interacts_with DB06271?
Impact of genetic factors ( P11712 , Q9BQB6 and P78329 ) on warfarin dose requirement in the Turkish population . DB00682 has a narrow therapeutic index and displays marked person-to-person variation in dose requirement . Functional polymorphisms at candidate genes can therefore offer utility as biomarkers to individualize warfarin treatment . The main objective of this study was to determine whether and to what extent variability in warfarin dose requirements was determined by polymorphisms in P11712 , Q9BQB6 , P78329 ( rs2108622 ) and P07099 ( rs2292566 ) in the Turkish population . Patients ( n = 107 ) who had stable doses and international normalized ratio ( INRs ) at their last three consecutive visits were registered . Their demographic factors , concurrent medications , warfarin-related bleedings or thromboembolisms , smoking , alcohol intake and weekly green vegetable consumption were recorded . From a blood sample , DNA was isolated and genotyped by real-time PCR for polymorphisms of P11712 , Q9BQB6 , P78329 and P07099 . A regression analysis was used to determine the independent effects of genetic and non-genetic factors on warfarin dose optimization . In our study , in addition to age , genetic variants of P11712 , Q9BQB6 and P78329 were found to be significant predictor variables for the maintenance dose for warfarin , explaining 39.3 % of dose variability . Q9BQB6 and P11712 genotypes remain predictor variables of the warfarin dose , and we first found that P78329 ( rs2108622 ) contributes to dose variability in the Turkish population as well . These observations may be of benefit to future translation research with a view to global personalized medicine in regions hitherto understudied such as the Turkish population so as to rationalize initial warfarin dose and reduce the burden of frequent INR measurements . Functional autoradiography of neuropeptide Y Q03519 and P49146 subtypes in rat brain using agonist stimulated [35S]GTPgammaS binding . Neuropeptide Y , one of the most abundant brain peptides , has been found to modulate several important biological functions via a family of G-protein coupled receptors . To investigate the localization of functional P01303 receptor subtypes in the rat brain , we performed agonist-induced [35S]GTPgammaS autoradiography . The Q03519 /Y4/Y5 agonist DB00149 (31) , Pro(34)- P01303 increased [35S]GTPgammaS binding in several brain areas with a regional distribution consistent with that produced when labeling adjacent sections with [ 125I ] - DB00149 (31) , Pro(34)- P10082 . The Q03519 selective antagonist BIBP3226 antagonized the DB00149 (31) , Pro(34)- P01303 stimulated increase in [35S]GTPgammaS binding in all areas examined . The P28062 agonist P06681 - P01303 stimulated [35S]GTPgamma binding in numerous brain areas with a regional distribution similar to the binding observed with [ 125I ] - DB05004 . No increase in [35S]GTPgammaS binding above basal was observed in any brain area evaluated using Y4 and Y5 selective agonists . This study demonstrates abundant Q03519 and P49146 activation in the rat brain , while evidence for functional Y4 and Y5 receptors was not observed . Mitogenic signaling of urokinase receptor-deficient kidney fibroblasts : actions of an alternative urokinase receptor and P01130 -related protein . The urokinase receptor ( Q03405 ) attenuates myofibroblast recruitment and fibrosis in the kidney . This study examined the role of Q03405 and its co-receptor P01130 -related protein ( Q14764 ) in the regulation of kidney fibroblast proliferation and extracellular signal-regulated kinase ( P29323 ) signaling . Compared with Q03405 +/+ cells , Q03405 -/- kidney fibroblasts were hyperproliferative . Q03405 -/- fibroblast proliferation was 60 % inhibited by an P29323 kinase inhibitor . Q14764 protein was reduced and extracellular accumulation of urokinase-type plasminogen activator ( uPA ) and plasminogen activator inhibitor type 1 ( P05121 ) proteins were greater in Q03405 -/- cultures . Addition of functional uPA protein or Q14764 antisense RNA significantly increased P29323 signaling and cell mitosis in both genotypes . Enhanced Q03405 -/- fibroblast proliferation was reversed by a recombinant nonfunctional uPA peptide . The density of cell-bound fluor-uPA was similar between Q03405 -/- and Q03405 +/+ fibroblasts ( 78 +/- 6 versus 92 +/- 16 units ) . These data suggest that Q03405 -deficient kidney fibroblasts express lower levels of its scavenger co-receptor Q14764 , resulting in greater extracellular accumulation of uPA and P05121 . Enhanced proliferation of Q03405 -/- fibroblasts seems to be mediated by uPA-dependent P29323 signaling via an alternative urokinase receptor . Synthesis and biological evaluation of novel oxindole-based RTK inhibitors as anti-cancer agents . Given that receptor tyrosine kinases ( RTKs ) have emerged as key regulators of all aspects of cancer development , including proliferation , invasion , angiogenesis and metastasis , the RTK family represents an important therapeutic target for anti-cancer drug development . Oxindole structure has been used in RTK inhibitors such as DB02058 and intedanib . In this study , two series of new heterocyclic compounds containing oxindole scaffold have been designed and synthesized , and their inhibitory activity against the proliferation of nine cancer cell lines has been evaluated . Among them , compounds 9a and 9b displayed the strongest anti-proliferative activity with the IC50s below 10μM . Flow cytometric analysis showed that the compounds 9a and 9b dose-dependently arrested the cell cycle at G0/ P55008 phase . Although the leading compounds DB02058 and intedanib targets P11362 , the kinase activity test revealed that these compounds only showed slight inhibitory activity on P11362 kinase . Further enzymatic test aided by molecular docking simulation in the DB00171 -binding site demonstrated that 9a and 9b are potent inhibitors of c-Kit kinase . These compounds are worthy of further evaluation as anticancer agents . Genomic imbalance of O75330 / O75330 regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition . Malignant peripheral nerve sheath tumours ( MPNST ) are rare , hereditary cancers associated with neurofibromatosis type I . MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence . O14965 ( O14965 ) is an emerging target in cancer and an aurora kinase inhibitor ( AKI ) , termed DB05220 , shows promise against MPNST cell lines in vitro and in vivo . Here , we test DB05220 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication , which cumulates in stabilized disease . Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities , so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI . We find that the sensitivity of cell-lines with amplification of O14965 depends upon the activity of the kinase , which correlates with the expression of the regulatory gene products Q9ULW0 and O75330 / O75330 . Silencing of O75330 / O75330 , but not Q9ULW0 , augments O14965 activity and sensitizes MPNST cells to AKI . Furthermore , we find that O14965 activity is critical to the propagation and self-renewal of sphere-enriched MPNST cancer stem-like cells . AKI treatment significantly reduces the formation of spheroids , attenuates the self-renewal of spheroid forming cells , and promotes their differentiation . Moreover , silencing of O75330 / O75330 is sufficient to endow MPNST cells with an ability to form and maintain sphere culture . Collectively , our data indicate that O14965 is a rationale therapeutic target for MPNST and tumour cell responses to AKI , which include differentiation , are modulated by the abundance of O75330 / O75330 . Overexpression of cytochrome P450 4F2 in mice increases 20-hydroxyeicosatetraenoic acid production and arterial blood pressure . P78329 ( P78329 ) activity is thought to be a factor in the pathogenesis of hypertension through its bioactive metabolite 20-hydroxyeicosatetraenoic acid ( 20-HETE ) . We previously found that a gain-in-function P78329 variant in a Chinese cohort was associated with elevated urinary 20-HETE and hypertension . To further explore this association we generated a transgenic mouse model expressing P78329 driven by a modified mouse kidney androgen-regulated protein promoter . This heterologous promoter regulated the expression of luciferase and his-tagged P78329 in transfected P29320 293 cells . In the kidney of transgenic mice , P78329 was localized to renal proximal tubule epithelia and was expressed at a higher level than in control mice , leading to increased urinary 20-HETE excretion . Assessment of P78329 activity by an arachidonic acid hydroxylation assay showed that 20-HETE production was significantly higher in kidney microsomes of transgenic mice compared to control mice , as was their systolic blood pressure . There was a positive correlation of blood pressure with urinary 20-HETE levels . Our results show that increased expression of P78329 in mice enhanced 20-HETE production and elevated blood pressure . Identification of antithrombin-modulating genes . Role of O95461 , a gene encoding a bifunctional glycosyltransferase , in the secretion of proteins ? The haemostatic relevance of antithrombin together with the low genetic variability of P01008 , 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 , 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 rs2227589 genotype , all factors influencing antithrombin levels ( p = 0.02 ) . Additional results sustained this association . O95461 silencing inHepG2 and P29320 -EBNA cells did not affect P01008 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 as the first known modifier of plasma antithrombin , and proposes a new role for O95461 in modulating extracellular secretion of certain glycoproteins . Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor ( PR-047 ) . Proteasome inhibition has been validated as a therapeutic modality in the treatment of multiple myeloma and non-Hodgkin 's lymphoma . DB08889 , an epoxyketone currently undergoing clinical trials in malignant diseases , is a highly selective inhibitor of the chymotrypsin-like ( CT-L ) activity of the proteasome . A chemistry effort was initiated to discover orally bioavailable analogues of carfilzomib , which would have potential for improved dosing flexibility and patient convenience over intravenously administered agents . The lead compound , 2-Me-5-thiazole- DB00133 (OMe)- DB00133 (OMe)- DB00120 -ketoepoxide ( 58 ) ( PR-047 ) , selectively inhibited CT-L activity of both the constitutive proteasome ( beta5 ) and immunoproteasome ( P28062 ) and demonstrated an absolute bioavailability of up to 39 % in rodents and dogs . It was well tolerated with repeated oral administration at doses resulting in > 80 % proteasome inhibition in most tissues and elicited an antitumor response equivalent to intravenously administered carfilzomib in multiple human tumor xenograft and mouse syngeneic models . The favorable pharmacologic profile supports its further development for the treatment of malignant diseases . Q8N1N2 -spectrum antioxidant therapy featuring astaxanthin coupled with lipoprivic strategies and salsalate for management of non-alcoholic fatty liver disease . Owing to the worldwide epidemic of obesity , and the popularity of diets rich in sugar and saturated fat , nonalcoholic fatty liver disease ( NAFLD ) is increasingly common ; it is usually associated with insulin resistance , and may be considered a component of the metabolic syndrome . The pathologies which can complicate hepatic steatosis -- steatohepatitis , cirrhosis , and hepatic cancer -- appear to result from an interaction of hepatic lipid overload and hepatic oxidative stress . It is therefore proposed that comprehensive regimens which effectively target each of these precipitating factors should achieve the best therapeutic benefit in NAFLD . Appropriate weight loss , and a diet low in saturated fat , glycemic index , and added sugars , should decrease hepatic lipid load . Measures which enhance adipocyte insulin sensitivity -- such as pioglitazone , astaxanthin , and spirulina -- may also be helpful in this regard , as may agents that boost hepatocyte capacity for fatty acid oxidation , such as metformin , carnitine , hydroxycitrate , long-chain omega-3 fats , and glycine . Astaxanthin and spirulina appear to have considerable potential for controlling the oxidative stress associated with NAFLD - the former because it may help to prevent the mitochondrial damage that renders mitochondria a key source of superoxide in this syndrome , the latter because it is exceptionally rich in phycocyanobilin , a phytochemical inhibitor of NAPDH oxidase . Other antioxidants which show some promise in this syndrome include high-dose folate , lipoic acid , melatonin , DB06151 , vitamin E , and taurine . Finally , treatment with salsalate , an inhibitor of O15111 -beta , has potential for blunting the adverse impact of hepatic steatosis on oxidative stress and inflammation . Neuropeptide Y expression , localization and cellular transducing effects in HUVEC . BACKGROUND INFORMATION : P01303 ( neuropeptide Y ) may have an effect on the properties of vascular endothelial cells such as pro-angiogenic effects and potentiation of noradrenaline-induced vasoconstriction . In HUVEC ( human umbilical-vein endothelial cells ) , immunoreactive neuropeptide Y has been detected , but P01303 synthesis , storage and secretion have not been studied . The aim of the present study was to establish P01303 expression , storage and cellular transducing effects in HUVEC . RESULTS : HUVEC contain 0.19 fmol of P01303 /microg of protein and 0.46 fmol of pro- P01303 /microg of protein , as measured by ELISA . RT ( reverse transcriptase ) -PCR confirmed the expression of P01303 in HUVEC . Immunofluorescence revealed the presence of P01303 in small punctate structures , with a fluorescence pattern different from that observed for P04275 , indicating distinct storage compartments . Double labelling for P01303 and Rab3A demonstrated similar granular patterns , with at least partial co-localization . Electron microscopy showed P01303 immunoreactivity in vesicle-like cytoplasmic structures , of a fine fibrillar texture , as well as in mitochondria and in the nucleus . A similar general distribution pattern was also obtained for Rab3A . Q03519 and P28062 receptors were expressed in HUVEC as assessed by RT-PCR , and they were functional since P01303 induced a 42 nM intracellular calcium increase within 100 s , representing 22 % of the histamine-induced response . In contrast with histamine , P01303 did not induce acute P04275 secretion . CONCLUSIONS : HUVEC produce , store and respond to P01303 , suggesting an autocrine regulatory role for P01303 in the endothelium . 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 ( P04275 ) release and morphological change in response to injury-associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1( P05121 ) , antithrombin III ( P01008 ) , 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 ) ( 1 , 10 , 100 ng/ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs. P09038 ( 10 ng/ml ) significantly increased P04275 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 . DB08818 promotes angiogenesis by inducing O75330 -TGFβ receptor interaction via P16070 -PKCδ . DB08818 ( HA ) has been shown to promote angiogenesis . However , the mechanism behind this effect remains largely unknown . Therefore , in this study , the mechanism of HA-induced angiogenesis was examined . P16070 and PKCδ were shown to be necessary for induction of the receptor for HA-mediated cell motility ( O75330 ) , a HA-binding protein . O75330 was necessary for HA-promoted cellular invasion and endothelial cell tube formation . Cytokine arrays showed that HA induced the expression of plasminogen activator-inhibitor-1 ( P05121 ) , a downstream target of TGFβ receptor signaling . The induction of P05121 was dependent on P16070 and PKCδ . HA also induced an interaction between O75330 and TGFβ receptor I , and induction of P05121 was dependent on O75330 and TGFβ receptor I . O15379 ( O15379 ) , which is decreased by HA via rac1 , reduced induction of plasminogen activator inhibitor-1 ( P05121 ) by HA . P29323 , which interacts with O75330 , was necessary for induction of P05121 by HA . Snail , a downstream target of TGFβ signaling , was also necessary for induction of P05121 . The down regulation of P05121 prevented HA from enhancing endothelial cell tube formation and from inducing expression of angiogenic factors , such as P05362 , P19320 and P08253 . O15379 also exerted reduced expression of P08253 . In this study , we provide a novel mechanism of HA-promoted angiogenesis , which involved O75330 -TGFβRI signaling necessary for induction of P05121 . DB09222 binding potentiates P09038 but not P15692 induced expression of u-PA , u-PAR , and P05121 in endothelial cells . Endothelial cell responses at sites of injury occur in a fibrin matrix and are regulated by growth factors including those of the FGF and P15692 families . The pericellular proteolytic balance is important in these responses , and P09038 and P15692 up-regulate endothelial cell u-PA , u-PAR and P05121 . Because both P15692 and P09038 bind to fibrinogen , we have examined the capacity of fibrinogen to modulate the up-regulation of these proteins by P09038 and P15692 . Confluent cultures of endothelial cells were exposed to P09038 , P15692 , and fibrinogen or to combinations of growth factors with fibrinogen . Changes in mRNA levels of u-PA , u-PAR and P05121 were measured by Northern blot . P09038 increased u-PA , u-PAR , and P05121 mRNA , but there was a significantly greater induction when fibrinogen was added to P09038 at all concentrations . The potentiation by fibrinogen was particularly evident at an P09038 concentration of 0.1 ng mL(-1) , which resulted in non-significant change in transcript levels by itself , but significantly increased up to 2.6-fold with fibrinogen . P15692 also increased endothelial cell expression of u-PA , u-PAR and P05121 , but this effect was not potentiated by fibrinogen . Addition of LM609 , a monoclonal antibody to alphaVbeta3 , significantly inhibited induction of u-PA mRNA and activity by fibrinogen-bound P09038 compared to P09038 . A monoclonal antibody to P11362 also inhibited u-PA mRNA expression induced by fibrinogen-bound P09038 . We conclude that fibrinogen increases the capacity of P09038 , but not of P15692 , to up-regulate u-PA , u-PAR , and P05121 in endothelial cells and that fibrinogen-bound P09038 requires alphaVbeta3 binding to up-regulate endothelial cell u-PA . 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 ) . 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 ( SLX ) which catalyzes thrombin inhibition by P01008 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 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP . [ Association study of renin-angiotensin system genes and hemostasis system genes with ischemic stroke among Russians of Central Russia ] . The analysis of alleles and genotypes frequencies of 14 SNP in genes of rennin-angiotensin system ( REN , AGT , P30556 , P50052 , P30411 , P07550 ) and hemostasis system ( P02675 , F2 , P12259 , P08709 , P05106 , P05121 , P42898 ) , as well as P12821 insertion-deletion polymorphism in patients with stroke comparing to healthy controls matched by age , sex and ethnicity has been carried out . The genotyping procedure included the amplification of selected gene sequences following by hybridization of fluorescently labeled fragments with SNP-specific DNA probes . The analysis of allele frequencies of each gene separately revealed no statistically significant differences between groups of patients with stroke and healthy donors . Also the complex study has been performed to estimate the contribution of rennin-angiotensin system and hemostasis system genes to the genetic susceptibility to ischemic stroke among Russians from Central Russia using method MDR ( Multifactor Dimensionality Reduction ) . The combination with increased risk for development of ischemic stroke was presented by complex genotype P02675 G/- x P12821 I/- x P42898 C/- x P05121 5G/5G ( p = 0.03 , OR = 2.4 , 95 % CI 1.1-5.3 ) , which frequency was statistically significant higher in patients with stroke compared to healthy control . Modular synthesis of heparin oligosaccharides . A general , modular strategy for the first completely stereoselective synthesis of defined heparin oligosaccharides is described . Six monosaccharide building blocks ( four differentially protected glucosamines , one glucuronic and one iduronic acid ) were utilized to prepare di- and trisaccharide modules in a fully selective fashion . Installation of the alpha-glucosamine linkage was controlled by placing a conformational constraint on the uronic acid glycosyl acceptors thereby establishing a new concept for stereochemical control . Combination of disaccharide modules to form trans-uronic acid linkages was completely selective by virtue of P06681 participating groups . Coupling reactions between disaccharide modules exhibited sequence dependence . While the union of many glucosamine uronic acid disaccharide modules did not meet any problems , certain sequences proved not accessible . Elaboration of glucosamine uronic acid disaccharide building blocks to trisaccharide modules by addition of either one additional glucosamine or uronic acid allowed for stereoselective access to oligosaccharides as demonstrated on the example of a hexasaccharide resembling the P01008 -binding sequence . Final deprotection and sulfation yielded the fully synthetic heparin oligosaccharides . Combination of DB05210 and gefitinib induces apoptosis of triple-negative breast cancer cells through the PI3K/AKT- P42345 pathway . To investigate the apoptotic mechanism of triple-negative breast cancer ( TNBC ) cells induced by gefitinib and PI3K inhibitor DB05210 . MDA-MB-231 , MDA-MB-436 , and MCF-7 cells were incubated with 0.1 μmol/l gefitinib , 1 μmol/l gefitinib , 10 μmol/l gefitinib , 1 μmol/l DB05210 , 0.1 μmol/l gefitinib+1 μmol/l DB05210 , 1 μmol/l gefitinib+1 μmol/l DB05210 , and 10 μmol/l gefitinib+1 μmol/l DB05210 . Then , cell viability and survival were determined using an 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide ( MTT ) assay and Hoechst staining . The apoptosis-related factors and phosphoinositide-3-kinase/protein kinase B , the mammalian target of rapamycin ( PI3K/AKT- P42345 ) signaling pathway-related factors were detected by western blot . For TNBC cells , cell viability or survival was not significantly inhibited by gefitinib or DB05210 alone ; however , marked cell apoptosis was noted in the gefitinib and DB05210 combination groups , and this effect was dose dependent . Also , the expressions of apoptosis markers , such as cleaved caspase-3 , Bcl-2/Bax , were altered by the gefitinib and DB05210 combination . Moreover , phosphorylated AKT ( p-AKT ) and 70 kDa ribosomal protein S6-kinase ( p-p70S6K ) were also inhibited by the gefitinib and DB05210 combination , which may be responsible for the apoptosis . Gefitinib combined with DB05210 could induce cell apoptosis in TNBC cells and this effect was mediated through the P00533 -PI3K-AKT- P42345 -p70S6K pathway . Our studies have set the stage for future clinical trials of TNBC therapy by the combination of gefitinib and DB05210 . DB02342 causes functional repression of transforming growth factor β3 signaling by ameliorating Smad and non-Smad signaling pathways in immortalized uterine fibroid cells . OBJECTIVE : To investigate the effects and the mechanism of action of 2-methoxyestradiol ( 2ME(2) ) on transforming growth factor ( TGF ) β3-induced profibrotic response in immortalized human uterine fibroid smooth muscle ( huLM ) cells . DESIGN : Laboratory study . SETTING : University research laboratory . PATIENTS(S) : Not applicable . INTERVENTIONS(S) : Not applicable . MAIN OUTCOME MEASURE(S) : huLM cells were treated with TGF-β3 ( 5 ηg/mL ) in the presence or absence of specific P84022 inhibitor SIS3 ( 1 μmol/L ) , inhibitor of the PI3K/Akt ( LY294002 , 10 μmol/L ) , or 2ME(2) ( 0.5 μmol/L ) , and the expression of collagen ( Col ) type I(αI) , Col III(αI) , plasminogen activator inhibitor ( P05121 ) 1 , connective tissue growth factor ( P29279 ) , and α-smooth muscle actin ( α-SMA ) were determined by real-time reverse-transcription polymerase chain reaction and immunoblotting . The effect of 2ME(2) on Smad-microtubule binding was evaluated by coimmunoprecipitation . RESULT(S) : Our data revealed that TGF-β3-induced fibrogenic response in huLM is mediated by both Smad-dependent and Smad-independent PI3K/Akt/ P42345 signaling pathways . 2ME(2) abrogates TGF-β3-induced expression of Col I(αI) , Col III(αI) , P05121 , P29279 , and α-SMA . Molecularly , 2ME(2) ameliorates TGF-β3-induced Q15796 /3 phosphorylation and nuclear translocation . In addition , 2ME(2) inhibits TGF-β3-induced activation of the PI3K/Akt/ P42345 pathway . CONCLUSION(S) : TGF-β3-induced profibrotic response in fibroid cells is mediated by Smad-dependent and Smad-independent PI3K/Akt/ P42345 pathways . 2ME(2) inhibits TGF-β3 profibrotic effects in huLM cells by ameliorating both Smad-dependent and Smad-independent signaling pathways . Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins . Low-density lipoprotein-cholesterol ( LDL-C ) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk . P04035 inhibitors ( statins ) are currently the most effective LDL-C-lowering drugs . However , a substantial number of patients do not reach treatment targets with statins . Therefore , an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels , either by monotherapy or combination therapy . Upregulation of the P01130 with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat ( DB05317 ) has recently been discontinued . DB00973 combined with statins allowed significantly more patients to reach their LDL-C targets . Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate ( DB05449 ) and bile acid transport inhibitors have shown positive results in early development trials , whereas the prospect of acyl coenzyme A : cholesterol acyltransferase inhibition in cardiovascular prevention is dire . Selective inhibition of messenger RNA ( mRNA ) by antisense oligonucleotides is a new approach to modify cholesterol levels . The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium ( ISIS 301012 ) has shown striking results in phase II studies both as monotherapy as well as in combination with statins . Helicobacter pylori-induced interleukin-12 p40 expression . Interleukin-12 ( IL-12 ) is a heterodimeric cytokine produced by antigen-presenting cells that promotes the development of T-helper lymphocyte 1 ( Th1 ) . Chronic gastritis induced by Helicobacter pylori is considered a Th1-mediated process . IL-12 levels in gastric biopsy samples of H. pylori-infected patients are higher than in those of uninfected individuals , but the cellular source of IL-12 remains elusive . IL-12 staining was detected in mucosal epithelial cells , lymphocytes , and macrophages in specimens of patients with H. pylori-positive gastritis . Therefore , we investigated IL-12 p40 mRNA induction by H. pylori in gastric epithelial cells and T cells . Although cag pathogenicity island ( P05121 ) -positive H. pylori induced IL-12 p40 mRNA expression , an isogenic mutant of the cag P05121 failed to induce it in both cell types . Supernatants from H. pylori cultures and H. pylori VacA induced IL-12 p40 mRNA expression in T cells but not in epithelial cells . The activation of the IL-12 p40 promoter by H. pylori was mediated through NF-kappaB . The transfection of O15111 and NF-kappaB-inducing kinase dominant-negative mutants inhibited H. pylori-induced IL-12 p40 activation . Inhibitors of NF-kappaB , phosphatidylinositol 3-kinase , p38 mitogen-activated protein kinase , and Hsp90 suppressed H. pylori- and VacA-induced IL-12 p40 mRNA expression . The results indicate that H. pylori induces IL-12 p40 expression by the activation of NF-kappaB , phosphatidylinositol 3-kinase , and p38 mitogen-activated protein kinase . Hsp90 is also a crucial regulator of H. pylori-induced IL-12 p40 expression . In addition to the cag P05121 , VacA might be relevant in the induction of IL-12 expression and a Th1-polarized response only in T cells . [ Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor in patients with chronic glomerulonephritis ] . P30556 blocker ( ARB ) and angiotensin-converting enzyme inhibitor ( ACEI ) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis . Recently , an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy , but the mechanism responsible for the effect has not yet been determined . In this study , we examined additive effect of these two drugs in chronic glomerulonephritis patients . Ten patients with biopsy-proven primary glomerulonephritis ( eight IgA nephropathy patients , two membranous nephropathy patients ) , non-nephrotic proteinuria ( protein , 0.5 to 3.5 g/day ) received candesartan cilexetil ( 2 or 4 mg ) for 8 weeks . After the 8 weeks , a combination of perindopril erbumine ( 1 or 2 mg ) and candesartan cilexetil was administered to the patients . DB00790 was stopped after the 8-week administration of the two drugs . DB00796 alone reduced proteinuria by 13 % . Combination of these two drugs induced a more remarkable reduction of proteinuria ( 48 % ; p < 0.05 vs other periods ) . The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria . The combination of drugs also reduced the amount of urinary type-IV collagen excretion . An additive effect of ACEI and ARB on proteinuria and urinary type-IV collagen excretion was recognized in patients with chronic glomerulonephritis .