MH_dev_285

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 REA ( + ) 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 REA ( for Q9NPG8 ) or P08700 REA ( for DC2 ) in the presence of P05112 REA 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 REA , P38570 REA , Q14956 REA , Q03405 REA , P25089 REA , Q8NHJ6 , P05121 REA , P16050 REA , P24557 REA , P19878 REA , P10147 REA , P18510 REA , P09486 REA , 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 REA , O14495 REA , Q8WXG1 , and O15438 REA 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 MEN 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 MEN ( 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 REA and GluR 1 ) and brain-derived neurotrophic factor ( P23560 REA ) 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 REA 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 GluR 1 and Q13224 REA , 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 REA and enhanced glutamatergic transmission in rats with oxaliplatin-induced neuropathic pain , which was markedly attenuated by gabapentin .

In vivo effects of a combined P28222 REA receptor / P31645 REA antagonist in experimental pulmonary hypertension . AIMS : A mechanism for co-operation between the serotonin ( 5 - hydroxytryptamine , 5 - HT ) transporter and P28222 REA 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 REA 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 REA + mice ) before and after hypoxic exposure . We also compared their effectiveness at reversing PAH in P31645 REA + 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 REA receptor / serotonin transporter interactions in mouse isolated pulmonary artery . DB00215 SUB 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 REA receptor and serotonin transporter inhibitors against serotonin-induced vasoconstriction in mouse pulmonary arteries . CONCLUSION : P28222 REA 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 REA receptor may be a novel therapeutic approach to PAH .

Purification and characterization of mouse O15528 REA overproduced by an Escherichia coli system coexpressing molecular chaperonins GroEL / ES . The expression of mouse O15528 REA in Escherichia coli has been dramatically enhanced by coexpression of GroEL / ES . To reveal the enzymatic properties of O15528 REA , we measured its hydroxylation activity toward vitamin D3 and DB01436 MEN ( 1alpha ( OH ) D3 ) in addition to the physiological substrate DB00146 . Surprisingly , O15528 REA 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 REA between 1alpha - hydroxylation and 25 - hydroxylation . Based on these results and the fact that human Q02318 REA and Streptomyces CYP 105A1 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 REA binding activities . The macrolide rapamycin arrests T lymphocytes stimulated by interleukin - 2 ( P60568 REA ) at P55008 / S . We have recently found that P60568 REA induced an increase in the binding of discrete transcription factors of the P39905 REA / 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 REA - 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 REA ) , an obligate cofactor of DNA polymerase-delta , an important component for DNA replication . DB00877 inhibited the P60568 REA - induced P12004 REA mRNA , and the murine P12004 REA promoter activity in P60568 REA - stimulated cells . Inducible CRE-binding proteins were shown previously to be required for P12004 REA promoter activity in P60568 REA - stimulated T lymphocytes . Using DNA binding gel mobility shift assay we demonstrated that rapamycin potently inhibited the binding of CREB / P39905 REA transcription factors to CRE elements in the murine proximal P12004 REA promoter . These results suggest that P12004 REA is a preferred target in a rapamycin-sensitive transduction pathway , and that the mechanism by which rampamycin inhibits P12004 REA gene expression may involve the inhibition of the interaction of CREB / P39905 REA transcription factors with CRE elements in the proximal P12004 REA promoter .

A transcriptional block in the P60568 REA promoter at the - 150 AP - 1 site in effector CD8 + T cells . Both P01730 REA + and CD8 + T cells that produce P60568 REA in response to Ag recognition have been isolated . However , most effector CD8 + T cells recovered after exposure to Ag do not produce sufficient P60568 REA to sustain growth , and depend on P01730 REA + T helper cells for this obligate growth factor . P60568 REA expression in P01730 REA + T cells is primarily controlled at the level of transcription , but mechanisms restricting P60568 REA production in CD8 + T cells have not been elucidated . To evaluate transcriptional regulation of the P60568 REA gene in CD8 + T cells , we stably transfected reporter genes into Ag-specific CD8 + T cell clones . P10747 REA + CD8 ( + ) T cells unable to transcribe the P60568 REA gene in response to antigenic stimulation had a block in transactivation of the - 150 P10747 REA response element ( CD28RE ) / AP - 1 site of the P60568 REA promoter , but did transactivate the composite NFAT / AP - 1 and O75051 REA / 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 REA promoter .

Multiple messenger ribonucleic acid transcripts and revised gene organization of the human DB00024 MEN receptor . Northern blot analysis of human DB00024 MEN 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 REA 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 REA mRNAs with distinct poly ( A ) sites and five alternatively spliced forms of P16473 REA 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 REA ) 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 REA - 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 REA production . DB00215 SUB 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 REA 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 REA ) on N-methyl-d-aspartate ( DB01221 ) receptor-mediated currents ( I ( DB01221 ) ) in rat cultured hippocampal neurons and human embryonic kidney ( P29320 REA ) 293 cells expressing recombinant DB01221 receptors . We found that P60568 REA ( 0.01- 1ng / ml ) immediately and significantly decreased peak I ( DB01221 ) in cultured neurons . Interestingly , the peak I ( DB01221 ) induced in P29320 REA 293 cells was also inhibited by P60568 REA . We also found that P60568 REA differentially decreased the peak amplitudes of Q12879 REA - and Q13224 REA - containing DB01221 receptor-mediated currents ( I ( Q12879 REA ) and I ( Q13224 REA ) ) by 54 + / - 5 % and 30 + / - 4 % , respectively . These results provide new evidence that P60568 REA induces rapid inhibition of peak currents of DB01221 receptor-mediated responses with possible Q9UHB4 / Q12879 REA and Q9UHB4 / Q13224 REA subtype-differentiation , and suggest that the inhibition is mediated by direct interaction between P60568 REA and DB01221 receptors .

Novel pyrrolyllactone and pyrrolyllactam indolinones as potent cyclin-dependent kinase 2 inhibitors . P12004 REA - 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 REA in complex with an imidazole indolinone compound 1 ( DB03428 MEN ) , 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 REA 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 REA ) receptor agonists . To examine whether the P43220 REA 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 REA 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 REA , P05231 REA , P13500 REA , 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 Reg 3b but not Il6 , Ccl 2 , Nfkb 1 , or Vamp 8 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 MEN for the treatment of type 2 diabetes . DB09045 MEN 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 ( HbA 1c ) 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 REA agonist to be available in a ready-to-use pen device with an automatic injector .

Effect of lipoteichoic acid on P60568 REA and P05113 REA release from T lymphocytes in asthma and P48444 REA . Susceptibility to infections with gram-positive bacteria , which are an important trigger of exacerbations , is increased in P48444 REA 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 REA ) , a danger signal from gram-positive bacteria , on T cell cytokines related to bacterial infection defense in P48444 REA 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 REA . P60568 REA and P05113 REA 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 REA and mild to moderate asthmatics ( A ) ( each n = 10 ) . P60568 REA and P05113 REA baseline levels were without differences between the cohorts . After T cell activation , P60568 REA and P05113 REA releases were increased in all cohorts , however , for P60568 REA this increase was significantly higher in S and by trend in P48444 REA compared to the other groups . P01374 REA time-dependently suppressed P60568 REA release in NS , S and P48444 REA but not in A . P01374 REA reduced P05113 REA release in P48444 REA and A but not in NS and S . Summarized , P01374 REA reduces T ( H ) 2 / T ( C ) 2 cytokines indicating immunosuppressive effects , which are dysregulated in P48444 REA 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 REA and asthma .

Down-regulation of cholesterol 7alpha - hydroxylase ( P22680 REA ) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway . DB04540 7alpha - hydroxylase ( P22680 REA ) , 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 REA transcription through induction of small heterodimer protein ( Q15466 REA - 1 ) . In this study , we provide evidence that bile acids rapidly down-regulate P22680 REA transcription via activation of the JNK / c-Jun pathway . Furthermore , we demonstrate that Q15466 REA - 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 REA - alpha , a potent activator of JNK , also rapidly activated JNK and down-regulated P22680 REA mRNA levels . Overexpression of dominant-negative P45983 REA or a transactivating domain mutant of c-Jun significantly blocked the ability of TCA to down-regulate P22680 REA mRNA . In contrast , overexpression of wild-type c-Jun ( c-Jun ( wt ) ) enhanced the repression of P22680 REA by TCA . Moreover , overexpression of c-Jun ( wt ) resulted in increased Q15466 REA - 1 promoter activity . Mutation of a putative AP - 1 ( c-Jun ) element suppressed c-Jun-mediated activation of the Q15466 REA - 1 promoter construct . These results indicate that the bile acid-activated JNK pathway plays a pivotal role in regulating P22680 REA 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 REA ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 REA ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long-term outcomes were defined by Modified Rankin Scale ( P59665 REA ) at 3 and 12 months . P10632 REA * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 REA levels ( P= 0.003 and P= 0.007 ) and were 2.2- and 2.5- fold more likely to develop P42126 REA and CND ( P= 0.039 and P= 0.041 ) , respectively . P34913 REA 55Arg , P51589 REA * 7 , P10632 REA * 1B , and P10632 REA g . 36785A allele carriers had lower EET and DHET P04141 REA levels . P10632 REA g . 25369T and P10632 REA g . 36755A allele carriers had higher EET levels . Patients with P10632 REA * 2C and P34913 REA 404del variants had worse long-term outcomes while those with P34913 REA 287Gln , P51589 REA * 7 , and P11712 REA g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .

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 REA ) agonist antibodies in the manifestations of Graves ' disease ( GD ) is recognized . There are , however , no convincing reports of P16473 REA - specific T cells . We have previously cloned T cells specific for thyroglobulin and thyroid peroxidase ( P07202 REA ) from GD lymphoid infiltrates and used autologous EBV-transformed B cell lines ( EBVL ) transfected with an expression vector encoding P07202 REA to efficiently detect P07202 REA - specific T cells . Here we used EBVL transfected with P16473 REA to seek P16473 REA - 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 REA , with a mean stimulation index > 7 . Their release of P60568 REA , P05112 REA , and P22301 REA after stimulation with soluble anti-CD 3 and phorbol ester was indistinguishable from the other clones from this thyroid . However , they produced relatively little IFN gamma ( median P05112 REA / IFN gamma ratio of 0.80 ) compared with the other clones ( median P05112 REA / 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 REA T cells in GD thyroid , with distinct Th0 / Th2 characteristics , unlike previously cloned P07202 REA - responsive cells which have Th1 characteristics .

P08246 REA inhibitors as treatment for P48444 REA . 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 MEN , 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 MEN 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 REA ) , 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 REA ) , 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 REA alpha regulates expression of the orphan receptor small heterodimer partner . Hormonal status can influence diverse metabolic pathways . Q15466 REA ( Q15466 REA ) is an orphan nuclear receptor that can modulate the activity of several transcription factors . DB00286 MEN are here shown to directly induce expression of the Q15466 REA in the mouse and rat liver and in human HepG 2 cells . Q15466 REA 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 REA induction by these estrogens is completely absent in ERalphaKO mice . Mutation of the human Q15466 REA 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 REA promoter activity . This ERalpha binding site overlaps the known farnesoid X receptor ( Q96RI1 ) binding site in the Q15466 REA promoter , and the combination of EE plus Q96RI1 agonists did not produce an additive induction of Q15466 REA expression in mice . Surprisingly , induction of Q15466 REA by EE did not inhibit expression of the known Q15466 REA target genes cholesterol 7alpha - hydroxylase ( P22680 REA ) or sterol 12alpha - hydroxylase ( Q9UNU6 ) . However , the direct regulation of Q15466 REA expression may provide a basis for some of the numerous biological effects of estrogens .

Modulation of the P22301 REA / 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 REA . In light of the recently proposed paradigm that an P22301 REA / 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 REA , P60568 REA , P05112 REA , or P05113 REA 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 REA and a concurrent decreased production of IL - 12 . Moreover , the in vivo modulation of the P22301 REA / 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 REA / 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 REA , P08684 REA / 5 and Q9BQB6 genes polymorphisms . DB00946 MEN 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 MENMAX DB00946 MEN metabolism is mediated by P11712 REA and CYP 3A 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 REA , P08684 REA and P20815 REA 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 REA * 2 and / or P11712 REA * 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 REA * 1B , P20815 REA * 3 and P20815 REA * 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 REA 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 REA 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 REA and CD8 effector T cells in bronchoalveolar lavage that largely produced IFN-γ , as well as P01375 REA and P60568 REA . 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 REA - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 REA - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 REA , an agonist of P40189 REA , was used for the activation of P40189 REA on DC . The effects of cytokines and of anti - P40189 REA mAb on the proliferation of DC , and their expression of IL - 12 and P33681 REA ( P33681 REA - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 REA receptor alpha chain , but expressed P40189 REA . Anti - P40189 REA mAb promoted the proliferation of DC , induced by P05112 REA and granulocyte macrophage colony stimulating factor ( GM - P04141 REA ) , by up-regulating the GM - P04141 REA receptor on DC . DC induced by P40189 REA 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 REA ( P33681 REA - 1 ) was observed in DC activated by anti - P40189 REA mAb . Thus , P40189 REA signal transduction is important for the differentiation and maturation of DC .