interacts_with DB01088?
Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process . DB09053 treatment ameliorates murine chronic graft-versus-host disease . Chronic graft-versus-host disease ( cGVHD ) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation , and current therapies do not completely prevent and/or treat cGVHD . P01730 + T cells and B cells mediate cGVHD ; therefore , targeting these populations may inhibit cGVHD pathogenesis . DB09053 is an FDA-approved irreversible inhibitor of Bruton 's tyrosine kinase ( Q06187 ) and P60568 inducible T cell kinase ( Q08881 ) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity . Here , we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models , a model interrogating T cell-driven sclerodermatous cGVHD and an alloantibody-driven multiorgan system cGVHD model that induces bronchiolar obliterans ( BO ) . In the T cell-mediated sclerodermatous cGVHD model , ibrutinib treatment delayed progression , improved survival , and ameliorated clinical and pathological manifestations . In the alloantibody-driven cGVHD model , ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition . Animals lacking Q06187 and Q08881 did not develop cGVHD , indicating that these molecules are critical to cGVHD development . Furthermore , ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD . Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent , warranting consideration for cGVHD clinical trials . Human cytokines interleukin ( IL ) -3 and P05231 affect the growth and insulin binding of the unicellular organism Tetrahymena . Interleukin ( IL ) -3 and P05231 significantly increase the growth rate of the unicellular organism , Tetrahymena . The effect elicited by P08700 is long lasting as it was also detectable after 20 generations . Effect of P05231 was detectable as long as the substance was present in the cell culture . Pretreatment with P08700 did not enhance the proliferative response to subsequent P08700 treatment , but the second exposure to P08700 considerably depressed the active proliferation of Tetrahymena cells . However , a positive ' priming effect ' elicited by P05231 resulted in an increased growth rate following repeated P05231 stimulation . P01308 binding to the plasma membrane of Tetrahymena was increased by P05231 but not by P08700 after 24 hours , and this enhancement appeared even after one hour incubation . If the cells were pretreated with insulin , P05231 did not influence insulin binding , while an inhibition by P08700 was observed . These results direct attention to the similarities of actions induced by P08700 and P05231 at different levels of phylogeny probably due to the presence of cytokine receptor-like structures on this unicellular organism . P43119 -induced P40763 phosphorylation in human erythroleukemia cells is mediated via Galpha(s) and Galpha(16) hybrid signaling . Human prostacyclin receptor ( hIP ) stimulates P40763 via pertussis toxin-insensitive G proteins in human erythroleukemia ( HEL ) cells . Since hIP can utilize G(s) and G(q) proteins for signal transduction and that both G proteins can induce P40763 phosphorylation and activation via complex signaling networks , we sought to determine if one of them is predominant in mediating the hIP signal . Stimulation of P40763 DB00135 (705) and DB00133 (727) phosphorylations by the IP-specific agonist , cicaprost , was sensitive to inhibition of protein kinase A , phospholipase Cbeta , protein kinase C , calmodulin-dependent protein kinase II and O60674 /3 . Unlike Galpha(16)-mediated regulation of P40763 in the same cells , cicaprost-induced P40763 DB00135 (705) phosphorylation was resistant to inhibition of Src and MEK while P40763 DB00133 (727) phosphorylation distinctly required phosphatidylinositol-3 kinase . This unique inhibitor-sensitivity pattern of P40763 phosphorylation was reproduced in HEL cells by stimulating the G(16)-coupled C5a receptor in the presence of dibutyryl- DB02527 , suggesting that the change in inhibitor-sensitivity was due to activation of the G(s) pathway . This postulation was confirmed by expressing constitutively active Galpha(16)QL and Galpha(s)QL in human embryonic kidney 293 cells and the inhibitor-sensitivity of Galpha(16)QL-induced P40763 phosphorylations could be converted by the mere presence of Galpha(s)QL to resemble that obtained with cicaprost in HEL cells . In addition , the restoration of the Galpha(16)-mediated inhibitor-sensitivity upon cicaprost induction in Galpha(s)-knocked down HEL cells again verified the pivotal role of G(s) signal . Taken together , our observations illustrate that co-stimulation of G(s) and G(q) can result in the fine-tuning of P40763 activation status , and this may provide the basis for cell type-specific responses following activation of hIP . Catalog of 178 variations in the Japanese population among eight human genes encoding G protein-coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single-nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein-coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive-sequence elements . This approach identified 147 SNPs and 31 insertion/deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty-one SNPs were located in 5' flanking regions , 76 in introns , 32 in exons , and 18 in 3' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy . Ex vivo binding of flibanserin to serotonin P08908 and 5- Q13049 receptors . DB04908 has been reported to be an agonist at P08908 -receptors and an antagonist at 5- Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5- Q13049 antagonism at doses ( 4-5 mg kg-1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5- Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [3H]8-OH-DPAT and [3H]ketanserin to label P08908 and 5- Q13049 receptors , respectively . DB04908 was given at 1 , 10 and 30 mg kg-1 intraperitoneally . The dose of 1 mg kg-1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg-1 reduced the binding of both radioligands in all the three brain regions non-selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0.5 h and was reduced or not evident after 3 h . We conclude that 5-HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects . aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy-Nine consecutive elderly patients , 31 late onset AD and 48 non-demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t =2.200 , p = 0.036 for MMSE and t =2.724 , p= 0.011 for IADL , respectively ) . DB00989 was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long-term studies on this issue are needed . DB00227 , a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3-Hydroxy-3-methylglutaryl coenzyme A ( HMG- DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization/flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3-dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer . DB00989 improves hippocampal neurogenesis and depression-like behaviors via P08908 receptor stimulation in olfactory bulbectomized mice . DB00989 is a non-competitive inhibitor of both acetylcholinesterase ( P22303 ) and butylcholinesterase ( BuChE ) used to treat mild to moderate dementia in Alzheimer 's disease ( AD ) patients . Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients , its ability to improve Behavioral and Psychological Symptoms of Dementia ( BPSD ) remains unclear . To determine whether rivastigmine treatment antagonizes depression-like behaviors , we chronically administered rivastigmine ( 0.1-1.0mg/kg ) to olfactory bulbectomized ( OBX ) mice once a day for 2weeks , starting 2weeks after bulbectomy . Chronic treatment at 0.3 or 1.0mg/kg dose dependently and significantly improved depression-like behaviors , as assessed by tail suspension ( Q16762 ) , forced swim ( P19883 ) , locomotion and novelty-suppressed feeding ( NSFT ) tests . Importantly , co-administration with WAY-100635 ( 1.0mg/kg ) , a P08908 receptor antagonist , but not ketanserin ( 1.0mg/kg , ) , a 5- Q13049 receptor antagonist , completely blocked rivastigmine-induced anti-depressive effects , suggesting that P08908 receptor stimulation mediates this activity . Consistent with this observation , rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a P08908 receptor-dependent manner . Furthermore , enhanced protein kinase B ( Akt ) and extracellular signal-regulated kinase ( P29323 ) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis . These effects were blocked by WAY-100635 but not ketanserin treatment . Finally , we confirmed that P08908 but not 5- Q13049 receptor stimulation by specific agonists mimicked rivastigmine-induced anti-depression activity and promoted hippocampal neurogenesis . We conclude that , in addition to enhancing the cholinergic system , rivastigmine treatment restores normal function of the hippocampal serotonergic system , an activity that likely ameliorates depressive behaviors in AD patients . DB01590 prolonged survival in transgenic mice with P00533 -driven lung tumors . DB01590 is an orally administered P42345 inhibitor . The effect , and mechanism of action , of everolimus on lung cancers with an epidermal growth factor receptor ( P00533 ) mutation remain unclear . Four gefitinib-sensitive and -resistant cell lines were used in the present work . Growth inhibition was determined using the MTT assay . Transgenic mice carrying the P00533 L858R mutation were treated with everolimus ( 10 mg/kg/day ) , or vehicle alone , from 5 to 20 weeks of age , and were then sacrificed . To evaluate the efficacy of everolimus in prolonging survival , everolimus ( 10 mg/kg/day ) or vehicle was administered from 5 weeks of age . The four cell lines were similarly sensitive to everolimus . Expression of phosphorylated ( p ) P42345 and pS6 were suppressed upon treatment with everolimus in vitro , whereas the pAKT level increased . The numbers of lung tumors with a long axis exceeding 1mm in the everolimus-treated and control groups were 1.9 ± 0.9 and 9.4 ± 3.2 ( t-test , p < 0.001 ) , respectively . pS6 was suppressed during eve r olimus treatment . Although apoptosis and autophagy were not induced in everolimus-treated P00533 transgenic mice , angiogenesis was suppressed . The median survival time in the everolimus-treated group ( 58.0 weeks ) was significantly longer than that in the control group ( 31.2 weeks ) ( logrank test , p < 0.001 ) . These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating P00533 gene mutation . [ Thrombocyte prostacyclin receptors in gestational hypertension and pre-eclampsia ] . OBJECTIVE : To determine prostacyclin ( DB01240 ) receptor characteristics in pregnancies complicated by hypertension and to assess any relation to the clinical outcome . METHODS : Radioligand binding studies with [ 3H ] - DB01088 were performed to measure receptor capacity ( Bmax ) and affinity ( Kd-1 ) using platelet membranes from patients with preeclampsia , gestational hypertension or normal pregnancy . RESULTS : P43119 capacity did not differ between the patient groups . In contrast , P43119 affinity was diminished in gestational hypertension and considerably reduced in preeclampsia compared to normal pregnancy . A similar pattern was found in fetal growth ( normal pregnancy > gestational hypertension > preeclampsia ) . Furthermore , the rate of low Apgar scores and acidosis was increased in preeclampsia . CONCLUSIONS : In preeclampsia reduced platelet P43119 affinity was found as well as poor pregnancy outcome in comparison with normal pregnancy , whereas these differences were less pronounced in gestational hypertension . This suggests a role of DB01240 and its receptor in gestational hypertension and in particular in preeclampsia . Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of DB06684 , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5-HT(1A) ) receptor agonist [ Bartoszyk , G.D. , Hegenbart , R. , Ziegler , H. , 1997. P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties. Eur. J. Pharmacol. 322 , 147-153. ] , on change in affect following predator stress . DB06684 and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus-maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle . In prophylactic testing , DB06684 affected stress potentiation of startle at doses above 5 mg/kg . DB06684 increased stress elevation of startle at 10 mg/kg . Higher doses of DB06684 ( 20 and 40 mg/kg ) blocked stress potentiation of startle . In contrast , DB06684 had no effect on stress potentiation of anxiety in the plus-maze . In therapeutic testing , DB06684 increased stress elevation of startle at all doses . In contrast , therapeutic DB06684 had no effect on stress potentiation of anxiety in the plus-maze . Taken together , the data suggest a prophylactic potential for DB06684 in the treatment of changes in hypervigilance following severe stress . DB01088 has potent anti-inflammatory properties on human monocyte-derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte-derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT-PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co-culture of DCs with P01730 + CD45RA+ T cells was analysed by flow cytometry . RESULTS : Human monocyte-derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL-12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T-cell priming capacity of DCs : in co-culture experiments of iloprost-treated mDC and naïve CD45RA+ T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP-3beta-induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans . Altered expression of inflammation-related genes in human carotid atherosclerotic plaques . OBJECTIVE : Inflammation is a pivotal process in atherosclerosis development and progression , but the underlying molecular mechanisms remain largely obscure . We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis . METHODS : We studied 11 human carotid plaques , their respective adjacent regions and 7 control arteries from different subjects . Expression of 92 genes was studied by TaqMan low-density array human inflammation panel . Human aortic endothelial and smooth muscle cells were used for in vitro experiments . RESULTS : The mRNA levels of 44/92 genes ( 48 % ) differed significantly between the tissues examined ( 13 up-regulated and 31 down-regulated ) . Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway . The expression of Q16647 and P43119 genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and P01375 -α . CONCLUSIONS : This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development . The decrease of Q16647 and P43119 expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries , which suggests that oxidation is important for Q16647 and P43119 regulation in human vessel cells during atherosclerosis development . [ P35354 inhibitor non-steroidal anti-inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox-1 constitutive and Cox-2 inducible , has prompted the development of new molecules with high Cox-2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12.5 to 25 mg/d ) and celecoxib is indicated in osteoarthritis ( 200 mg/d ) and in rheumatoid arthritis ( 200 to 400 mg/d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( DB01050 ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg/d but not investigated for rofecoxib . The selective inhibition of Cox-2 with no effect on Cox-1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox-2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis . 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 . Contact sensitization to oxazolone : involvement of both interferon-gamma and interleukin-4 in oxazolone-specific Ig and T-cell responses . The synthesis and role of several lymphokines were examined during contact sensitization to oxazolone ( OX ) . Application of OX to the skin of mice increased the delayed-type hypersensitivity ( DTH ) response to challenge , serum titres of OX-specific IgG1 and IgG2a , and draining lymph node cell ( LNC ) numbers . At day 3 , LN contained detectable interleukin-4 ( P05112 ) , interferon-gamma ( P01579 ) and granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) but not P60568 or P08700 mRNAs ; P08700 and higher levels of P05112 , P01579 and GM- P04141 mRNAs were measured after 24 hr culture with anti-CD3 antibody in OX-primed but not unprimed LNC . As a result of sensitization , LNC secreted P08700 constitutively and produced elevated levels of P60568 , P08700 , P05112 and P01579 in response to anti-CD3 antibody ; a similar but weaker lymphokine response was recalled by OX-protein conjugate . P01730 + cells were the major source of the anti-CD3-induced lymphokines except P01579 , which was derived mainly from CD8+ cells . Since both P05112 and P01579 were synthesized by OX-primed LNC in vivo and in vitro , their role was investigated by administering anti-lymphokine antibodies at the time of sensitization . Anti- P05112 treatment reduced OX-specific serum IgG1 titres without affecting IgG2a titres , whereas anti- P01579 treatment reduced IgG2a but not IgG1 titres . Although neither antibody altered DTH responsiveness , anti- P01579 treatment markedly increased P05112 production by P01730 + LNC and reduced P01579 production in vitro , particularly by P01730 + cells . We conclude that endogenous P05112 and P01579 reciprocally influence the isotype of the Ig response to OX and that P01579 also affects the relative levels of P05112 and P01579 synthesis by P01730 + LNC . Expression profile of genes associated with the dopamine pathway in vitiligo skin biopsies and blood sera . BACKGROUND : Dopamine has been proven to be toxic for melanocytes . In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed . METHODS : With the use of quantitative real-time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway ( PAH , P61457 , TH , DDC , P09172 , PNMT , P07203 , P21397 , P27338 , P21964 , P21728 - P21918 , P54219 and Q05940 ) was observed in vitiligo patients ' and control subjects ' skin and blood . RESULTS : The mRNA expression of P07203 , DDC , P21397 , P21728 and P21918 differs in vitiligo skin and the protein level of DDC , P21397 , P27338 , P21728 and P21918 is changed in vitiligo patients ' skin and/or blood sera . CONCLUSIONS : The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway . We provide new data about changes of expression profile of the dopamine-synthesizing enzyme DDC , the dopamine-degrading enzymes P21397 and P27338 and the D1-like family dopamine receptors in vitiligo skin and blood sera . [ Detection of a high-affinity prostaglandin I2 binding site in the human thyroid ] . This study is concerned with the identification and the pharmacological properties of P43119 binding sites on human thyroid membrane fractions . Scatchard analysis is not linear , revealing a high- and a low-affinity receptor binding site . ( 3 H ) DB01088 binding experiments were performed under various clinical conditions : in thyroid cancer the low-affinity binding sites disappear totally and the specific high-affinity binding sites are diminished according to the grade of differentiation of the cancer . An alteration in Bmax and Kd is also observed in cold nodules , in Hashimoto 's and Riedl 's thyroiditis and in hyperthyroidism , whereas hot nodules exhibit an increase in both the receptor subpopulations . The data provide evidence for specific DB01240 binding sites and support the suggestion of a direct regulatory key-role of DB01240 in thyroid intermediary metabolism . P43119 up-regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1/2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven-transmembrane G protein-coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid-receptor signaling in angiogenesis . In this study we examined the temporal-spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT-PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 /2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin-1 , and angiopoietin-2 , in an epidermal growth factor receptor ( P00533 ) -dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 -IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 . The relationship of P04141 and plasma cytokine levels to cerebral white matter injury in the premature newborn . Ischemia and systemic infection are implicated in the etiology of periventricular white matter injury , a major cause of adverse motor and cognitive outcome in preterm infants . Cytokines are signaling proteins that can be produced as part of the inflammatory response to both ischemia and infection . The aim of this study was to relate cerebrospinal fluid ( P04141 ) concentrations of P05231 , P10145 , P22301 , tumor necrosis factor alpha ( P01375 ) , and interferon gamma ( P01579 ) to magnetic resonance-defined white matter injury in preterm infants . Relationships between P04141 and plasma cytokine concentrations were also examined . Preterm infants ( < or=32 wk ) and more mature infants from The Royal Women 's Hospital , Melbourne , Australia , and Christchurch Women 's Hospital , Christchurch , New Zealand , were eligible for study if they required a clinically indicated lumbar puncture . Plasma samples were obtained in a subgroup of Christchurch infants . Preterm infants underwent advanced quantitative volumetric magnetic resonance imaging using a 1.5-Tesla scanner at term equivalent . One hundred forty-six infants were enrolled and 190 P04141 and 42 plasma samples obtained . There was no significant correlation between paired P04141 and plasma concentrations for any cytokine . In comparing plasma and P04141 concentrations , levels of P10145 were significantly higher in P04141 than plasma . Preterm infants with Q9BWK5 -defined cerebral white matter injury had higher levels of P05231 , P22301 , and P01375 in the P04141 than infants without such injury . Plasma cytokine concentrations may not reflect P04141 cytokine levels or inflammatory events within the brain . Elevated P04141 levels of cytokines in infants with white matter injury suggest an altered inflammatory balance . 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 . DB09053 inhibits P11274 and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue-resident CLL cells show prominent activation of both B-cell receptor ( P11274 ) and NF-κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 ( Q06187 ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway-specific gene signatures , we detected a rapid and sustained downregulation of P11274 and NF-κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . DB09053 reduced phosphorylation of PLCγ2 and P29323 and decreased nuclear protein expression of NF-κB p50 . DB09053 significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on-target effects of Q06187 inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www.clinicaltrials.gov as # NCT01500733 . P35354 -derived prostacyclin confers atheroprotection on female mice . Female gender affords relative protection from cardiovascular disease until the menopause . We report that estrogen acts on estrogen receptor subtype alpha to up-regulate the production of atheroprotective prostacyclin , DB01240 , by activation of cyclooxygenase 2 ( P35354 ) . This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice . Deletion of the P43119 removed the atheroprotective effect of estrogen in ovariectomized female mice . This suggests that chronic treatment of patients with selective inhibitors of P35354 could undermine protection from cardiovascular disease in premenopausal females . 8-OH-DPAT ( P08908 agonist ) Attenuates 6-Hydroxy- dopamine-induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE(S) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8-OH-DPAT on 6-OHDA-induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6-OHDA ( 8 μg/2 μl/rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar-test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8-OH-DPAT ( P08908 receptor agonist ; 0.25 , 0.5 and 1mg/kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8-OH-DPAT administration and analyzed by ELISA method to measure levels of P01375 -α , IL-1β and P05231 . RESULTS : Chronic injection of 8-OH-DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti-cataleptic effect was observed at the dose of 1 mg/kg of 8-OH-DPAT . Levels of P01375 -α in P04141 increased three weeks after 6-OHDA injection while there was a significant decrease in P01375 -α level of parkinsonian animals treated with 8-OH-DPAT ( 1 mg/kg , IP for 10 days ) . IL-1β and P05231 decreased and increased in parkinsonian rats and in 8-OH-DPAT-treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8-OH-DPAT improves catalepsy in 6-OHDA-induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines . DB01590 -treated renal transplant recipients have a more robust CMV-specific CD8+ T-cell response compared with cyclosporine- or mycophenolate-treated patients . BACKGROUND : In renal transplant recipients , mammalian target of rapamycin ( P42345 ) inhibitors have been reported to protect against cytomegalovirus ( CMV ) disease . Here , we questioned whether P42345 inhibitors specifically influence human CMV-induced T-cell responses . METHODS : We studied renal transplant recipients treated with prednisolone , cyclosporine A ( DB00091 ) , and mycophenolate sodium ( MPS ) for the first 6 months after transplantation followed by double therapy consisting of prednisolone/everolimus , which is an P42345 inhibitor ( P/ Q9UI08 ; n=10 ) , prednisolone/ DB00091 ( P/ DB00091 ; n=7 ) , or prednisolone/MPS ( P/MPS ; n=9 ) . All patients were CMV-IgG positive before transplantation . CMV reactivation was detectable in the first 6 months after transplantation and not thereafter . None of the patients included in this study suffered from CMV disease . Both CD27CD8 and CD27CD28CD4 effector-type T-cell counts , known to be associated with CMV infection , were measured before transplantation and at 6 and 24 months after transplantation . Additionally , we determined both number and function of CMV-specific CD8 T cells at these time points . RESULTS : The number of total CD8 T cells , CD27CD8 T cells , and CD28CD4 T cells increased significantly after switch to therapy with P/ Q9UI08 but not after switch to P/ DB00091 or P/MPS . Specifically , CMV-specific CD8 T-cell counts significantly increased after switch to therapy with P/ Q9UI08 . Furthermore , the P42345 inhibitor sirolimus strongly inhibited alloresponses in vitro , whereas it did not affect CMV-specific responses . CONCLUSION : We observed a significant increase in ( CMV-specific ) effector-type CD8 and P01730 T-cell counts in everolimus-treated patients . These findings may at least in part explain the reported low incidence of CMV-related pathology in everolimus-treated patients . Two types of prostacyclin receptor coupling to stimulation of adenylate cyclase and phosphatidylinositol hydrolysis in a cultured mast cell line , BNu-2cl3 cells . DB01240 ( DB01240 ) -mediated signal transduction was examined in interleukin 3 ( P08700 ) -dependent BNu-2cl3 mast cells . DB01088 , a stable DB01240 analogue , induced the accumulation of intracellular DB02527 and IP3 , and an increase in the intracellular Ca2+ concentration . Pretreatment of the cells with a protein kinase C activator , 12-O-tetradecanoyl phorbol 13-acetate , suppressed the iloprost-induced IP3 accumulation and Ca2+ mobilization , but inversely potentiated the DB02527 accumulation , suggesting that neither of these signal transduction pathways of iloprosts is the result of a secondary effect of activation of the other . Removal of P08700 from the culture medium reduced the iloprost-induced IP3 accumulation and Ca2+ mobilization , while it had no effect on the iloprost-induced DB02527 accumulation at all . These results taken together suggest that BNu-2cl3 cells express two types of P43119 ; one couples to stimulation of adenylate cyclase , its expression being independent of P08700 , while the other couples to phosphatidylinositol hydrolysis , its expression being dependent on P08700 . P43119 induces P42224 and P40763 phosphorylations in human erythroleukemia cells : a mechanism requiring PTX-insensitive G proteins , P29323 and JNK . The ability of the human prostacyclin receptor ( hIP ) to regulate the activities of signal transducers and activators of transcription ( STATs ) has not yet been documented . In the present study , we have delineated the mechanism by which hIP induces P40763 phosphorylations in human erythroleukemia ( HEL ) cells . Stimulation of endogenous hIP by its specific agonist , cicaprost , resulted in P40763 Tyr705 and Ser727 phosphorylations in a time- and concentration-dependent manner . Cicaprost-induced P40763 Tyr705 and Ser727 phosphorylations were resistant to pertussis toxin ( PTX ) treatment , suggesting that these responses were mediated through PTX-insensitive G proteins . In addition , extracellular signal-regulated kinase ( P29323 ) and c-Jun N-terminal kinase ( JNK ) , but not p38 MAPK , were shown to be phosphorylated by cicaprost in a time- and concentration-dependent manner via PTX-insensitive G proteins . The levels of the interaction between P40763 , P29323 and JNK were enhanced by cicaprost treatment . The involvement of P04049 , Q02750 /2 and JNK in cicaprost-induced phosphorylations of P40763 was illustrated by the use of their selective inhibitors . In contrast , p38 MAPK did not appear to be required . Similar observations were obtained with P42224 upon stimulation by cicaprost . Taken together , these results demonstrate for the first time that hIP activation by cicaprost can lead to P42224 and P40763 phosphorylations via signaling pathways involving PTX-insensitive G proteins , P29323 and JNK . Induction of prostacyclin receptor expression in human erythroleukemia cells . We have identified both high-affinity ( KD = 36 +/- 3 nM ) and low-affinity ( KD = 2.1 +/- 0.8 microM ) prostacyclin ( DB01240 ) -receptor sites on human erythroleukemia ( HEL ) cells using the radiolabelled prostacyclin analogue . [3H]iloprost . The addition of the phorbol ester , TPA , to the culture medium caused a 5-10-fold increase in the number of both the low- and the high-affinity sites , without any change in their affinity constants . DB01088 stimulated HEL cell membrane adenylate cyclase activity 5-fold . This stimulation was potentiated in the presence of GTP , indicating a conventional P43119 -G2-adenylate cyclase system . HEL cells represent a source of prostacyclin receptor mRNA which may be of value in expression cloning of this receptor . Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster-human cell hybrid containing a derivative chromosome 5 [ der(5)t(4;5) ( 5qter ---- 5p15.1::4p15.1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21-q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions . [ DB00988 -beta-hydroxylaseaktivität im Plasma von Dialysepatienten ( author 's transl ) ] . Plasma dopamin-b-hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50.0 +/- 29.3 IU . There was was no significant difference between males ( 53.9 +/1 33.8 IU ) and females ( 47.4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0.01 ) decreased ( 32.5 % /- 17.6 IU ) , suggesting lowered sympathetic activity and/or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .