MH_dev_263

[ Anticoagulants of primary haemostasis ] . Inhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases . Established antiplatelet agents use different pharmacological targets for this role . Acetyl salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of P23219 REA . DB00208 or clopidogrel are ADP - Q9H244 REA receptor antagonists . Tirofiban , abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb / IIIa receptor which is activated at the surface of platelets preceding the final step of their aggregation . The mechanism of dipyridamole is based on the inhibition of adenosine uptake and of phosphodiesterase - 5 . Efforts are made to improve antiplatelet therapy with the aim to find agents with favorable clinical outcome and lower bleeding risk . Current clinical studies focus on a new generation of ADP receptor antagonists ( prasugrel , cangrelor and ticagrelor ) as successors of ticlopidine and clopidogrel after coronary arterial interventions . Developments using platelet targets different from established drugs are thrombin receptor antagonists ( like SCH 530348 ) or thromboxane receptor antagonists ( like S18886 / terutroban ) in patients with cerebrovascular events . Results from recent experimental studies could lead to new strategies for antiplatelet therapy ( like inhibition of GP Ib receptor , GP VI receptor , platelet-leukocyte interaction , factor XII and others ) in the future .

Attenuation of anti-tuberculosis therapy induced hepatotoxicity by Spirulina fusiformis , a candidate food supplement . Therapy using Isoniazid ( DB00951 ) and DB01045 MENMAX DB01045 MEN ( Q9HBH0 ) leads to induction of hepatotoxicity in some individuals undergoing anti-tuberculosis treatment . In this study , we assessed the effect of Spirulina fusiformis on DB00951 and Q9HBH0 induced hepatotoxicity in rats compared with hepatoprotective drug Silymarin . Induction of hepatotoxicity was measured by changes in the liver marker enzymes ( aspartate transaminase , alanine transaminase , and alkaline phosphatase ) . The antioxidant status was also analyzed in liver tissue homogenate and plasma by measurement of superoxide dismutase , catalase , glutathione-S-transferase , glutathione reductase , and lipid peroxidation levels . We also aimed to study the binding and interactions of the transcription factors Pregnane X Receptor ( O75469 REA ) and Farnesoid X Receptor ( Q96RI1 ) with DB00951 , Q9HBH0 , and representative active compounds of Spirulina fusiformis by in silico methods . The administration of DB00951 and Q9HBH0 resulted in significant ( p < 0.05 ) decrease in the antioxidant levels and total protein levels . There was also a significant ( p < 0.05 ) increase in the levels of liver marker enzymes . Spirulina fusiformis was seen to protect the parameters from significant changes upon challenge with DB00951 and Q9HBH0 in a dose-dependent manner . This was corroborated by histological examination of the liver . The results of the in silico analyses further support the wet lab results .

Multipotent cancer stem cells derived from human malignant peritoneal mesothelioma promote tumorigenesis . During the progression of malignant peritoneal mesothelioma ( MPeM ) , tumor nodules propagate diffusely within the abdomen and tumors are characterized by distinct phenotypic sub-types . Recent studies in solid organ cancers have shown that cancer stem cells ( CSCs ) play a pivotal role in the initiation and progression of tumors . However , it is not known whether tumorigenic stem cells exist and whether they promote tumor growth in MPeM . In this study , we developed and characterized a CSC model for MPeM using stably expandable tumorigenic stem cells derived from patient tumors . We found morphologically distinct populations of CSCs that divide asymmetrically or symmetrically in MPeM in vitro cell culture . The MPeM stem cells ( MPeMSCs ) express stem cell markers c-MYC , P48681 and P35968 REA and in the presence of matrix components cells form colony spheres . MPeMSCs are multipotent , differentiate into neuronal , vascular and adipose progeny upon defined induction and the differentiating cells express lineage-specific markers such as Q13509 REA , an early neuronal marker ; P04275 REA , P15692 REA , P49767 REA and P10145 REA , endothelial markers ; and PPARγ and P15090 REA , adipose markers . Xenotransplantation experiments using MPeMSCs demonstrated early tumor growth compared with parental cells . Limiting dilution experiments using MPeMSCs and endothelial lineage-induced cells derived from a single MPeMSC resulted in early tumor growth in the latter group indicating that endothelial differentiation of MPeMSCs is important for MPeM tumor initiation . Our observation that the MPeM tumors contain stem cells with tumorigenic potential has important implications for understanding the cells of origin and tumor progression in MPeM and hence targeting CSCs may be a useful strategy to inhibit malignant progression .

DB02709 MEN is a peroxidase-mediated inactivator of P23219 REA but not P35354 REA : a mechanistic approach to the design of P23219 REA selective agents . DB02709 MEN ( 3,4 ' , 5 - trihydroxy-trans-stilbene ) is a phytoalexin found in grapes that has anti-inflammatory , cardiovascular protective , and cancer chemopreventive properties . It has been shown to target prostaglandin H ( 2 ) synthase ( P36551 REA ) - 1 and P35354 REA , which catalyze the first committed step in the synthesis of prostaglandins via sequential cyclooxygenase and peroxidase reactions . DB02709 MEN discriminates between both P36551 REA isoforms . It is a potent inhibitor of both catalytic activities of P23219 REA , the desired drug target for the prevention of cardiovascular disease , but only a weak inhibitor of the peroxidase activity of P35354 REA , the isoform target for nonsteroidal anti-inflammatory drugs . We have investigated the unique inhibitory properties of resveratrol . We find that it is a potent peroxidase-mediated mechanism-based inactivator of P23219 REA only ( k ( inact ) = 0.069 + / - 0.004 s ( - 1 ) , K ( i ( inact ) ) = 1.52 + / - 0.15 microm ) , with a calculated partition ratio of 22 . Inactivation of P23219 REA was time - and concentration-dependent , it had an absolute requirement for a peroxide substrate , and it was accompanied by a concomitant oxidation of resveratrol . DB02709 MEN - inactivated P23219 REA was devoid of both the cyclooxygenase and peroxidase activities , neither of which could be restored upon gel-filtration chromatography . Inactivation of P23219 REA by [ ( 3 ) H ] resveratrol was not accompanied by stable covalent modification as evident by both SDS-PAGE and reverse phase-high performance liquid chromatography analysis . Structure activity relationships on methoxy-resveratrol analogs showed that the m-hydroquinone moiety was essential for irreversible inactivation of P23219 REA . We propose that resveratrol inactivates P23219 REA by a " hit-and-run " mechanism , and offers a basis for the design of selective P23219 REA inactivators that work through a mechanism-based event at the peroxidase active site .

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 .

Identification of candidate genes and mutations in QTL regions for immune responses in chicken . There are two categories of immune responses - innate and adaptive immunity - both having polygenic backgrounds and a significant environmental component . In our study , adaptive immunity was represented by the specific antibody response toward DB05299 ( KLH ) ; innate immunity was represented by natural antibodies toward lipopolysaccharide ( LPS ) and lipoteichoic acid ( P01374 REA ) . Defining genetic bases of immune responses leads from defining quantitative trait loci ( QTL ) toward a single mutation responsible for variation in the phenotypic trait . The goal of the reported study was to define candidate genes and mutations for the immune traits of interest in chicken by performing an association study of SNPs located in candidate genes defined in QTL regions . Candidate genes and SNPs in QTL regions were selected in silico . SNP association was based on a custom SNP panel , GoldenGate genotyping assay ( Illumina ) and two statistical models : random mixed model and CAR score . The most significant SNP for immune response toward KLH was located in the Q6NYC1 gene located on GGA 18 . Four SNPs in candidate genes Q92949 ( GGA 18 ) , P54762 REA ( GGA 9 ) , P35408 REA ( GGAZ ) and P05771 REA ( GGA 14 ) showed association with natural antibodies for LPS . A single SNP in P16144 REA ( GGA 18 ) was associated with natural antibodies for P01374 REA . All associated SNPs mentioned above showed additive effects .

P15121 REA regulates TGF-beta 1 - induced production of fibronectin and type IV collagen in cultured rat mesangial cells . AIM : To study the effects of aldose reductase ( AR ) on production of fibronectin and type IV collagen in rat mesangial cells ( MsC ) . METHODS : The vector , pcDNA 3 - AR , was constructed based on pET - 15b - AR . Lipofect AMINE was used for stable transfection and G418 was used for selecting positive clones . DB02712 MEN and zopolrestat were added for suppressing the activity of AR , respectively . The production of fibronectin and type IV collagen and the activation of Smads and MAPK signal transduction pathway were analysed by western blot and AP - 1 activity was analysed by electrophoretic mobility shift assays ( EMSA ) . RESULTS : The normal MsC showed increased expression of fibronectin and type IV collagen with stimulation of TGF-beta 1 . Compared with the normal MsC , the MsC pre-incubated with Q9Y4X5 REA showed reduced expression ( P < 0.05 ) and the AR-transfected MsC showed increased expression ( P < 0.05 ) . The normal MsC showed activation of P29323 REA , JNK and p38 with stimulation of TGF-beta 1 , while the activation of JNK and p38 was inhibited in the MsC pre-incubated with Q9Y4X5 REA and only the activation of JNK was enhanced in the AR-transfected MsC . The normal MsC showed enhanced AP - 1 activity with the stimulation of TGF-beta 1 , and similarly the activity was inhibited in the MsC pre-incubated with Q9Y4X5 REA and was more enhanced in the AR transfected MsC . CONCLUSION : AR can regulate the expression of fibronectin and type IV collagen with the stimulation of TGF-beta 1 in MsC , which may have relations with the activation of JNK-MAPK and p38 - MAPK signalling pathways and AP - 1 .

Structures of murine carbonic anhydrase IV and human carbonic anhydrase II complexed with brinzolamide : molecular basis of isozyme-drug discrimination . P22748 REA ( CAIV ) is a membrane-associated enzyme anchored to plasma membrane surfaces by a phosphatidylinositol glycan linkage . We have determined the 2.8- angstroms resolution crystal structure of a truncated , soluble form of recombinant murine CAIV . We have also determined the structure of its complex with a drug used for glaucoma therapy , the sulfonamide inhibitor brinzolamide ( DB01194 MEN ) . The overall structure of murine CAIV is generally similar to that of human CAIV ; however , some local structural differences are found in the active site resulting from amino acid sequence differences in the " 130 ' s segment " and the residue - 63 loop ( these may affect the nearby catalytic proton shuttle , DB00117 - 64 ) . Similar to human CAIV , the C-terminus of murine CAIV is surrounded by a substantial electropositive surface potential that may stabilize the interaction with the phospholipid membrane . Binding interactions observed for brinzolamide rationalize the generally weaker affinity of inhibitors used in glaucoma therapy toward CAIV compared with CAII .

Purinergic receptors contribute to early mesangial cell transformation and renal vessel hypertrophy during angiotensin II-induced hypertension . Chronic P03950 REA II infusions lead to increases in intrarenal P03950 REA II levels , hypertension , and tissue injury . Increased blood pressure also elicits increases in renal interstitial fluid ( Q9HBH0 ) DB00171 concentrations that stimulate cell proliferation . We evaluated the contribution of purinergic receptor activation to P03950 REA II-induced renal injury in rats by treating with clopidogrel , a Q9H244 REA receptor blocker , or with PPADS , a nonselective P2 receptor blocker . alpha-Actin expression in mesangial cells , afferent arteriolar wall thickness ( AAWT ) , cortical cell proliferation , and macrophage infiltration were used as early markers of renal injury . DB00758 SUB and PPADS did not alter blood pressure , renin or kidney P03950 REA II content . alpha-Actin expression increased from control of 0.6 + / - 0.4 % of mesangial area to 6.3 + / - 1.9 % in P03950 REA II-infused rats and this response was prevented by clopidogrel ( 0.4 + / - 0.2 % ) and PPADS . The increase in AAWT from 4.7 + / - 0.1 to 6.0 + / - 0.1 mm in P03950 REA II rats was also prevented by clopidogrel ( 4.8 + / - 0.1 mm ) and PPADS . P03950 REA II infusion led to interstitial macrophage infiltration ( 105 + / - 16 vs . 62 + / - 4 cell / mm ( 2 ) ) and tubular proliferation ( 71 + / - 15 vs . 20 + / - 4 cell / mm ( 2 ) ) and these effects were prevented by clopidogrel ( 52 + / - 4 and 36 + / - 3 cell / mm ( 2 ) ) and PPADS . Q9HBH0 DB00171 levels were higher in P03950 REA II-infused rats than in control rats ( 11.8 + / - 1.9 vs . 5.6 + / - 0.6 nmol / l , P < 0.05 ) . The results suggest that activation of vascular and glomerular purinergic P2 receptors may contribute to the mesangial cell transformation , renal inflammation , and vascular hypertrophy observed in P03950 REA II-dependent hypertension .

Biomarker analysis of neoadjuvant doxorubicin / cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer . PURPOSE : Predictive biomarkers offer the potential to improve the benefit : risk ratio of a therapeutic agent . DB04845 MEN achieves comparable pathologic complete response ( pCR ) rates to other active drugs in the neoadjuvant setting . This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent . EXPERIMENTAL DESIGN : Women with untreated , histologically confirmed primary invasive breast adenocarcinoma received neoadjuvant doxorubicin / cyclophosphamide , followed by 1:1 randomization to ixabepilone ( n = 148 ) or paclitaxel ( n = 147 ) . Rates of pCR were compared between treatment arms based on predefined biomarker sets : Q13509 REA , Q9Y6A5 REA , and CAPG gene expression , a 20 - and 26 - gene expression model , P08183 REA protein expression , and other potential markers of sensitivity . βIII-tubulin protein expression is reported separately but is referred to here for completeness . All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis before chemotherapy . Gene expression profiling data were used for molecular subtyping . RESULTS : There was no significant difference in the rate of pCR in both treatment arms in βIII-tubulin-positive patients . Higher pCR rates were observed among βIII-tubulin-positive patients than in βIII-tubulin-negative patients . Furthermore , no correlation was evident between Q13509 REA , Q9Y6A5 REA , and CAPG gene expression , P08183 REA protein expression , multi-gene expression models , and the efficacy of ixabepilone or paclitaxel , even within the estrogen receptor-negative subset . CONCLUSION : These results indicate that βIII-tubulin protein and mRNA expression , P08183 REA protein expression , Q9Y6A5 REA and CAPG gene expression , and multigene expression models ( 20 - and 26 - gene ) are not predictive markers for differentiating treatment benefit between ixabepilone and paclitaxel in early-stage breast cancer .

Temporal and pharmacological characterization of angiostatin release and generation by human platelets : implications for endothelial cell migration . Platelets play an important role in thrombosis and in neo-vascularisation as they release and produce factors that both promote and suppress angiogenesis . Amongst these factors is the angiogenesis inhibitor angiostatin , which is released during thrombus formation . The impact of anti-thrombotic agents and the kinetics of platelet angiostatin release are unknown . Hence , our objectives were to characterize platelet angiostatin release temporally and pharmacologically and to determine how angiostatin release influences endothelial cell migration , an early stage of angiogenesis . We hypothesized anti-platelet agents would suppress angiostatin release but not generation by platelets . Human platelets were aggregated and temporal angiostatin release was compared to vascular endothelial growth factor ( P15692 REA ) . Immuno-gold electron microscopy and immunofluorescence microscopy identified α-granules as storage organelles of platelet angiostatin . Acetylsalicylic acid , MRS 2395 , P08514 REA / IIIa blocking peptide , and aprotinin were used to characterize platelet angiostatin release and generation . An endothelial cell migration assay was performed under hypoxic conditions to determine the effects of pharmacological platelet and angiostatin inhibition . Compared to P15692 REA , angiostatin generation and release from α-granules occurred later temporally during platelet aggregation . Consequently , collagen-activated platelet releasates stimulated endothelial cell migration more potently than maximally-aggregated platelets . Platelet inhibitors prostacyclin , S-nitroso-glutathione , acetylsalicylic acid , and P08514 REA / IIIa blocking peptide , but not a Q9H244 REA inhibitor , suppressed angiostatin release but not generation . Suppression of angiostatin generation in the presence of acetylsalicylic acid enhanced platelet-stimulated endothelial migration . Hence , the temporal and pharmacological modulation of platelet angiostatin release may have significant consequences for neo-vascularization following thrombus formation .

Hippocampal injury and alterations in neuronal chemokine co-receptor expression in patients with AIDS . Hippocampal neurons express high levels of HIV chemokine co-receptors , activation of which causes injury or death in vitro . To determine if their in vivo expression correlates with injury , we evaluated neuronal P61073 REA and P51681 REA immunoreactivity and reactive gliosis in autopsy hippocampus of 10 control cases , 11 AIDS cases without HIV encephalitis ( HIVnE ) or opportunistic infections / lymphomas ( OI / L ) , and 11 AIDS cases with HIV encephalitis ( HIVE ) . All groups had higher P61073 REA and P51681 REA expression in P07451 REA and P22748 REA neurons than P00915 REA neurons ( p < 0.05 ) . HIVE cases had increased neuronal P61073 REA and decreased neuronal P51681 REA expression as well as increased numbers of hippocampal P14136 REA - positive astrocytes and LN3 - positive microglia . Changes were most severe in P07451 REA and P22748 REA and lowest in P00915 REA regions . These findings also were noted in the 4 HIVE cases with neither hippocampal HIVE nor brain OI / L and in the HIVnE groups . This study quantitates the regional distribution of hippocampal neuronal P61073 REA and P51681 REA and shows their respective increase and decrease in AIDS . It suggests a relationship between neuronal loss and gliosis with intensity of neuronal chemokine expression and raises the possibility of a selective vulnerability of hippocampal neurons to AIDS-related injury .

Gene polymorphisms in association with emerging cardiovascular risk markers in adult women . BACKGROUND : Evidence on the associations of emerging cardiovascular disease risk factors / markers with genes may help identify intermediate pathways of disease susceptibility in the general population . This population-based study is aimed to determine the presence of associations between a wide array of genetic variants and emerging cardiovascular risk markers among adult US women . METHODS : The current analysis was performed among the National Health and Nutrition Examination Survey ( NHANES ) III phase 2 samples of adult women aged 17 years and older ( sample size n = 3409 ) . Fourteen candidate genes within P07550 REA , P13945 REA , CAT , CRP , F2 , P12259 REA , P02675 REA , P05106 REA , P42898 REA , NOS 3 , P27169 REA , P37231 REA , O00206 REA , and P01375 REA were examined for associations with emerging cardiovascular risk markers such as serum P02741 REA , homocysteine , uric acid , and plasma fibrinogen . Linear regression models were performed using SAS-callable SUDAAN 9.0 . The covariates included age , race / ethnicity , education , menopausal status , female hormone use , aspirin use , and lifestyle factors . RESULTS : In covariate-adjusted models , serum P02741 REA concentrations were significantly ( P value controlling for false-discovery rate < or = 0.05 ) associated with polymorphisms in CRP ( rs3093058 , rs1205 ) , P42898 REA ( rs1801131 ) , and P13945 REA ( rs4994 ) . Serum homocysteine levels were significantly associated with P42898 REA ( rs1801133 ) . CONCLUSION : The significant associations between certain gene variants with concentration variations in serum P02741 REA and homocysteine among adult women need to be confirmed in further genetic association studies .

Clinical utility of ramucirumab in advanced gastric cancer . Gastric cancer is currently the third most common cause of cancer deaths worldwide . Prognosis remains poor with most patients presenting with advanced or metastatic disease . A better understanding of angiogenesis has led to the investigation of drugs that inhibit the vascular endothelial growth factor ( P15692 REA ) pathway including anti - P15692 REA antibody therapy ( eg , bevacizumab ) , inhibitors of angiogenic receptor tyrosine kinases ( eg , sunitinib , sorafenib , apatinib , regorafenib ) , and inhibitors of vascular endothelial growth factor receptors ( VEGFRs ) ( eg , ramucirumab ) . DB05578 MEN , a P35968 REA inhibitor , is the first anti-angiogenic agent approved by the US Food and Drug Administration for use in the treatment of advanced gastric cancers . This review will focus on the clinical utility and potential use of ramucirumab in advanced gastric cancer .

Additive role of tiotropium in severe asthmatics and Arg 16Gly in P07550 REA as a potential marker to predict response . BACKGROUND : Recent findings have raised new interests about the use of anticholinergics , especially tiotropium , for the treatment of asthma . This study was performed to determine whether an additional improvement in lung function is obtained when tiotropium is administrated in addition to conventional therapies in severe asthmatics , and to identify factors capable of predicting the response to tiotropium , using a pharmacogenetic approach . METHODS : A total of 138 severe asthmatics on conventional medications and with decreased lung function were randomly recruited . DB01409 MEN 18 microg was added once a day and lung functions were measured every 4 weeks . Responders were defined as those with an improvement of > or = 15 % ( or 200 ml ) in the forced expiratory volume in 1 s ( FEV 1 ) that was maintained for at least 8 successive weeks . Eleven single nucleotide polymorphisms ( SNPs ) in P11229 REA - 3 ( coding muscarinic receptors one to three ) which were identified by re-sequencing , and Arg 16Gly and Gln 27Glu in P07550 REA ( coding beta ( 2 ) adrenoreceptor ) were scored in 80 of the 138 asthmatics . RESULTS : Forty-six of the 138 asthmatics ( 33.3 % ) responded to tiotropium treatment . Logistic regression analyses ( controlled for age , gender , and smoking status ) showed that Arg 16Gly in P07550 REA [ P = 0.003 , OR ( 95 % CI ) = 0.21 ( 0.07- 0.59 ) in a minor allele-dominant model ] was significantly associated with response to tiotropium . CONCLUSIONS : As many as 30 % of severe asthmatics on conventional medications with reduced lung function were found to respond to adjuvant tiotropium . The presence of Arg 16Gly in P07550 REA may predict response to tiotropium .

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 SUB 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 .

Comparison of three GPCR structural templates for modeling of the Q9H244 REA nucleotide receptor . The P2Y ( 12 ) receptor ( P2Y ( 12 ) R ) is an ADP-activated G protein-coupled receptor ( GPCR ) that is an important target for antithrombotic drugs . Three homology models of P2Y ( 12 ) R were compared , based on different GPCR structural templates : bovine rhodopsin ( bRHO ) , human A ( 2A ) adenosine receptor ( A ( 2A ) AR ) , and human P61073 REA ( P61073 REA ) . By criteria of sequence analysis ( 25.6 % identity in transmembrane region ) , deviation from helicity in the second transmembrane helix ( TM2 ) , docked poses of ligands highlighting the role of key residues , accessibility of a conserved disulfide bridge that is reactive toward irreversibly-binding antagonists , and the presence of a shared disulfide bridge between the third extracellular loop ( EL3 ) and the N-terminus , the P61073 REA - based model appeared to be the most consistent with known characteristics of P2Y ( 12 ) R . The docked poses of agonist 2MeSADP and charged anthraquinone antagonist PSB - 0739 in the binding pocket of P2Y ( 12 ) R-CXC agree with previously published site-directed mutagenesis studies of Arg 256 and Lys 280 . A sulfonate at position 2 of the anthraquinone core created a strong interaction with the Lys 174 ( EL2 ) side chain . The docking poses of the irreversibly-binding , active metabolite ( existing as two diastereoisomers in vivo ) of the clinically utilized antagonist DB00758 SUB were compared . The free thiol group of the 4S diastereoisomer , but not the 4R isomer , was found in close proximity ( ~ 4.7 Å ) to the sulfur atom of a disulfide bridge involving Cys 175 , suggesting greater activity in covalent binding . Therefore , ligand docking to the P61073 REA - based model of the P2Y ( 12 ) R predicted poses of both reversibly and irreversibly-binding small molecules , consistent with observed pharmacology and mutagenesis studies .

DB04866 MEN suppresses the lung metastasis of chemically induced hepatocellular carcinoma in rats through MMP inhibition . DB04866 MEN , an inhibitor of collagen synthesis , appears to be a promising antitumoral drug in preclinical studies . We used a relevant rat model of autochthonous , chemically induced , spontaneously metastasizing hepatocellular carcinoma ( HCC ) to test the efficacy of halofuginone on tumor progression and matrix metalloproteinase ( MMP ) expression . Following sequential administration of diethylnitrosamine and N-nitrosomorpholine for 14 weeks , all animals developed HCC and then received halofuginone or its solvent for 10 weeks . The final number of liver tumors was lower in the halofuginone group than in the solvent group ( 57.2 + / - 4.6 vs 68 + / - 5.0 ; P < . 01 ) . The percentage of the lung surface infiltrated by metastasis was much smaller in the halofuginone group ( 0.3 + / - 0.2 % ) than in the solvent group ( 13.5 + / - 10.1 % ; P < . 02 ) . P14780 REA activity was decreased in the halofuginone group by 89 % and 63 % in non-neoplastic parts of the liver and tumor , respectively . The percentage of active P08253 REA was reduced by 90 % in non-neoplastic parts of the liver and by 61 % in tumors . This was likely subsequent to a decreased expression of both P50281 REA and tissue inhibitor of matrix metalloproteinase - 2 , which are required for pro - P08253 REA activation . These results , obtained from a clinically relevant model , further suggest the potential benefit of halofuginone in HCC .

A field synopsis and meta-analysis of genetic association studies in peripheral arterial disease : The CUMAGAS-PAD database . In an electronic search of the literature , the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease ( PAD ) . They created a comprehensive database of all eligible studies , collecting detailed genetic and bioinformatics data on each polymorphism . Data from eligible studies were synthesized using meta-analysis techniques . Gene variants were classified into distinct pathophysiologic pathways , and their potential involvement in PAD pathogenesis was determined . Forty-one publications that examined 44 gene polymorphisms were included . For 37 polymorphisms , the variant form had a functional effect . Twenty-three polymorphisms in 22 potential PAD candidate genes ( F2 , P02675 REA , P42898 REA , P05106 REA , P12821 REA , AGT , P05231 REA , P13500 REA , P05362 REA , P16581 REA , P14780 REA , P37231 REA , P03956 REA , P35611 REA , Q9H244 REA , P11150 REA , Q13093 REA , Q8WTV0 , P08254 REA , P55157 REA , P08519 REA , P32297 REA ) showed a significant association in individual studies . Eighty-eight percent of the studies had statistical power of less than 50 % , and in 15 studies the genotype distribution in the control group did not conform to Hardy-Weinberg equilibrium . Data on 12 polymorphisms ( P12259 REA 1691 G / A , P42898 REA 677C / T , F2 20210 G / A , P05106 REA 1565 T / C , P12821 REA I / D , AGT 704C / T , AGT - 6G / A , AGT 733C / T , P05231 REA - 174 G / C , P14780 REA - 1562C / T , P05362 REA 1462A / G , P32297 REA 831C / T ) were synthesized , and a positive association was found for 3 ( P05231 REA - 174 G / C , P05362 REA 1462A / G , P32297 REA 831C / T ) .

Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet-rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 REA ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 REA ) antagonist DB00758 SUB . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 REA and other agonists , while no aggregation was elicited with P08473 REA or AA alone . DB00758 SUB blocked the ADP-induced aggregation responses in a dose-dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 REA . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 REA and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 REA . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .

Regional expression of prostaglandin E2 and F2alpha receptors in human myometrium , amnion , and choriodecidua with advancing gestation and labor . The change from uterine quiescence to enhanced contractile activity may be due to the differential expression of prostaglandin receptors within the myometrium and fetal membranes , in a temporal and topographically distinct manner . To address this question , we determined the localization and expression of the DB00917 MEN receptor subtypes ( P34995 REA - 4 ) and the PGF 2alpha receptor ( P43088 REA ) in paired upper and lower segment myometrium , amnion , and choriodecidual samples throughout human pregnancy , with and without labor . All receptor subtypes were found throughout the muscle layers in both the upper and lower uterine segments , colocalizing with alpha smooth muscle actin . A change in intracellular localization was observed at term labor , where P34995 REA and P35408 REA were predominately associated with the nucleus . Minimal changes in the expression of the DB00917 MEN and PGF 2alpha receptor subtypes were observed with gestational age , labor , or between the upper and lower myometrial segments . Receptor expression in maternal and fetal tissues differed between the receptor subtypes ; P34995 REA and P35408 REA were predominately expressed in the fetal membranes , PTGER 2 was greatest in the myometrium , whereas P43115 REA and P43088 REA were similarly expressed in the myometrium and fetal membranes . Myometrial activation through the prostaglandin receptors is perhaps more subtle and may be mediated by a balance between one or several of the prostaglandin receptor subtypes together with other known contraction associated proteins . Lack of coordination in receptor expression between the myometrium and fetal membranes may indicate different regulatory mechanisms between these tissues , or it may suggest a function for these receptors in the amnion and choriodecidua that is independent of that seen in the myometrium .

High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety-five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . DB00758 SUB efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 REA ( PlA 1 / PlA 2 ) , P25116 REA ( IVSn - 14A / T ) , Q9H244 REA ( 32C / T ) , Q9H244 REA ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator-stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP-induced platelet reactivity significantly . Twenty-eight hours after drug administration , differences in suppression of ADP-induced platelet reactivity were observed between polymorphism-positive and polymorphism-negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA 2 ( P= 0.009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA 2 carriers in comparison with PlA 1 / PlA 1 patients ( 54 vs . 24 % , P= 0.082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA 2 polymorphism .