MH_dev_14

Gossypin up-regulates P01130 REA through activation of P29323 REA pathway : a signaling mechanism for the hypocholesterolemic effect . Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease . This study aims to elucidate the effect of gossypin on cholesterol metabolism in HepG 2 cells . Results indicated that gossypin significantly reduced the total cholesterol concentration in a dose-dependent manner . There was a time - and dose-dependent increase in the expression of low-density lipoprotein receptor ( P01130 REA ) protein . However , 3 - hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase , the rate-limiting enzyme in cholesterol synthesis , was not affected by gossypin . Moreover , gossypin had no effect on nuclear sterol regulatory element binding proteins ( SREBP ) - 2 abundance . The activity of gossypin on P01130 REA expression was inhibited by the extracellular signal-regulated kinase ( P29323 REA ) inhibitor PD98059 . Western blotting analysis revealed that gossypin treatment dose - and time-dependently increased P29323 REA activation and preceded the up-regulation of P01130 REA expression . Collectively , these new findings identify gossypin as a new hypocholesterolemic agent that up-regulates P01130 REA expression independent of Q12772 REA but is dependent on P29323 REA activation .

DB01076 Increases P17813 , Q15796 REA , Phosphorylated Q15796 REA / 3 and P29474 REA Expression in ApoE / P01130 REA Double Knockout Mice . AIM : P17813 is a homodimeric transmembrane glycoprotein that has been demonstrated to affect transforming growth factor beta ( TGF-beta ) signaling and endothelial nitric oxide synthase ( P29474 REA ) expression by affecting SMAD proteins in vitro . Thus , in this study we stepped forward to elucidate whether endoglin is co-expressed with Q15796 REA , phosphorylated Q15796 REA / 3 proteins and P29474 REA in vivo in atherosclerotic lesions in ApoE / P01130 REA double knockout mice . In addition , we sought whether endoglin expression as well as the expression of Q15796 REA , phosphorylated Q15796 REA / 3 and P29474 REA is affected by atorvastatin treatment . METHODS : Two-month-old female ApoE / P01130 REA double knockout mice were divided into two groups . The control group was fed with the western type diet whereas in the atorvastatin group , atorvastatin at dose 100 mg / kg per day was added to the same diet . Immunohistochemical and western blot analysis of endoglin , Q15796 REA , phosphorylated Q15796 REA / 3 and P29474 REA expressions in aorta were performed . RESULTS : The biochemical analysis showed that administration of atorvastatin significantly decreased level of total cholesterol , VLDL , LDL , TAG , and significantly increased level of HDL cholesterol . Fluorescence immunohistochemistry showed endoglin co-expression with Q15796 REA , phosphorylated Q15796 REA / 3 and P29474 REA in aortic endothelium covering atherosclerotic lesions in both control and atorvastatin treated mice . Western blot analysis demonstrated that atorvastatin significantly increased expression of endoglin , Q15796 REA , phosphorylated Q15796 REA / 3 , and P29474 REA in mice aorta . CONCLUSION : These findings suggest , that endoglin might be interesting marker of endothelial dysfunction and / or atherogenesis which is upregulated by statins implicating potential beneficial role of endoglin and its pathway in atherosclerosis .

P01308 REA / P05019 REA signaling pathways enhances tumor cell invasion through bisecting GlcNAc N-glycans modulation . an interplay with P12830 REA . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 REA . We and others have previously demonstrated that P12830 REA has a role in the regulation of bisecting GlcNAc N-glycans expression , remaining to be determined the P12830 REA - dependent signaling pathway involved in this N-glycans expression regulation . In this study , we analysed the impact of P12830 REA expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 REA ( IGF-IR ) . We demonstrated that exogenous P12830 REA expression inhibits IR , IGF-IR and P29323 REA 1/2 phosphorylation . Stimulation with insulin and P05019 REA in MDA-MD - 435 cancer cells overexpressing P12830 REA induces a decrease of bisecting GlcNAc N-glycans that was accompanied with alterations on P12830 REA cellular localization . Concomitantly , IR / IGF-IR signaling activation induced a mesenchymal-like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 REA and IR / IGF-IR signaling as major networking players in the regulation of bisecting N-glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 REA / P05019 REA signaling play during cancer progression through glycosylation modifications .

Effects of a Topical Angiotensin-Converting Enzyme Inhibitor and a Selective P35354 REA Inhibitor on the Prevention of Hypertrophic Scarring in the Skin of a Rabbit Ear .    P12821 REA ( P12821 REA ) inhibitors have been reported to inhibit fibrogenesis , and cyclooxygenase - 2 ( P35354 REA ) inhibitors , to reduce scarring by reducing the initial inflammation . The authors reasoned that the topical application of these 2 agents may have a complementary effect on scar reduction . METHODS : DB01197 MEN ( P12821 REA inhibitor ) , celecoxib ( P35354 REA inhibitor ) , or a combination of captopril and celecoxib were topically applied to a skin wound in a rabbit ear , and investigated for the effects on scar formation . RESULTS : The level of scar elevation decreased in the captopril group and the level of infiltration of inflammatory cells decreased in the celecoxib group . In the group where a combination of the 2 drugs was used , the level of scar elevation decreased the most , and collagen deposition and organization returned to normal most rapidly . Celecoxib was found to inhibit the initial inflammation in the ear wound of the rabbit , and captopril inhibited scar elevation . CONCLUSION : Clinical application of these drugs will require further studies with regard to adverse events and their absorptivity as topical agents . However , these findings suggest that the combined topical administration of an P12821 REA inhibitor and P35354 REA inhibitor to a skin wound could be an effective treatment for the prevention of hypertrophic scarring .    .

P78347 enhances activation of the c-fos promoter through interactions with upstream elements . The transcription factor P78347 was initially isolated as a factor that can bind to initiator elements in core promoters . Recent evidence suggests that P78347 may also have a role in signal transduction . We have found that overexpression of P78347 can enhance the response of the wild-type c-fos promoter to a variety of stimuli . This effect depends on the c-fos DB00102 - platelet-derived growth factor-inducible factor binding element ( SIE ) and serum response element ( SRE ) . There is no effect of cotransfected P78347 on the TATA box containing the c-fos basal promoter . Three P78347 binding sites can be found in c-fos promoter . Two of these overlap the c-fos SIE and SRE , and another is located just upstream of the TATA box . Mutations that distinguish between serum response factor ( P11831 REA ) , P35610 REA , and P78347 binding to the c-fos SIE and SRE suggest that the binding of P78347 to these elements is important for c-fos induction in conjunction with the P11831 REA and P35610 REA transcription factors . Moreover , P78347 can form in vivo protein-protein complexes with the c-fos upstream activators P11831 REA , P42224 REA , and P40763 REA . These results suggest that P78347 may mediate the functional interdependence of the c-fos SIE and SRE elements . In addition , the ras pathway is required for P78347 to exert its effects on the c-fos promoter , and growth factor stimulation enhances tyrosine phosphorylation of P78347 . These results indicate that P78347 is involved in signal transduction as well as transcriptional activation of the c-fos promoter .

P08235 REA antagonism in the treatment of chronic central serous chorioretinopathy : a pilot study . PURPOSE : Based on experimental data showing that central serous chorioretinopathy could result from overactivation of mineralocorticoid receptor pathway in choroid vessels , the authors studied eplerenone , a mineralocorticoid receptor antagonist , as a potential treatment for chronic central serous chorioretinopathy . METHODS : This nonrandomized pilot study included 13 patients with central serous chorioretinopathy of at least 4 - month duration , treated with 25 mg / day of oral eplerenone for a week followed by 50 mg / day for 1 or 3 months . The primary outcome measure was the changes in central macular thickness recorded by optical coherence tomography , and the secondary outcomes included changes in foveal subretinal fluid ( P11831 REA ) measured by O75051 REA , in best-corrected visual acuity ( BCVA ) and the percentage of eyes achieving complete resolution of subretinal fluid during the treatment period . RESULTS : Central macular thickness decreased significantly from 352 ± 139 μm at baseline to 246 ± 113 μm and 189 ± 99 μm at 1 and 3 months under eplerenone treatment ( P < 0.05 and P < 0.01 , respectively ) . At 3 months , the subretinal fluid significantly decreased compared with baseline subretinal fluid ( P < 0.01 ) and best-corrected visual acuity significantly improved compared with baseline best-corrected visual acuity ( P < 0.001 ) . CONCLUSION : DB00700 SUB treatment was associated with a significant reduction in central macular thickness , subretinal fluid level , and an improvement in visual acuity . Randomized controlled trials are needed to confirm these encouraging results .

DB01197 MEN reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin-converting enzyme ( P12821 REA ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 REA ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 REA inhibitor captopril reduces plasma P05121 REA inhibitor activity , we measured changes in plasma P05121 REA activity ( IU / ml ) , tissue plasminogen activator ( t-PA ) antigen ( ng / ml ) , and serum P12821 REA activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37.5 mg daily ) and compared them with the values in 15 placebo-treated patients chosen at random . Blood sampling was performed at 07.00 h . In the captopril-treated group , serum P12821 REA activity decreased significantly , from 14.0 + / - 0.8 to 11.5 + / - 1.2 IU / L 24 h after captopril therapy ( p < 0.01 ) , and those of P05121 REA activity and t-PA antigen also decreased significantly-from 11.9 + / - 2.8 to 5.5 + / - 2.2 IU / ml ( p < 0.02 ) and from 9.9 + / - 1.0 to 7.5 + / - 0.9 ng / ml ( p < 0.05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 REA activity , P05121 REA activity , and t-PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .

Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of DB01285 MEN release by corticotroph tumor cells . In a series of human corticotroph adenomas , we recently found predominant mRNA expression of somatostatin ( SS ) receptor subtype 5 ( sst 5 ) . After 72 h , the multiligand SS analog DB06663 , which has a very high sst 5 binding affinity , but not DB00104 ( O75051 REA ) , significantly inhibited basal DB01285 MEN release . To further explore the role of sst 5 in the regulation of DB01285 MEN release , we conducted additional studies with mouse AtT - 20 cells . DB06663 showed a 7 - fold higher ligand binding affinity and a 19 - fold higher potency in stimulating guanosine 5 ' - O - ( 3 - thiotriphosphate ) binding in AtT - 20 cell membranes compared with O75051 REA . DB06663 potently suppressed P06850 REA - induced DB01285 MEN release , which was not affected by 48 - h dexamethasone ( DEX ) pretreatment . However , DEX attenuated the inhibitory effects of O75051 REA on DB01285 MEN release , whereas it increased the inhibitory potency of O43521 REA - 23268 , an sst 5 - specific analog , on DB01285 MEN release . Quantitative PCR analysis showed that DEX lowered sst ( 2A + 2B ) mRNA expression significantly after 24 and 48 h , whereas sst 5 mRNA levels were not significantly affected by DEX treatment . Moreover , Scatchard analyses showed that DEX suppressed maximum binding capacity ( B ( max ) ) by 72 % when 125I - Tyr 3 - labeled O75051 REA was used as radioligand , whereas B ( max ) declined only by 17 % when AtT - 20 cells were treated with [ 125I - Tyr 11 ] SS - 14 . These data suggest that the sst 5 protein , compared with sst 2 , is more resistant to glucocorticoids . Finally , after SS analog preincubation , compared with O75051 REA both DB06663 and O43521 REA - 23268 showed a significantly higher inhibitory effect on P06850 REA - induced DB01285 MEN release . In conclusion , our data support the concept that the sst 5 receptor might be a target for new therapeutic agents to treat Cushing ' s disease .

Inhibition of cyclooxygenases 1 and 2 by the phospholipase-blocker , arachidonyl trifluoromethyl ketone . BACKGROUND AND PURPOSE : Arachidonyl trifluoromethyl ketone ( Q06187 REA ) is widely used as an inhibitor of cytosolic group IV phospholipase A ( 2 ) ( cPLA ( 2 ) ) and calcium-independent group VI phospholipase A ( 2 ) ( iPLA ( 2 ) ) . Q06187 REA thus reduces arachidonic acid ( AA ) substrate for cyclooxygenase ( P36551 REA ; also known as prostaglandin H synthase ) and attenuates prostaglandin ( PG ) synthesis . It has been shown previously , that Q06187 REA blocks thromboxane B ( 2 ) production induced by exogenous AA in human platelets . It remains , however , unknown whether Q06187 REA also directly modulates the activity of cyclooxygenase ( P36551 REA ) . EXPERIMENTAL APPROACH : Time courses for inhibition of P36551 REA by Q06187 REA was obtained using osteoblast-like MC3T3 - E1 cells , with exogenous AA as substrate and the pure enzymes P23219 REA and P35354 REA . PGE ( 2 ) was measured by GC-MS . KEY RESULTS : Q06187 REA was a potent inhibitor of P23219 REA and P35354 REA with IC ( 50 ) values of 0.5 and 0.1 microM in MC3T3 - E1 cells and of 1.7 and 2.6 microM using the pure enzymes . Inhibition was reversible , with slow - and tight-binding characteristics . The arachidonyl carbon chain was essential , as the saturated palmitoyl analogue had no effect . CONCLUSIONS AND IMPLICATIONS : Attenuation of PG synthesis by Q06187 REA is taken to be the consequence of PLA ( 2 ) inhibition and the findings of many studies are interpreted on that basis . If there are , however , alternative routes for AA liberation ( such as phospholipase C / diacyl glycerol lipase or phospholipase D ) , this interpretation can lead to false conclusions . As Q06187 REA is a widely used and important pharmacological tool in eicosanoid research , knowledge of its interactions with other major enzymes of the cascade is of considerable importance .

Zeranol upregulates corticotropin releasing hormone expression in the placental cell line JEG - 3 . DB01285 MEN - releasing hormone ( P06850 REA ) plays a pivotal role in the control of parturition in human . Increased amount of plasma P06850 REA is associated with pre-mature delivery . Zeranol or α-zearalanol is a mycotoxin produced by fungi in the Fusarium family . Unlike other mycotoxins , exposure to zeranol appears to have minimal health risk . In North America , it is used as a growth-promoting agent in livestock . Because of the health concern of zeranol residue in meat , this practice has not been adopted in Europe . In our study zeranol could induce P06850 REA protein expression in JEG - 3 cells as low as 0.1 nM . As electrophoretic mobility shift assay indicated an increase in the CRE binding activity in P06850 REA promoter , the induction was likely triggered by transcriptional regulation . We further looked into the signal transduction pathway and PKCδ and P27361 REA / 2 were found to be activated . This study showed that zeranol could increase P06850 REA expression in placental cells , and the findings might be a concern for pregnant women .

[ DB00707 MEN sodium ( Photofrin-II ) ] . DB00707 MEN sodium ( DB00707 MEN ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 REA activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . DB00707 MEN sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84.8 % , 50.0 % , 90.0 % , 87.5 % and 94.4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .

Paraoxonase - 1 activity affects the clopidogrel response in P33261 REA loss-of-function carriers . BACKGROUND : The impact of paraoxonase - 1 ( P27169 REA ) activity on the response to clopidogrel may differ in patients treated with drug-eluting stents ( DES ) in association with P33261 REA loss-of-function ( LOF ) polymorphisms . METHODS : This study included 112 Japanese patients receiving clopidogrel ( 75 mg / day ) and aspirin ( 100mg / day ) who underwent optical coherence tomography ( O75051 REA ) examination 9 months after DES implantation . The P33261 REA genotype was analyzed and LOF carriers ( 1/2 , 1/3 , 2/2 , 3/3 , 2/3 ) were identified . At the 9 - month follow-up , platelet reactivity was determined by measuring the Q9H244 REA reactivity unit ( PRU ) using a VerifyNow Q9H244 REA assay , P27169 REA activity was evaluated and intra-stent thrombus was evaluated by O75051 REA . RESULTS : Of the 112 Japanese patients , 75 were LOF carriers ( 67.0 % ) . The patients were divided into tertiles according to the P27169 REA activity ( tertile 1 ; < 230 U / L , tertile 2 ; 230-283 U / L , tertile 3 ; > 283 U / L ) . In the VerifyNowP 2Y12 analysis , tertile 1 had a higher PRU than tertiles 2 and 3 in LOF carriers , and there was no difference among tertiles in non-carriers . The highest incidence of intra-stent thrombus was observed in tertile 1 followed by tertiles 2 and 3 in LOF carriers , whereas there was no such difference in non-carriers . Multivariate analysis revealed that LOF carriers and P27169 REA activity tertile 1 were independent predictors of intra-stent thrombus in all patients . In LOF carriers , tertile 1 was the only independent predictor for intra-stent thrombus . CONCLUSION : Low P27169 REA activity is associated with a low response to clopidogrel and a high frequency of intra-stent thrombus only in LOF carriers .

DB09053 MEN inhibits P11274 REA and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue-resident CLL cells show prominent activation of both B-cell receptor ( P11274 REA ) and NF-κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 REA ( Q06187 REA ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway-specific gene signatures , we detected a rapid and sustained downregulation of P11274 REA and NF-κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . DB09053 MEN reduced phosphorylation of PLCγ 2 and P29323 REA and decreased nuclear protein expression of NF-κB p50 . DB09053 MEN significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 REA , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 REA signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on-target effects of Q06187 REA inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www.clinicaltrials.gov as # NCT 01500733 .

Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name DB06209 MEN , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 REA receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON-TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .

Structure of the human Q9H244 REA receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G-protein-coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 REA - like receptors and Q9H244 REA - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R - - including the prodrugs clopidogrel ( Plavix ) and prasugrel ( DB06209 MEN ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor - - have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half-life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2.6 Å resolution crystal structure of human P2Y12R in complex with a non-nucleotide reversible antagonist , AZD 1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD 1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD 1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand-binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .

Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 REA , P07550 REA , P13945 REA , P21964 REA , P16671 REA , P25025 REA , P24385 REA , P35354 REA , P11509 REA , P05093 REA , P11511 REA , IGF 1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 REA , P10145 REA , P22301 REA , P41159 REA , Le , L-myc , P05164 REA , Q99707 REA , P42898 REA , P21397 REA , P15559 REA , O15527 REA , p53 , p73 , Se , P31213 REA , TGF-B , P01375 REA - A , P01375 REA - B , P18074 REA , and P18887 REA ) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 REA A52C , P25025 REA C785T , P24385 REA G870A , IGF 1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 REA Ins / Del 17C , P10145 REA A - 278T and C74T , IL - 10 T - 819C , P41159 REA A - 2548G , P31213 REA 2 - bp VNTR , P18074 REA Lys 751Gln , and P18887 REA Arg 399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 REA - A G - 308A and P01375 REA - B A252G , P31213 REA Val 89Leu and 2 - bp VNTR , and P18887 REA Arg 399Gln and P18074 REA Lys 751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .

Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen-only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to DB00294 MEN users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo-pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post-treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre-decidualized state by 48 h post-treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 REA - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor-positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using DB00294 MEN who were treated with a single dose of mifepristone .

Altered expression of beta-catenin , P12830 REA , cycloxygenase - 2 , and p53 protein by ovine intestinal adenocarcinoma cells . Around 1.6 % of sheep in New Zealand develop small-intestinal adenocarcinomas . These neoplasms typically develop widespread metastases . The common development of these neoplasms and their subsequent behavior suggests that sheep could be a useful animal model of human colonic cancer . However , for an animal model of human disease to be relevant , similar genetic mutations should be present . Genetic mutations within human colonic cancers frequently result in expression of cycloxygenase - 2 ( P35354 REA ) , loss of membranous expression of beta-catenin and P12830 REA , and accumulation of p53 protein within the neoplastic cells . Immunohistochemistry was used to investigate the presence of these 4 proteins within 26 ovine intestinal adenocarcinomas . Loss of membranous beta-catenin reactivity was observed in 14 of 26 ovine intestinal adenocarcinomas ( 54 % ) . The loss of membranous beta-catenin reactivity was accompanied by cytoplasmic and nuclear reactivity in 2 neoplasms . Loss of P12830 REA was observed within 8 of 26 neoplasms ( 31 % ) . Neoplastic cell expression of P35354 REA was observed in 12 of 26 neoplasms ( 46 % ) , whereas cells within 3 of 26 neoplasms ( 11 % ) contained visible p53 protein . In conclusion , all 4 proteins that commonly have altered expression in human colonic cancers were also altered in a proportion of the ovine intestinal adenocarcinomas . These results provide additional evidence that sheep could be useful for the study of human colonic cancer .

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 MEN . 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 MEN 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 .

Nonsteroidal anti-inflammatory drugs ( NSAID ) sparing effects of glucosamine hydrochloride through N-glycosylation inhibition ; strategy to rescue stomach from NSAID damage . Gastrointestinal or cardiovascular complications limit nonsteroidal anti-inflammatory drugs ( NSAID ) prescription . DB01296 MEN hydrochloride ( GS-HCl ) alternatively chosen , but debates still exist in its clinical efficiency . P35354 REA instability through inhibiting P35354 REA N-glycosylation of GS-HCl raised the possibility of NSAID sparing effect . Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect . IEC - 6 cells were stimulated with P01375 REA - α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS-HCl by Western blotting and RT-PCR . C57BL / 6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS-HCl after 3 weeks . P01375 REA - α increased the expression of P35354 REA , P35228 REA and inflammatory cytokines , but GS-HCl significantly attenuated P01375 REA - α-induced P35354 REA expression . Decreased P35354 REA after GS-HCl was caused by N-glycosylation inhibition as much as tunicamycin . Combination of reduced dose of indomethacin and GS-HCl significantly reduced the expressions of P05362 REA , P19320 REA , P10145 REA , IL - 1β , P08253 REA , P09237 REA , P14780 REA , and P24347 REA mRNA as well as NF-κB activation better than high dose indomethacin alone . These NSAID sparing effect of GS-HCl was further proven in collagen-induced arthritis model . Combination of GS-HCl and 2.5 mg / kg indomethacin showed significant protection from gastric damages as well as efficacious anti-arthritic effect . Taken together , P35354 REA N-glycosylation inhibition by GS-HCl led to indomethacin sparing effects , based on which combination of GS-HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID-induced gastric damage as well as excellent anti-arthritic effects .

Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 REA ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 REA protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 REA expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 REA and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .

Role of cardiovascular aldosterone in hypertension . DB04630 plays an important role in the pathogenesis of cardiovascular disease . We have reported that aldosterone is synthesized in cardiovascular tissues and local aldosterone synthesis plays important roles for hypertension and cardiac hypertrophy . High sodium intake develops and accelerates vascular injury and cardiac hypertrophy in SHRSP . Plasma aldosterone concentrations and P06703 were decreased by high salt intake in SHRSP . DB04630 production , the expression of P19099 REA mRNA and angiotensin II receptor AT1R mRNA in blood vessels were significantly increased by high salt intake . These results suggest that high salt intake increases aldosterone production and expression of the AT1R mRNA in the vascular tissue in SHRSP , which may contribute to the development of malignant hypertension in salt-loaded SHRSP . However , there are several reports of conflicting data . P08235 REA ( MR ) binding is tightly regulated by the enzyme 11beta - hydroxysteroid dehydrogenase type 2 ( 11beta - HSD 2 ) which selectively metabolizes glucocorticoids to inactive metabolites , thus allowing for MR activation by aldosterone . We have reported that decreased 11beta - HSD 2 in blood vessels in Dahl salt-sensitive ( DS ) rats , a model for salt-sensitive hypertension . Local aldosterone excess may play a significant role in the salt sensitivity and development of hypertension . High sodium intake decreased circulating rennin-angiotensin-aldosterone system and increased blood pressure and cardiac hypertrophy in DS rats , which were prevented by the treatment with a selective MR antagonist , eplerenone . DB00700 SUB also improved endothelial nitric oxide synthase ( P29474 REA ) activity and P29474 REA mRNA expression in blood vessels in DS rats . These results further suggest that not only circulating aldosterone but also local aldosterone is of critical importance in the pathophysiology of cardiovascular disorders .

The sulphydryl containing P12821 REA inhibitor Zofenoprilat protects coronary endothelium from Doxorubicin-induced apoptosis . Pediatric and adult cancer patients , following the use of the antitumor drug Doxorubicin develop cardiotoxicity . Pharmacological protection of microvascular endothelium might produce a double benefit : ( i ) reduction of myocardial toxicity ( the primary target of Doxorubicin action ) and ( ii ) maintenance of the vascular functionality for the adequate delivery of chemotherapeutics to tumor cells . This study was aimed to evaluate the mechanisms responsible of the protective effects of the angiotensin converting enzyme inhibitor ( ACEI ) Zofenoprilat against the toxic effects exerted by Doxorubicin on coronary microvascular endothelium . We found that exposure of endothelial cells to Doxorubicin ( 0.1- 1μM range ) impaired cell survival by promoting their apoptosis . P27361 REA / 2 related p53 activation , but not reactive oxygen species , was responsible for Doxorubicin induced caspase - 3 cleavage . P04637 REA mediated-apoptosis and impairment of survival were reverted by treatment with Zofenoprilat . The previously described PI - 3K / P29474 REA / endogenous fibroblast growth factor signaling was not involved in the protective effect , which , instead , could be ascribed to cystathionine gamma lyase dependent availability of H2S from Zofenoprilat . Furthermore , considering the tumor environment , the treatment of endothelial / tumor co-cultures with Zofenoprilat did not affect the antitumor efficacy of Doxorubicin . In conclusion the ACEI Zofenoprilat exerts a protective effect on Doxorubicin induced endothelial damage , without affecting its antitumor efficacy . Thus , sulfhydryl containing ACEI may be a useful therapy for Doxorubicin-induced cardiotoxicity .

A kinase independent function for Tec kinase Q08881 REA in regulating antigen receptor induced serum response factor activation . The Tec family kinases are critical downstream regulators of antigen receptor signals in lymphocytes . As kinases , they act on critical substrates to regulate signals such as calcium increase leading to activation of transcription factors such as NFAT , NFkappaB and P11831 REA . We now show here that Q08881 REA , a member of the Tec family of tyrosine kinases , has a kinase independent function . Mutants of Q08881 REA that lack kinase activity or a kinase domain can rescue cells lacking Tec family kinases for antigen receptor induced P11831 REA activation , but not for NFAT , AP - 1 or NFkappaB activation . Furthermore , expression of these mutants in WT cells enhanced P11831 REA activation . This kinase independent function required the SH2 domain since a mutant lacking both the kinase and SH2 domains was much less effective at rescuing P11831 REA activation . This kinase-deleted mutant could partially rescue P29323 REA activation , and interact with multiple tyrosine phosphorylated proteins during antigen receptor signaling , suggesting that Q08881 REA uses a scaffolding function that regulates signals leading to specific regulation of P11831 REA activation .

p38 Mitogen-activated protein kinase is required for glucosamine-induced endothelial nitric oxide synthase uncoupling and plasminogen-activator inhibitor expression . BACKGROUND : Hexosamine biosynthetic pathway ( HBP ) is implicated in increased plasminogen activator inhibitor - 1 ( P05121 REA ) , and endothelial nitric oxide synthase ( P29474 REA ) dysfunction in diabetes . DB01296 MEN ( GlcN ) that directly activates HBP is a dietary supplement and is clinically used to treat osteoarthritis despite uncertain efficacy and adverse cardiovascular effects observed in animal models . p38 mitogen-activated protein kinase ( p38mapk ) has been shown to be involved in HBP-mediated biological processes . The aim of the present study was to investigate the role of p38mapk in GlcN-induced endothelial P05121 REA expression and P29474 REA dysfunction . METHODS AND RESULTS : In cultured human endothelial cells , GlcN time - and concentration-dependently increased P05121 REA protein level that was further enhanced by tumor necrosis factor ( P01375 REA ) - α , which was accompanied by a transient synergistic activation of p38mapk . The stimulation of P05121 REA by GlcN alone or by GlcN and P01375 REA - α in combination was inhibited by the specific inhibitor of p38mapk , but not that of JNK or P27361 REA / 2 . Moreover , in isolated mouse aortas , GlcN caused P29474 REA uncoupling resulting in enhanced superoxide and decreased NO production , as well as impaired endothelium-dependent relaxations , which were also fully prevented by the p38mapk inhibitor . CONCLUSIONS : HBP activated by GlcN increases P05121 REA expression and P29474 REA uncoupling depending on p38mapk , which not only explains hyperglycemic vascular complications , but also may bring into question the clinical use of GlcN . The present results , support currently ongoing clinical application of p38mapk inhibitor in patients with cardiovascular disease .

Characterization of plant P18887 REA and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 REA ( Pol beta ) and P49916 REA ( Lig 3 ) genes . Thus , the plant short-patch base excision repair ( short-patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X-ray repair cross complementing 1 ( P18887 REA ) , a well-known BER protein . The plant P18887 REA lacks the N-terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 REA ( OsXRCC 1 ) protein binds single-stranded DNA ( ssDNA ) as well as double-stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull-down assay . Through immunoprecipitation , we demonstrated that OsXRCC 1 forms a complex with P12004 REA in vivo . OsXRCC 1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV-B . DB00290 MEN also increased the fraction of OsXRCC 1 associated with chromatin . These results suggest that OsXRCC 1 contributes to DNA repair pathways that differ from the mammalian BER system .

Protective effects of mineralocorticoid receptor blockade against neuropathy in experimental diabetic rats . AIMS : P08235 REA ( MR ) blockade is an effective treatment for hypertension and diabetic nephropathy . There are no data on the effects of MR blockade on diabetic peripheral neuropathy ( DPN ) . The aim of this study was to determine whether MRs are present in the peripheral nerves and to investigate the effectiveness of MR blockade on DPN in streptozotocin ( Q11206 REA ) - induced diabetic rats . METHODS : Expression of MR protein and messenger RNA ( mRNA ) was examined in the peripheral nerves using Western blot analysis and RT-PCR . We next studied the effects of the selective MR antagonist eplerenone and the angiotensin II receptor blocker candesartan on motor and sensory nerve conduction velocity ( NCV ) , morphometric changes and cyclooxygenase - 2 ( P35354 REA ) gene and NF-κB protein expression in the peripheral nerves of Q11206 REA - induced diabetic rats . RESULTS : Expression of MR protein and mRNA in peripheral nerves was equal to that in the kidney . Motor NCV was significantly improved by 8 weeks of treatment with either eplerenone ( Q04695 REA ± 1.2 m / s ) or candesartan ( 46.4 ± 6.8 m / s ) compared with control diabetic rats ( 33.7 ± 2.0 m / s ) ( p < 0.05 ) . Sensory NCV was also improved by treatment with candesartan or eplerenone in diabetic rats . DB00700 SUB and candesartan caused significant improvement in mean myelin fibre area and mean myelin area compared with control diabetic rats ( p < 0.05 ) . P35354 REA mRNA and NF-κB protein were significantly elevated in the peripheral nerves of diabetic rats compared with control rats , and treatment with eplerenone or candesartan reduced these changes in gene expression ( p < 0.05 ) . CONCLUSION : MR blockade may have neuroprotective effects on DPN .

S-sulfhydration of Q02750 REA leads to P09874 REA activation and DNA damage repair . The repair of DNA damage is fundamental to normal cell development and replication . Hydrogen sulfide ( H2S ) is a novel gasotransmitter that has been reported to protect cellular aging . Here , we show that H2S attenuates DNA damage in human endothelial cells and fibroblasts by S-sulfhydrating Q02750 REA at cysteine 341 , which leads to P09874 REA activation . H2S - induced Q02750 REA S-sulfhydration facilitates the translocation of phosphorylated P27361 REA / 2 into nucleus , where it activates P09874 REA through direct interaction . Mutation of Q02750 REA cysteine 341 inhibits P29323 REA phosphorylation and P09874 REA activation . In the presence of H2S , activated P09874 REA recruits P18887 REA and P49916 REA to DNA breaks to mediate DNA damage repair , and cells are protected from senescence .

DB01285 MEN releasing factor receptor 1 ( CRF 1 ) and CRF 2 agonists exert an anti-inflammatory effect during the early phase of inflammation suppressing LPS-induced P01375 REA release from macrophages via induction of P35354 REA and DB00917 . P06850 REA ( CRF ) , the principal regulator of the hypothalamus-pituitary-adrenal ( Q9Y251 REA ) axis , also modulates the inflammatory response directly , via its effect on mast cells and macrophages . On macrophages , it augments production of lipopolysaccharide ( LPS ) - induced pro-inflammatory cytokines . CRF and its related peptides may also act as anti-inflammatory agents . Aim of the present work was to examine the role of macrophages on the anti-inflammatory effects of CRF-peptides and the mechanism involved . Thus , we examined if CRF receptor 1 ( CRF 1 ) and CRF 2 agonists exert any anti-inflammatory effect on primary mouse macrophages . We have found that : ( a ) CRF , P55089 REA ( P55089 REA ) 1 and Q96RP3 transiently suppressed the release of Tumor Necrosis Factor-alpha ( P01375 REA ) in LPS-activated macrophages , an effect peaking at 4 h . This effect did not involve changes on P01375 REA transcription . ( b ) CRF peptide-induced suppression of P01375 REA release depended on induction of P35354 REA and DB00917 synthesis . ( c ) Use of specific CRF 1 and CRF 2 antagonists suggested that this effect involved both CRF receptor types . ( d ) The effect of CRF-peptides on P35354 REA was mediated via PI3K and p38MAPK . ( e ) Longer exposure of macrophages to CRF-peptides resulted in induction of P01375 REA production via enhancement of its transcription . In conclusion , this is the first report suggesting that CRF 1 and CRF 2 agonists exert a biphasic effect on macrophages . During the early stages of the inflammatory response , they suppress P01375 REA release via induction of P35354 REA / DB00917 while later on they induce P01375 REA transcription . Hence , the reported anti-inflammatory effect of CRF-peptides appears to involve macrophages and is confined at the early stage of inflammation .

Inhibitors of Q06187 REA and Q08881 REA : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 REA and Q08881 REA are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein-Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 REA or Q08881 REA during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 REA or Q08881 REA . Furthermore , a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 REA inhibitor P05154 REA - 32765 , recently renamed DB09053 MEN , has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 REA inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 REA and Q08881 REA with their signalling pathways and review the development of the corresponding inhibitors .

Direct injection of calcitriol or its analog improves abnormal gene expression in the hyperplastic parathyroid gland in uremia . AIMS : In this study , we investigated the effects of direct injection ( DI ) of calcitriol or maxacalcitol into the hyperplastic parathyroid gland ( PTG ) on altered gene expression related to the advanced status of secondary hyperparathyroidism ( SHPT ) . METHODS : Sprague-Dawley rats were 5/6- nephrectomized ( uremic ) or sham-operated ( normal ) . In each uremic rat , one of the bilateral PTG was treated by DI of calcitriol ( PTG ( Q9HD26 ) ) or maxacalcitol ( PTG ( O75051 REA ) ) , and the other gland was treated with control solution ( PTG ( CONT ) ) . The PTG were evaluated for levels of expression of various mRNA and immunohistochemical staining of proliferating cell nuclear antigen ( P12004 REA ) . RESULTS : Significant differences in levels of expression of mRNA and P12004 REA were confirmed between the uremic and normal groups . In PTG ( Q9HD26 ) and PTG ( O75051 REA ) , expressions of almost all mRNA and P12004 REA were significantly improved ; both agents were able to normalize the abnormalities of the uremic PTG , in contrast to the baseline and individual PTG ( CONT ) . However , the difference in effect between PTG ( Q9HD26 ) and PTG ( O75051 REA ) was only small . CONCLUSION : Our results suggest that very high concentrations of calcitriol or maxacalcitol in the PTG improve abnormal gene expression and proliferation activity of parathyroid cells , and might explain the better control of SHPT using the DI technique .

Counteraction between angiotensin II and angiotensin - ( 1-7 ) via activating angiotensin type I and Mas receptor on rat renal mesangial cells . In the updated concept of renin-angiotensin system ( DB01367 ) , it contains the angiotensin converting enzyme ( P12821 REA ) - angiotensin ( Ang ) II-angtiogensin type 1 receptor ( AT1 ) axis and the angiotensin-converting enzyme-related carboxypeptidase ( Q9BYF1 ) - Ang - ( 1-7 ) - Mas axis . The former axis has been well demonstrated performing the vasoconstrictive , proliferative and pro-inflammatory functions by activation of AT1 receptors , while the later new identified axis is considered counterbalancing the effects of the former . The present study is aimed at observing the interaction between Ang - ( 1-7 ) and Ang II on cultured rat renal mesangial cells ( MCs ) . RT-PCR , Western blot and immunofluorescent staining and confocal microscopy results showed that both AT1 and Mas receptor were co-distributed in rat renal MCs . Ang - ( 1-7 ) showed similar effects on Ang II in cultured MCs that stimulated phosphorylated extracellular signal-regulated kinase ( P29323 REA ) 1/2 phosphorylation and transforms growth factor-β 1 synthesis , and cell proliferation and extracellular matrix synthesis . Co-treatment of the cell with Ang - ( 1-7 ) and Ang II , Ang - ( 1-7 ) counteracted AngII-induced effects in a concentration dependent manner , but failed to alter the changes induced by endothelin - 1 . The stimulating effect of Ang II was mediated by AT1 receptor while all the effects of Ang - ( 1-7 ) were blocked by Mas receptor antagonist A - 779 , but not by AT1 receptor antagonist losartan or P50052 REA receptor antagonist PD123319 . These results suggest that Ang - ( 1-7 ) and Ang II specifically interact with each other on rat renal MCs via activation of their specific receptors , Mas and AT1 receptor respectively .

Effect of P06850 REA on NO bioavailability , ROS production and antioxidant defense systems in endothelial EAhy 926 cells . Local or ' Immune ' DB01285 MEN - Releasing Hormone ( P06850 REA ) is secreted in peripheral tissues and plays a direct immunomodulatory role as an endocrine or paracrine mediator of inflammation . The present study was undertaken to determine whether P06850 REA affects the endothelial redox state . Accordingly , intracellular reactive oxygen species ( ROS ) content and peroxynitrite levels , endothelial nitric oxide synthase ( P29474 REA ) activity and nitric oxide ( NO ) levels as well as catalase activity , superoxide dismutase ( SOD ) activity and glutathione ( DB00143 ) levels were measured in the presence or absence of selective P06850 REA receptor - 1 and P06850 REA receptor - 2 inhibitors in endothelial EAhy 926 cells exposed in vitro in 10 ( - 7 ) M P06850 REA for 2 h . P06850 REA acting through both receptors induced a significant increase of ROS content ( p < 0.001 ) , catalase activity ( p < 0.001 ) and SOD activity ( p < 0.001 ) , accompanied by a simultaneous significant decrease of P29474 REA activity and NO levels ( p < 0.001 ) , as well as a significant increase in nitrotyrosine ( peroxynitrite ) levels ( p < 0.05 ) . The data indicate that P06850 REA may act as a regulator of pro-inflammatory mechanisms inducing adaptation of endothelial cell function to local stress .

P35354 REA promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL / 6 mice . Cyclooxygenase ( P36551 REA ) 2 is expressed in atherosclerotic lesions . We have previously reported that selective inhibition of P35354 REA reduces early atherosclerosis in P01130 REA deficient mice . To examine the role of P35354 REA in atherosclerosis in other mouse models , we studied the effects of selective P35354 REA inhibition ( by rofecoxib and NS - 398 ) and nonselective P36551 REA inhibition ( by indomethacin ) on early atherosclerotic lesion formation in apolipoprotein E-deficient ( apoE ( - / - ) ) mice . Selective P35354 REA and nonselective P36551 REA inhibition reduced atherosclerosis in female apoE ( - / - ) mice by 35-38 % and 38-51 % in the proximal and en face aortas , respectively . Next we investigated the role of macrophage P35354 REA by transplanting P35354 REA ( - / - ) fetal liver cells into C57BL / 6 mice and challenging the mice with an atherogenic diet . Genetic deletion of P35354 REA from hematopoietic cells reduced atherosclerosis by 51 % . In addition , LPS activated P35354 REA ( - / - ) macrophages had decreased expression of monocyte chemoattractant protein - 1 ( P13500 REA ) and tumor necrosis factor-alpha ( TNFalpha ) . The results demonstrate that selective inhibition of P35354 REA and elimination of P35354 REA from macrophages significantly reduces early atherosclerotic lesion formation in apoE-deficient and C57BL / 6 mice . These results are compatible with P35354 REA expression by macrophages having a proatherogenic role , and support the potential of anti-inflammatory therapeutic approaches for atherosclerosis .

[ DB09053 MEN : A new drug of B-cell malignancies ] . DB09053 MEN ( Imbruvica ® ) is a first-in-class , orally administered once-daily , that inhibits B-cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 REA ) . DB09053 MEN has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 REA mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression-free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . DB09053 MEN had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B-cell lymphomas subtypes such as in diffuse large B-cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B-cell malignancies .

DB03404 upregulates Egr - 1 expression in vascular smooth muscle cells via reactive oxygen species P27361 REA / 2 - Elk - 1 and NF-kappaB . Reactive oxygen species ( ROS ) and oxidant stress are important mediators of cardiovascular pathologies including atherosclerosis . One source of ROS in the vasculature is free heme released from hemoglobin . Because Egr - 1 , the regulator of cell proliferation and apoptosis , is also induced by oxidant stress and is likewise implicated in atherosclerosis , we examined the regulation of Egr - 1 by heme in vascular smooth muscle cells ( SMCs ) . DB03404 increased Egr - 1 expression ( mRNA , protein ) within 30 minutes and P27361 REA / 2 phosphorylation and nuclear translocation within 5 minutes . Inhibiting hemin-induced P27361 REA / 2 activation by U0126 ( MAPK-inhibitor ) , the antioxidant N-acetyl cysteine , the NADPH oxidase inhibitors apocynin and diphenyleneiodonium chloride , the superoxide scavenger tiron , or tricarbonyldichlororuthenium ( II ) - dimer ( carbon-monoxide donor ; CORM - 2 ) blocked hemin-induced Egr - 1 expression . DB03404 activated Elk - 1 , P11831 REA , and NF-kappaB and promoted their interaction with the Egr - 1 promoter . Downregulating Elk - 1 ( via siRNA ) or blocking NF-kappaB activation ( via BAY -11-7082 ) abolished hemin induction of Egr - 1 . Finally , hemin-induced Egr - 1 bound the promoters of tissue factor ( TF ) , P00747 REA Activator Inhibitor ( P05121 REA ) - 1 , and P01138 REA - 1A Binding ( NAB ) - 2 , upregulating their expression , and increased the biochemical activity of TF and P05121 REA . Upregulation of Egr - 1 and its target genes by heme-induced oxidant stress may be an important event in the initiation and progression of inflammatory vascular diseases such as atherosclerosis .

Negative feedback regulation between microRNA let - 7g and the oxLDL receptor P78380 REA . Lectin-like oxidized P01130 REA - 1 ( P78380 REA ) is a surface scavenger receptor for oxidized low-density lipoprotein ( oxLDL ) . Several transcription factors have been reported to regulate P78380 REA expression . MicroRNAs are small noncoding RNAs that control gene expression , but there have been no reports of P78380 REA expression being regulated by microRNAs . Because the microRNA let - 7g has been predicted to bind to P78380 REA mRNA , we investigated whether let - 7g can regulate P78380 REA expression . Our experiments first demonstrated that oxLDL can reduce let - 7g expression . We later confirmed that there is a let - 7g binding site on the 3 ' - untranslated region of P78380 REA mRNA . We showed that intracellular Ca ( 2 + ) - activated protein kinase C is involved in the oxLDL - P78380 REA - let - 7g pathway . Bioinformatics predicted that the let - 7g promoter has a binding site for the transcriptional repressor O75051 REA - 1 . We used a promoter assay and chromatin immunoprecipitation to confirm this binding . Consequently , knockdown of O75051 REA - 1 was found to increase let - 7g expression . Transfection of let - 7g inhibited oxLDL-induced P78380 REA and O75051 REA - 1 expression , cell proliferation and migration . Mice fed with a high-fat diet showed a decrease in let - 7g and an increase in P78380 REA and O75051 REA - 1 . A study on humans showed the serum levels of let - 7g are lower in subjects with hypercholesterolemia compared with normal controls . Our findings identify a negative feedback regulation between let - 7g and P78380 REA , and indicate that let - 7g could be a target to treat cardiovascular disease .

Mechanism of purinergic activation of endothelial nitric oxide synthase in endothelial cells . BACKGROUND : Decreased endothelial nitric oxide ( NO ) synthase ( P29474 REA ) activity and NO production are critical contributors to the endothelial dysfunction and vascular complications observed in many diseases , including diabetes mellitus . Extracellular nucleotides activate P29474 REA and increase NO generation ; however , the mechanism of this observation is not fully clarified . METHODS AND RESULTS : To elucidate the signaling pathway ( s ) leading to nucleotide-mediated P29474 REA phosphorylation at DB00133 - 1177 , human umbilical vein endothelial cells were treated with several nucleotides , including DB00171 , UTP , and ADP , in the presence or absence of selective inhibitors . These experiments identified P47900 REA , P41231 REA , and possibly P51582 REA as the purinergic receptors involved in P29474 REA phosphorylation and demonstrated that this process was adenosine independent . Nucleotide-induced P29474 REA phosphorylation and activity were inhibited by BAPTA-AM ( an intracellular free calcium chelator ) , rottlerin ( a protein kinase Cdelta inhibitor ) , and protein kinase Cdelta siRNA . In contrast , blockade of AMP-activated protein kinase , calcium / calmodulin-dependent kinase II , calcium / calmodulin-dependent kinase kinase , serine / threonine protein kinase B , protein kinase A , extracellular signal-regulated kinase 1/2 , and p38 mitogen-activated protein kinase did not affect nucleotide-mediated P29474 REA phosphorylation . CONCLUSIONS : The present study indicates that extracellular nucleotide-mediated P29474 REA phosphorylation is calcium and protein kinase Cdelta dependent . This newly identified signaling pathway opens new therapeutic avenues for the treatment of endothelial dysfunction .

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 .

Contribution of captopril thiol group to the prevention of spontaneous hypertension . We aimed to compare the effect of angiotensin converting enzyme ( P12821 REA ) inhibitors captopril ( containing thiol group ) and enalapril ( without thiol group ) on the development of spontaneous hypertension and to analyze mechanisms of their actions , particularly effects on oxidative stress and NO production . Six-week-old SHR were divided into three groups : control , group receiving captopril ( 50 mg / kg / day ) or enalapril ( 50 mg / kg / day ) for 6 weeks . At the end of experiment , systolic blood pressure ( SBP ) increased by 41 % in controls . Both captopril and enalapril prevented blood pressure increase , however , SBP in the captopril group ( 121 + / - 5 mmHg ) was significantly lower than that in the enalapril group ( 140 + / - 5 mmHg ) . Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group . DB01197 MEN and enalapril increased NO synthase activity in the heart and aorta to the similar level . Neither captopril nor enalapril was , however , able to increase the expression of P29474 REA . Both P12821 REA inhibitors increased the level of cGMP . However , cGMP level was significantly higher in the aorta of captopril group . We conclude that captopril , beside inhibition of P12821 REA , prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration .

[ The effect of blood pressure-reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 + / - 9.1 years , duration of diabetes 18 + / - 9.1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 REA ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 + / - 13 vs 140 + / - 13 mm Hg , P < 0.05 ; diastolic pressures 89 + / - 10 vs 87 + / - 10 mm Hg , not significant ) . Proteinuria ( > 0.5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2-20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20.3 + / - 14.4 vs 8.8 + / - 8.1 U / g creatinine ; P < 0.01 ) . DB01197 MENMAX DB01197 MEN did not affect metabolic control ( HbA 1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long-term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .

Is transforming growth factor-β signaling activated in human hypertrophied prostate treated by 5 - alpha reductase inhibitor ? BACKGROUND AND AIM : It is well known that androgen deprivation relates to penile fibrosis , so we hypothesize that long-term treatment with 5 - alphareductase inhibitors ( 5ARIs ) may increase the risk of fibrosis of prostate . PATIENTS AND METHODS : Thirty-two BPH patients who underwent transurethral resection of the prostate were enrolled . The patients were divided into two groups : group one , 16 patients underwent TURP who had been treated with tamsulosin for 2 years ; group two , 16 patients underwent TURP who had been treated with combination of tamsulosin and dutasteride for at least 1 year . We evaluated the expressions of P29475 REA , P35228 REA , P29474 REA , TGF-β 1 , TGF-β 2 , phosphorylated - Q15796 REA / 3 ( p - Q15796 REA / 3 ) , P12830 REA , P19022 REA , and α-smooth muscle actin in the resected prostate tissues by western blotting , and the TGF-β concentration was determined by ELISA kit . RESULTS : The expressions of 3 isoforms of NOS were significantly increased in group 2 except of P29474 REA in lateral prostate , and the expressions of TGF-β 1 , TGF-β 2 , and p - Q15796 REA / 3 increased about 2 - fold compared with group 1 . In group 2 , the P12830 REA expression decreased while P19022 REA expression increased significantly . CONCLUSIONS : The overexpression of P29475 REA may contribute to prostate smooth muscle relaxation ; however , long-time treatment with 5 Q9Y4X5 REA increases the risk of fibrosis of prostate .

Common variants of P29474 REA and P18887 REA genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery . PURPOSE : To evaluate the impact of functional polymorphisms in genes related to DNA repair mechanisms ( P18887 REA , P04637 REA , P43246 REA , P20585 REA , P18074 REA ) , oxidative stress response ( P09211 REA , P08263 REA , P29474 REA , P04179 REA ) and fibroblast proliferation ( TGFβ 1 ) on the risk of acute skin toxicity in breast cancer patients receiving radiotherapy . MATERIAL AND METHODS : Skin toxicity was scored according to the Radiation Therapy Oncology Group criteria in 286 breast cancer patients who received radiotherapy after breast conserving surgery . Genotyping was conducted by PCR-RFLP analysis and real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood . RESULTS : In the multivariate analysis , nominally significant associations , before multiple testing corrections , were found between P18887 REA T - 77C ( T carriers vs . CC , OR : 2.240 , 95 % CI : 1.015- 4.941 , P= 0.046 ) , P29474 REA G894T polymorphisms ( TT vs . G carriers , OR : 2.473 , 95 % CI : 1.220- 5.012 , P= 0.012 ) , breast diameter ( OR : 1.138 , 95 % CI : 1.001- 1.293 , P= 0.048 ) , boost dose-fractionation ( 3 Gy vs . no boost , OR : 4.902 , 95 % CI : 1.458- 16.483 , P= 0.010 ) and ≥ grade 2 acute radiation skin toxicity in breast cancer patients . CONCLUSIONS : As our exploratory study suggests that P18887 REA T - 77C and P29474 REA G874T may confer an increased risk of acute skin reactions to radiotherapy in breast cancer patients , further confirmatory studies are warranted to determine the clinical significance .

Thrombin inhibits migration of human hepatic myofibroblasts . Several lines of data recently pointed out a role of the serine proteinase thrombin in liver fibrogenesis , but its mechanism of action is unknown . The aim of this study was to evaluate the effect of thrombin on the migration of human liver myofibroblasts . We show here that thrombin inhibits both basal migration and platelet-derived growth factor ( PDGF ) - BB-induced migration of myofibroblasts . By using a thrombin antagonist , a protease-activated receptor ( PAR ) - 1 mimetic peptide , and a P25116 REA antibody , we show that this effect is dependent on the catalytic activity of thrombin and on P25116 REA activation . Thrombin ' s effect on basal migration was dependent on cyclooxygenase 2 ( P35354 REA ) activation because it was blocked by the P35354 REA inhibitors NS - 398 and nimesulide , and pharmacological studies showed that it was relayed through prostaglandin E ( 2 ) and its EP ( 2 ) receptor . On the other hand , thrombin-induced inhibition of DB00102 - induced migration was not dependent on P35354 REA . We show that thrombin inhibits PDGF-induced Akt - 1 phosphorylation . This effect was consecutive to inhibition of PDGF-beta receptor activation through active dephosphorylation . Thus thrombin , through two distinct mechanisms , inhibits both basal - and DB00102 - induced migration of human hepatic liver myofibroblasts . The fine tuning of myofibroblast migration may be one of the mechanisms used by thrombin to regulate liver fibrogenesis .

Swept-source optical coherence tomography of lower limb wound healing with histopathological correlation . Direct noninvasive visualization of wound bed with depth information is important to understand the tissue repair . We correlate skin swept-source-optical coherence tomography ( O75051 REA ) with histopathological and immunohistochemical evaluation on traumatic lower limb wounds under honey dressing to compare and assess the tissue repair features acquired noninvasively and invasively . Analysis of optical biopsy identifies an uppermost brighter band for stratum corneum with region specific thickness ( p < 0.0001 ) and gray-level intensity ( p < 0.0001 ) variation . Below the stratum corneum , variation in optical intensities is remarkable in different regions of the wound bed . Correlation between O75051 REA and microscopic observations are explored especially in respect to progressive growth and maturation of the epithelial and subepithelial components . Characteristic transition of uniform hypolucid band in O75051 REA image for depigmented zone to wavy highly lucid band in the pigmented zone could be directly correlated with the microscopic findings . The transformation of prematured epithelium of depigmented area , with low expression of P12830 REA , to matured epithelium with higher P12830 REA expression in pigmented zone , implicated plausible change in their optical properties as depicted in O75051 REA . This correlated evaluation of multimodal images demonstrates applicability of swept-source - O75051 REA in wound research and importance of integrated approach in validation of new technology .

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 MEN 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 .

Purinergic P47900 REA receptor signaling mediates wound stimuli-induced cyclooxygenase - 2 expression in intestinal subepithelial myofibroblasts . Intestinal subepithelial myofibroblasts ( ISMFs ) are crucial for barrier formation against inflammatory stimuli . Physical injury induces cyclooxygenase - 2 ( P35354 REA ) expression , which accelerates wound healing by ISMFs . However , the mechanism of P35354 REA induction remains unclear . Physically damaged cells release DB00171 . Here , we investigate the role of DB00171 - purinergic signaling in wound-induced P35354 REA induction in ISMFs . By 24h post-injury , bovine ISMFs had migrated to and closed the wounded area . A P36551 REA inhibitor , indomethacin or a purinergic P2 receptor antagonist , suramin , inhibited wound healing . However , additional treatment with indomethacin did not influence wound healing in suramin-treated ISMFs . RT-PCR showed an increase in P35354 REA mRNA expression 2h post-injury , which was inhibited by suramin . These results suggest that DB00171 mediates wound-induced P35354 REA elevation . We next assessed the contribution of various purinergic receptors in P35354 REA induction . An DB00171 analog , ATPγS and a purinergic P47900 REA , 11-13 receptors agonist , ADP , were among the agents tested which increased P35354 REA expression . ATPγS-induced P35354 REA mRNA expression was suppressed by suramin or a purinergic P2Xs , P47900 REA , 4 , 6 , and 13 receptors antagonist , PPADS . These data suggest the involvement of Gq-coupled purinergic P47900 REA receptor or Gi-coupled purinergic Q9BPV8 receptor in P35354 REA induction . U73122 , an inhibitor of phospholipase C , which is a downstream signal of Gq protein , showed suppression of P35354 REA mRNA expression . However , pertussis toxin , a Gi inhibitor , did not show suppression . We also revealed that inhibitors of p38 MAPK and PKC inhibited ATPγS-induced P35354 REA mRNA expression . Collectively , purinergic P47900 REA receptor signaling mediates wound-induced P35354 REA expression through p38 MAPK and PKC pathways in ISMFs .

Thrombin has biphasic effects on the nitric oxide-cGMP pathway in endothelial cells and contributes to experimental pulmonary hypertension . BACKGROUND : A potential role for coagulation factors in pulmonary arterial hypertension has been recently described , but the mechanism of action is currently not known . Here , we investigated the interactions between thrombin and the nitric oxide-cGMP pathway in pulmonary endothelial cells and experimental pulmonary hypertension . PRINCIPAL FINDINGS : Chronic treatment with the selective thrombin inhibitor melagatran ( 0.9 mg / kg daily via implanted minipumps ) reduced right ventricular hypertrophy in the rat monocrotaline model of experimental pulmonary hypertension . In vitro , thrombin was found to have biphasic effects on key regulators of the nitric oxide-cGMP pathway in endothelial cells ( HUVECs ) . Acute thrombin stimulation led to increased expression of the cGMP-elevating factors endothelial nitric oxide synthase ( P29474 REA ) and soluble guanylate cyclase ( sGC ) subunits , leading to increased cGMP levels . By contrast , prolonged exposition of pulmonary endothelial cells to thrombin revealed a characteristic pattern of differential expression of the key regulators of the nitric oxide-cGMP pathway , in which specifically the factors contributing to cGMP elevation ( P29474 REA and sGC ) were reduced and the cGMP-hydrolyzing O76074 REA was elevated ( qPCR and Western blot ) . In line with the differential expression of key regulators of the nitric oxide-cGMP pathway , a reduction of cGMP by prolonged thrombin stimulation was found . The effects of prolonged thrombin exposure were confirmed in endothelial cells of pulmonary origin ( HPAECs and HPMECs ) . Similar effects could be induced by activation of protease-activated receptor - 1 ( P25116 REA ) . CONCLUSION : These findings suggest a link between thrombin generation and cGMP depletion in lung endothelial cells through negative regulation of the nitric oxide-cGMP pathway , possibly mediated via P25116 REA , which could be of relevance in pulmonary arterial hypertension .

DB04630 stimulates vascular smooth muscle cell proliferation via big mitogen-activated protein kinase 1 activation . The nongenomic effects of aldosterone have been implicated in the pathogenesis of various cardiovascular diseases . DB04630 - induced nongenomic effects are attributable in part to the activation of extracellular signal-regulated kinase 1/2 ( P27361 REA / 2 ) , a classical mitogen-activated protein ( Q96HU1 ) kinase . Q13164 REA ( Q13164 REA ) , a newly identified Q96HU1 kinase , has been shown to be involved in cell proliferation , differentiation , and survival . We examined whether aldosterone stimulates Q13164 REA - mediated proliferation of cultured rat aortic smooth muscle cells ( RASMCs ) . P08235 REA ( MR ) expression and localization were evaluated by Western blotting analysis and fluorolabeling methods . P27361 REA / 2 and Q13164 REA activities were measured by Western blotting analysis with the respective phosphospecific antibodies . Cell proliferation was determined by Alamar Blue colorimetric assay . DB04630 ( 0.1 to 100 nmol / L ) dose-dependently activated Q13164 REA in RASMCs , with a peak at 30 minutes . To clarify whether aldosterone-induced Q13164 REA activation is an MR-mediated phenomenon , we examined the effect of eplerenone , a selective MR antagonist , on aldosterone-induced Q13164 REA activation . DB00700 SUB ( 0.1 to 10 micromol / L ) dose-dependently inhibited aldosterone-induced Q13164 REA activation in RASMCs . DB04630 also stimulated RASMC proliferation , which was inhibited by eplerenone . DB04630 - mediated phenomena were concluded to be attributable to a nongenomic effect because cycloheximide failed to inhibit aldosterone-induced Q13164 REA activation . Transfection of dominant-negative Q96HU1 kinase / P29323 REA kinase 5 ( Q13163 REA ) , which is an upstream regulator of Q13164 REA , partially inhibited aldosterone-induced RASMC proliferation , which was almost completely inhibited by MEK inhibitor PD98059 . In addition to the classical steroid activity , rapid nongenomic effects induced by aldosterone may represent an alternative etiology for vascular diseases such as hypertension .

DB01296 MEN sulfate inhibits P01375 REA and P01579 REA - induced production of P05362 REA in human retinal pigment epithelial cells in vitro . PURPOSE : DB01296 MEN sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine-induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 REA gene upregulated by P01375 REA or P01579 REA , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT-PCR ) . The activation and nuclear translocation of the nuclear factors NF-kappaB and P42224 REA were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 REA and P01579 REA increased the expression of P05362 REA at the mRNA and protein levels in a time - and dose-dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 REA - or P01579 REA - induced expression of P05362 REA in the protein and mRNA level in a dose-dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 REA and phosphorylated P42224 REA in P01579 REA - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 REA gene in ARPE - 19 cell stimulated with P01375 REA or P01579 REA through blockade of NF-kappaB subunit p65 and nuclear translocation of P42224 REA . This study has demonstrated a potentially important property of GS in reducing P05362 REA mediated inflammatory mechanisms in the eye .