MH_dev_184

Binding of human plasminogen to basement-membrane ( type IV ) collagen . P00747 REA , 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 REA 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 MEN . 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 MEN . 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 MEN analogues . The aim of this investigation was to characterise the effects of DB00171 MEN 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 MEN > ATPgammaS > ADP = 2MeS - DB00171 MEN ( 2 - methylthio - DB00171 MEN ) . DB00640 , AMP and beta , gamma-Me - DB00171 MEN ( 100 microM ) had no effect . DB04786 MEN ( 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 REA receptors are present in rat mesangial cells but it can not be excluded that there are receptors distinct from P41231 REA 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 REA , factor VIII , thrombomodulin , P25116 REA and P35354 REA 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 REA ( PL ) is considered as one of the safest target for diet-induced anti-obesity drug development . DB01083 MEN 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 MEN 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 MEN / 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 MEN - 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 REA ) inhibitors , or by a cytosolic phospholipase A ( 2 ) ( cPLA ( 2 ) ) inhibitor ; 2 ) both nucleotides induced increased release of PGE ( 2 ) and P49763 REA ( 2α ) ; 3 ) nucleotide-stimulated cPLA ( 2 ) phosphorylations were increased ; 4 ) P23219 REA and P35354 REA expressions were increased ; and 5 ) neither P41231 REA nor Q15077 REA receptor expression differed , but P51582 REA 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 REA ( 2α ) , 3 ) suppressed UTP-stimulated cPLA ( 2 ) phosphorylation , 4 ) normalized expressions of P35354 REA and P51582 REA receptors , and 5 ) reduced superoxide generation . Our data suggest that the diabetes-related enhancement of DB00171 MEN - mediated vasoconstriction was due to P2Y receptor-mediated activation of the cPLA ( 2 ) / P36551 REA 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 REA ) . 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 REA 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 REA 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 REA agonist OEA may provide a scaffold for the discovery of novel orally active Q07869 REA 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 MENMAX DB01109 MEN - induced thrombocytopenia and thrombosis ( HITT ) is characterized by thrombocytopenia due to the formation of antibodies against heparin : platelet factor 4 ( P02776 REA ) 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 REA 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 REA , HITT antibodies , heparin levels , and P16109 REA were measured . RESULTS : No patient had clinical symptoms of HITT . The LA - 15 column was found to efficiently remove P02776 REA . P02776 REA levels in peripheral blood plasma did not change significantly after LDL apheresis . However , Q02083 surface P02776 REA significantly decreased after treatment . HITT antibodies were found in only two patients and were nonfunctional . Q02083 surface P16109 REA did not change during treatment . CONCLUSIONS : We have demonstrated that LDL apheresis via dextran sulfate absorption removes plasma P02776 REA and reduces the amount of P02776 REA on the surface of circulating PLTs . Reduced surface P02776 REA 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 REA modulates the apolipoprotein interactions with O95477 REA required for removing cellular cholesterol . DB00171 MEN - binding cassette transporter A1 ( O95477 REA ) mediates transport of cellular cholesterol and phospholipids to high density lipoprotein ( HDL ) apolipoproteins , such as apoA-I . O95477 REA mutations can cause a severe HDL deficiency and atherosclerosis . Here we show that the protein-tyrosine kinase ( TK ) O60674 REA ( O60674 REA ) modulates the apolipoprotein interactions with O95477 REA required for removing cellular lipids . The protein kinase A ( PKA ) inhibitor H89 , the TK inhibitor genistein , and the O60674 REA inhibitor AG490 suppressed apoA-I-mediated cholesterol and phospholipid efflux from O95477 REA - expressing cells without altering the membrane O95477 REA content . Whereas PKA inhibition had no effect on apoA-I binding to cells or to O95477 REA , TK and O60674 REA inhibition greatly reduced these activities . Conversely , PKA but not O60674 REA inhibition significantly reduced the intrinsic cholesterol translocase activity of O95477 REA . Mutant cells lacking O60674 REA had a severely impaired apoA-I-mediated cholesterol and phospholipid efflux and apoA-I binding despite normal O95477 REA protein levels and near normal cholesterol translocase activity . Thus , although PKA modulates O95477 REA lipid transport activity , O60674 REA appears to selectively modulate apolipoprotein interactions with O95477 REA . TK-mediated phosphorylation of O95477 REA was undetectable , implicating the involvement of another O60674 REA - targeted protein . Acute incubation of O95477 REA - expressing cells with apoA-I had no effect on O95477 REA phosphorylation but stimulated O60674 REA autophosphorylation . These results suggest that the interaction of apolipoproteins with O95477 REA - expressing cells activates O60674 REA , which in turn activates a process that enhances apolipoprotein interactions with O95477 REA 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 REA ) inhibitors , benzodiazepine receptor ( BZR ) ligands , estrogen receptor ( ER ) ligands , dihydrofolate reductase ( P00374 REA ) 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 REA 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 CNS 284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 REA - 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 REA . Treatment of cultured HL - 60 cells led to dose-dependent accumulation in the subG 1 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 REA - 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 MEN - sensitive K ( + ) channels ( K ( DB00171 MEN ) ) of pancreatic cells and Q07869 REA - 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 REA 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 REA in physiological functions in nonneuronal cells such as glucose-stimulated insulin secretion in pancreatic cells . Inhibition of Q00535 REA averts the decrease of insulin gene expression through the inhibition of nuclear translocation of P52945 REA which is a transcription factor for the insulin gene . The present pieces of evidence designate that Q00535 REA 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 REA ) - 2 antagonists for the treatment of preterm labour ( P16233 REA ) , more emphasis has been placed on investigating the terminal synthases involved in the production of prostaglandins ( PGs ) to allow more targeted therapy in P16233 REA . Prostaglandin E ( 2 ) ( PGE ( 2 ) ) is synthesized by one of three enzymes , cytosolic prostaglandin E synthase ( Q15185 REA ) , microsomal O14684 REA - 1 ( mPGES - 1 ) and microsomal O14684 REA - 2 ( Q9H7Z7 REA ) . We have determined ( i ) the immuno-localization of all three O14684 REA enzymes in lower segment pregnant human myometrium , ( ii ) the expression of O14684 REA and P35354 REA mRNA expression at term and preterm gestation with and without labour and ( iii ) the effect of interleukin ( IL ) - 1beta on P35354 REA and O14684 REA 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 REA protein is largely in stromal cells surrounding the SMC and Q15185 REA is diffusely located throughout the myometrium . Expression of Q9H7Z7 REA mRNA increased with term labour and P16233 REA and expression of P35354 REA and mPGES - 1 mRNA with term labour , whereas Q15185 REA expression did not change . IL - 1beta stimulated release of PGE ( 2 ) by HMSM cells and increased P35354 REA and mPGES - 1 mRNA and protein expression . Thus , P35354 REA 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 REA ( P00374 REA ) has a proven track record as a drug target . The lipophilic antifolate trimetrexate ( DB01157 MEN ) , which is an FDA-approved drug for the treatment of Pneumocystis carinii infection in AIDS patients , is a potent inhibitor of T . cruzi P00374 REA 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 MEN is also a good inhibitor of human P00374 REA , 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 REA 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 REA ) , which are protected from bleomycin-induced pulmonary fibrosis , exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 ( DB00917 ) . P00747 REA 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 Pai 1 - / - mice . Although enhanced DB00917 formation required the generation of plasmin , it was independent of proteinase-activated receptor 1 ( P25116 REA ) and instead reflected proteolytic activation and release of P14210 REA with subsequent induction of P35354 REA . That the P14210 REA / P35354 REA / DB00917 axis mediates in vivo protection from fibrosis in Pai 1 - / - mice was demonstrated by experiments showing that a selective inhibitor of the P08581 REA c - DB00134 increased lung collagen to WT levels while reducing P35354 REA 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 REA and , therefore , unable to upregulate DB00917 synthesis in response to plasmin or P14210 REA . 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 REA ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 REA ) 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 REA 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 REA inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 REA isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 REA 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 SUB ) , 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 REA 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-β 1 ( TGF-β 1 ) , cyclooxygenase - 2 ( P35354 REA ) , peroxisome proliferator-activated receptor-γ ( Q07869 REA - 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-β 1 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 REA ( P < 0.05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 REA - 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-β 1 , P35354 REA , 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 MEN - 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 REA / 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 MEN , the most active paullone , was demonstrated to act by competing with DB00171 MEN for binding to GSK - 3beta . DB04014 MEN inhibits the phosphorylation of tau in vivo at sites which are typically phosphorylated by GSK - 3beta in Alzheimer ' s disease . DB04014 MEN also inhibits the Q00535 REA / 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 REA signalling and modulates P50281 REA regulation of P35354 REA in mesenchymal stromal cells . Pharmacological targeting of inflammation through P40763 REA and NF-κB signaling pathways is , among other inflammatory biomarkers , associated with cyclooxygenase ( P36551 REA ) - 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 REA ) , an MMP also involved in transducing NF-κB intracellular signaling pathways , we tested whether P40763 REA regulation by P50281 REA may also contribute to the expression balance of P35354 REA in O60682 . We demonstrate that P40763 REA phosphorylation was triggered in O60682 treated with the P50281 REA inducer lectin Concanavalin-A ( ConA ) , and that this phosphorylation was abrogated by the O60674 REA inhibitor AG490 . P50281 REA gene silencing significantly inhibited ConA-induced P40763 REA phosphorylation and this was correlated with reduced proMMP - 2 activation and P35354 REA expression . On the other hand , P40763 REA gene silencing potentiated ConA-induced P35354 REA expression , providing evidence for a new P50281 REA / JAK / P40763 REA signaling axis that may , in part , explain how P50281 REA 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 REA and that may enable O60682 to be active participants within inflamed tissues .

P15121 REA regulates high glucose-induced ectodomain shedding of tumor necrosis factor ( P01375 REA ) - alpha via protein kinase C-delta and P01375 REA 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 REA from rat aortic smooth muscle cells in culture . Our results show that exposure to HG decreases membrane-associated P01375 REA . This decrease in unprocessed P01375 REA 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 REA converting enzyme ( P78536 REA ) ( P78536 REA ) , which were attenuated by sorbinil or AR-specific small interference RNA . HG-induced P78536 REA phosphorylation and P01375 REA processing were also prevented by P01375 REA protease inhibitor - 1 , an inhibitor of P78536 REA . Inhibition of protein kinase C ( PKC ) - delta by rottlerin prevented HG-induced P78536 REA activation and the accumulation of unprocessed P01375 REA . Treatment with sorbinil decreased elevated levels of circulating P01375 REA in streptozotocin-treated diabetic rats . DB02712 MEN treatment also decreased the expression of P01375 REA , 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 REA shedding could be attributed to P78536 REA activation , which is regulated , in part , by PKC-delta and AR . Therefore , inhibition of P78536 REA by P01375 REA 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 REA receptor such as prasugrel , an oral irreversible thienopyridine ; two adenosine triphosphate analogues that bind reversibly to the Q9H244 REA receptor : ticagrelor ( oral ) and cangrelor ( intravenous ) ; elinogrel , a direct-acting reversible Q9H244 REA receptor inhibitor ( the only antiplatelet compound that can be administered both intravenously and orally ) ; BX 667 , an orally active and reversible small-molecule Q9H244 REA receptor antagonist ; P35240 REA 530348 , P35240 REA 205831 , P35240 REA 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 MEN , a second-generation , nuclease resistant aptamer which inhibits P04275 REA - dependent platelet aggregation ; Q96JZ2 - 0081 , a bivalent humanized nanobody targeting the GPIb binding site of P04275 REA and AJW 200 , an IgG 4 monoclonal antibody of P04275 REA . 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 .