369T and P10632 g.36755A allele carriers had higher EET levels . Patients with P10632 *2C and P34913 404del variants had worse long-term outcomes while those with P34913 287Gln , P51589 *7 , and P11712 g.816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH . Identification of thyroid stimulating hormone receptor-specific T cells in Graves ' disease thyroid using autoantigen-transfected Epstein-Barr virus-transformed B cell lines . The importance of thyrotropin receptor ( P16473 ) agonist antibodies in the manifestations of Graves ' disease ( GD ) is recognized . There are , however , no convincing reports of P16473 -specific T cells . We have previously cloned T cells specific for thyroglobulin and thyroid peroxidase ( P07202 ) from GD lymphoid infiltrates and used autologous EBV-transformed B cell lines ( EBVL ) transfected with an expression vector encoding P07202 to efficiently detect P07202 -specific T cells . Here we used EBVL transfected with P16473 to seek P16473 -specific T cells in the GD infiltrates , after cloning the in vivo activated T cells without antigen . 3 out of 30 clones responded vigorously and reproducibly to EBVL- P16473 , with a mean stimulation index > 7 . Their release of P60568 , P05112 , and P22301 after stimulation with soluble anti-CD3 and phorbol ester was indistinguishable from the other clones from this thyroid . However , they produced relatively little IFN gamma ( median P05112 /IFN gamma ratio of 0.80 ) compared with the other clones ( median P05112 /IFN gamma ratio 0.06 ) . Thus , this new potent method of antigen presentation , using autoantigen-transfected EBVL , has permitted the first unequivocal identification of P16473 T cells in GD thyroid , with distinct Th0/Th2 characteristics , unlike previously cloned P07202 -responsive cells which have Th1 characteristics . P08246 inhibitors as treatment for P48444 . Chronic obstructive pulmonary disease , characterised by a slowly progressive , irreversible airways limitation , is a major worldwide cause of chronic morbidity and mortality . The imbalance between human neutrophil elastase and endogenous antiproteases may cause excess human neutrophil elastase in pulmonary tissues , which may be considered a major pathogenic factor in chronic obstructive pulmonary disease . Great effort has been devoted to finding a method to restore the balance , resulting in the discovery of potent two-typed small-molecular-weight human neutrophil elastase inhibitors . In the application of chronic obstructive pulmonary disease therapy , the human neutrophil elastase inhibitors mainly focused upon include ONO-5046 , MR-889 , L-694,458 , CE-1037 , GW-311616 and TEI-8362 as the acyl-enzyme inhibitors ; and DB03925 , AE-3763 , FK-706 , ICI-200,880 , ZD-0892 and ZD-8321 as the transition-state inhibitors . In this review , various problems that remain to be solved in the clinical use of human neutrophil elastase inhibitors are discussed . Vitamin D analogues . The plethora of actions attributed to 1,25(OH)2D3 throughout the body have suggested potential therapeutic applications for the treatment of hyperproliferative diseases , immune dysfunction , endocrine disorders , and metabolic bone disease . However , the potent calcemic activity of the natural vitamin D hormone has precluded its use in most cases . New vitamin D analogues are under development that display greater specificity , in most cases , by retaining the therapeutic properties of 1,25(OH)2D3 , but with lower calcemic activity . Two analogues have been approved for use in patients : calcipotriol ( DB02300 from Leo Pharmaceuticals , Copenhagen , Denmark ) for the treatment of psoriasis ; and 19-nor-1,25(OH)2D2 ( DB00910 from Abbott Laboratories , Abbott Park , IL ) for secondary hyperparathyroidism . Many others analogues are currently being tested in preclinical and clinical trials for the treatment of various types of cancer and osteoporosis , and for immunosuppression . The selectivity of the analogues can be attributed to the combined interactions with four proteins : the vitamin D receptor ( P11473 ) , the serum vitamin D binding protein ( DBP ) , the vitamin D-24-hydroxylase and to a newly described membrane receptor . Low DBP affinity has been shown to be responsible for the reduced calcemic actions of calcipotriol and 22-oxacalcitriol ( O75051 ) , which is being tested for secondary hyperparathyroidism . However , the low calcemic activity of other analogues , including 19-nor-1,25(OH)2D2 , involves other , as yet undefined , mechanisms . Understanding of the molecular basis for the selectivity of the vitamin D analogues will allow the design of more effective and safer vitamin D compounds for the treatment of a wide range of clinical disorders . P03372 alpha regulates expression of the orphan receptor small heterodimer partner . Hormonal status can influence diverse metabolic pathways . Q15466 ( Q15466 ) is an orphan nuclear receptor that can modulate the activity of several transcription factors . DB00286 are here shown to directly induce expression of the Q15466 in the mouse and rat liver and in human HepG2 cells . Q15466 is rapidly induced within 2 h following treatment of mice with ethynylestradiol ( EE ) or the estrogen receptor alpha ( ERalpha ) -selective compound propyl pyrazole triol ( PPT ) . Q15466 induction by these estrogens is completely absent in ERalphaKO mice . Mutation of the human Q15466 promoter defined HNF-3 , HNF-4 , GATA , and AP-1 sites as important for basal activity , whereas EE induction required two distinct elements located between -309 and -267 . One of these elements contains an estrogen response element half-site that bound purified ERalpha , and ERalpha with a mutated DNA binding domain was unable to stimulate Q15466 promoter activity . This ERalpha binding site overlaps the known farnesoid X receptor ( Q96RI1 ) binding site in the Q15466 promoter , and the combination of EE plus Q96RI1 agonists did not produce an additive induction of Q15466 expression in mice . Surprisingly , induction of Q15466 by EE did not inhibit expression of the known Q15466 target genes cholesterol 7alpha-hydroxylase ( P22680 ) or sterol 12alpha-hydroxylase ( Q9UNU6 ) . However , the direct regulation of Q15466 expression may provide a basis for some of the numerous biological effects of estrogens . Modulation of the P22301 /IL-12 cytokine circuit by interferon-beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis . IFN-beta has been shown to be effective in the treatment of multiple sclerosis ( MS ) . However , the primary mechanism by which IFN-beta mediates its therapeutic effect remains unclear . Recent studies indicate that under defined conditions , IFN-beta may downregulate DC expression of IL-12 . We and others have shown that IFN-beta may also downregulate P22301 . In light of the recently proposed paradigm that an P22301 /IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease , we examined the effect of IFN-beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis ( EAE ) , an animal model sharing many features with MS . SWXJ mice were immunized with the immunodominant p139-151 determinant of myelin proteolipid protein ( PLP ) , and at onset of EAE were treated every other day with IFN-beta . After eight weeks of treatment , we assessed autoreactivity and observed no significant IFN-beta effect on splenocyte proliferation or splenocyte production of P01579 , P60568 , P05112 , or P05113 in response to the priming determinant used to initiate disease . However , in IFN-beta treated mice , the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of P22301 and a concurrent decreased production of IL-12 . Moreover , the in vivo modulation of the P22301 /IL-12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading . Our results indicate that IFN-beta induces a reciprocal modulation of the P22301 /IL-12 cytokine circuit in vivo . This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self-priming thereby inhibiting the progression of disease associated with epitope spreading . A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 /5 and Q9BQB6 genes polymorphisms . DB00946 is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non-genetic factors . DB00946 metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms -1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 *2 and/or P11712 *3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 *1B , P20815 *3 and P20815 *6 polymorphisms . Among non-genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β-blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3.92 mg/week and 3.54 mg/week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm . Aerosol vaccination with AERAS-402 elicits robust cellular immune responses in the lungs of rhesus macaques but fails to protect against high-dose Mycobacterium tuberculosis challenge . Development of a vaccine against pulmonary tuberculosis may require immunization strategies that induce a high frequency of Ag-specific P01730 and CD8 T cells in the lung . The nonhuman primate model is essential for testing such approaches because it has predictive value for how vaccines elicit responses in humans . In this study , we used an aerosol vaccination strategy to administer AERAS-402 , a replication-defective recombinant adenovirus ( rAd ) type 35 expressing Mycobacterium tuberculosis Ags Ag85A , Ag85B , and TB10.4 , in bacillus Calmette-Guérin ( BCG ) -primed or unprimed rhesus macaques . Immunization with BCG generated low purified protein derivative-specific P01730 T cell responses in blood and bronchoalveolar lavage . In contrast , aerosolized AERAS-402 alone or following BCG induced potent and stable Ag85A/b-specific P01730 and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN-γ , as well as P01375 and P60568 . Such responses induced by BCG , AERAS-402 , or both failed to confer overall protection following challenge with 275 CFUs M. tuberculosis Erdman , although vaccine-induced responses associated with reduced pathology were observed in some animals . Anamnestic T cell responses to Ag85A/b were not detected in blood of immunized animals after challenge . Overall , our data suggest that a high M. tuberculosis challenge dose may be a critical factor in limiting vaccine efficacy in this model . However , the ability of aerosol rAd immunization to generate potent cellular immunity in the lung suggests that using different or more immunogens , alternative rAd serotypes with enhanced immunogenicity , and a physiological challenge dose may achieve protection against M. tuberculosis . P40189 -linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 -linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B- P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti- P40189 mAb on the proliferation of DC , and their expression of IL-12 and P33681 ( P33681 -1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti- P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM- P04141 ) , by up-regulating the GM- P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC-derived CC chemokine , as measured by RT-PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up-regulated expression of IL-12 and P33681 ( P33681 -1 ) was observed in DC activated by anti- P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .