MH_dev_200

Synergy between vitamin D ( 3 ) and Toll-like receptor agonists regulates human dendritic cell response during maturation . Human dendritic cells ( DC ) can be differentiated from blood monocytes in the presence of GM - P04141 REA and P05112 REA and matured by lipopolysaccharide ( LPS ) . DB00169 MEN inhibits the maturation of human DC measured by changes in surface expression of HLA-DR , P08571 REA , P25942 REA , P33681 REA , Q01151 , and P42081 REA . We here examine the function of vitamin D3 during DC maturation . One of the earliest changes to LPS-induced maturation was an increase in Q01151 expression . DB00169 MEN inhibited the increase in expression of HLA-DR , P25942 REA , P33681 REA , Q01151 , and P42081 REA and the decrease in expression of P08571 REA , which was paralleled morphologically by vitamin D3 - induced inhibition of dendritic cell differentiation . DB00169 MEN acted in synergy with the TLR agonists LPS and peptidoglycan ( Q9UQ90 ) in inducing P05231 REA , P10145 REA , and P22301 REA , whereas vitamin D3 completely inhibited LPS-induced secretion of IL - 12 . The synergy occurred at concentrations where neither vitamin D3 nor the TLR agonists alone induced measurable cytokine secretion . Both LPS and Q9UQ90 enhanced the level of the vitamin D3 receptor ( P11473 REA ) . Taken together , these data demonstrated that vitamin D3 and TLR agonists acted in synergy to alter secretion of cytokines from human DC in a direction that may provide an anti-inflammatory environment .

Ex vivo binding of flibanserin to serotonin P08908 REA and 5 - Q13049 REA receptors . DB04908 MENMAX DB04908 MEN has been reported to be an agonist at P08908 REA - receptors and an antagonist at 5 - Q13049 REA receptors , with higher affinity for P08908 REA 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 REA antagonism at doses ( 4-5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 REA receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 REA and 5 - Q13049 REA 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 REA and 5 - Q13049 REA receptors , respectively . DB04908 MEN 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 .

Andrographis paniculata extract ( DB05767 MEN ) for active ulcerative colitis . OBJECTIVES : Andrographis paniculata has in vitro inhibitory activity against P01375 REA - α , IL - 1β and NF-κB . A pilot study of A . paniculata extract ( DB05767 MEN ) suggested similar efficacy to mesalamine for ulcerative colitis . METHODS : A randomized , double-blind , placebo-controlled trial evaluated the efficacy of A . paniculata extract ( DB05767 MEN ) in 224 adults with mild-to-moderate ulcerative colitis . Patients were randomized to A . paniculata extract ( DB05767 MEN ) 1,200 mg or 1,800 mg daily or placebo for 8 weeks . RESULTS : In total , 45 and 60 % of patients receiving A . paniculata 1,200 mg and 1,800 mg daily , respectively , were in clinical response at week 8 , compared with 40 % of those who received placebo ( P= 0.5924 for 1,200 mg vs . placebo and P= 0.0183 for 1,800 mg vs . placebo ) . In all , 34 and 38 % of patients receiving A . paniculata 1,200 mg and 1,800 mg daily , respectively , were in clinical remission at week 8 , compared with 25 % of those who received placebo ( P= 0.2582 for 1,200 mg vs . placebo and P= 0.1011 for 1,800 mg vs . placebo ) . Adverse events developed in 60 and 53 % of patients in the A . paniculata 1,200 mg and 1,800 mg daily groups , respectively , and 60 % in the placebo group . CONCLUSIONS : Patients with mildly to moderately active ulcerative colitis treated with A . paniculata extract ( DB05767 MEN ) at a dose of 1,800 mg daily were more likely to achieve clinical response than those receiving placebo .

[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 REA inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non-lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) DB08816 SUB is especially more effective in intermediate-and high-risk non-ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 REA ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non-invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 REA inhibitor therapy for patients undergoing invasive strategy .

DB08816 SUB reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 REA receptor antagonists have been reported to exert anti-inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 REA receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild-type C57BL / 6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg / kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet-neutrophil aggregates , neutrophil activation and P29965 REA expression on platelets . CLP-induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor-treated animals . Moreover , ticagrelor abolished CLP-provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet-neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 REA in septic mice . Our data indicate that ticagrelor can reduce CLP-induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis .

The anti - P33681 REA primatized monoclonal antibody , galiximab , is well-tolerated but has limited activity in relapsed Hodgkin lymphoma : Cancer and Leukemia Group B 50602 ( Alliance ) . Relapsed Hodgkin lymphoma remains a clinical challenge , with few non-cytotoxic treatment options . P33681 REA is a surface antigen that normally functions as a co-stimulatory molecule but is aberrantly and uniformly expressed on Reed-Sternberg cells . DB04901 MEN is a primatized monoclonal antibody against P33681 REA , with a favorable toxicity profile demonstrated in other lymphomas . Cancer and Leukemia Group B ( CALGB ) 50602 ( Alliance ) tested single-agent galiximab in a highly refractory group of patients with Hodgkin lymphoma ( median 3 prior regimens , 83 % failing after prior stem cell transplant ) to determine the efficacy . The overall response rate was 10.3 % and the median progression-free survival was 1.6 months . DB04901 MEN was well-tolerated , with minimal grade 3 or 4 toxicities . Despite this preclinical rationale , single-agent galiximab had limited activity in heavily pretreated Hodgkin lymphoma .

P2Y receptor antagonists in thrombosis . The dual role of P47900 REA and Q9H244 REA receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , DB08816 SUB and prasugrel ) , all target the Q9H244 REA receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 REA receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas DB08816 SUB is in clinical development as an orally active agent .

DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor . DB00171 and ADP activate functionally distinct G protein-coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide-specific P2Y receptors on cord blood-derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP-specific P47900 REA , Q9H244 REA , and Q9BPV8 receptors ; the DB00171 / UTP-specific P41231 REA receptor ; and the DB00171 - selective Q96G91 REA receptor . ADP ( 0.05- 50 muM ) induced calcium flux that was completely blocked by a P47900 REA receptor-selective antagonist and was not cross-desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 REA and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 REA - and Q9H244 REA - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 REA in response to the O60603 REA ligand , peptidoglycan , and blocked the production of P01375 REA , P10145 REA , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 ' - O - ( 3 - thiotriphosphate ) and 2 ' , 3 ' - O - ( 4 - benzoyl-benzoyl ) adenosine 5 ' - triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 ' - O - ( 3 - thiotriphosphate ) , and 2 ' , 3 ' - O - ( 4 - benzoyl-benzoyl ) adenosine 5 ' - triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up-regulated the expression of inducible DB02527 early repressor , a CREB-dependent inhibitor of cytokine transcription . Human MCs thus express several ADP-selective P2Y receptors and at least one G ( s ) - coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC-dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .

The use of the VerifyNow Q9H244 REA point-of-care device to monitor platelet function across a range of Q9H244 REA inhibition levels following prasugrel and clopidogrel administration . Variability in response to antiplatelet agents has prompted the development of point-of-care ( POC ) technology . In this study , we compared the VerifyNow Q9H244 REA ( VN - Q9H244 REA ) POC device with light transmission aggregometry ( P01374 REA ) in subjects switched directly from clopidogrel to prasugrel . Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose ( LD ) followed by a 75 mg / d maintenance dose ( MD ) for 10 days . Subjects were then switched to a prasugrel 60 mg LD and then 10 mg / d MD for 10 days ( n = 16 ) , or to a prasugrel 10 mg / d MD for 11 days ( n = 19 ) . Platelet function was measured by P01374 REA and VN - Q9H244 REA at baseline and after dosing . DB00758 600 mg LD / 75 mg MD treatment led to a reduction in P2Y ( 12 ) reaction units ( PRU ) from baseline . A switch from clopidogrel MD to prasugrel 60 mg LD / 10 mg MD produced an immediate decrease in PRU , while a switch to prasugrel 10 mg MD resulted in a more gradual decline . Consistent with the reduction in PRU , device-reported percent inhibition increased during both clopidogrel and prasugrel regimens . Inhibition of platelet aggregation as measured by P01374 REA showed a very similar pattern to that found with VN - Q9H244 REA measurement , irrespective of treatment regimens . The dynamic range of VN - Q9H244 REA appeared to be narrower than that of P01374 REA . With two different thienopyridines , the VN - Q9H244 REA device , within a somewhat more limited range , reflected the overall magnitude of change in aggregation response determined by P01374 REA . The determination of the clinical utility of such POC devices will require their use in clinical outcome studies .

Selective elimination of a chemoresistant side population of B-CLL cells by cytotoxic T lymphocytes in subjects receiving an autologous hCD 40L / P60568 REA tumor vaccine . Side-population ( SP ) analysis identifies precursor cells in normal and malignant tissues . Cells with this phenotype have increased resistance to many cytotoxic agents , and may represent a primary drug-resistant population in malignant diseases . To discover whether drug-resistant malignant SP cells are nonetheless sensitive to immune-mediated killing , we first established the presence of a malignant P06127 ( + ) P15391 REA ( + ) SP subset in the blood of 18/21 subjects with B-cell chronic lymphocytic leukemia ( B-CLL ) . We examined the fate of these cells in six of these individuals who received autologous human P29965 REA and interleukin - 2 ( hCD 40L / P60568 REA ) gene-modified tumor cells as part of a tumor vaccine study . Vaccinated patients showed an increase in B-CLL-reactive T cells followed by a corresponding decline in circulating P06127 ( + ) P15391 REA ( + ) SP cells . T-cell lines and clones generated from vaccinated patients specifically recognized B-CLL SP tumor cells . Elimination of SP cells is likely triggered by their increased expression of target antigens , such as receptor for hyaluronan-mediated motility ( O75330 REA ) , after stimulation of the malignant cells by hCD 40L , as CD8 ( + ) O75330 REA - specific T cells could be detected in the peripheral blood of immunized patients and were associated with the decline in B-CLL SP cells . Hence , malignant B cells with a primary drug-resistant phenotype can be targeted by T - cell-mediated effector activity after immunization of human subjects .

Inhibition of neuronal nitric oxide reduces anxiety-like responses to pair housing . Many psychological disorders are characterized by anxiety and alterations in social interactions . Recent studies demonstrate that the chemical messenger nitric oxide ( NO ) can regulate both anxiety and social behaviours . We tested whether an enzyme that produces NO in the brain , neuronal nitric oxide synthase ( P29475 REA ) , serves as an interface between social interactions and anxiety-like behaviour . Several investigators have observed that mice increase anxiety-like responses in the elevated plus-maze after pair housing . P29475 REA gene deletion and DB01997 MEN were used to inhibit the production of neuronal NO . Similar to previous studies , pair housing reduced open arm exploration in the elevated plus-maze . Pair housing also increased corticotropin-releasing hormone ( P06850 REA ) immunoreactive cells in the paraventricular nucleus ( PVN ) of the hypothalamus . Inhibition of NO production increased open arm exploration in pair-housed mice but decreased open arm exploration in individually housed mice . These results suggest that the effect of P29475 REA inhibition on anxiety-like responses is context dependent and that behavioural responses to social housing are altered after P29475 REA inhibition . This research suggests that NO may play an important role in mediating the effect social interactions have on anxiety .

P22309 REA * 28 is associated with greater decrease in serum K ⁺ levels following oral intake of procaterol . BACKGROUND AND OBJECTIVE : DB01366 MEN is a potent β2 - agonist frequently used for the management of asthma and chronic obstructive pulmonary disease . The efficacy and adverse effects of β2 - agonists are heterogeneous in individual patients , which may be partly caused by genetic variations in metabolizing enzymes and receptor molecules . The present study was designed to analyze the relationship between gene polymorphisms and physiological effects of procaterol in healthy subjects . METHODS : Ninety-two non-smoking healthy volunteers were given 1 µg / kg body weight ( max 50 µg ) of procaterol as a dry syrup preparation , and the serum concentrations of procaterol , serum K ( + ) , and the physical responses were monitored for 240 min . We genotyped β2 - adrenergic receptor ( P07550 REA ) ( Arg 16Gly and Gln 27Glu ) , cytochrome P450 3A4 ( rs2246709 , rs4646437 ) , and uridine diphosphate glucuronosyltransferase 1A1 ( P22309 REA ) ( rs4148323 [ allele A , * 6 ] , rs12479045 , rs4148328 , rs4663971 , rs12052787 , rs4148329 , A ( TA ) 6/7 TAA [ seven-repeat allele , * 28 ] ) . DB01366 MEN concentrations in serum were measured by liquid chromatography-tandem mass spectrometry . RESULTS : No gene polymorphisms affected serum procaterol concentrations . Meanwhile , overall serum K ( + ) level changes were significantly lower in carriers of P22309 REA * 28 than in non-carriers after correcting for strong effects of serum procaterol concentrations and baseline K ( + ) levels . No other polymorphisms were associated with serum K ( + ) levels . None of polymorphisms of P07550 REA were associated with any physical responses . CONCLUSION : The present study indicates that significant hypokalemia may occur in carriers of P22309 REA * 28 by systemic administration of procaterol and potentially by other β2 - agonists metabolized in the liver .

( N ) - methanocarba - 2MeSADP ( MRS 2365 ) is a subtype-specific agonist that induces rapid desensitization of the P47900 REA receptor of human platelets . DB00640 diphosphate ( ADP ) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq-coupled P47900 REA receptor and the Gi-coupled Q9H244 REA receptor . We recently described the synthesis and P47900 REA receptor-specific agonist activity of ( N ) - methanocarba - 2MeSADP ( MRS 2365 ) . Consequences of selective activation of the P47900 REA receptor by MRS 2365 have been further examined in human platelets . Whereas MRS 2365 alone only induced shape change , addition of MRS 2365 following epinephrine treatment , which activates the Gi / z-linked , alpha 2A - adrenergic receptor , resulted in sustained aggregation that was indistinguishable from that observed with ADP . Conversely , the platelet shape change promoted by ADP in the presence of the P08514 REA / IIIa antagonist eptifibatide was similar to that promoted by MRS 2365 . Preaddition of the high affinity P47900 REA receptor antagonist MRS 2500 inhibited the effect of MRS 2365 , whereas addition of MRS 2500 subsequent to MRS 2365 reversed the MRS 2365 - induced shape change . Preactivation of the P47900 REA receptor with MRS 2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20 - fold rightward shift in the concentration effect curve of ADP . This inhibitory effect of P47900 REA receptor activation was dependent on the concentration of MRS 2365 ( EC50 = 34 nm ) . The inhibitory effect of preincubation with MRS 2365 was circumvented by activation of the Gq-coupled 5 - Q13049 REA receptor suggesting that MRS 2365 induces loss of the ADP response as a consequence of desensitization of the Gq-coupled P47900 REA receptor . The time course of MRS 2365 - induced loss of aggregation response to epinephrine was similar to that observed with ADP . These results further demonstrate the P47900 REA receptor selectivity of MRS 2365 and illustrate the occurrence of agonist-induced desensitization of the P47900 REA receptor of human platelets studied in the absence of Q9H244 REA receptor activation .

DB08816 SUB increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 REA ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : DB08816 SUB is a direct-acting Q9H244 REA - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non-platelet-directed properties . Animal and in vitro models suggested that the " pleiotropic " properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 REA was measured by liquid chromatography . To assess the mechanism of P25054 REA variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 REA - adenosine diphosphate receptor blockade was assessed by the vasodilator-stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 REA than patients receiving clopidogrel ( 1.5 μM [ interquartile range : 0.98 to 1.7 μM ] vs . 0.68 μM [ interquartile range : 0.49 to 0.78 μM ] ; p < 0.01 ) . The P25054 REA was not correlated with vasodilator-stimulated phosphoprotein ( p = 0.16 ) . Serum-containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0.01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0.1 ) . DB08816 SUB and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : DB08816 SUB increases P25054 REA in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .

Purinergic receptor ligands stimulate pro-opiomelanocortin gene expression in AtT - 20 pituitary corticotroph cells . Although recent studies have suggested that purinergic receptors are expressed in the anterior pituitary gland , their involvement in the regulation of pituitary hormone gene expression is not completely understood . In the present study , we examined the expression of purinergic receptors and the effects of purinergic receptor ligands on pro-opiomelanocortin ( P01189 REA ) gene expression , in AtT 20 mouse corticotroph cells . We identified the expression of most of the purinergic receptor subtypes ( A1 , A2 , P51575 REA , 3-7 , P47900 REA , 2 , 4 ) mRNAs , analysed by the reverse transcriptase-polymerase chain reaction . We also found that adenosine and DB00171 , two representative and endogenous agonists of A1 - 3 and P2X / P2Y receptors , respectively , stimulated the 5 ' - promoter activity of the P01189 REA gene in a dose - and time-related manner . When these ligands were simultaneously used with corticotrophin-releasing hormone ( P06850 REA ) , effects that were more than additive were observed , suggesting an enhancing role of these compounds in P06850 REA - mediated adrenocorticotrophic hormone ( DB01285 ) synthesis . These ligands also stimulated the expression of transcription factors involved in the regulation of the P01189 REA gene , but did not enhance DB01285 secretion . Finally , the positive effect of adenosine as well as P06850 REA was completely inhibited by the protein kinase A inhibitor H89 , whereas that of DB00171 was not influenced , indicating that different intracellular signalling pathways mediate these effects . Altogether , our results suggest a stimulatory role for these purinergic receptor ligands in the regulation of P01189 REA gene expression in corticotroph cells . Because adenosine and DB00171 are known to be produced within the pituitary gland , it is possible they may be acting in an autocrine / paracrine fashion .

Purinergic receptors involved in the immunomodulatory effects of DB00171 in human blood . We recently showed that the physiological compound DB00171 simultaneously inhibited P01375 REA and stimulated P22301 REA release in LPS-PHA stimulated blood . The purpose of the present study was to determine the mechanism involved in the concerted modulatory effect of DB00171 on P01375 REA and P22301 REA . Incubation of blood with DB00171 in the presence of selective P2 receptor antagonists showed that the stimulatory effect of DB00171 on P22301 REA release was completely annihilated by both 2 - MeSAMP ( a Q9H244 REA / 13 receptor antagonist ) and PSB - 0413 ( a Q9H244 REA receptor antagonist ) . On the other hand , the inhibitory effect of DB00171 on P01375 REA release was completely reversed by 5 ' - P30566 REA ( a Q96G91 REA receptor antagonist ) as well as by H - 89 , an inhibitor of DB02527 - activated PKA . The concerted inhibition by DB00171 of P01375 REA release via Q96G91 REA activation and stimulation of P22301 REA release via Q9H244 REA activation implicates a novel approach towards immunomodulation by altering the balance among pro - and anti-inflammatory cytokines .

Human monocyte derived dendritic cells express functional P2X and P2Y receptors as well as ecto-nucleotidases . We investigated the expression and function of P2 receptors and ecto-nucleotidases on human monocyte derived dendritic cells ( DC ) . In addition we analyzed the effect of extracellular DB00171 on the maturation of DC . By RT-PCR , DC were found to express mRNA for several P2X ( P51575 REA , Q99571 REA , Q93086 REA , Q99572 REA ) and P2Y ( P47900 REA , P41231 REA , P51582 REA , P43657 REA , Q15077 REA , O00398 REA , Q96G91 REA ) receptors . As shown by FURA - 2 measurement , triggering of P2 receptors resulted in an increase in free intracellular Ca2 + . In combination with P01375 REA - alpha , DB00171 increased the expression of the DC surface markers P33681 REA , Q01151 and P42081 REA indicating a maturation promoting effect . DC expressed the ecto-apyrase P49961 REA and the ecto - 5 ' - nucleotidase CD73 as demonstrated by RT-PCR . Extracellular DB00171 was rapidly hydrolyzed by these ecto-enzymes as shown by separation of 3H - labeled DB00171 metabolites using a thin layer technique . These data suggest that DB00171 acts as a costimulatory factor on DC maturation .

Pharmacogenetic pathway analysis of irinotecan . DB00762 , a chemotherapeutic agent against various solid tumors , is a prodrug requiring activation to SN - 38 . DB00762 ' s complex pharmacokinetics potentially allow for many genetic sources of variability . We explored relationships between pharmacokinetic pathways and polymorphisms in genes associated with irinotecan ' s metabolism and transport . We fitted a seven-compartment pharmacokinetic model with enterohepatic recirculation ( EHR ) to concentrations of irinotecan and metabolites SN - 38 , SN - 38 glucuronide ( SN - 38G ) , and aminopentanoic acid ( P25054 REA ) . Principal component analysis ( DB11245 ) of patient-specific parameter estimates produced measures interpretable along pathways . Nine principal components provided good characterization of the overall variation . Polymorphisms in genes P22309 REA , Q9HAW7 , and O60656 REA had strong associations with a component corresponding to the irinotecan-to-SN - 38 pathway and SN - 38 recirculation and to a component relating to SN - 38 - to-SN - 38G conversion and elimination of SN - 38G . The component characterizing irinotecan ' s compartments was associated with HNF 1alpha and Q92887 REA polymorphisms . The exploratory analysis with DB11245 in this pharmacogenetic analysis was able to identify known associations and may have allowed identification of previously uncharacterized functional polymorphisms .

Preexisting antigen-specific immune responses are modulated by oral KLH feeding in humans . Oral tolerance is the antigen-specific inhibition of a systemic immune response after oral antigen uptake and well established in animal models . We recently showed that DB05299 MEN ( KLH ) feeding modulates subsequently induced systemic immune responses in humans as well . In the present study , we investigated whether oral KLH can also modulate preexisting antigen-specific systemic B - and T-cell responses . We induced delayed-type hypersensitivity ( DTH ) reactions as well as systemic KLH-specific B - and T-cell responses by subcutaneous KLH injections . Subsequent oral KLH administration decreased the small proportion of antigen-specific P01730 REA ( + ) T cells positive for the cytokine Q16552 REA at the end of the feeding regimen even further . After reimmunization , there was no difference in DTH reactions and the KLH-specific B-cell responses , but KLH-fed volunteers had an increased proportion of antigen-specific P01730 REA ( + ) T cells positive for P22301 REA and a reduced proportion of antigen-specific P01730 REA ( + ) T cells positive for the skin-homing receptor cutaneous lymphocyte antigen and P60568 REA and IFN-γ . Taken together , oral KLH can modulate a preexisting systemic KLH-specific immune response . These results suggest that feeding antigen may offer therapeutic strategies for the suppression of unwanted immune reactions in humans .

DB08818 MEN and cell locomotion . DB08818 MEN ( HA ) , a glycosaminoglycan , has long been implicated in cell locomotion . We have shown that HA production regulates the locomotion of H-ras-transformed cells . This autocrine motility mechanism is mediated by a novel HA receptor termed O75330 REA , an acronym for Receptor for HA Mediated Motility . HA : O75330 REA interactions regulate directional locomotion of tumor cells and result in enhanced protein tyrosine phosphorylation that may be a critical messenger mechanism for initiation of locomotion .

Pharmacological characterization of 3 - [ 3 - tert-butylsulfanyl - 1 - [ 4 - ( 6 - methoxy-pyridin - 3 - yl ) - benzyl ] - 5 - ( pyridin - 2 - ylmethoxy ) - 1H - indol - 2 - yl ] -2,2- dimethyl-propionic acid ( DB05225 MEN ) , a novel selective P09917 REA - activating protein inhibitor that reduces acute and chronic inflammation . Leukotrienes ( LTs ) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid ( AA ) to P01374 REA ( 4 ) by the enzyme P09917 REA ( P09917 REA ) in the presence of P09917 REA - activating protein ( P20292 REA ) . 3 - [ 3 - tert-Butylsulfanyl - 1 - [ 4 - ( 6 - methoxy-pyridin - 3 - yl ) - benzyl ] - 5 - ( pyridin - 2 - ylmethoxy ) - 1H - indol - 2 - yl ] -2,2- dimethyl-propionic acid ( DB05225 MEN ) is a novel selective P20292 REA inhibitor in development for the treatment of respiratory conditions such as asthma . In a rat ex vivo whole-blood calcium ionophore-induced Q06643 REA ( 4 ) assay , DB05225 MEN ( administered orally at 1 mg / kg ) displayed > 50 % inhibition for up to 6 h with a calculated EC ( 50 ) of approximately 60 nM . When rat lung was challenged in vivo with calcium ionophore , DB05225 MEN inhibited Q06643 REA ( 4 ) and cysteinyl leukotriene ( CysLT ) production with ED ( 50 ) values of 0.8 and 1 mg / kg , respectively . In this model , the EC ( 50 ) derived from plasma DB05225 MEN was approximately 330 nM for inhibition of both Q06643 REA ( 4 ) and CysLT . In an acute inflammation setting , DB05225 MEN displayed dose-dependent inhibition of Q06643 REA ( 4 ) , CysLT , and plasma protein extravasation induced by peritoneal zymosan injection . In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB / c mice , DB05225 MEN reduced the concentrations of eosinophil peroxidase , CysLTs , and interleukin - 5 in the bronchoalveolar lavage fluid . Finally , DB05225 MEN increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor . In summary , DB05225 MEN is a novel , potent and selective P20292 REA inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock .

DB08816 SUB : from discovery to Phase III clinical trial . DB08816 SUB ( AZD 6140 ) , a cyclopentyl-triazolo-pyrimidine , is the first orally available antagonist of the ADP receptor of the Q9H244 REA subtype . DB08816 SUB inhibits platelets in a reversible manner and does not require hepatic bioactivation . The pharmacology of ticagrelor indicates that it provides more consistent , more rapid and more potent platelet inhibition than clopidogrel . Preclinical and clinical studies with ticagrelor have demonstrated that this drug has excellent oral bioavailability . The Phase III clinical study of Platelet Inhibition and Patient Outcomes ( PLATO ) has shown that ticagrelor reduced ischemic events and all-cause mortality without an increase in major bleeding complications . Potential advantages of ticagrelor include more flexibility in its use if rapid onset of action is needed before percutaneous coronary interventions or when cessation is required before coronary artery bypass graft surgery . Potential disadvantages include more side effects such as dyspnea , ventricular pauses or an increase in concentrations of uric acid and creatinine . However , ticagrelor did not only reduce death due to vascular causes but also all-cause mortality . Further clinical trials in indications other than acute coronary syndrome are awaited .