interacts_with DB00461?
Binding of human plasminogen to basement-membrane ( type IV ) collagen . P00747 , the zymogen form of the serine proteinase plasmin , has been implicated in numerous physiological and pathological processes involving extracellular-matrix remodelling . We have previously demonstrated that the activation of plasminogen catalysed by tissue plasminogen activator is dramatically stimulated in the presence of basement-membrane-specific type IV collagen [ Stack , Gonzalez-Gronow & Pizzo ( 1990 ) Biochemistry 29 , 4966-4970 ] . The present paper describes the binding of plasminogen to type IV collagen . P00747 binds to both the alpha 1(IV) and alpha 2(IV) chains of basement-membrane collagen , with binding to the alpha 2(IV) chain preferentially inhibited by DB00513 . This binding is specific and saturable , with Kd,app. values of 11.5 and 12.7 nM for collagen and gelatin respectively . Although collagen also binds to immobilized plasminogen , this interaction is unaffected by DB00513 . Limited elastase proteolysis of plasminogen generated distinct collagen-binding fragments , which were identified as the kringle 1-3 and kringle 4 domains . No binding of collagen to mini-plasminogen was observed . These studies demonstrate a specific interaction between plasminogen and type IV collagen and provide further evidence for regulation of plasminogen activation by protein components of the extracellular matrix . Ca2+ response of rat mesangial cells to DB00171 analogues . The aim of this investigation was to characterise the effects of DB00171 analogues and UTP on the single cell intracellular Ca2+ concentration ( [Ca2+]i ) in cultured rat mesangial cells . Typically , there were two phases in the Ca2+ response to the agonists , an initial fast transient peak and a subsequent slower decline , or plateau , phase . For the peak amplitude in [Ca2+]i the agonists had about equal effect . But when taking in consideration the percentage of responding cells and the integrated Ca2+ response over 1 min , the order of efficacy of nucleotide agonists ( 100 microM ) was UTP = DB00171 > ATPgammaS > ADP = 2MeS- DB00171 ( 2-methylthio- DB00171 ) . DB00640 , AMP and beta,gamma-Me- DB00171 ( 100 microM ) had no effect . DB04786 ( 100 microM ) and reactive blue ( 50 microM ) decreased the number of responding cells . Removing Ca2+ from the bath diminished neither the peak in [Ca2+]i nor the percentage of responding cells , but the average [Ca2+]i increase in 1 min was significantly reduced . The results indicate that P41231 receptors are present in rat mesangial cells but it can not be excluded that there are receptors distinct from P41231 which also mediate a rise in [Ca2+]i . [ Thrombotic complications following the treatment of multiple myeloma with new agents ] . Patients with multiple myeloma ( MM ) are at an increased risk of venous and arterial thrombosis . The risk factors and pathomechanisms for thrombotic complications in multiple myeloma patients can be divided into the disease-related and treatment-specific risk factors . With the introduction of novel therapies , including talidomide , lenalidomide and bortezomib , the outcomes of the patients with newly diagnosed or previously treated multiple myeloma have improved , however the treatment affected the prothrombotic and anticoagulant processes . The risk of venous thromboembolism ( VTE ) in patients receiving immunomodulatory agent-based regimens ( thalidomide or lenalidomide ) , especially when used in combination with high-dose deamethasone- and/or anthracycline-based chemiotherapy is high . The proposed mechanisms for prothrombotic state include changes in P04275 , factor VIII , thrombomodulin , P25116 and P35354 epression , and some abnormalities in transcription factors and genetic risk factors . Moreover , dysregulation of anticoagulation and impairment of fibrinolysis may also contribute to hypercoagulability state . The incidence of VTE in bortezomib-containing regimens is very low . It may be due to inhibitory effect of bortezomib on platelet aggregation and NF-kappa/beta . This article presents the latest outlook upon the pathogenesis of thrombotic complications in multiple myeloma patients undergoing the therapy with new agents . Potential pancreatic lipase inhibitory activity of an endophytic Penicillium species . P16233 ( PL ) is considered as one of the safest target for diet-induced anti-obesity drug development . DB01083 is the only PL inhibitor approved for anti-obesity treatment till date . In the process of exploration of new PL inhibitors , we have screened culture filtrates of 70 endophytic fungi of medicinal plants using qualitative as well as quantitative in-vitro PL assays . The qualitative assays indicated potential PL inhibition in only three isolates , namely # 57 TBBALM , # 33 TBBALM and # 1 CSSTOT . Only ethyl acetate extracts of the culture filtrates of these isolates exhibited the PL inhibition . # 57 TBBLAM ethyl acetate extract of culture filtrate exhibited potential PL inhibition with an IC50 of 3.69 µg/ml which was comparable to the positive control , i.e. DB01083 exhibiting IC50 value of 2.73 µg/ml . Further molecular phylogenetic tools and morphological studies were used to identify the isolate # 57 TBBALM as Penicillium species . Mechanisms underlying altered extracellular nucleotide-induced contractions in mesenteric arteries from rats in later-stage type 2 diabetes : effect of P03950 II type 1 receptor antagonism . Little is known about the vascular contractile responsiveness to , and signaling pathways for , extracellular nucleotides in the chronic stage of type 2 diabetes or whether the P03950 II type 1 receptor blocker losartan might alter such responses . We hypothesized that nucleotide-induced arterial contractions are augmented in diabetic Goto-Kakizaki ( GK ) rats and that treatment with losartan would normalize the contractions . Here , we investigated the vasoconstrictor effects of DB00171 /UTP in superior mesenteric arteries isolated from GK rats ( 37-42 wk old ) that had or had not received 2 wk of losartan ( 25 mg·kg(-1)·day(-1) ) . In arteries from GK rats ( vs. those from Wistar rats ) , 1 ) DB00171 - and UTP-induced contractions , which were blocked by the nonselective P2 antagonist suramin , were enhanced , and these enhancements were suppressed by endothelial denudation , by cyclooxygenase ( P36551 ) inhibitors , or by a cytosolic phospholipase A(2) ( cPLA(2) ) inhibitor ; 2 ) both nucleotides induced increased release of PGE(2) and P49763 (2α) ; 3 ) nucleotide-stimulated cPLA(2) phosphorylations were increased ; 4 ) P23219 and P35354 expressions were increased ; and 5 ) neither P41231 nor Q15077 receptor expression differed , but P51582 receptor expression was decreased . Mesenteric arteries from GK rats treated with losartan exhibited ( vs. untreated GK ) 1 ) reduced nucleotide-induced contractions , 2 ) suppressed UTP-induced release of PGE(2) and P49763 (2α) , 3 ) suppressed UTP-stimulated cPLA(2) phosphorylation , 4 ) normalized expressions of P35354 and P51582 receptors , and 5 ) reduced superoxide generation . Our data suggest that the diabetes-related enhancement of DB00171 -mediated vasoconstriction was due to P2Y receptor-mediated activation of the cPLA(2)/ P36551 pathway and , moreover , that losartan normalizes such contractions by a suppressing action within this pathway . Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties . Oleoylethanolamide ( OEA ) is an endogenous lipid mediator that reduces food intake , promotes lipolysis , and decreases body weight gain in rodents by activating peroxisome proliferator-activated receptor-alpha ( Q07869 ) . The biological effects of OEA are terminated by two intracellular lipid hydrolase enzymes , fatty-acid amide hydrolase and Q02083 . In the present study , we describe OEA analogs that resist enzymatic hydrolysis , activate Q07869 with high potency in vitro , and persistently reduce feeding when administered in vivo either parenterally or orally . The most potent of these compounds , ( Z ) -(R)-9-octadecenamide,N-(2-hydroxyethyl,1-methyl) ( Q9H2K8 -5104 ) , stimulates transcriptional activity of Q07869 with a half-maximal effective concentration ( EC50 ) of 100 +/- 21 nM ( n = 11 ) . Parenteral administration of Q9H2K8 -5104 in rats produces persistent dose-dependent prolongation of feeding latency and postmeal interval ( half-maximal effective dose , ED50 = 2.4 +/- 1.8 mg kg(-1) i.p. ; n = 18 ) , as well as increased and protracted tissue exposure compared with OEA . Oral administration of the compound also results in a significant tissue exposure and reduction of food intake in free-feeding rats . These results suggest that the endogenous high-affinity Q07869 agonist OEA may provide a scaffold for the discovery of novel orally active Q07869 ligands . Low-density lipoprotein apheresis reduces platelet factor 4 on the surface of platelets : a possible protective mechanism against heparin-induced thrombocytopenia and thrombosis . BACKGROUND : DB01109 -induced thrombocytopenia and thrombosis ( HITT ) is characterized by thrombocytopenia due to the formation of antibodies against heparin : platelet factor 4 ( P02776 ) complexes . Despite the exposure to heparin during treatment and predisposition of patients with atherosclerosis to HITT , HITT in patients undergoing low-density lipoprotein ( LDL ) apheresis is rare . We investigated the possibility that LDL apheresis decreases P02776 on platelet ( Q02083 ) surfaces and/or plasma HITT antibody levels , either of which would disfavor HITT . STUDY DESIGN AND METHODS : We enrolled 25 patients undergoing LDL apheresis at the Hospital of the University of Pennsylvania . Blood samples were drawn before and after treatment . Plasma samples were drawn proximal and distal to the LA-15 treatment column . P02776 , HITT antibodies , heparin levels , and P16109 were measured . RESULTS : No patient had clinical symptoms of HITT . The LA-15 column was found to efficiently remove P02776 . P02776 levels in peripheral blood plasma did not change significantly after LDL apheresis . However , Q02083 surface P02776 significantly decreased after treatment . HITT antibodies were found in only two patients and were nonfunctional . Q02083 surface P16109 did not change during treatment . CONCLUSIONS : We have demonstrated that LDL apheresis via dextran sulfate absorption removes plasma P02776 and reduces the amount of P02776 on the surface of circulating PLTs . Reduced surface P02776 may decrease antibody formation and/or recognition by HITT antibodies . These data provide a potential explanation for the near lack of HITT in hypercholesterolemic patients undergoing LDL apheresis . They also suggest the possibility that LDL apheresis using dextran sulfate adsorption may have therapeutic value in the treatment of HITT . O60674 modulates the apolipoprotein interactions with O95477 required for removing cellular cholesterol . DB00171 -binding cassette transporter A1 ( O95477 ) mediates transport of cellular cholesterol and phospholipids to high density lipoprotein ( HDL ) apolipoproteins , such as apoA-I . O95477 mutations can cause a severe HDL deficiency and atherosclerosis . Here we show that the protein-tyrosine kinase ( TK ) O60674 ( O60674 ) modulates the apolipoprotein interactions with O95477 required for removing cellular lipids . The protein kinase A ( PKA ) inhibitor H89 , the TK inhibitor genistein , and the O60674 inhibitor AG490 suppressed apoA-I-mediated cholesterol and phospholipid efflux from O95477 -expressing cells without altering the membrane O95477 content . Whereas PKA inhibition had no effect on apoA-I binding to cells or to O95477 , TK and O60674 inhibition greatly reduced these activities . Conversely , PKA but not O60674 inhibition significantly reduced the intrinsic cholesterol translocase activity of O95477 . Mutant cells lacking O60674 had a severely impaired apoA-I-mediated cholesterol and phospholipid efflux and apoA-I binding despite normal O95477 protein levels and near normal cholesterol translocase activity . Thus , although PKA modulates O95477 lipid transport activity , O60674 appears to selectively modulate apolipoprotein interactions with O95477 . TK-mediated phosphorylation of O95477 was undetectable , implicating the involvement of another O60674 -targeted protein . Acute incubation of O95477 -expressing cells with apoA-I had no effect on O95477 phosphorylation but stimulated O60674 autophosphorylation . These results suggest that the interaction of apolipoproteins with O95477 -expressing cells activates O60674 , which in turn activates a process that enhances apolipoprotein interactions with O95477 and lipid removal from cells . Spline-fitting with a genetic algorithm : a method for developing classification structure-activity relationships . Classification methods allow for the development of structure-activity relationship models when the target property is categorical rather than continuous . We describe a classification method which fits descriptor splines to activities , with descriptors selected using a genetic algorithm . This method , which we identify as SFGA , is compared to the well-established techniques of recursive partitioning ( RP ) and soft independent modeling by class analogy ( SIMCA ) using five series of compounds : cyclooxygenase-2 ( P35354 ) inhibitors , benzodiazepine receptor ( BZR ) ligands , estrogen receptor ( ER ) ligands , dihydrofolate reductase ( P00374 ) inhibitors , and monoamine oxidase ( MAO ) inhibitors . Only 1-D and 2-D descriptors were used . Approximately 40 % of compounds in each series were assigned to a test set , " cherry-picked " from the complete set such that they lie outside the training set as much as possible . SFGA produced models that were more predictive for all but the P00374 set , for which SIMCA was most predictive . RP gave the least predictive models for all but the MAO set . A similar trend was observed when using training and test sets to which compounds were randomly assigned and when gradually eliminating compounds from the ( designed ) training set . The stability of models was examined for the random and reduced sets , where stability means that classification statistics and the selected descriptors are similar for models derived from different sets . Here , SIMCA produced the most stable models , followed by SFGA and RP . We show that a consensus approach that combines all three methods outperforms the single best model for all data sets . Novel marine phenazines as potential cancer chemopreventive and anti-inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 -α-induced NFκB activity ( IC₅₀ values of 4.1 , 24.2 , and 16.3 μM , respectively ) and LPS-induced nitric oxide production ( IC₅₀ values of > 48.6 , 15.1 , and 8.0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7.5 , 0.89 , and 0.63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects . P12004 -Dependent Kinase 5/p35/p39 : A Novel and Imminent Therapeutic Target for Diabetes Mellitus . Present therapies to minify hyperglycaemia and insulin resistance mainly target DB00171 -sensitive K(+) channels ( K( DB00171 ) ) of pancreatic cells and Q07869 -γ to enhance the insulin secretion and potential for GLUT expression , respectively . These current approaches are frequently associated with the various side effects such as hypoglycaemia and cardiovascular adverse events . Q00535 is a serine/threonine protein kinase , which forms active complexes with p35 or p39 found principally in neurons and in pancreatic β cells . Pieces of evidence from recent studies recommend the vital role of Q00535 in physiological functions in nonneuronal cells such as glucose-stimulated insulin secretion in pancreatic cells . Inhibition of Q00535 averts the decrease of insulin gene expression through the inhibition of nuclear translocation of P52945 which is a transcription factor for the insulin gene . The present pieces of evidence designate that Q00535 might be a potential drug target for the regulation of glucose-stimulated insulin secretion in the treatment of diabetes mellitus . Expression and regulation of prostaglandin E synthase isoforms in human myometrium with labour . Since the controversies regarding the use of non-steroidal anti-inflammatory drugs ( NSAIDs ) and selective cyclo-oxygenase ( P36551 ) -2 antagonists for the treatment of preterm labour ( P16233 ) , more emphasis has been placed on investigating the terminal synthases involved in the production of prostaglandins ( PGs ) to allow more targeted therapy in P16233 . Prostaglandin E(2) ( PGE(2) ) is synthesized by one of three enzymes , cytosolic prostaglandin E synthase ( Q15185 ) , microsomal O14684 -1 ( mPGES-1 ) and microsomal O14684 -2 ( Q9H7Z7 ) . We have determined ( i ) the immuno-localization of all three O14684 enzymes in lower segment pregnant human myometrium , ( ii ) the expression of O14684 and P35354 mRNA expression at term and preterm gestation with and without labour and ( iii ) the effect of interleukin ( IL ) -1beta on P35354 and O14684 mRNA and protein expression in human myometrial smooth muscle ( HMSM ) cell cultures . We show mPGES-1 protein located predominantly in myometrial and vascular smooth muscle cells ( SMCs ) , whilst Q9H7Z7 protein is largely in stromal cells surrounding the SMC and Q15185 is diffusely located throughout the myometrium . Expression of Q9H7Z7 mRNA increased with term labour and P16233 and expression of P35354 and mPGES-1 mRNA with term labour , whereas Q15185 expression did not change . IL-1beta stimulated release of PGE(2) by HMSM cells and increased P35354 and mPGES-1 mRNA and protein expression . Thus , P35354 expression and mPGES-1 expression are co-ordinately up-regulated in lower segment myometrium with term labour and with IL-1beta treatment in HMSM cells . Lipophilic antifolate trimetrexate is a potent inhibitor of Trypanosoma cruzi : prospect for chemotherapy of Chagas ' disease . Trypanosoma cruzi , a protozoan parasite , is the causative agent for Chagas ' disease , which poses serious public health problem in Latin America . The two drugs available for the treatment of this disease are effective only against recent infections and are toxic . P00374 ( P00374 ) has a proven track record as a drug target . The lipophilic antifolate trimetrexate ( DB01157 ) , which is an FDA-approved drug for the treatment of Pneumocystis carinii infection in AIDS patients , is a potent inhibitor of T. cruzi P00374 activity , with an inhibitory constant of 6.6 nM . The compound is also highly effective in killing T. cruzi parasites . The 50 and 90 % lethal dose values against the trypomastigote are 19 and 36 nM , and the corresponding values for the amastigote form are 26 and 72 nM , respectively . However , as DB01157 is also a good inhibitor of human P00374 , further improvement of the selectivity of this drug would be preferable . Identification of a novel antifolate selective against T. cruzi would open up new therapeutic avenues for treatment of Chagas ' disease . The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice . P00747 activation to plasmin protects from lung fibrosis , but the mechanism underlying this antifibrotic effect remains unclear . We found that mice lacking plasminogen activation inhibitor-1 ( P05121 ) , which are protected from bleomycin-induced pulmonary fibrosis , exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 ( DB00917 ) . P00747 activation upregulated DB00917 synthesis in alveolar epithelial cells , lung fibroblasts , and lung fibrocytes from saline- and bleomycin-treated mice , as well as in normal fetal and adult primary human lung fibroblasts . This response was exaggerated in cells from Pai1-/- mice . Although enhanced DB00917 formation required the generation of plasmin , it was independent of proteinase-activated receptor 1 ( P25116 ) and instead reflected proteolytic activation and release of P14210 with subsequent induction of P35354 . That the P14210 / P35354 / DB00917 axis mediates in vivo protection from fibrosis in Pai1-/- mice was demonstrated by experiments showing that a selective inhibitor of the P08581 c- DB00134 increased lung collagen to WT levels while reducing P35354 protein and DB00917 levels . Of clinical interest , fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce P35354 and , therefore , unable to upregulate DB00917 synthesis in response to plasmin or P14210 . These studies demonstrate crosstalk between plasminogen activation and DB00917 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway . Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase-2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long-term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( DB00461 ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti-inflammatory drugs ( NSAIDs ) , and the meta-analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10-fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared . Effect of milk hydrolysates on inflammation markers and drug-induced transcriptional alterations in cell-based models . Nonsteroidal anti-inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor-β1 ( TGF-β1 ) , cyclooxygenase-2 ( P35354 ) , peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) and nuclear factor κB ( NFκB ) by real-time PCR . Furthermore , the effect of CH on lipopolysaccharide-induced inflammation was evaluated in macrophages by measuring PG E(2) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF-β1 and NFκB ( P < 0.05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0.05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 -γ was not affected ( P > 0.05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro-inflammatory effect on macrophages via PG E(2) stimulation ( P < 0.05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF-β1 , P35354 , and NFκB . Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25 . Paullones constitute a new family of benzazepinones with promising antitumoral properties . They were recently described as potent , DB00171 -competitive , inhibitors of the cell cycle regulating cyclin-dependent kinases ( CDKs ) . We here report that paullones also act as very potent inhibitors of glycogen synthase kinase-3beta ( GSK-3beta ) ( IC50 : 4-80 nM ) and the neuronal Q00535 /p25 ( IC50 : 20-200 nM ) . These two enzymes are responsible for most of the hyperphosphorylation of the microtubule-binding protein tau , a feature observed in the brains of patients with Alzheimer 's disease and other neurodegenerative ' taupathies ' . DB04014 , the most active paullone , was demonstrated to act by competing with DB00171 for binding to GSK-3beta . DB04014 inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK-3beta in Alzheimer 's disease . DB04014 also inhibits the Q00535 /p25-dependent phosphorylation of Q9UD71 in mouse striatum slices in vitro . This dual specificity of paullones may turn these compounds into very useful tools for the study and possibly treatment of neurodegenerative and proliferative disorders . Concanavalin-A triggers inflammatory response through JAK/ P40763 signalling and modulates P50281 regulation of P35354 in mesenchymal stromal cells . Pharmacological targeting of inflammation through P40763 and NF-κB signaling pathways is , among other inflammatory biomarkers , associated with cyclooxygenase ( P36551 ) -2 inhibition and is believed to play a crucial role in prevention and therapy of cancer . Recently , inflammatory factors were found to impact on mesenchymal stromal cells ( O60682 ) contribution to tumor angiogenesis . Given O60682 chemotaxis and cell survival are regulated , in part , by the membrane type-1 matrix metalloproteinase ( P50281 ) , an MMP also involved in transducing NF-κB intracellular signaling pathways , we tested whether P40763 regulation by P50281 may also contribute to the expression balance of P35354 in O60682 . We demonstrate that P40763 phosphorylation was triggered in O60682 treated with the P50281 inducer lectin Concanavalin-A ( ConA ) , and that this phosphorylation was abrogated by the O60674 inhibitor AG490 . P50281 gene silencing significantly inhibited ConA-induced P40763 phosphorylation and this was correlated with reduced proMMP-2 activation and P35354 expression . On the other hand , P40763 gene silencing potentiated ConA-induced P35354 expression , providing evidence for a new P50281 /JAK/ P40763 signaling axis that may , in part , explain how P50281 contributes to proinflammatory intracellular signaling . Given that O60682 are avidly recruited within inflammatory microenvironments and within experimental vascularizing tumors , these mechanistic observations support a possible dual control of cell adaptation to inflammation by P50281 and that may enable O60682 to be active participants within inflamed tissues . P15121 regulates high glucose-induced ectodomain shedding of tumor necrosis factor ( P01375 ) -alpha via protein kinase C-delta and P01375 converting enzyme in vascular smooth muscle cells . Chronic low-grade inflammation has emerged as a key contributor to the cardiovascular complications of diabetes , however , the mechanisms by which diabetes increases inflammation remain poorly understood . Here , we report that exposure to high glucose ( HG ) stimulates ectodomain shedding of P01375 from rat aortic smooth muscle cells in culture . Our results show that exposure to HG decreases membrane-associated P01375 . This decrease in unprocessed P01375 was prevented by the aldose reductase ( AR ) inhibitor sorbinil and AR small interference RNA . Treatment with HG , but not equimolar mannitol or 3-O-methyl glucose , resulted in phosphorylation and activation of P01375 converting enzyme ( P78536 ) ( P78536 ) , which were attenuated by sorbinil or AR-specific small interference RNA . HG-induced P78536 phosphorylation and P01375 processing were also prevented by P01375 protease inhibitor-1 , an inhibitor of P78536 . Inhibition of protein kinase C ( PKC ) -delta by rottlerin prevented HG-induced P78536 activation and the accumulation of unprocessed P01375 . Treatment with sorbinil decreased elevated levels of circulating P01375 in streptozotocin-treated diabetic rats . DB02712 treatment also decreased the expression of P01375 , matrix metalloproteinase-2 , matrix metalloproteinase-9 , and increased tissue inhibitor of metalloproteinase-3 in vascular smooth muscle cells treated with HG and in balloon-injured carotid arteries of diabetic rats . These results indicate that HG-induced P01375 shedding could be attributed to P78536 activation , which is regulated , in part , by PKC-delta and AR . Therefore , inhibition of P78536 by P01375 protease inhibitor-1 , or pharmacological inhibition of PKC-delta or AR may represent useful strategies for treating vascular inflammation associated with diabetes . Pharmacokinetic , pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases . Platelet inhibitors are the mainstay treatment for patients with vascular diseases . The current ' gold standard ' antiplatelet agent clopidogrel has several pharmacological and clinical limitations that have prompted the search for more effective platelet antagonists . The candidates include various blockers of the purinergic Q9H244 receptor such as prasugrel , an oral irreversible thienopyridine ; two adenosine triphosphate analogues that bind reversibly to the Q9H244 receptor : ticagrelor ( oral ) and cangrelor ( intravenous ) ; elinogrel , a direct-acting reversible Q9H244 receptor inhibitor ( the only antiplatelet compound that can be administered both intravenously and orally ) ; BX 667 , an orally active and reversible small-molecule Q9H244 receptor antagonist ; P35240 530348 , P35240 205831 , P35240 602539 and E5555 , highly selective and orally active antagonists on the protease-activated receptor 1 . A number of drugs also hit new targets : terutroban , an oral , selective and specific inhibitor of the thromboxane receptor ; DB05202 , a second-generation , nuclease resistant aptamer which inhibits P04275 -dependent platelet aggregation ; Q96JZ2 -0081 , a bivalent humanized nanobody targeting the GPIb binding site of P04275 and AJW200 , an IgG4 monoclonal antibody of P04275 . The pharmacology and clinical profiles of new platelet antagonists indicate that they provide more consistent , more rapid and more potent platelet inhibition than agents currently used . Whether these potential advantages will translate into clinical advantages will require additional comparisons in properly powered , randomized , controlled trials .