interacts_with DB09053?
[ DB09053 : A new drug of B-cell malignancies ] . DB09053 ( Imbruvica® ) is a first-in-class , orally administered once-daily , that inhibits B-cell antigen receptor signaling downstream of Bruton 's tyrosine kinase ( Q06187 ) . DB09053 has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed/refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed/refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression-free survival , response rate and overall survival in patients with relapsed/refractory CLL , including in those with del 17p . DB09053 had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B-cell malignancies . DB04873 ( SB 207266 ) , a selective Q13639 receptor antagonist , reduces serotonin potentiation of neurally-mediated contractile responses of human detrusor muscle . The aim of this study is to evaluate the potency of piboserod ( SB 207266 ) , a selective 5-HT(4) receptor antagonist , at inhibiting the 5-HT(4)-mediated potentiating effect of serotonin ( 5-HT ) on the neurally-mediated contractile responses of human detrusor strips to electrical field stimulations ( O43281 ) . Strips of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting tension of 500 mg and O43281 ( 20 Hz , 1 ms duration at 300 mA for 5 s ) was applied continuously at 1 min intervals . After stabilization of the O43281 -induced contractions , concentration-response curves to 5-HT ( 0.1 nM-100 microM ) were constructed in the absence or presence of 1 or 100 nM of piboserod . The experiments were performed in the presence of methysergide ( 1 microM ) and ondansetron ( 3 microM ) to block 5HT(1)/5HT(2) and 5-HT(3) receptors , respectively . 5-HT potentiated the contractile responses to O43281 of human bladder strips in a concentration-dependent manner , with a maximum mean of 60.0+/-19.9 % of the basal O43281 -evoked contractions . DB04873 did not modify the basal contractions but concentration-dependently antagonized the ability of 5-HT to enhance bladder strip contractions to O43281 . In presence of 1 and 100 nM of piboserod , the maximal 5-HT-induced potentiations were reduced to 45.0+/-7.9 and 38.7+/-8.7 % , respectively . A mean apparent antagonist dissociation constant value ( K(B) ) of 0.56+/-0.09 nM was determined . These data show the ability of piboserod to antagonize with high potency the enhancing properties of 5-HT on neurally-mediated contractions of isolated human bladder strips . Therefore , the 5-HT(4) receptor might represent an attractive pharmacological target for the treatment of overactive bladder . Inhibitors of P11274 signalling interrupt the survival signal mediated by the micro-environment in mantle cell lymphoma . Several studies provide evidences for mantle cell lymphoma ( Q8WXI8 ) cell survival relying on B-cell receptor ( P11274 ) -mediated signalling pathways , whereas the nature of this activation is unknown . Significant progress in Q8WXI8 treatment is achieved through therapies targeting P11274 -associated kinases , i.e. , DB09053 and Fostamatinib , inhibitors of Q06187 and P43405 , respectively . Our study addresses survival signals emanating from the P11274 or the tumour environment and how inhibiting P11274 signalling effectors might impact these survival signals . We found that Q06187 was constitutively activated and that P43405 phosphorylation was highly increased and sustained upon P11274 activation of primary Q8WXI8 cells . Moreover , Q8WXI8 cells from leukaemic patients secreted high amount of IL-1β , P05231 , P10145 and P13501 . Activation of the P11274 induced ( i ) cell survival , ( ii ) P40763 activation and ( iii ) increased autocrine secretion of IL-1β , P05231 , P10145 , P13501 , P22301 , TNFα and P15692 . Specific inhibition of Q06187 by DB09053 or P43405 by Fostamatinib ( R406 ) reversed these protective effects and decreased both basal and P11274 -induced autocrine cytokine secretions associated with P40763 phosphorylation . Interestingly , targeting Q06187 and P43405 prevented and inhibited P11274 -induced Q8WXI8 cell adhesion to human bone marrow stromal cells ( HMSCs ) in short- and long-term co-culture . We demonstrated that P11274 -induced survival relies on autocrine secretion of IL-1β , TNFα and P13501 that might facilitate adhesion of Q8WXI8 cells to HMSC . Treatment with DB09053 or Fostamatinib blocked the chemotactic signal thus increasing apoptosis . DB02701 pre-treatment ameliorates NAD(H) hyperoxidation and improves neuronal function after severe hypoxia . Prolonged hypoxia leads to irreversible loss of neuronal function and metabolic impairment of nicotinamide adenine dinucleotide recycling ( between NAD(+) and DB00157 ) immediately after reoxygenation , resulting in DB00157 hyperoxidation . We test whether the addition of nicotinamide ( to enhance NAD(+) levels ) or P09874 inhibition ( to prevent consumption of NAD(+) ) can be effective in improving either loss of neuronal function or hyperoxidation following severe hypoxic injury in hippocampal slices . After severe , prolonged hypoxia ( maintained for 3min after spreading depression ) there was hyperoxidation of DB00157 following reoxygenation , an increased soluble NAD(+)/ DB00157 ratio , loss of neuronal field excitatory post-synaptic potential ( fEPSP ) and decreased DB00171 content . DB02701 incubation ( 5mM ) 2h prior to hypoxia significantly increased total NAD(H) content , improved neuronal recovery , enhanced DB00171 content , and prevented DB00157 hyperoxidation . The nicotinamide-induced increase in total soluble NAD(H) was more significant in the cytosolic compartment than within mitochondria . Prolonged incubation with PJ-34 ( > 1h ) led to enhanced baseline DB00157 fluorescence prior to hypoxia , as well as improved neuronal recovery , DB00157 hyperoxidation and DB00171 content on recovery from severe hypoxia and reoxygenation . In this acute model of severe neuronal dysfunction prolonged incubation with either nicotinamide or PJ-34 prior to hypoxia improved recovery of neuronal function , enhanced DB00157 reduction and DB00171 content , but neither treatment restored function when administered during or after prolonged hypoxia and reoxygenation . [ P11511 inhibitors -- theoretical concept and present experiences in the treatment of endometriosis ] . The medical treatment of endometriosis needs to be optimized . Therapeutic management strategies of endometriosis-associated pain or recurrent disease is primarily aimed at downregulating the ovarian function or at antagonizing the effect of estrogen in ectopic endometrial implants . In this context , basic research is delivering powerful tools for the possible development of new , specific treatment modalities . Recently , aromatase overexpression has been detected in endometriotic tissue . P11511 ( p450arom ) is responsible for conversion of C19 androgens to estrogen in several human tissues . P11511 activity gives rise to local estrogen biosynthesis , which , in turn , stimulates prostaglandin E(2) production by upregulation of cyclooxygenase-2 ( P35354 ) , thus establishing a positive feedback cycle . Another abnormality in endometriosis , i. e. the deficiency in 17 beta-hydroxysteroiddehydrogenase type-II ( 17 beta-HSD-Type-II ) expression , impairs the inactivation of estradiol to estrone . In contrast to the eutopic endometrium , these molecular aberrations collectively favour accumulation of increasing amounts of local estradiol and prostaglandin E(2) in endometriosis . In several human cell lines , prostaglandin and estrogen concentrations are associated with proliferation , migration , angiogenesis , apoptosis resistance , and even invasiveness . Consequently , aromatase and P35354 are promising new therapeutic targets . In summary , specific aromatase inhibitors ( such as Letrozole , DB01217 or Exemestan ) or selective P35354 inhibitors ( e.g. Celecoxib , DB00533 ) are of great interest to be studied in clinical trials in premenopausal woman with endometriosis to extend the spectrum of currently available treatment options . Thrombin receptors and their antagonists : an update on the patent literature . IMPORTANCE OF THE FIELD : Thrombin plays a central role in cardiovascular inflammation . Most of the cellular responses to thrombin are mediated by cell surface protease-activated receptors ( PARs ) . Several preclinical studies indicate that PARs are potential targets for treating cardiovascular diseases such as thrombosis , atherosclerosis and restenosis . Among PARs , P25116 has emerged as an important therapeutic target . AREAS COVERED IN THIS REVIEW : This review covers recent advances in the development of thrombin receptors antagonists . It is focused on the search for P25116 antagonists as this is at the moment the most promising and attractive target . However , some early promising studies on PAR-3 and -4 antagonists are also reported . WHAT THE READER WILL GAIN : The review has been written in order to give to the reader hints and references that cover , in our opinion , the most interesting and/or promising approaches in this research field . TAKE HOME MESSAGE : Research on P25116 antagonists has finally led to good clinical candidates such as DB05692 ( Schering-Plough ) and E-5555 ( Eisai Co. ) . Clinical trials clearly demonstrate that development of PAR1 antagonists is not only possible but most likely will lead to development of antiplatelet drugs as well as of drugs useful for the treatment of inflammatory , proliferative and neurodegenerative diseases . Induction of lymphokine-activated cytotoxic T lymphocytes stimulated by dendritic cells and autologous tumor from a patient with gastric cancer and their effects in vitro . BACKGROUND/AIMS : The purpose of the study was to generate lymphokine-activated cytotoxic T lymphocytes stimulated by dendritic cells ( DC ) and autologous tumor from a patient with gastric cancer and to clarify their cytotoxic effects in vitro . METHODOLOGY : DC was induced by interleukin-4 ( P05112 ) and granulocyte-macrophage-colony-stimulating factor ( GM- P04141 ) from the peripheral blood mononuclear cells ( PBMC ) . Then , PBMC was incubated with mitomycin C-treated tumor cells and DC , and following that was activated with P60568 and anti-CD3 . Induction of DC and cytotoxic T cells ( CTL ) were confirmed by the analyses of the cell surface antigens , killing activities , and blocking tests . RESULTS : Induction of DC and cytotoxic T cells ( CTL ) was confirmed by the analyses of the cell surface antigens , killing activities , and blocking tests . In vitro study demonstrated that lymphokine-activated lymphocytes pulsed by DCs and autologous tumor contained the largest population of CTLs , the greatest production of P01579 , and the greatest Q06187 activity . CONCLUSIONS : Those results indicated that CTLs could be generated in vitro from a patient with gastric cancer more successfully by this method than by conventional methods , suggesting the possibility of a new immunotherapy for the treatment of gastric cancer . Proliferation of endothelial cell on polytetrafluoroethylene vascular graft materials carried P15692 gene plasmid . OBJECTIVE : To investigate whether vascular endothelial growth factor ( P15692 ) gene plasmid carried by polytetrafluoroethylene ( PTFE ) vascular graft materials could transfect endothelial cells ( ECs ) and promote their growth . METHODS : PTFE vascular graft materials carried with pCDI-hVEGF(121) , pCDI or pEGFP were incubated in DB03754 -buffer solution and the values of optical density of 260 nm at different time were plotted , then the DNA controlled release curve was made . ECs derived from human umbilical vein were seeded on the pCDI-hVEGF(121)/pCDI/pEGFP-PTFE materials or tissue culture plates , ECs numbers were counted and P15692 protein concentrations at different time were measured by enzyme-linked immunoadsorbent assay method . Green fluorescent protein ( GFP ) expression in ECs on pEGFP-PTFE materials was examined with fluorescence microscopy . RESULTS : The controlled release curve showed that the gene released from PTFE materials was rapid within 8 h , then slowed down and that the gene released continuously even after 72 h . At 24 , 72 and 120 h , ECs number and proliferation rate of pCDI-hVEGF(121)-PTFE materials were higher than those of pCDI or pEGFP-PTFE materials ( P < 0.05 ) . P15692 protein concentration of pCDI-hVEGF(121)-PTFE materials was higher than that of pCDI or pEGFP-PTFE materials at 6 , 24 , 72 and 120 h ( P < 0.01 ) . GFP expression in ECs on the pEGFP-PTFE materials could be detected by fluorescence microscopy . CONCLUSION : PTFE graft can be used as a carrier of P15692 gene plasmid , P15692 gene carried by PTFE can transfect ECs and promote ECs growth . 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 . Effect of non-selective , non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 selective inhibitors on the PFA-100 closure time . The place of cyclo-oxygenase ( P36551 ) -2 selective non-steroidal anti-inflammatory drugs ( NSAIDs ) in the peri-operative period remains under discussion . Due to the absence of P35354 in platelets , the risk of bleeding in patients who use selective NSAIDs is thought to be decreased . We studied the influence of aspirin , diclofenac , lornoxicam and rofecoxib on the in vitro bleeding time using the platelet function analyser ( PFA-100 ) . The PFA-100 simulates the process of platelet adhesion and aggregation after vascular injury in vitro . Measurements in 43 volunteers were performed at three time points : before , 3 h , and 12 h after oral ingestion of one of the randomly assigned study medications . DB00945 , diclofenac and lornoxicam had a significant effect on the in vitro closure time , while rofecoxib did not show this effect . This supports the use of P35354 selective drugs in the peri-operative period to minimise the risk of bleeding . Inhibition of cyclooxygenases 1 and 2 by the phospholipase-blocker , arachidonyl trifluoromethyl ketone . BACKGROUND AND PURPOSE : Arachidonyl trifluoromethyl ketone ( Q06187 ) is widely used as an inhibitor of cytosolic group IV phospholipase A(2) ( cPLA(2) ) and calcium-independent group VI phospholipase A(2) ( iPLA(2) ) . Q06187 thus reduces arachidonic acid ( AA ) substrate for cyclooxygenase ( P36551 ; also known as prostaglandin H synthase ) and attenuates prostaglandin ( PG ) synthesis . It has been shown previously , that Q06187 blocks thromboxane B(2) production induced by exogenous AA in human platelets . It remains , however , unknown whether Q06187 also directly modulates the activity of cyclooxygenase ( P36551 ) . EXPERIMENTAL APPROACH : Time courses for inhibition of P36551 by Q06187 was obtained using osteoblast-like MC3T3-E1 cells , with exogenous AA as substrate and the pure enzymes P23219 and P35354 . PGE(2) was measured by GC-MS . KEY RESULTS : Q06187 was a potent inhibitor of P23219 and P35354 with IC(50) values of 0.5 and 0.1 microM in MC3T3-E1 cells and of 1.7 and 2.6 microM using the pure enzymes . Inhibition was reversible , with slow- and tight-binding characteristics . The arachidonyl carbon chain was essential , as the saturated palmitoyl analogue had no effect . CONCLUSIONS AND IMPLICATIONS : Attenuation of PG synthesis by Q06187 is taken to be the consequence of PLA(2) inhibition and the findings of many studies are interpreted on that basis . If there are , however , alternative routes for AA liberation ( such as phospholipase C/diacyl glycerol lipase or phospholipase D ) , this interpretation can lead to false conclusions . As Q06187 is a widely used and important pharmacological tool in eicosanoid research , knowledge of its interactions with other major enzymes of the cascade is of considerable importance . A granulocytic population with rearranged immunogenotype in chronic myelocytic leukemia blast crisis and Philadelphia-chromosome-positive acute leukemia with cross-lineage nature . Two patients with chronic myelocytic leukemia ( CML ) mixed crisis and one with Philadelphia-chromosome-positive ( Ph1 + ) acute lymphoblastic leukemia ( ALL ) with cross-lineage nature had a considerable number of granulocytes with monoclonally rearranged immunogenotype . The gene configurations of immunoglobulin heavy chain ( IgH ) , T-cell receptor beta chain ( TCR beta ) , and gamma chain ( TCR gamma ) in the granulocytic cells were identical to those in the blasts , indicating that both the blasts and the granulocytes were derived from common leukemic progenitors with the IgH gene rearrangements . In a colony assay of cells from in the Ph1 + ALL patient , the leukemic cells showed the potential to differentiate into granulocytes in the presence of either granulocyte-macrophage colony-stimulating factor ( GM- P04141 ) or granulocyte- P04141 ( DB00099 ) . Interleukin 7 ( P13232 ) exerted synergistic effects on colony and cluster formation in cultures with these cytokines . Further , P08700 , GM- P04141 , and Q99062 gene expression was found in the leukemic cells . Our findings indicate that the Ph1 + common progenitors in these three patients preserved the potential for granulocytic differentiation even after the occurrence of the Ig ( and TCR ) gene rearrangements as the first genomic event in lymphocyte differentiation . The phenomenon of cross-lineage in leukemic cells , at least in Ph1 + leukemia , can be considered to demonstrate the potential of leukemic progenitors to differentiate in multiple directions . Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein-Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy/hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 -32765 , recently renamed DB09053 , has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors . Unmet needs in ovarian cancer : dividing histologic subtypes to exploit novel targets and pathways . Ovarian cancer ( OC ) carries a poor prognosis ; however , accumulating molecular data for the major histologic subtypes may lead to subtype-specific treatment paradigms . The present review discusses what is currently understood about the major molecular and histologic subgroups of OC . Areas specifically addressed include hormonal pathways , tumor protein p53 ( P04637 ) and AT rich interactive domain 1A ( SWI-like ; O14497 ) mutation , and the breast cancer 1/2 , early onset ( P38398 /2 ) mutation/poly ( ADP-ribose ) polymerase 1 ( P09874 ) , phosphatidylinositol-4,5-bisphosphate 3- kinase , catalytic subunit alpha ( PI3KCA ) /v-akt murine thymoma viral oncogene homolog 1 ( P31749 ) /mechanistic target of rapamycin ( P42345 ) , and mitogen-activated protein kinase kinase 1 and 2 ( Q02750 /2 ) pathways . This molecular characterization only very recently has impacted clinical research efforts to develop targeted therapies for both common and rare OC subtypes . This targeted strategy is illustrated by ongoing low-grade serous , clear-cell , and mucinous subtypeexclusive clinical trials evaluating agents based on common molecular abnormalities among patients ( i.e. , P09874 inhibitors for P38398 /2 mutation-positive OC ) . This report also reviews the published clinical trial efficacy data for investigational therapies within specific subgroups , and summarizes the currently active clinical trials evaluating these agents ( e.g. , temsirolimus , sunitinib , P04637 immunotherapy , olaparib , iniparib , veliparib ) . Available data suggest that histologic profiles and molecular tumor markers are valuable resources for identifying patients who may benefit from these specific agents , and future research should focus on targeting molecules and signaling pathways that are most commonly altered in each subtype . Phenotypic analysis of conditionally immortalized cells isolated from the Q06187 model of ARPKD . To study the pathophysiology of autosomal recessive polycystic kidney disease ( ARPKD ) , we sought to develop conditionally immortalized control and cystic murine collecting tubule ( CT ) cell lines . CT cells were isolated from intercross breedings between Q06187 mice ( bpk(+/-) ) , a murine model of ARPKD , and the Immorto mice ( H-2K(b)-ts-A58(+/+) ) . Second-generation outbred offspring ( Q06187 x Immorto ) homozygous for the Q06187 mutation ( bpk(-/-) ; Im(+/+/-) ; cystic Q06187 /H-2K(b)-ts-A58 ) , were phenotypically indistinguishable from inbred cystic Q06187 animals ( bpk(-/-) ) . Cystic Q06187 /H-2K(b)-ts-A58 mice developed biliary ductal ectasia and massively enlarged kidneys , leading to renal failure and death by postnatal day 24 . Principal cells ( PC ) were isolated from outbred cystic and noncystic Q06187 /H-2K(b)-ts-A58 littermates at specific developmental stages . Epithelial monolayers were under nonpermissive conditions for markers of epithelial cell polarity and PC function . Cystic and noncystic cells displayed several properties characteristic of PCs in vivo , including amiloride-sensitive sodium transport and aquaporin 2 expression . Cystic cells exhibited apical epidermal growth factor receptor ( P00533 ) mislocalization but normal expression of ZO-1 and P12830 . Hence , these cell lines retain the requisite characteristics of PCs , and cystic Q06187 /H-2K(b)-ts-A58 PCs retained the abnormal P00533 membrane expression characteristic of ARPKD . These cell lines represent important new reagents for studying the pathogenesis of ARPKD . Phosphodiesterase 4B mediates extracellular signal-regulated kinase-dependent up-regulation of mucin P98088 protein by Streptococcus pneumoniae by inhibiting DB02527 -protein kinase A-dependent P28562 phosphatase pathway . Otitis media ( OM ) is the most common childhood bacterial infection and the major cause of conductive hearing loss in children . Mucus overproduction is a hallmark of OM . Streptococcus pneumoniae is the most common gram-positive bacterial pathogen causing OM . Among many mucin genes , P98088 has been found to be greatly up-regulated in the middle ear mucosa of human patients with OM . We previously reported that S. pneumoniae up-regulates P98088 expression in a MAPK P29323 -dependent manner . We also found that MAPK phosphatase-1 ( P28562 ) negatively regulates S. pneumoniae-induced P29323 -dependent P98088 up-regulation . Therapeutic strategies for up-regulating the expression of negative regulators such as P28562 may have significant therapeutic potential for treating mucus overproduction in OM . However , the underlying molecular mechanism by which P28562 expression is negatively regulated during S. pneumoniae infection is unknown . In this study we show that phosphodiesterase 4B ( Q07343 ) mediates S. pneumoniae-induced P98088 up-regulation by inhibiting the expression of a negative regulator P28562 , which in turn leads to enhanced MAPK P29323 activation and subsequent up-regulation of P98088 . Q07343 inhibits P28562 expression in a DB02527 -PKA-dependent manner . DB05876 -specific inhibitor rolipram inhibits S. pneumoniae-induced P98088 up-regulation both in vitro and in vivo . Moreover , we show that Q07343 plays a critical role in P98088 induction . Finally , topical and post-infection administration of rolipram into the middle ear potently inhibited S. pneumoniae-induced P98088 up-regulation . Collectively , these data demonstrate that Q07343 mediates P29323 -dependent up-regulation of mucin P98088 by S. pneumoniae by inhibiting DB02527 -PKA-dependent P28562 pathway . This study may lead to novel therapeutic strategy for inhibiting mucus overproduction . Regulation of phosphodiesterase-4 ( DB05876 ) expression in mouse brain by repeated antidepressant treatment : comparison with rolipram . Cyclic nucleotide phosphodiesterase-4 ( DB05876 ) is a component of signaling pathways involved in the mediation of antidepressant activity . Of the four DB05876 subtypes , Q08499 appears to be of particular importance , given the finding that Q08499 -deficient mice exhibit an antidepressant-like behavioral phenotype . In mouse hippocampus and cerebral cortex , the effects of repeated treatment with the antidepressants desipramine and fluoxetine or the DB05876 inhibitor rolipram on the expression of Q08499 was compared to that of P27815 and Q07343 , the other two subtypes expressed in the brain . Expression of Q08499 was increased by all drugs tested , with the exception of desipramine in hippocampus . By contrast , these treatments affected P27815 and Q07343 expression differentially . In hippocampus , antidepressants increased P27815 and decreased Q07343 , whereas ROL decreased P27815 and did not change Q07343 . In cerebral cortex , antidepressants increased P27815 and did not change Q07343 , whereas ROL did not change P27815 and increased Q07343 . 3H- DB01954 binding was increased in cytosolic , but not in membrane , fractions of cerebral cortex by all drugs tested ; there were no changes observed in hippocampus . Overall , the present results suggest some species-dependence of the regulation of DB05876 subtypes , based on data obtained previously using rats . They also suggest that the Q08499 subtype may be of particular importance as an antidepressant target in that it is regulated by repeated treatment with both norepinephrine and serotonin reuptake inhibitors as well as by the DB05876 inhibitor rolipram , drugs that produce antidepressant effects via different neuropharmacological mechanisms . Ras-dependent P29323 activation by the human G(s)-coupled serotonin receptors Q13639 (b) and P34969 (a) . Receptor tyrosine kinases activate mitogen-activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein-coupled receptors coupling to G(i) and G(q) . The human G protein-coupled serotonin receptors 5-HT(4(b)) and 5-HT(7(a)) couple to G(s) and elevate intracellular DB02527 . Certain G(s)-coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A- and Rap1-dependent pathway . We report the activation of the extracellular signal-regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5-HT(4(b)) and 5-HT(7(a)) in COS-7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5-HT-induced activation of P27361 /2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 /2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5-HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5-HT-mediated activation of P27361 /2 , the activation of P27361 /2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 /2 activation was reduced in the presence of " dominant negative " Raf1 ( RafS621A ) and slightly reduced by dominant negative B-Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 /2 through the human G(s)-coupled serotonin receptors 5-HT(4(b)) and 5-HT(7(a)) in HEK293 cells is dependent on Ras , but independent of Rap1 . Antagonism of Q9GZP0 by human antibody DB05139 prevents renal scarring in experimental glomerulonephritis . Glomerular mesangial cell proliferation and/or matrix accumulation characterizes many progressive renal diseases . Q9GZP0 was identified recently as a novel mediator of mesangial cell proliferation in vitro and in vivo . This study investigated the long-term consequences of Q9GZP0 inhibition in vivo . Rats with progressive mesangioproliferative glomerulonephritis ( uninephrectomy plus anti-Thy-1.1 antibody ) received the Q9GZP0 -neutralizing , fully human mAb DB05139 on days 3 , 10 , and 17 after disease induction . Glomerular mesangioproliferative changes on day 10 were significantly reduced by anti- Q9GZP0 treatment as compared with control antibody . Eight weeks after disease induction , anti- Q9GZP0 therapy significantly ameliorated focal segmental glomerulosclerosis , podocyte damage ( de novo desmin expression ) , tubulointerstitial damage , and fibrosis as well as the accumulation of renal interstitial matrix including type III collagen and fibronectin . Treatment with anti- Q9GZP0 also reduced the cortical infiltration of monocytes/macrophages on day 56 , possibly related to lower renal cortical complement activation ( C5b-9 deposition ) and/or reduced epithelial-to-mesenchymal transition ( preserved cortical expression of P12830 and reduced expression of vimentin and alpha-smooth muscle actin ) . In conclusion , these data provide evidence for a causal role of Q9GZP0 in the pathogenesis of renal scarring and point to a new therapeutic approach to progressive mesangioproliferative renal disease . Thrombin regulates the function of human blood dendritic cells . Thrombin is the key enzyme in the coagulation cascade and activates endothelial cells , neutrophils and monocytes via protease-activated receptors ( PARs ) . At the inflammatory site , immune cells have an opportunity to encounter thrombin . However little is known about the effect of thrombin for dendritic cells ( DC ) , which are efficient antigen-presenting cells and play important roles in initiating and regulating immune responses . The present study revealed that thrombin has the ability to stimulate blood DC . Plasmacytoid DC ( P20941 ) and myeloid DC ( MDC ) isolated from PBMC expressed P25116 and released P13500 , P22301 , and IL-12 after thrombin stimulation . Unlike blood DC , monocyte-derived DC ( MoDC ) , differentiated in vitro did not express P25116 and were unresponsive to thrombin . Effects of thrombin on blood DC were significantly diminished by the addition of anti- P25116 Ab or hirudin , serine protease inhibitor . Moreover , thrombin induced HLA-DR and P42081 expression on DC and the thrombin-treated DC induced allogenic T cell proliferation . These findings indicate that thrombin plays a role in the regulation of blood DC functions .