MH_dev_202

Natriuretic peptide / natriuretic peptide receptor-A ( P16066 REA ) system has inhibitory effects in renal fibrosis in mice . OBJECT : This study was designed to examine whether natriuretic peptide / natriuretic peptide receptor-A ( P16066 REA ) system attenuates renal fibrosis in a unilateral ureteral obstruction ( UUO ) model and also examined the mechanism involved . METHODS : Three groups were studied : untreated UUO in wild-type mice ; untreated UUO in P16066 REA KO mice ; and P01160 REA treated ( 0.05 microg / kg / min ) UUO in wild-type mice . We measured histological and immunohistochemical findings ( alpha-SMA and F4 /8 0 ) , tissue cGMP levels , various mRNA expression levels by real-time PCR analysis , and transcription factor levels ( AP - 1 and NF-kappaB ) in renal tissue . RESULTS : Compared with wild-type UUO mice , NPRA-KO UUO mice had abnormal morphological findings ( fibrous area : + 26 % , alpha-SMA expression : + 30 % ) with lower tissue cGMP levels and increases in the mRNA expression levels of TGF-beta , collagen I , collagen III , P05121 REA , renin and angiotensinogen , whereas there were no differences in F4 /8 0 positive cells or the mRNA expression levels of P05362 REA , osteopontin , or P13500 REA between the two groups . In contrast , P01160 REA pre-treatment significantly improved morphological changes with increase of tissue cGMP levels and reduction in the mRNA expression level of TGF-beta , collagen I , collagen III , P05121 REA , P05362 REA , osteopontin , P13500 REA , renin , and angiotensinogen . NPRA-KO UUO mice had higher AP - 1 levels than wild-type UUO mice and P01160 REA pre-treatment reduced AP - 1 and NF-kappaB activity . CONCLUSION : The endogenous natriuretic peptide / P16066 REA system may inhibit renal fibrosis partly via inhibition of the angiotensin / AP - 1 / TGF-beta / collagen pathway and exogenous P01160 REA pre-treatment may inhibit it partly via both the angiotensin / AP - 1 / TGF-beta / collagen and NF-kappaB / inflammatory pathways .

P08473 REA inhibitor suppresses the early phase of atrial electrical remodeling in a canine rapid atrial pacing model . INTRODUCTION : We examined the acute effects of neutral endopeptidase inhibitor on the hemodynamics and electrical properties of dogs subjected to rapid atrial pacing . METHODS : Ten beagle dogs were used and divided into two groups with and without candoxatril , a neutral endopeptidase inhibitor preadministration . Before and after the 6 hours rapid atrial pacing from the right atrial appendage , the hemodynamics , atrial effective refractory period , and monophasic action potential duration of the right atrial appendage were measured and blood samples were collected . Atrial tissue was also excised after the experiment . RESULTS : DB00616 MEN significantly increased plasma P01160 REA levels ( Control : 88.4 + / - 50.25 vs . DB00616 MEN : 197.1 + / - 32.09 pg / ml , p = 0.004 ) and prevented reductions in atrial effective refractory period and monophasic action potential duration . We further demonstrated that the treated animals exhibited significantly higher levels of atrial tissue cyclic GMP ( Control : 28.1 + / - 1.60 fmol / mg vs . DB00616 MEN : 44.5 + / - 12.28 fmol / mg , p = 0.034 ) as well as that of plasma cyclic GMP ( Control : 32 + / - 5.5 vs . DB00616 MEN : 42 + / - 7.1 pg / ml , p = 0.028 ) . CONCLUSION : DB00616 MEN suppressed the shortening of atrial effective refractory period and monophasic action potential duration in the rapid atrial pacing model . As plasma P01160 REA and the atrial tissue levels of cyclic GMP were higher in the DB00616 MEN group than the control , this effect was considered to appear through the reduction of calcium overload caused by P01160 REA and cyclic GMP .

Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon-rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid-like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 REA however exhibited an altered binding activity in cancer specimens . DB04839 MENMAX DB04839 MEN did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet-related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .

Unprecedented acetoacetyl-coenzyme A synthesizing enzyme of the thiolase superfamily involved in the mevalonate pathway . Acetoacetyl - DB01992 MEN is the precursor of 3 - hydroxy - 3 - methylglutaryl ( HMG ) - DB01992 MEN in the mevalonate pathway , which is essential for terpenoid backbone biosynthesis . Acetoacetyl - DB01992 MEN is also the precursor of poly-beta-hydroxybutyrate , a polymer belonging to the polyester class produced by microorganisms . The de novo synthesis of acetoacetyl - DB01992 MEN is usually catalyzed by acetoacetyl - DB01992 MEN thiolase via a thioester-dependent Claisen condensation reaction between two molecules of acetyl - DB01992 MEN . Here , we report that nphT 7 , found in the mevalonate pathway gene cluster from a soil-isolated Streptomyces sp . strain , encodes an unusual acetoacetyl - DB01992 MEN synthesizing enzyme . The recombinant enzyme overexpressed in Escherichia coli catalyzes a single condensation of acetyl - DB01992 MEN and malonyl - DB01992 MEN to give acetoacetyl - DB01992 MEN and DB01992 MEN . Replacement of malonyl - DB01992 MEN with malonyl - ( acyl carrier protein ) resulted in loss of the condensation activity . No acetoacetyl - DB01992 MEN synthesizing activity was detected through the condensation of two molecules of acetyl - DB01992 MEN . Based on these properties of NphT 7 , we propose to name this unusual enzyme of the thiolase superfamily acetoacetyl - Q13057 REA . Coexpression of nphT 7 with the HMG - Q13057 REA gene and the P04035 REA gene in a heterologous host allowed 3.5- fold higher production of mevalonate than when only the HMG - Q13057 REA and P04035 REA genes were expressed . This result suggests that nphT 7 can be used to significantly increase the concentration of acetoacetyl - DB01992 MEN in cells , eventually leading to the production of useful terpenoids and poly-beta-hydroxybutyrate .

The association of P29274 REA and P29275 REA polymorphisms with the risk and severity of chronic heart failure : a case-control study of a northern Chinese population . The causes of chronic heart failure ( CHF ) and its progression are likely to be due to complex genetic factors . DB00640 MEN receptors A2A and A2B ( P29274 REA and P29275 REA , respectively ) play an important role in cardio-protection . Therefore , polymorphisms in the genes encoding those receptors may affect the risk and severity of CHF . This study was a case-control comparative investigation of 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls . Four common single-nucleotide polymorphisms ( SNPs ) of P29274 REA ( rs2236625 , rs2236624 , rs4822489 , and rs5751876 ) and one SNP of P29275 REA ( rs7208480 ) were genotyped and an association between SNPs and clinical outcomes was evaluated . Odds ratios ( ORs ) with 95 % confidence intervals ( CIs ) were used to assess the association . The rs4822489 was significantly associated with the severity of CHF after adjustment for traditional cardiovascular risk factors ( p = 0.040 , OR = 1.912 , 95 % CI = 1.029- 3.550 ) . However , the five SNPs as well as the haplotypes were not found to be associated with CHF susceptibility . The findings of this study suggest that rs4822489 may contribute to the severity of CHF in the northern Chinese . However , further studies performed in larger populations and aimed at better defining the role of this gene are required .

The peopling of São Tomé ( Gulf of Guinea ) : origins of slave settlers and admixture with the Portuguese . The geographic origins of African slave settlers and the Portuguese genetic contribution to the population of São Tomé ( Gulf of Guinea ) were assessed through the analysis of beta-globin haplotypes in 44 chromosomes bearing the betaS allele and through the study of the genetic variation in eight autosomal markers ( P02647 REA , P01008 REA , FY , P06858 REA , Q04671 REA , P06400 REA , Sb19 . 3 , and GC ) informative for admixture in a sample of 224 individuals . The observed betaS haplotype distribution ( 36.4 % Bantu , 52.3 % Benin , 4.5 % Cameroon , 4.5 % Senegal , and 2.3 % atypical ) is in accordance with the historical information on the major geographic sources of slave settlers of São Tomé , although it captures a more important contribution of Central-West Africa regions than previously anticipated . European admixture , estimated to be 10.7 + / - 0.9 % , has created a considerable level of genetic structure , as indicated by the finding of significant linkage disequilibrium between 33 % of unlinked marker loci pairs . Recent admixture was found to have an important contribution to these values , since removal of individuals with Portuguese or Cape Verdian parents or grandparents from the sample dropped the miscegenation level to 6.5 + / - 0.8 % and reduced significant linkage disequilibrium to 11 % of unlinked marker pairs . Taken together , these results indicate that the peopling of São Tomé might have provided one of the first examples of the combination of diverse African contributions and European admixture that emerged from the overseas population relocations promoted by the Atlantic slave trade .

Genetic variants in pre-eclampsia : a meta-analysis . BACKGROUND Pre-eclampsia has a clear familial component , suggesting that the condition may be partly attributable to genetic susceptibility . The search for susceptibility genes has led to a drastic increase in the number of published studies associating genetic factors with pre-eclampsia . However , attempts to replicate these findings have yielded inconsistent results . This meta-analysis assessed the pooled effect of each genetic variant that is reproducibly associated with pre-eclampsia . METHODS Studies that assessed the association between genes and pre-eclampsia were searched in PubMed , Embase and Web of Science . We selected all genetic variants that were significantly associated with pre-eclampsia in an initial study and were subsequently independently reproduced in at least one additional study . All studies that assessed these reproduced variants were then included . The association between genetic variants and pre-eclampsia was calculated at the allele level , and the main measure of effect was a pooled odds ratio in a random-effects model . RESULTS The literature search yielded 2965 articles , of which 542 investigated genetic associations in pre-eclampsia . We identified 22 replicated genetic variants , of which 7 remained significantly associated with pre-eclampsia following meta-analysis . These variants were in or near the following genes : P12821 REA , P16410 REA , F2 , FV , P06858 REA and P05121 REA . CONCLUSIONS This meta-analysis identified seven genetic variants associated with pre-eclampsia . Importantly , many of these variants are also risk factors for developing cardiovascular disease , revealing that pre-eclampsia and cardiovascular disease have shared genetic risk factors . The contribution of the identified genetic variants in the pathogenesis of pre-eclampsia should be the focus of future studies .

[ Endothelial progenitor cells related gene expression changes before and early after revascularization in patients with acute myocardial infarction ] . OBJECTIVE : The purpose of this study was to observe the endothelial progenitor cells ( EPCs ) related gene expression changes before and early after revascularization in patients with acute myocardial infarction . METHODS : Peripheral blood samples were taken from patients with acute anterior myocardial infarction 6 hours and 7 days after P05154 REA and stenting . Mononuclear cells ( MNCs ) were isolated by Ficoll-density centrifugation and cultured in M - 199 medium . After 14 days culture , attaching cells incorporated DiI-acetylated low-density lipoprotein ( EPCs ) were collected and RNA was isolated by Trizol for microarray analysis on 24 genes associated with permissibility / vessel tone ( angiotensin system : P12821 REA , AGTR - 1 , AGTR - 2 ; NO system : P29474 REA ; prostacyclin system : P35354 REA ; endothelin system : ET - 1 , P25101 REA , ETB ; superoxide anions system : SOD - 1 ) , angiogenesis ( adhesion molecule : P33151 REA ; growth factors and receptors : P17948 REA , P35968 REA , P15692 REA ) and endothelial cell activation ( adhesion molecules expression : P05362 REA , P13598 REA , P32942 REA , P16284 REA , E-Selectin , L-Selection , P19320 REA ; change phenotype from antithrombotic to prothrombotic : tPA , uPA , P05121 REA , P04275 REA ) . P35968 REA , P16284 REA and P33151 REA positive cells were identified by flow cytometry . RESULT : Eight gene expressions ( AGTR - 1 , AGTR - 2 , P35354 REA , P29474 REA , ET - 1 , P25101 REA , P15692 REA ) were significantly downregulated 7 days post P05154 REA compared to pre - P05154 REA ( P < 0.05 ) . Flow cytometry results showed that P35968 REA positive cells were also significantly reduced post P05154 REA than that of before P05154 REA ( P < 0.05 ) . CONCLUSION : P05154 REA down-regulated endothelial progenitor cells related gene expressions in patients with acute myocardial infarction .

Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis . Disruption of the blood-brain barrier ( BBB ) underlies the development of experimental autoimmune encephalomyelitis ( EAE ) and multiple sclerosis . Environmental factors , such as Bordetella pertussis , are thought to sensitize central endothelium to biogenic amines like histamine , thereby leading to increased BBB permeability . B . pertussis-induced histamine sensitization ( Bphs ) is a monogenic intermediate phenotype of EAE controlled by histamine H ( 1 ) receptor ( Hrh 1 / H ( 1 ) R ) . Here , we transgenically overexpressed H ( 1 ) R in endothelial cells of Hrh 1 - KO ( H ( 1 ) RKO ) mice to test the role of endothelial H ( 1 ) R directly in Bphs and EAE . Unexpectedly , transgenic H ( 1 ) RKO mice expressing endothelial H ( 1 ) R under control of the P04275 REA promoter ( H ( 1 ) RKO - P04275 REA ( P35367 REA ) Tg ) were Bphs-resistant . Moreover , H ( 1 ) RKO - P04275 REA ( P35367 REA ) Tg mice exhibited decreased BBB permeability and enhanced protection from EAE compared with H ( 1 ) RKO mice . Thus , contrary to prevailing assumptions , our results show that endothelial H ( 1 ) R expression reduces BBB permeability , suggesting that endothelial H ( 1 ) R signaling may be important in the maintenance of cerebrovascular integrity .

A cell-based luciferase-dependent assay for the quantitative determination of free extracellular adenosine with paracrine signaling activity . Extracellular adenosine exerts powerful paracrine effects on immune cells . Thus , adenosine signaling has to be strictly regulated . This is achieved by its rapid internalization or enzymatic degradation . Consequently , free adenosine is extremely difficult to measure in cell culture systems and may escape from detection by time-consuming endpoint measurements like high-performance liquid chromatography ( HPLC ) . Therefore , we have now developed a highly sensitive assay which enables the quantification of biologically relevant extracellular adenosine via the activation of an ectopically expressed DB00640 MEN 2a - receptor ( P29274 REA ) in P29320 REA - 293 reporter cells . Binding of the short-lived nucleoside to this receptor induces a DB02527 - dependent signal which can be detected via a DB02527 - responsive luciferase construct . Tests with exogenously added adenosine confirmed that the resulting luminescence signals correlate with the respective adenosine levels and thus allow quantitative measurements in a range from 20 nM to 80 μM free extracellular adenosine . Inhibition of adenosine uptake by dipyridamole further increased the sensitivity of the assay . We further validated our approach by quantifying the adenosine levels that are generated by regulatory T cells via ectonucleotidase-mediated cleavage of DB00171 . As expected , values returned to baseline when P29274 REA was inhibited . This confirmed that this new cell-based reporter assay constitutes a biologically relevant , technically easy , versatile , scalable and cost-effective approach that allows the non-radioactive quantification of adenosine as a signaling intermediate .

DB06403 MEN for pulmonary arterial hypertension . Endothelin receptor antagonists ( ERAs ) are an important class of agents used for the treatment of pulmonary arterial hypertension ( PAH ) . DB06403 MEN is an oral , once-daily , endothelin type-A receptor ( P25101 REA ) - selective , propanoic acid class ERA under clinical investigation for the treatment of PAH . In a Phase II study , ambrisentan improved 6 - minute walk distance , Borg dyspnea index , World Health Organization Functional Class , and hemodynamics . DB06403 MEN was well tolerated and adverse events were not dose related , including a low incidence and severity of liver function test abnormalities . There are no relevant interactions between ambrisentan and cytochrome P450 isoenzymes ( metabolism , induction or inhibition ) that might alter the activity of P450 - metabolized drugs . Potential benefits of ambrisentan include oral , once-daily dosing , ET ( A ) - receptor selectivity , and the decreased risks of liver toxicity and adverse drug-drug interactions compared with other ERAs .

Identification of antithrombin-modulating genes . Role of O95461 REA , a gene encoding a bifunctional glycosyltransferase , in the secretion of proteins ? The haemostatic relevance of antithrombin together with the low genetic variability of P01008 REA , and the high heritability of plasma levels encourage the search for modulating genes . We used a hypothesis-free approach to identify these genes , evaluating associations between plasma antithrombin and 307,984 polymorphisms in the GAIT study ( 352 individuals from 21 Spanish families ) . Despite no SNP reaching the genome wide significance threshold , we verified milder positive associations in 307 blood donors from a different cohort . This validation study suggested O95461 REA , a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin-like linear polysaccharides , as a potential modulator of antithrombin based on the significant association of one SNPs , rs762057 , with anti-FXa activity , particularly after adjustment for age , sex and P01008 REA rs2227589 genotype , all factors influencing antithrombin levels ( p = 0.02 ) . Additional results sustained this association . O95461 REA silencing inHepG 2 and P29320 REA - EBNA cells did not affect P01008 REA mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention . Milder effects were observed on α1 - antitrypsin , prothrombin and transferrin . Our study suggests O95461 REA as the first known modifier of plasma antithrombin , and proposes a new role for O95461 REA in modulating extracellular secretion of certain glycoproteins .

Contribution of the 37 - kDa laminin receptor precursor in the anti-metastatic P08118 - derived peptide DB04985 MEN cell surface binding . PURPOSE : DB04985 MEN is an anti-metastatic synthetic peptide with promising therapeutic efficacy against hormone-refractory prostate cancer . The characterization of the DB04985 MEN peptide cell surface binding / internalization mechanisms and of the receptors involved remained to be explored . RESULTS : [ ( 14 ) C ] DB04985 MEN cell surface binding assays showed rapid and transient kinetic profile , that was inhibited by RGD peptides , laminin , hyaluronan , and type-I collagen . RGD peptides were however unable to inhibit DB04985 MEN intracellular uptake . Far-Western ligand binding studies enabled the identification of the 37 - kDa laminin receptor precursor ( P08865 REA ) as a potential ligand for DB04985 MEN . Overexpression of the recombinant P08865 REA indeed led to an increase in DB04985 MEN binding but unexpectedly not to its uptake . CONCLUSIONS : Our data support the implication of laminin receptors in cell surface binding and in transducing DB04985 MEN anti-metastatic effects , and provide a rational for targeting cancers that express high levels of such laminin receptors .

The role of tumor suppressor dysregulation in prostate cancer progression . P10275 REA activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 REA ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 REA and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type P06400 REA and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 REA and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 REA and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .

Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II-dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 REA ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , DB06271 SUB ( SLX ) which catalyzes thrombin inhibition by P01008 REA and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti-thrombin U / kg , respectively . SLX ( 16 anti-thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti-thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 REA and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .

Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 REA ( P04275 REA ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 REA , plasminogen activator inhibitor type 1 ( P05121 REA ) , antithrombin III ( P01008 REA ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 REA ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 REA secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 REA are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 REA and P01008 REA difference between FAECs and FVECs . P09038 REA ( 10 ng / ml ) significantly increased P04275 REA secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .

The anticoagulant effect of PGI 2S and tPA in transgenic umbilical vein endothelial cells is linked to up-regulation of PKA and PKC . The selection of vascular grafts for coronary artery bypass surgery is crucial for a positive outcome . This study aimed to establish a novel line of vascular endothelial cells with a potent anticoagulant effect . A lentiviral vector was used to stably transfect human umbilical vein endothelial cells ( HUVECs ) with PGI 2S alone ( HUVEC-PGI 2S ) or both PGI 2S and tPA ( HUVEC-PGI 2S - tPA ) . Both HUVEC-PGI 2S and HUVEC-PGI 2S - tPA cells over-expressing PGI 2S and tPA were compared to mock-transfected cells . The enzyme-linked immuno sorbent assay ( ELISAs ) demonstrated that the anticoagulation components , P01008 REA and P00747 REA , were up-regulated and coagulation factor FVIII was down-regulated in both cell lines . QRT-PCR and western blotting demonstrated the vasodilation and platelet disaggregation proteins PKA , PKC , and P43119 REA were up-regulated in both cell lines , but MAPK expression was not altered in either cell line . However , cell viability and colony formation assays and cell cycle analysis demonstrated that both cell lines had a lower rate of cell growth and induced P55008 phase arrest . HUVEC-PGI 2S and HUVEC-PGI 2S - tPA cells have a potent anticoagulant effect and their use in vascular heterografts may decrease the risk of thrombosis .

Clinical significance of arginase after liver transplantation . Liver graft function after transplantation is dependent on ischemia-reperfusion injury , toxicity of drugs ( immunosuppression , antibiotics and other ) and transplant rejection . Although routinely monitored with enzymatic tests ( Q9NRA2 , ALT , P19440 REA , ALP ) , bilirubin and coagulation parameters , differentiation between these pathologies is hardly possible without liver biopsy . Arginase ( 3.5 . 3.1 ) mostly exists in the liver and in trace amounts in extra-hepatic tissue . Thus , we hypothesized that activity of arginase could be a more specific test of liver function . Sera of 32 liver transplant recipients were tested for Q9NRA2 , ALT , P01008 REA , bilirubin and arginase . Samples were obtained daily in first 2 weeks after LTx and weekly afterwards . Correlation of arginase activity with other liver function markers was calculated . Serum arginase peaked at day 1 post LTx ( mean 64,6+ / - 91 IU / L ) , and decreased more rapidly than other tests if good liver function was observed . The values showed strong and significant correlation with Q9NRA2 and ALT activities ( Pearsons R 0,65 and 0,47 respectively ) . We conclude that activity of arginase in the serum is an exact test of liver function .

DB05229 MEN sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 REA and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium-derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : DB05229 MEN sodium elicited dose-dependent ( 0.1 pM -0.1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 REA ( IP ) antagonist CAY 10441 . DB05229 MEN sodium-induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N ( G ) - nitro-L-arginine methyl ester ( L-NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H -1,2 , 4 - oxadiazolo [ 4,3- a ] quinoxalin - 1 - one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp - 8 - Br-cAMPS were comparable to L-NAME . DB05229 MEN sodium-induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate-sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : DB05229 MEN sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium-dependent and - independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively .

Platelet-derived growth factor stimulates membrane lipid synthesis through activation of phosphatidylinositol 3 - kinase and sterol regulatory element-binding proteins . We analyzed the transcriptional program elicited by stimulation of normal human fibroblasts with platelet-derived growth factor ( PDGF ) using cDNA microarrays . 103 significantly regulated transcripts that had not been previously linked to PDGF signaling were identified . Among them , a cluster of genes involved in fatty acid and cholesterol biosynthesis , including stearoyl - DB01992 MEN desaturase ( O00767 REA ) , fatty acid synthase , and hydroxymethylglutaryl - Q13057 REA ( Q01581 REA ) , was up-regulated by PDGF after 24 h of treatment , and their expression correlated with increased membrane lipid production . These genes are known to be controlled by sterol regulatory element-binding proteins ( SREBP ) . PDGF increased the amount of mature P36956 REA and regulated the promoters of O00767 REA and Q01581 REA in an SREBP-dependent manner . In line with these results , blocking SREBP processing by addition of 25 - hydroxycholesterol blunted the effects of PDGF on lipogenic enzymes . SREBP activation was dependent on the phosphatidylinositol 3 - kinase ( PI3K ) pathway , as judged from the effects of the inhibitor LY294002 and mutation of the PDGFbeta receptor tyrosines that bind the PI3K adaptor subunit p8 5 . Fibroblast growth factors ( P09038 REA and P08620 REA ) and other growth factors mimicked the effects of PDGF on NIH 3T3 and human fibroblasts . In conclusion , our results suggest that growth factors induce membrane lipid synthesis via the activation SREBP and PI3K .

Characterization of antihistamines using biphasic cutaneous reaction in BALB / c mice . Effects of 11 histamine H1 receptor antagonists on IgE-mediated biphasic cutaneous reaction in mice were examined . The immediate phase reaction ( IPR ) assessed at 1 hour after antigen application was significantly inhibited by all antihistamines examined . The inhibition of IPR by cetirizine and mequitazine were potent , but those by cyproheptadine and diphenhydramine were weak . The later phase reaction ( LPR ) assessed at 24 hours after antigen application was inhibited by chlorpheniramine , oxatomide , ketotifen , mequitazine , emedastine , terfenadine and azelastine . The inhibition of LPR by emedastine was potent , but those by ketotifen and terfenadine were only partial . DB01084 MEN inhibited both IPR and LPR comparably . Present results indicate that H1 receptor activation is involved in the IPR of the biphasic cutaneous reaction , and that the blockade of H1 receptors at IPR does not contribute to the attenuation of following LPR . P35367 REA antagonists inhibiting the LPR have a property distinct from H1 receptor antagonism , which may have an additional benefit for the treatment of allergic diseases .

[ Differentially expressed proteins in the precancerous stage of rat hepatocarcinogenesis induced by diethylnitrosamine ] . OBJECTIVE : To screen the differentially expressed proteins especially at the precancerous stage of diethylnitrosamine ( DEN ) induced hepatocarcinogenesis by comparative proteome research . METHODS : Rats were divided into normal and DEN groups and sacrificed periodically . The liver samples were stained with gamma-glutamyl transpeptidase ( P19440 REA ) and HE to distinguish the preneoplastic lesion ( pre-HCC ) from the normal and HCC tissues . The two-dimensional electrophoresis ( 2 - DE ) and mass spectrometry ( MALDI-TOF-MS / MS ) were then applied to analyze the differentially expressed protein between pre-HCC and normal tissues , pre-HCC and HCC , as well as HCC and normal tissues . A few of the candidate proteins such as laminin receptor 1 ( P08865 REA ) and agmatinase were validated by Western blot and RT-PCR . RESULTS : Totally , there were 82 proteins that differentially expressed two fold or more in one kind of tissues sample than the other , 47 of which occurred in the pre-HCC tissues . Eight proteins including P08865 REA were consistently up-regulated from normal tissue to pre-HCC and then to HCC tissues , while 22 proteins including agmatinase showed progressively down-regulated in these tissues samples . CONCLUSION : The protein expression profiles are different during the process of hepatocarcinogenesis . Further study on the differentially expressed protein , especially these upregulated in the precancerous stage such as P08865 REA and agmatinase , might contribute to prevention and early diagnosis of human HCC .

Antibody-based immunotherapy for ovarian cancer : where are we at ? Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment . However , as mortality from advanced ovarian cancer remains very high , novel therapies are required to be integrated into existing treatment regimens . Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers , and on the clinical success of immunotherapy in other malignancies . Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell , but research in this field is active . This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria : ( i ) they are antibody-based , ( ii ) target a distinct immunological pathway , and ( iii ) have reached the clinical trial stage . Specifically , the focus is on Catumaxomab ( anti-EpCAM × anti-CD 3 ) , Abagovomab , DB04964 MEN ( anti - Q8WXI7 ) , DB00111 ( anti-CD 25 ) , DB06186 ( anti - P16410 REA ) , and MXD - 1105 ( anti - Q9NZQ7 ) . Catumaxomab has reached phase III clinical trials and exhibits promise with reports , showing that it can cause a significant and sustained reduction in ascites . Phase I-III clinical trials continue to be conducted on the other antibodies , some of which have had encouraging reports . We will also provide our perspective on the future of immunotherapy for ovarian cancer , and how it may be best employed in treatment regimens .