MH_dev_226

Mechanism of oral absorbent DB05269 MEN in lipid abnormalities in experimental uremic rats . BACKGROUND : We have reported that oral sorbent DB05269 MEN ( Q9NRA2 ) is effective in delaying the induction of dialysis in patients with chronic renal failure ( CRF ) because of its effect on lipid metabolism . To clarify the precise mechanism of Q9NRA2 in lipid abnormalities in CRF , we examined the effect of Q9NRA2 on plasma lipid profile , total bile acids ( TBA ) , and lipoprotein lipase ( P06858 REA ) activity in experimental uremic rats . METHODS : Uremic rats were prepared using male Wistar rats by ligating 5/6 of the renal artery . Uremic rats were randomly divided into two groups as follows : a control group in which rats were maintained on the standard diet and an Q9NRA2 group in which rats were maintained on a diet containing 5 g of Q9NRA2 per 100 g of standard diet for 10 weeks . Plasma P06858 REA activity was measured as free fatty acid ( FFA ) generation after intravenous administration of heparin . RESULTS : Plasma creatinine at 1.5 + / - 0.1 mg / dl was lower in the Q9NRA2 group than the 1.9 + / - 0.5 mg / ml level in the control group . Q9NRA2 significantly decreased plasma total cholesterol from 192 + / - 29 to 142 + / - 25 mg / dl , triglycerides from 198 + / - 71 to 99 + / - 38 mg / dl , and TBA from 19.6 + / - 2.6 mumol / liter to 8.8 + / - 3.5 mumol / ml . Plasma P06858 REA activity at 0.22 + / - 0.01 mumol FFA / min / hr was significantly higher in the Q9NRA2 group than 0.15 + / - 0.03 mumol FFA / min / hr in the control group . CONCLUSIONS : These results suggest that Q9NRA2 may improve plasma lipid abnormalities by binding to bile acids in the intestinal lumen and preventing their reabsorption and inhibiting the reduction of P06858 REA activity in experimental uremic rats .

Mechanism of action of the bimodal antidepressant vilazodone : evidence for serotonin 1A - receptor-mediated auto-augmentation of extracellular serotonin output . RATIONALE : The recently approved antidepressant vilazodone , a serotonin ( 5 - HT ) 1A receptor partial agonist / selective 5 - HT reuptake inhibitor offers new possibilities to study the underlying mechanisms of depression pharmacotherapy and of 5 - HT augmenting antidepressants . OBJECTIVE : The role of the P08908 REA receptor with respect to the regulation of 5 - HT output in the mechanism of action of vilazodone . METHOD : We measured 5 - HT levels in two subregions of the rat prefrontal cortex by microdialysis , and 5 - hydroxytryptophan ( 5 - HTP ) accumulation and tissue 5 - HT concentrations ex vivo . RESULTS : DB06684 MENMAX DB06684 MEN - induced maximal 5 - HT levels were similar in the medial and the lateral cortex and were up to sixfold higher than those induced by paroxetine , citalopram , or fluoxetine tested in parallel . Depolarization / autoreceptor-insensitive 5 - HT release by vilazodone could be excluded . The citalopram ( 1 μM , locally infused ) - induced increase of 5 - HT was further increased by vilazodone ( 1 mg / kg i . p . ) , but not by citalopram ( 10 mg / kg i . p . ) . Unlike fluoxetine , vilazodone-induced extracellular 5 - HT output was not potentiated by cotreatment with the P08908 REA receptor blocker N - [ 2 - ( 4 - { 2 - methoxyphenyl } - 1 - piperazinyl ) - ethyl ] - N - 2 - pyridinylcyclohexanecarboxamide ( WAY 100635 ) . In contrast to fluoxetine , vilazodone exhibited intrinsic P08908 REA agonist activity : it reduced , similar to ( ± )-8 - hydroxy - 2 - ( dipropylamino ) - tetralin ( 8 - OH-DPAT ) , 5 - HTP accumulation in striatum and n . raphe of reserpinized rats . Hence , vilazodone ' s agonistic actions must be P08908 REA receptor-related since endogenous 5 - HT is lacking in the reserpine-depleted animal . CONCLUSIONS : In spite of high intrinsic P08908 REA activity in reserpinized rats , the net effect of vilazodone at release-regulating P08908 REA autoreceptors must be inhibitory , leading to markedly increased 5 - HT output . Another possibility is that vilazodone rapidly desensitizes autoinhibitory P08908 REA receptors by an unknown mechanism .

Differential recruitment of coregulator proteins steroid receptor coactivator - 1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by beta-estradiol and 4 - hydroxytamoxifen in human breast cancer . P03372 REA ( ER ) - alpha and Q92731 REA function as transcription factors , and both interact with nuclear regulatory proteins to enhance or inhibit transcription . We hypothesized that coregulators are expressed in breast cancer and may be differentially recruited by ERs in the presence of estrogen and tamoxifen . Q92731 REA was found to be expressed more frequently in node-negative patients ( P < 0.05 ) . Expression of steroid receptor coactivator - 1 ( Q15788 REA ) was associated with nodal positivity ( P < 0.05 ) and resistance to endocrine treatment ( P < 0.001 ) . The spatial coexpression of P03372 REA , Q92731 REA , and the coregulatory proteins was established using immunofluorescence . In both cell lines ( MCF - 7 and T47D ) and in primary breast cancer cell cultures , beta-estradiol up-regulated Q92731 REA and coregulator protein expression and increased P03372 REA / Q92731 REA interaction with the estrogen response element ( ERE ) . 4 - Hydroxy-tamoxifen ( DB04468 MEN ) increased P03372 REA and silencing mediator for retinoid and thyroid receptors ( Q9Y618 REA ) expression and increased ER-ERE binding . Q15788 REA and Q9Y618 REA were identified at the ER-ERE complex , and interactions between ER isoforms and coregulatory proteins were determined using immunoprecipitation . Both P03372 REA and Q92731 REA preferentially bound Q15788 REA in the presence of beta-estradiol . Conversely , in cells treated with DB04468 MEN , P03372 REA and Q92731 REA bound Q9Y618 REA . Differential recruitment of Q15788 REA and Q9Y618 REA by P03372 REA and Q92731 REA in the presence of beta-estradiol and DB04468 MEN may be central to the response of the tumor to endocrine treatment .

Single agent and combination studies of pralatrexate and molecular correlates of sensitivity . BACKGROUND : DB06813 MEN is a dihydrofolate reductase ( P00374 REA ) inhibitor with high affinity for reduced folate carrier 1 ( P41440 REA - 1 ) and folylpolyglutamate synthetase ( Q05932 REA ) , resulting in extensive internalization and accumulation in tumour cells . DB06813 MEN is approved in the US for the treatment of relapsed or refractory peripheral T-cell lymphoma and is being investigated in various malignancies . Here , we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents . METHODS : Antiproliferative effects of pralatrexate were evaluated in 15 human-cancer cell lines using the MTT assay . Gene expression was evaluated using qRT-PCR . RESULTS : DB06813 MEN and methotrexate had a similar pattern of cytotoxicity , pralatrexate being more potent . DB06813 MEN potentiated the effects of platinum drugs , antimetabolites and P00533 REA inhibitors . Dose - and time-dependent cytotoxicity of pralatrexate correlated with high mRNA expression of Q05932 REA . Acquired resistance to pralatrexate was associated with decreased P41440 REA - 1 expression , whereas methotrexate resistance correlated with increased P00374 REA expression , suggesting different mechanisms of acquired resistance . CONCLUSION : DB06813 MEN was more potent than methotrexate in a panel of solid tumour lines . Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies , and suggest that P41440 REA - 1 , Q05932 REA and P00374 REA may be potential biomarkers of outcome .

Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells . Histone deacetylase inhibitors are promising anti-tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies . However , little is known about any effects of these drugs on the central nervous system . The aim of the present study was to analyze the effects of trichostatin A ( P32119 REA ) - - a broad-spectrum histone deacetylase inhibitor - - on the transcriptional regulation of several genes involved in dopamine - and serotonergic neurotransmission . To this end , short-term parallel cultures of SK-NF-I neuroblastoma cells were treated with P32119 REA either alone or in combination with hypoxia , and mRNA levels of dopamine receptor D3 ( P35462 REA ) and D4 ( P21917 REA ) , dopamine transporter ( Q01959 REA ) , dopamine hydroxylase ( P09172 REA ) , dopamine receptor regulating factor ( DRRF ) , catechol-O-methyltransferase ( P21964 REA ) , serotonin receptor 1A ( P08908 REA ) , monoamino oxidase A ( P21397 REA ) , serotonin transporter ( P31645 REA ) and tryptophan hydroxylase 2 ( Q8IWU9 ) were determined by quantitative PCR . We found that P32119 REA did not antagonize the hypoxia-induced activation of D3 and D4 dopamine receptor genes , implying that induction of these genes is not mediated directly by hypoxia inducible factor - 1alpha . On the other hand , P32119 REA dramatically upregulated the expression of Q01959 REA and P31645 REA ( 45 - fold and 15 - fold , respectively ) , while transcript levels of P21397 REA and P21964 REA were significantly reduced ( by 70 % and by more than 90 % , respectively ) . Induction of Q01959 REA protein expression was detected by western blotting . These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons .

Effects of phenacetin and its metabolite p-phenetidine on P23219 REA and P35354 REA activities and expression in vitro . The present study was aimed to test the possible cyclooxygenase ( P36551 REA ) - 1 / P35354 REA selectivity of the old analgesic drug phenacetin and its metabolite p-phenetidine , which exhibits high renal toxicity . DB00316 ( acetaminophen ) , the main metabolite of phenacetin with low renal toxicity , and indomethacin were selected as reference compounds . Collagen-stimulated platelet thromboxane B2 ( TxB 2 ) production and phorbol 12 - myristate - 13 - acetate ( PMA ) - induced neutrophil prostaglandin E2 ( DB00917 ) synthesis were used as indicators for P23219 REA and P35354 REA activity , respectively . DB03783 MEN was even less potent than paracetamol to reduce the production of both TxB 2 and DB00917 , and no clear preference for either of the P36551 REA - enzymes was seen . P-phenetidine was a more potent inhibitor , already at nanomolar level , of the synthesis of these prostanoids than indomethacin and showed some preference to P35354 REA inhibition . Somewhat higher , micromolar , concentrations of p-phenetidine also reduced P35354 REA expression in neutrophils . We suggest that the very potent inhibitory activity of p-phenetidine on DB00917 synthesis combined with the reduction of P35354 REA expression could explain the renal papillary necrosis in phenacetin kidney .

Inhibition of aldehyde dehydrogenase 2 activity enhances antimycin-induced rat cardiomyocytes apoptosis through activation of MAPK signaling pathway . Aldehyde dehydrogenase 2 ( P05091 REA ) , a mitochondrial-specific enzyme , has been proved to be involved in oxidative stress-induced cell apoptosis , while little is known in cardiomyocytes . This study was aimed at investigating the role of P05091 REA in antimycin A-induced cardiomyocytes apoptosis by suppressing P05091 REA activity with a specific P05091 REA inhibitor DB02115 MEN . Antimycin A ( 40μg / ml ) was used to induce neonatal cardiomyocytes apoptosis . DB02115 MEN ( 60μM ) effectively inhibited P05091 REA activity by 50 % without own effect on cell apoptosis , and significantly enhanced antimycin A-induced cardiomyocytes apoptosis from 33.5 ± 4.4 to 56.5 ± 6.4 % ( Hochest method , p < 0.05 ) , and from 57.9 ± 1.9 to 74.0 ± 11.9 % ( FACS , p < 0.05 ) . Phosphorylation of activated MAPK signaling pathway , including extracellular signal-regulated kinase ( P27361 REA / 2 ) , c-Jun NH2 - terminal kinase ( JNK ) and p38 was also increased in antimycin A and daidzin treated cardiomyocytes compared to the cells treated with antimycin A alone . These findings indicated that modifying mitochondrial P05091 REA activity / expression might be a potential therapeutic option on reducing oxidative insults induced cardiomyocytes apoptosis .

A randomized , placebo-controlled study of the effects of the p38 MAPK inhibitor SB - DB05250 MEN on blood biomarkers of inflammation in P48444 REA patients . The p38 mitogen-activated protein kinase ( MAPK ) signaling upregulates inflammation and is known to be increased in chronic obstructive pulmonary disease ( P48444 REA ) . The authors assessed the pharmacology of the novel p38 MAPK inhibitor SB - DB05250 MEN using blood biomarkers in P48444 REA . Seventeen P48444 REA patients ( forced expiratory volume in 1 second 50 % - 80 % predicted ) using short-acting bronchodilators participated in a double-blind , double-dummy , randomized , crossover study . Patients received single oral doses of SB - DB05250 MEN 7.5 mg and 25 mg , prednisolone 10 mg and 30 mg , and placebo . Blood was obtained predose and at 1 , 2 , 6 , and 24 hours postdose . Whole-blood sorbitol-induced phosphorylated ( p ) heat shock protein ( HSP ) 27 levels as a marker of p38 pathway activation and lipopolysaccharide-induced tumor necrosis factor ( P01375 REA ) - alpha production were assessed . Both doses of SB - DB05250 MEN , but not prednisolone , significantly ( P < . 0001 ) reduced weighted mean ( WM ) pHSP 27 ( 0-6 hours ) by 58 % compared with placebo . WM P01375 REA production ( 0-24 hours ) was significantly reduced compared with placebo by SB - DB05250 MEN 25 mg ( 40 % , P = . 005 ) and 7.5 mg ( 33.4 % , P = . 02 ) , while prednisolone 30 mg and 10 mg caused 81.5 % and 58.2 % suppression , respectively ( both P < . 0001 ) . SB - DB05250 MEN inhibited the p38 MAPK pathway to a greater degree than prednisolone did . SB - DB05250 MEN inhibited P01375 REA production . SB - DB05250 MEN is a potent p38 MAPK inhibitor that potentially suppresses inflammation in P48444 REA .

Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 REA , P17643 REA , P40126 REA , P21583 REA , P00533 REA , P14416 REA and Q03181 REA ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 REA , P17643 REA and P21583 REA ) and in Asians ( Q04671 REA , P40126 REA , P21583 REA , P00533 REA and P14416 REA ) , whereas signals were scarce in Africans ( P40126 REA , P00533 REA and P14416 REA ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans .

DB02709 MEN , a polyphenol found in grapes , suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats . Oxidative stress , neutrophil infiltration , proinflammatory cytokines and eicosanoid generation are clearly involved in the pathogenesis of intestinal bowel disease . DB02709 MEN , a polyphenolic compound found in grapes and wine , has been shown to have anti-inflammatory , antioxidant , antitumour and immunomodulatory activities , however , its effects on experimental colitis remain unknown . We have investigated the effects of resveratrol on the colon injury caused by intracolonic instillation of trinitrobenzenesulphonic acid ( TNBS ) in rats . We determined the production of prostaglandin ( PG ) E ( 2 ) and P52209 REA ( 2 ) in colon mucosa and the expression of cyclo-oxygenases ( P36551 REA ) - 1 and - 2 immunohistochemically . The inflammatory response was assessed by histology and myeloperoxidase activity , as an index of neutrophil infiltration . P01584 REA production , histological and histochemical analysis of the lesions were also carried out . Finally , since resveratrol has been found to modulate apoptosis we intended to elucidate its effects on colonic mucosa under early acute inflammatory conditions . DB02709 MEN ( 5-10 mg / kg / day ) significantly reduced the degree of colonic injury , the index of neutrophil infiltration and the levels of the cytokine . DB02709 MEN did not revert the increased PGE ( 2 ) levels but produced a significant fall in the P52209 REA ( 2 ) concentration . Compared with inflamed colon , no changes in staining for P23219 REA were observed in colon of resveratrol and TNBS-treated rats . In contrast , P35354 REA expression was decreased . Furthermore , resveratrol enhanced apoptosis compared with already high level induced by TNBS . In conclusion , resveratrol reduces the damage in experimentally induced colitis , alleviates the oxidative events and stimulates apoptosis .

Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 REA , P05177 REA , P10632 REA , P11712 REA - arg 144 , P11712 REA - cys 144 , P33261 REA , P10635 REA , P08684 REA and P20815 REA supplemented with an NADPH-generating system . DB01267 SUB was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7.5 , 0.4 and 0.2 pmol pmol ( - 1 ) CYP min ( - 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 REA and 3A activities . Thus , both P10635 REA and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 REA ) and ketoconazole ( inhibitor of P08684 REA ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP 3A contributes significantly to the metabolism of risperidone in rat .

The silencing mediator of retinoic acid and thyroid hormone receptors can interact with the aryl hydrocarbon ( Ah ) receptor but fails to repress P35869 REA - dependent gene expression . Exposure to 2,3 , 7,8- tetrachlorodibenzo-p-dioxin ( TCDD ) and related chemicals causes a variety of tissue - and species-specific biological and toxicological effects , most of which are mediated by the aryl hydrocarbon receptor ( P35869 REA ) . The P35869 REA complex is a ligand-dependent transcription factor that binds to its specific DNA recognition site as a dimer with the P35869 REA nuclear translocator ( P27540 REA ) and activates gene transcription . Here , we have examined the ability of a nuclear corepressor , the silencing mediator of retinoic acid and thyroid hormone receptors ( Q9Y618 REA ) , to interact with and modulate P35869 REA - dependent gene expression . Using glutathione S-transferase ( Q86UG4 ) " pull-down " binding assays , we have mapped a major interaction between these factors to the silencing domain of Q9Y618 REA and the DB00233 B ligand binding domain of P35869 REA , and this interaction is unaffected by the addition of an P35869 REA ligand . Association of Q9Y618 REA with the P35869 REA : P27540 REA :D NA complex was not detected by Q86UG4 pull-down or gel retardation assays . Transient cotransfections of mammalian cells ( Hepa 1c1c7 , MCF - 7 , and BG - 1 ) with Q9Y618 REA and a TCDD-inducible luciferase reporter containing the dioxin-responsive domain from the mouse P04798 REA regulatory region revealed that Q9Y618 REA does not repress , but enhances , P35869 REA signaling . However , when a reporter containing a human P04798 REA upstream region was cotransfected with Q9Y618 REA into human MCF - 7 cells , P35869 REA - driven reporter activity was decreased by half , suggesting that Q9Y618 REA acts on the human P04798 REA promoter via a factor other than the P35869 REA in MCF - 7 cells . Furthermore , the interaction between Q9Y618 REA and the P35869 REA may have implications in pathways other than the P35869 REA signaling pathway .

[ Clinical and genetic characteristics of long-livers in Moscow region ] . In Moscow region long-livers we have studied distribution of P06858 REA , P11597 REA , P02649 REA , F2 , P12259 REA , P08709 REA , F13 , P02675 REA , P17301 REA , P05106 REA , P05121 REA , P42898 REA , Q9UBK8 , HLA - Q8IUH3 , HLA-DQA 1 , P01920 REA genes polymorphisms , associated with predisposition to age pathology . Long-livers are characterized by favorable course of cardiovascular diseases accompanied by certain genetic factors . We have established that genotype H-H - of P06858 REA , allele epsilon 2 of P02649 REA , genotype CC of P42898 REA ( 677C > T ) , genotype TC of P05106 REA , genotype GA of P02675 REA , HLA - Q8IUH3 * 11 positively correlate with longevity .

P14416 REA signaling dynamics of dopamine D2 - neurotensin 1 receptor heteromers . Biochemical , histochemical and coimmunoprecipitation experiments have indicated the existence of antagonistic dopamine D2 ( D2R ) and neurotensin 1 ( NTS 1R ) receptor-receptor interactions in the dorsal and ventral striatum indicating a potential role of these receptor-receptor interactions in Parkinson ' s disease and schizophrenia . By means of Bioluminiscence Resonance energy transfer ( BRET ( 2 ) ) evidence has for the first time been obtained in the current study for the existence of both D2LR / NTS 1R and D2SR / NTS 1R heteromers in living HEK 293T cells . Through confocal laser microscopy the NTS 1R ( GFP 2 ) and D2R ( YFP ) were also shown to be colocated in the plasma membrane of these cells . A bioinformatic analysis suggests the existence of a basic set of three homology protriplets ( TVM , DLL and / or LRA ) in the two participating receptors which may contribute to the formation of the D2R / NTS 1R heteromers by participating in guide-clasp interactions in the receptor interface . The CREB reporter gene assay indicated that the neurotensin receptor agonist JMV 449 markedly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal . In contrast , the neurotensin agonist was found to markedly increase the quinpirole potency to activate the MAPK pathway as also studied with luciferase reporter gene assay measuring the degree of SRE activity as well as with P27361 REA / 2 phosphorylation assays . These dynamic changes in D2R signaling produced by the neurotensin receptor agonist may involve antagonistic allosteric receptor-receptor interactions in the D2LR - NTS 1R heteromers at the plasma membrane level ( CREB pathway ) and synergistic interactions in PKC activation at the cytoplasmatic level ( MAPK pathway ) .

Therapy with interferon-beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis . OBJECTIVE : To investigate the endogenous dopaminergic / adrenergic system of lymphocytes in multiple sclerosis ( MS ) patients during treatment with interferon ( IFN ) - beta . METHODS : Patients with relapsing-remitting MS undergoing IFN-beta treatment were prospectively studied during the first year of treatment . Circulating lymphocytes were obtained at baseline and after 1 , 3 , 6 and 12 months of treatment and assayed for catecholamine ( CA ) production and mRNA expression of tyrosine hydroxylase ( TH , the rate-limiting enzyme in the synthesis of CA ) , beta ( 2 ) - adrenoceptors ( AR ) and D2 , D3 and D5 dopaminergic receptors ( DR ) . RESULTS : In cells from patients treated with IFN-beta for 12 months the production of CA hugely increased and was less sensitive to P01579 REA - induced inhibition . Expression of mRNA for TH , beta ( 2 ) - AR and P21918 REA was already enhanced after 1 month and further increased up to 6-12 months of treatment . On the contrary , P14416 REA mRNA progressively decreased and P35462 REA mRNA did not significantly change over the whole study period . CONCLUSIONS : In MS patients IFN-beta treatment enhances the ability of lymphocytes to produce CA , and induces extensive modifications of both beta ( 2 ) - AR and DR-operated pathways . The clinical relevance of these effects deserves consideration .

Q8N0V5 V ( Mgat 5 ) - mediated N-glycosylation negatively regulates Th1 cytokine production by T cells . The differentiation of naive P01730 REA ( + ) T cells into either proinflammatory Th1 or proallergic Th2 cells strongly influences autoimmunity , allergy , and tumor immune surveillance . We previously demonstrated that beta 1,6 GlcNAc-branched complex-type ( Q8N0V5 V ( Mgat 5 ) ) N-glycans on TCR are bound to galectins , an interaction that reduces TCR signaling by opposing agonist-induced TCR clustering at the immune synapse . Mgat 5 ( - / - ) mice display late-onset spontaneous autoimmune disease and enhanced resistance to tumor progression and metastasis . In this study we examined the role of beta 1,6 GlcNAc N-glycan expression in Th1 / Th2 cytokine production and differentiation . beta 1,6 GlcNAc N-glycan expression is enhanced by TCR stimulation independent of cell division and declines at the end of the stimulation cycle . DB00075 - activated splenocytes and naive T cells from Mgat 5 ( - / - ) mice produce more P01579 REA and less P05112 REA compared with wild-type cells , the latter resulting in the loss of P05112 REA - dependent down-regulation of IL - 4Ralpha . DB02034 MEN , an inhibitor of Q16706 REA , blocked beta 1,6 GlcNAc N-glycan expression and caused a similar increase in P01579 REA production by T cells from humans and mice , but no additional enhancement in Mgat 5 ( - / - ) T cells . Mgat 5 deficiency did not alter P01579 REA / P05112 REA production by polarized Th1 cells , but caused an approximately 10 - fold increase in P01579 REA production by polarized Th2 cells . These data indicate that negative regulation of TCR signaling by beta 1,6 GlcNAc N-glycans promotes development of Th2 over Th1 responses , enhances polarization of Th2 cells , and suggests a mechanism for the increased autoimmune disease susceptibility observed in Mgat 5 ( - / - ) mice .

Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 REA , Q16678 REA , P11712 REA , P33261 REA , P05181 REA , P05093 REA , P11511 REA , P35869 REA , P03372 REA , Q92731 REA , ERRRG , P06401 REA , P07099 REA , P34913 REA , P37059 REA , P37058 REA , P28161 REA , P21266 REA , GSTT 2 , P09211 REA , NAT 1 , NAT 2 , P21964 REA , P07327 REA , P00325 REA , P00326 REA , P05091 REA , P35228 REA , NOS 3 , P01583 REA , P01584 REA , O15527 REA , P36639 REA [ P36639 REA ] , P14416 REA , P35462 REA , P21917 REA , P31645 REA , P04150 REA [ GCCR ] , P42898 REA , and P15559 REA . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .

Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages . 2,3 , 7,8- Tetrachlorodibenzo ( p ) dioxin ( TCDD ) has been known to induce inflammatory signaling in a number of cell types and tissues . We found that in U937 macrophages TCDD causes rapid activation of cytosolic phospholipase A2 ( P47712 REA ) within 30min as judged by the increase in the serine 505 phosphorylated form of P47712 REA protein and the increased cellular release of free arachidonic acid . This initial action of TCDD is accompanied with the up-regulation of an important inflammation marker , P35354 REA mRNA expression within 1h , and by 3h , several other markers become up-regulated . These effects appear to be dependent on the initial increase in the intracellular concentration of Ca ( 2 + ) , and activation of P47712 REA and P35354 REA . A comparative study among three different human cell lines showed that activation of P35354 REA within 1h of action of TCDD is a common feature exhibited by all cell lines . On the other hand , the U937 macrophage line appears to be unique among them with respect to its ability to activate P01375 REA and P10145 REA mRNA expressions , and not requiring Src kinase in propagating the initial signaling of P47712 REA . Based on the rapidity of activation of P47712 REA and P35354 REA , which occurs within 1h of cell exposure to TCDD , when no change in mRNA expression of P04798 REA has been observed , it is apparent that this unique action of TCDD is carried out through a distinct " nongenomic " pathway which , is clearly discernable from the classical , " genomic " action pathway of the P35869 REA by not requiring the participation of P27540 REA .