interacts_with DB00197?
Obesity and breast cancer : the roles of peroxisome proliferator-activated receptor-γ and plasminogen activator inhibitor-1 . Breast cancer is the most prominent cancer among females in the United States . There are a number of risk factors associated with development of breast cancer , including consumption of a high-fat diet and obesity . P00747 activator inhibitor-1 ( P05121 ) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer . As a key mediator of adipogenesis and regulator of adipokine production , peroxisome proliferator-activated receptor-γ ( Q07869 -γ ) is involved in P05121 expression from adipose tissue . We summarize the current knowledge linking Q07869 -γ and P05121 expression to high-fat diet and obesity in the risk of breast cancer . DB06589 inhibits the activation of P09619 β-expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one-third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 -transfected MDA-MB-231 human breast carcinoma cells ( 231-BR- P04626 ) . A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β ( at tyrosine 751 ; p751- P09619 β ) was identified around perivascular brain micrometastases . p751- P09619 β(+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte-enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231-BR- P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . DB06589 treatment resulted in 70 % ( P = 0.023 ) decrease of the p751- P09619 β(+) astrocyte population , at the lowest dose of 30 mg/kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients . Intercellular adhesion molecule-1 ( P05362 ) expression and soluble P05362 ( sICAM-1 ) production by cytokine-activated human aortic endothelial cells : a possible role for P05362 and sICAM-1 in atherosclerotic aortic aneurysms . The interactions of inflammatory cells , cytokines , and cell adhesion molecules ( P62158 ) may be important in the pathogenesis of vascular diseases such as abdominal aortic aneurysms ( AAA ) , in which inflammation plays a role . The aim of this study was to investigate the pathogenic role of P05362 , a molecule involved in leucocyte-endothelial interactions , in vascular inflammation . ELISA of human explant culture supernatants revealed a four-fold increase in sICAM-1 production by AAA ( n = 9 ) versus normal ( n = 8 ) aortic explants . Human aortic endothelial cell ( hAEC ) culture was used for further studies as an in vitro model for aortic inflammatory conditions . Tumour necrosis factor-alpha ( P01375 ) or P01584 treatment of hAEC resulted in an up to 1.8-fold significant increase in sICAM-1 production compared with resting cells . In addition , the expression of P05362 on cytokine-stimulated versus resting hAEC was measured by radioimmunoassay . P01375 significantly induced P05362 expression on these cells . These results suggest that different forms of P05362 , present on or released by the activated aortic endothelium , may be involved in leucocyte adhesion to and migration into the vessel wall . Anti-inflammatory effects of troglitazone in nondiabetic obese subjects independent of changes in insulin sensitivity . BACKGROUND : Obesity is characterised by insulin resistance and by elevated levels of proinflammatory markers . We investigated whether , in the absence of changes in glucose , thiazolidinediones ( TZDs ) have anti-inflammatory effects and whether improvement of insulin sensitivity correlates with suppression of inflammatory markers . METHODS : We performed a randomised double-blind placebo-controlled crossover study with troglitazone ( 400 mg daily for eight weeks ) in 15 normoglycaemic obese subjects . We measured plasma high-sensitivity P02741 ( hsCRP ) , interleukin-6 ( P05231 ) , leptin , tissue-type plasminogen activator ( tPA ) , plasminogen activator inhibitor-1 ( P05121 ) and tumour necrosis factor-alpha ( P01375 ) after each of the two treatment periods and in 13 age- and sex-matched lean individuals . RESULTS : Obese subjects were insulin resistant ( decreased glucose infusion rate ( GIR ) during euglycaemic hyperinsulinaemic clamp ) and had higher plasma levels of hsCRP , P05231 , leptin , tPA , and P05121 compared with lean subjects . P01375 also tended to be higher . DB00197 improved insulin sensitivity ( mean increase in whole body glucose uptake 23.1 +/- 10.5 % ( p = 0.047 ) ) and normalised plasma concentrations of hsCRP , tPA and P01375 , whereas it did not significantly change P05231 , leptin and P05121 . Changes in GIR did not correlate with changes in inflammatory markers . CONCLUSION : DB00197 induces suppression of some of the inflammatory markers that are elevated in normoglycaemic obese subjects . The suppression of inflammatory markers , however , does not correlate with improvement in insulin sensitivity , suggesting involvement of partially differential mechanisms in these effects of TZDs . DB00197 regulates peroxisome proliferator-activated receptors and inducible nitric oxide synthase in murine ovarian macrophages . Peroxisome proliferator-activated receptor-gamma ( P37231 ) and Q07869 ( Q07869 ) control metabolic processes in many cell types and act as anti-inflammatory regulators in macrophages . Q07869 -activating ligands include thiazolidinediones ( TZDs ) , such as troglitazone , once frequently used to treat insulin resistance as well as symptoms of polycystic ovary syndrome ( PCOS ) . Since macrophages within the ovary mediate optimal follicle development , TZD actions to improve PCOS symptoms are likely to be partly mediated through these specifically localized immune cells . In mouse ovary , P37231 protein was expressed in granulosa cells and in isolated cells localized to theca , stroma , and corpora lutea , consistent with Q14246 + macrophages . Isolation of immune cells ( Q14246 + or H2+ ) showed that Pparg and Ppara were expressed in ovarian macrophages at much higher levels than in peritoneal macrophages . Ovulatory human chorionic gonadotropin downregulated expression of Pparg and Ppara in Q14246 + ovarian macrophages , but no hormonal responsiveness was observed in H2+ cells . Downstream anti-inflammatory effects of P37231 activation were analyzed by in vitro treatment of isolated macrophages with troglitazone . P01584 ( Il1b ) expression was not altered , and tumor necrosis factor-alpha ( Tnf ) expression was affected in peritoneal macrophages only . In ovarian macrophages , inducible nitric oxide synthase ( Nos2 ) , an important proinflammatory enzyme that regulates ovulation , was significantly reduced by troglitazone treatment , an effect that was restricted to cells from the preovulatory ovary . Thus , expression of PPARs within ovarian macrophages is hormonally regulated , reflecting the changing roles of these cells during the ovulatory cycle . Additionally , ovarian macrophages respond directly to troglitazone to downregulate expression of proinflammatory Nos2 , providing mechanistic information about ovarian effects of TZD treatment . [ P01308 resistance and hyperlipidemia in the elderly ] . To elucidate the relationship between hyperlipidemias and insulin resistance in the elderly , we conducted three studies : 1 ) determination of the prevalence of hyperlipidemias in elderly subjects with impaired glucose tolerance or non-insulin dependent diabetes mellitus , 2 ) measurement of plasma glucose and insulin levels in patients with phyerlipidemias and atherosclerotic vascular disease , and 3 ) computation of correlation between levels of substances involved in coagulation and fibrinolysis ( F-VII , F-X , and P05121 ) and levels of triglycerides and insulin in serum in hyperlipidemic patients with atherosclerotic vascular disease . The prevalence of hypertriglyceridemia was 4 % in non-diabetic control subjects , 38 % in subjects with impaired glucose tolerance , 22 % in those with diabetes , and 29 % in those with both conditions . Levels of glucose and insulin in plasma were measured after oral intake of 75 g of glucose . The insulin response was greater in the group with hypertriglyceridemia than in the group with normal triglyceride levels , although the glucose responses did not differ between the groups . The activities and levels of F-VII , F-X , and P05121 correlated with triglycerides in serum and also with fasting insulin levels in hyperlipidemic patients with atherosclerotic vascular disease . We conclude that hypertriglyceridemia plays an important role in the development of atherothrombotic vascular disease ; it accompanies elevation of coagulation and antifibrinolytic activities in elderly patients with insulin resistance . Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc. are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq/ P49842 signaling , PI3K , MAPK pathways , Na/H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK/ P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations . DB00197 increases IL-1beta induced cyclooxygenase-2 and inducible nitric oxide synthase expression via enhanced phosphorylation of P25963 in vascular smooth muscle cells from Wistar-Kyoto rats and spontaneously hypertensive rats . P37231 ( PPARgamma ) agonists of the thiazolidinedione class are widely used for the treatment of type 2 diabetes subjects due to their ability to improve insulin resistance . DB00197 and ciglitazone belong to the PPARgamma agonists of thiazolidinediones . We report here that troglitazone but not ciglitazone increased IL-1beta induced cyclooxygenase-2 ( P35354 ) and inducible nitric oxide synthase ( P35228 ) expression in vascular smooth muscle cell ( VSMC ) from Wistar-Kyoto rats ( WKY ) and spontaneously hypertensive rats ( SHR ) . Potentiated expression of P35354 and P35228 by troglitazone was inhibited by MG-132 , a specific inhibitor of inhibitory factor kappaB ( IkappaB ) activation . DB00197 treatment of these cells also resulted in a dose-dependent increase in IL-1beta induced P25963 phosphorylation . These data suggest that troglitazone is capable of increasing IL-1beta induced P35354 and P35228 expression through an P25963 dependent mechanism in VSMC from WKY and SHR . Delineating biological pathways unique to embryonic stem cell-derived insulin-producing cell lines from their noninsulin-producing progenitor cell lines . To identify unique biochemical pathways in embryonic stem cell-derived insulin-producing cells as potential therapeutic targets to prevent or delay beta-cell dysfunction or death in diabetic patients , comparative genome-wide gene expression studies of recently derived mouse insulin-producing cell lines and their progenitor cell lines were performed using microarray technology . Differentially expressed genes were functionally clustered to identify important biochemical pathways in these insulin-producing cell lines . Biochemical or cellular assays were then performed to assess the relevance of these pathways to the biology of these cells . A total of 185 genes were highly expressed in the insulin-producing cell lines , and computational analysis predicted the pentose phosphate pathway ( PPP ) , clathrin-mediated endocytosis , and the peroxisome proliferator-activated receptor ( Q07869 ) signaling pathway as important pathways in these cell lines . P01308 -producing ERoSHK cells were more resistant to hydrogen peroxide ( H(2)O(2) ) -induced oxidative stress . Inhibition of PPP by dehydroepiandrosterone and 6-aminonicotinamide abrogated this H(2)O(2) resistance with a concomitant decrease in PPP activity as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide ( MTT ) assay . Clathrin-mediated endocytosis , which is essential in maintaining membrane homeostasis in secreting cells , was up-regulated by glucose in ERoSHK but not in their progenitor ERoSH cells . Its inhibition by chlorpromazine at high glucose concentration was toxic to the cells . DB00197 , a P37231 agonist , up-regulated expression of Ins1 and Ins2 but not Glut2 . Gene expression analysis has identified the PPP , clathrin-mediated endocytosis , and the Q07869 signaling pathway as the major delineating pathways in these insulin-producing cell lines , and their biological relevance was confirmed by biochemical and cellular assays . DB00197 and pioglitazone interactions via P37231 -independent and -dependent pathways in regulating physiological responses in renal tubule-derived cell lines . DB00197 ( Tro ) and pioglitazone ( Pio ) activation of peroxisome proliferator-activated receptor ( Q07869 ) -gamma and P37231 -independent pathways was studied in cell lines derived from porcine renal tubules . P37231 -dependent activation of Q07869 response element-driven luciferase gene expression was observed with Pio at 1 microM but not Tro at 1 microM . On the other hand , P37231 -independent P- P29323 activation was observed with 5 microM Tro but not with Pio ( 5-20 microM ) . In addition , Pio ( 1-10 microM ) increased metabolic acid production and activated AMP-activated protein kinase ( AMPK ) associated with decreased mitochondrial membrane potential , whereas Tro ( 1-20 microM ) did not . These results are consistent with three pathways through which glitazones may act in effecting metabolic processes ( ammoniagenesis and gluconeogenesis ) as well as cellular growth : 1 ) P37231 -dependent and P37231 -independent pathways , 2 ) P- P29323 activation , and 3 ) mitochondrial AMPK activation . The pathways influence cellular acidosis and glucose and glutamine metabolism in a manner favoring reduced plasma glucose in vivo . In addition , significant interactions can be demonstrated that enhance some physiological processes ( ammoniagenesis ) and suppress others ( ligand-mediated P37231 gene expression ) . Our findings provide a model both for understanding seemingly opposite biological effects and for enhancing therapeutic potency of these agents . Decreased synthesis of matrix metalloproteinase-7 and adhesion to the extracellular matrix proteins of human colon cancer cells treated with troglitazone . PURPOSE : In the present study , we investigated the effect of troglitazone , a selective ligand and agonist of P37231 , on the metastatic potential of human colon cancer cells . METHODS : High- and low- P37231 expression clones of the colon cancer cell line , HT29 , namely clones 21 and 3 respectively , were used . We investigated the effect of troglitazone on the proliferation , on the adhesion to extracellular matrix proteins and on the synthesis of matrix metalloproteinases ( MMPs ) of colon cancer cells . RESULTS : DB00197 inhibited the proliferation of both subclones , in a dose-dependent manner , and the inhibitory effect correlated with the level of P37231 expression . DB00197 strongly inhibited the production of P09237 , an enzyme associated with invasiveness of cancer cells , by both subclones . In addition , troglitazone caused a strong decrease in the adhesion of clone 21 to extracellular matrix ( Q13201 ) proteins , laminin and type IV collagen . This effect was independent of beta1-integrins expression CONCLUSION : In addition to inhibition of cancer cell growth , troglitazone had an inhibitory effect on two important events associated with the metastatic potential of cancer cells , production of MMPs and adhesion to Q13201 proteins . Consequently , troglitazone is a promising agent for the treatment and prevention of colon cancer metastasis . Synthesis and evaluation of ( S ) -2-(2-[18F]fluoroethoxy)-4- ( [ 3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl ] -methyl ) -benzoic acid ( [18F]repaglinide ) : a promising radioligand for quantification of pancreatic beta-cell mass with positron emission tomography ( PET ) . 18F-labeled non-sulfonylurea hypoglycemic agent ( S ) -2-(2-[(18)F]fluoroethoxy)-4- ( ( 3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl ) -methyl ) -benzoic acid ( [(18)F]repaglinide ) , a derivative of the sulfonylurea-receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [(18)F] DB00912 could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate . Specific activity was in the range of 50-60 GBq/micromol . Labeling was conducted by exchanging the ethoxy-moiety into a 2-[(18)F]fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non-radioactive (19)F-compound for binding to the human Q09428 isoform was assessed . [(19)F] DB00912 induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1.03 ) yielding a dissociation constant ( K(D) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [(18)F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection . Pancreatic tissue displayed a stable accumulation of approximately 0.12 % of the injected dose from 10 min to 30 min p.i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [(18)F]repaglinide might be suitable for in vivo investigation with PET . Differential activation of peroxisome proliferator-activated receptor-gamma by troglitazone and rosiglitazone . The antidiabetic thiazolidinediones , which include troglitazone and rosiglitazone , are ligands for the nuclear receptor peroxisome proliferator-activated receptor ( Q07869 ) -gamma and exert their antihyperglycemic effects by regulation of P37231 -responsive genes . We report here that P37231 activation by troglitazone depends on the experimental setting . DB00197 acts as a partial agonist for P37231 in transfected muscle ( C2C12 ) and kidney ( P29320 293T ) cells , producing a submaximal transcriptional response ( 1.8- to 2.5-fold activation ) compared with rosiglitazone ( 7.4- to 13-fold activation ) . Additionally , troglitazone antagonizes rosiglitazone-stimulated P37231 transcriptional activity . Limited protease digestion of P37231 suggests conformational differences in the receptor bound to troglitazone versus rosiglitazone . Consistent with this finding , an in vitro coactivator association assay demonstrated that troglitazone-bound P37231 recruited the transcriptional coactivators p300 and steroid receptor coactivator 1 less efficiently than rosiglitazone-bound receptor . In contrast to these observations , troglitazone behaves as a full agonist of P37231 in 3T3L1 adipocytes . Two-dimensional protein gel electrophoresis demonstrated that troglitazone and rosiglitazone regulated distinct but overlapping sets of genes in several cell types . Thus , troglitazone may behave as a partial agonist under certain physiological circumstances and as a full agonist in others . These differences could be caused by variations in the amount of specific cofactors , differences in Q07869 response elements , or the presence of different isoforms of P37231 . Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER-labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 increased ER-labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats . Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity-mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real-time PCR in two genetic models of obesity ( ob/ob and db/db mice ) and in a diet-induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte-derived 30-kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP/ P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3- Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB-94 ( DB03880 ) decreases adipose conversion of 3T3- Q9NUQ9 and primary rat preadipocytes . BB-94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP/ P01033 system in the control of proteolytic events and adipogenesis during obesity-mediated fat mass development . Regulation of protein turnover by L-glutamine in porcine intestinal epithelial cells . L-Glutamine ( Gln ) plays an important role in sustaining the intestinal mucosal mass of humans and animals . However , the underlying mechanisms are largely unknown . This study tested the hypothesis that Gln regulates protein turnover in intestinal epithelial cells . Intestinal porcine epithelial cells ( IPEC-1 ) were cultured for 3 h ( short-term study ) or 96 h ( long-term study ) in Gln-free Dulbecco 's modified Eagle- P00748 Ham medium containing 0 , 0.5 or 2.0 mM Gln . To determine effects of ammonia ( a metabolite of Gln , i.e. , 0.18 mM ammonia produced from 2 mM Gln in 3 h ) on protein turnover , additional experiments were conducted in which medium contained 0.5 mM Gln and 0 , 0.2 , 0.5 or 2.0 mM NH(4)Cl . Variables of analysis included cell growth , protein synthesis , proteolysis and mammalian target of rapamycin ( P42345 ) signaling . IPEC-1 cell growth increased with extracellular Gln concentrations . Compared with 0 mM Gln , the addition of 0.5 and 2 mM Gln to medium stimulated protein synthesis and inhibited protein degradation in those cells in both the short- and long-term studies . Ammonia ( 0.05 to 2.0 mM ) did not affect protein synthesis , although higher levels of ammonia ( 0.5 and 2.0 mM ) reduced protein degradation in IPEC-1 cells . Consistent with the data on protein turnover , 0.5 and 2 mM Gln increased abundance of phosphorylated P06730 -binding protein-1 and phosphorylated S6 kinase-1 proteins . Collectively , these results demonstrate that physiological levels of Gln regulate protein turnover independent of ammonia production in intestinal cells through the P42345 signaling pathway . Q07869 gamma ligands , rosiglitazone and pioglitazone , inhibit P09038 - and P15692 -mediated angiogenesis . OBJECTIVE : To study the effect of peroxisome proliferator-activated receptor-gamma ( Q07869 gamma ) agonists , pioglitazone and rosiglitazone , on vascular endothelial growth factor ( P15692 ) - and basic fibroblast growth factor ( P09038 ) -induced angiogenesis and on endothelial cell migration . METHODS : Chick chorioallantoic membrane ( P62158 ) model was used to evaluate the efficacy of pioglitazone and rosiglitazone on P15692 - and P09038 -induced angiogenesis . In addition , the effect of pioglitazone and rosiglitazone on endothelial cell migration was evaluated using 8 mm pore filter to a feeder layer containing vitronectin as chemoattractant . RESULTS : Pioglitazone and rosiglitazone inhibited the pro-angiogenic effects of P09038 and P15692 in the P62158 model significantly ( P < 0.001 ) to the same extent . Endothelial cell migration was also inhibited by both pioglitazone and rosiglitazone ( P < 0.001 ) . CONCLUSIONS : These results suggest that Q07869 gamma ligands , pioglitazone and rosiglitazone , in addition to their important regulatory role in adipogenesis and inflammation , possess anti-angiogenic properties . Thus , Q07869 gamma ligands may be useful in the treatment of diabetic retinopathy , macular degeneration , and other ocular disorders and may lower the risk to develop cancer in diabetic patients . Synthetic peroxisome proliferator-activated receptor-gamma agonists restore impaired vasorelaxation via DB00171 -sensitive K+ channels by high glucose . The present study was designed to examine whether in the human artery , synthetic peroxisome proliferator-activated receptor ( Q07869 ) -gamma agonists restore vasorelaxation as well as hyperpolarization via DB00171 -sensitive K+ channels impaired by the high concentration of D-glucose and whether the restoration may be mediated by the antioxidant capacity of these agents . The isometric force and membrane potential of human omental arteries without endothelium were recorded . The production rate of superoxide was evaluated using a superoxide-generating system with xanthine-xanthine oxidase in the absence of smooth muscle cells . DB01016 abolished vasorelaxation and hyperpolarization in response to levcromakalim . Addition of D-glucose ( 20 mM ) but not L-glucose ( 20 mM ) reduced this vasorelaxation and hyperpolarization . Synthetic P37231 agonists ( troglitazone and rosiglitazone ) and/or an inhibitor of superoxide generation ( 4,5-dihydroxy-1,3-benzene-disulfonic acid , Tiron ) , but not a Q07869 agonist ( fenofibrate ) , restored vasorelaxation and hyperpolarization in response to levcromakalim in arteries treated with D-glucose . DB00197 and rosiglitazone , but not fenofibrate , decreased the production rate of superoxide without affecting uric acid generation . These findings suggest that synthetic P37231 agonists recover the function of DB00171 -sensitive K+ channels reduced by the high concentration of glucose in human vascular smooth muscle cells and that the effect of these agonists may be mediated in part by their antioxidant capacity . Gene expression analysis of troglitazone reveals its impact on multiple pathways in cell culture : a case for in vitro platforms combined with gene expression analysis for early ( idiosyncratic ) toxicity screening . P37231 ( PPARgamma ) agonists of the thiazolidinedione family are used for the treatment of type 2 diabetes mellitus due to their ability to reduce glucose and lipid levels in patients with this disease . Three thiazolidinediones that were approved for treatment are Rezulin ( troglitazone ) , Avandia ( rosiglitazone ) , and Actos ( pioglitazone ) . DB00197 was withdrawn from the market due to idiosyncratic drug toxicity . Rosiglitazone and pioglitazone are still on the market for the treatment of type 2 diabetes . The authors present data from a gene expression screen that compares the impact these three compounds have in rats , in rat hepatocytes , and in the clone 9 rat liver cell line . The authors monitored the changes in expression in multiple genes , including those related to xenobiotic metabolism , proliferation , DNA damage , oxidative stress , apoptosis , and inflammation . Compared to the other two compounds , troglitazone had a significant impact on many of the pathways monitored in vitro although no major perturbation was detected in vivo . The changes detected predict not only general toxicity but potential mechanisms of toxicity . Based on gene expression analysis , the authors propose there is not just one but multiple ways troglitazone could be toxic , depending on a patient 's environment and genetic makeup , including immune response-related toxicity . Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism (PE). tPA has not been replaced by third generation plasminogen activators , e.g. DB00015 ( Ret ) and DB00031 ( TNK ) that circulate with longer life-spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor-1 ( e.g. P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility . DB00991 : kinetic and dynamic profile in the treatment of pain . DB00991 ( 4,5-diphenyl-2-oxazolepropionic acid ) is a non-steroidal anti-inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . DB00991 has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . DB00991 's strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF-kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . DB00991 and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF-36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti-rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc. in several different painful musculoskeletal conditions . DB00197 inhibits isolated cell proliferation , and induces apoptosis in isolated rat mesangial cells . BACKGROUND/AIMS : DB00197 is one of thiazolidinedione derivatives as a high affinity ligand for peroxisome proliferator-activated receptor-gamma ( P37231 ) . The in vivo studies demonstrated that troglitazone ameliorated microalbuminuria . There have been few reports about direct effect of thiazolidinedione derivatives on mesangial cell function . We determined the effect of troglitazone on isolated rat mesangial cell proliferation . METHODS : We determined P37231 mRNA expression in isolated rat mesangial cells . Chronic effects of 10(-6) to 10(-4) mol/l troglitazone on mesangial cell proliferation and mitogen-activated protein ( Q96HU1 ) kinase activity were also determined . The effects of troglitazone on apoptosis were investigated in rat mesangial cells . RESULTS : Rat P37231 mRNA was detected in isolated rat mesangial cells . Living cell number , assessed by colorimetric [ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide ] ( MTT ) assay , was significantly decreased with 10(-4) mol/l troglitazone . The addition of 10(-6) to 10(-4) mol/l troglitazone dose-dependently inhibited 5-bromo-2'-deoxyuridine ( BrdU ) uptake into isolated rat mesangial cells . The addition of 10(-4) and 10(-5) mol/l troglitazone significantly reduced Q96HU1 kinase activity . DB00197 at the concentrations of 10(-6) to 10(-4) mol/l dose-dependently increased DNA fragmentation rates , indicating that troglitazone may cause apoptosis in rat mesangial cells . Bax and Bcl-xL proteins were not changed , although Bcl-2 proteins increased with troglitazone . CONCLUSIONS : The present data demonstrated that troglitazone inhibits cell proliferation , and induces apoptosis in rat mesangial cells , raising a possibility that it directly affects renal function . Peroxisome-proliferator activator receptor-gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator-activated receptor ( Q07869 ) -gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well-established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co-culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co-cultured without prior treatment with CTZ ) . Next , attachment of CTZ-treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0.01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0.01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0.056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion . Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome-wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D-associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes/pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta-Analysis Gene-set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta-analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10(-5) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta-analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10(-4) , after removing known loci ) , highlighting new associations for follow-up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design . P35354 predicts adverse effects of tamoxifen : a possible mechanism of role for nuclear P04626 in breast cancer patients . P35354 ( P35354 ) is associated with breast tumour progression . Clinical and molecular studies implicate human epidermal growth factor receptor 2 ( P04626 ) in the regulation of P35354 expression . Recent reports raise the possibility that P04626 could mediate these effects through direct transcriptional mechanisms . The relationship between P04626 and P35354 was investigated in a cohort of breast cancer patients with or without endocrine treatment . A tissue microarray comprising tumours from 560 patients with 10-year follow-up was analysed for P04626 , P27361 /2 , polyoma enhancer activator 3 ( P43268 ) and P35354 expression . Subcellular localisation of P04626 was assessed by immunofluorescence and confocal microscopy . Expression of markers examined was analysed in relation to classic clinicopathological parameters and disease-free survival in the presence and absence of tamoxifen . P35354 expression associated with both membranous and nuclear expression of P04626 ( P=0.0033 and P < 0.00001 respectively ) . No association was detected between P35354 and either P27361 /2 or P43268 ( P=0.7 and P=0.3 respectively ) . None of the markers were found to be independently prognostic . Membrane P04626 , nuclear P04626 and P35354 , however , were all found to predict poor disease-free survival in patients on endocrine treatment ( P=0.0017 , P=0.0003 and P=0.0202 respectively ) . Moreover , patients who were positive for P35354 predicted adverse effects of tamoxifen ( P=0.0427 ) . These clinical ex vivo data are consistent with molecular observations that P04626 can regulate P35354 expression through direct transcriptional mechanisms . P35354 expression correlates with disease progression on endocrine treatment . This study supports a role for P35354 as a predictor of adverse effects of tamoxifen in breast cancer patients . High glucose enhances angiotensin-II-mediated peroxisome proliferation-activated receptor-gamma inactivation in human coronary artery endothelial cells . Activation of the renin-angiotensin system plays an important role in the pathogenesis of vascular complications of hyperglycemia . Clinical studies have demonstrated that hypoglycemic effects of peroxisome proliferation-activated receptor-gamma ( P37231 ) activation is potentially associated with a significant decrease of cardiovascular disease events in diabetes patients . We assessed the effect of high glucose on the angiotensin II ( Ang II ) , which induced the inactivation of P37231 and its signal pathways in human coronary artery endothelial cells ( HCAECs ) . The expression of angiotensin II receptor I ( AT1R ) protein was analyzed by Western blot and knocked down using siRNA . P37231 activation was examined using a luminometer and a Dual Luciferase Reporter Assay System . Adhesion molecule expressions of HCAECs were measured using ELISA . Both high glucose and Ang II induced a progressive increase in AT1R protein expression on the HCAECs . DB00197 , a P37231 activator , significantly increased the transcription activity of P37231 in HCAECs in vitro . However , activation of P37231 was significantly inhibited by high glucose and Ang II stimulation . Furthermore , silencing of AT1R expression was able to inhibit the inactivation of P37231 induced by Ang II and high glucose . Meanwhile , expression of proinflammatory adhesion molecules was increased by high glucose and Ang II in HCAECs , which is blocked by troglitazone and silencing of AT1R expression . These data strongly suggest high glucose enhanced Ang-II-mediated peroxisome proliferation-activated receptor-gamma inactivation and expression of proinflammatory adhesion molecules in human coronary artery endothelial cells . DB00197 stimulates beta-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1A receptor . P37231 ( Q07869 gamma ) agonists are commonly used to treat cardiovascular diseases , and are reported to have several effects on cardiovascular function that may be due to Q07869 gamma-independent signaling events . Select angiotensin receptor blockers ( ARBs ) interact with and modulate Q07869 gamma activity , thus we hypothesized that a Q07869 gamma agonist may exert physiologic effects via the angiotensin II type 1(A) receptor ( AT1(A)R ) . In AT1(A)R-overexpressing P29320 293 cells , both angiotensin II ( Ang II ) and the Q07869 gamma agonist troglitazone ( Trog ) enhanced AT1(A)R internalization and recruitment of endogenous beta-arrestin 1/2 ( beta arr1/2 ) to the AT1(A)R . A fluorescence assay to measure diacylglycerol ( DAG ) accumulation showed that although Ang II induced AT1(A)R-G(q) protein-mediated DAG accumulation , Trog had no impact on DAG generation . Trog-mediated recruitment of beta arr1/2 was selective to AT1(A)R as the response was prevented by an ARB- and Trog-mediated beta arr1/2 recruitment to beta1-adrenergic receptor ( beta 1AR ) was not observed . In isolated mouse cardiomyocytes , Trog increased both % and rate of cell shortening to a similar extent as Ang II , effects which were blocked with an ARB . Additionally , these effects were found to be beta arr2-dependent , as cardiomyocytes isolated from beta arr2-KO mice showed blunted contractile responses to Trog . These findings show for the first time that the Q07869 gamma agonist Trog acts at the AT1(A)R to simultaneously block G(q) protein activation and induce the recruitment of beta arr1/2 , which leads to an increase in cardiomyocyte contractility . P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104-115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2+ or Ca2+ to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104-115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2+ or Ca2+ . TnC and P62158 in the presence of either Ca2+ or Mg2+ bound to the TnI peptide 104-115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N-terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2+ but , in the presence of Mg2+ , did not bind to TnC and only bound weakly to P62158 . DB00623 bound to TnC and P62158 only in the presence of Ca2+ . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0.1 M DB00974 compared with the 0.01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins. ( ABSTRACT TRUNCATED AT 250 WORDS ) [ Dyslipidemia in insulin resistance and its improvement by troglitazone ] . Dyslipideia in insulin resistant state are characterized by 3 major components ; increased triglyceride levels , decreased high-density lipoprotein ( HDL ) cholesterol , and change in the composition of low-density lipoprotein ( LDL ) cholesterol particle which results in small-dense LDL . P01308 resistance is thought to lead to overproduction of very low-density lipoprotein ( VLDL ) cholesterol through the decreased peripheral lipoprotein lipase ( P06858 ) activity , increased production of apolipoprotein B-100 and decreased clearance of remnant particles . DB00197 , an insulin action enhancer , decreases the triglyceride level , increases HDL cholesterol level and decreases th proportion of small-dense LDL through the direct effect on lipoprotein metabolism . However , activation of P37231 is considered to possese potential atherogeneity and more closer examination is needed . DB00197 inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo . P37231 ( PPARgamma ) has been implicated in the differentiation and growth inhibition of cancer cells . We examined the effects of PPARgamma activation by troglitazone on hepatocellular carcinoma ( HCC ) cell growth , proliferation , and apoptosis in vitro and in vivo . We also studied relationships between PPARgamma activation and cyclooxygenase-2 ( P35354 ) expression . Human HCC cell lines Huh7 and Hep3B were cultured in the presence or absence of troglitazone . Cell growth was determined via WST-1 assay , proliferation by cell cycle analysis and proliferating cell nuclear antigen ( P12004 ) Western blotting , and apoptosis by flow cytometry and TUNEL . Tumor growth after subcutaneous implantation of Huh7 cells in nude mice was monitored , and the effects of treatment with troglitazone were determined . In resected HCCs , PPARgamma expression was less compared with the histologically normal surrounding liver . In cultures of Hep3B and Huh7 cells , basal expression of PPARgamma was relatively low , but troglitazone caused dose-dependent induction of PPARgamma expression . Cell cycle analysis revealed a decreased proportion of cells in S phase , with arrest at G0/ P55008 . Concomitant downregulation of P12004 and an increase in TUNEL staining , cells were consistent with decreased proliferation and induction of apoptosis by troglitazaone . DB00197 -mediated PPARgamma activation also suppressed P35354 expression and induced p27 in HCC cells . Administration of troglitazone to Huh7 tumor-bearing mice significantly reduced tumor growth and caused tumor regression . In conclusion , collectively , these results indicate that PPARgamma could be a regulator of cell survival and growth in HCC . PPARgamma therefore represents a putative molecular target for chemopreventive therapy or inhibition of liver cancer growth . A pleiotropic antiatherogenic action of ibuprofen . Ibuprofen is a cyclooxygenase ( P23219 and P35354 ) inhibitor known to reduce the production of prostaglandins that play prominent role in inflammation . Other properties of the drug , aside from its anti-inflammatory effects , have been recently studied . In this paper we shall discuss several properties of ibuprofen that making the drug interesting for treatment of conditions associated with atherosclerosis . Ibuprofen exerts pleiotropic effects such as inhibition of adhesion and transendothelial migration of leukocytes , suppressing intracellular production of reactive oxygen species and oxidative modification of LDL . Interestingly , ibuprofen increased HDL cholesterol levels and reduced the level of triglicerides . Ibuprofen can also modulate efficiency of fibrynolisis by inhibiting production of plasminogen activator inhibitor ( P05121 ) . This properties of ibuprofen may be due to changing the activity of transcription factors . Ibuprofen inhibits the activation of NF-kB and activates PPARa and PPARg . P37231 reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1 . P37231 ( PPARgamma ) forms a heterodimeric DNA-binding complex with the retinoid X receptor ( RXR ) and regulates the transcription of its target genes . Activation of PPARgamma has been shown to induce P55008 arrest and to inhibit cell growth of human pancreatic carcinoma cell lines . The purpose of the present study was to examine the effect of ligand activation of PPARgamma and RXR on cell growth and on the expression of P55008 cyclins in a pancreatic cancer cell line PANC-1 , which expresses PPARgamma at high levels . DB00197 , a specific ligand for PPARgamma , was found to cause a reduction in the growth rate and induced P55008 cell cycle arrest and this effect was additive with that of 9-cis retinoic acid ( 9-cis RA ) , a ligand for RXR . Of the P55008 cyclins tested , troglitazone specifically reduced the expression of cyclin D1 mRNA and the corresponding protein and this effect was also additive with 9-cis RA . These results suggest that the activation of PPARgamma together with RXR may be useful for the suppression of pancreatic cancer cell growth through the reduction in cyclin D1 levels . Thiazolidinediones downregulate stearoyl- DB01992 desaturase 1 gene expression in 3T3- Q9NUQ9 adipocytes . Thiazolidinediones ( TZDs ) are known to have potent increases of insulin sensitivity . Because peroxisome proliferator-activated receptor-gamma ( P37231 ) , a receptor for TZDs , is mainly expressed in adipocytes , we tried to search the TZD-targeted genes in mouse 3T3- Q9NUQ9 adipocytes . By the mRNA differential display method , one band repressed by troglitazone was obtained , which corresponded to the partial sequences of the stearoyl- DB01992 desaturase 1 ( SCD1 ) gene . DB00197 dramatically decreased SCD1 mRNA levels in 3T3- Q9NUQ9 adipocytes in a dose-dependent manner . Pioglitazone also repressed the SCD1 mRNA expression , whereas WY-14,643 had no apparent effect . Both troglitazone and pioglitazone raised the composition ( weight percentage ) of myristic acid ( C14:0 ) , palmitic acid ( C16:0 ) , and stearic acid ( C18:0 ) , but lowered the composition of the delta9-cis desaturated fatty acids such as myristoleic acid ( C14:1 , delta9 ) , palmitoleic acid ( C16:1 , delta9 ) , oleic acid ( C18:1 , delta9 ) , and linoleic acid ( C18:2 , delta9,12 ) . These results indicate that TZDs repress SCD1 activity in 3T3- Q9NUQ9 adipocytes via downregulating SCD1 enzyme gene expression . DB00171 -sensitive potassium channels ( K( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3- , lethal 20- and 40-min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K( DB00171 ) channel blockade on IPC protection were studied by treatment with 0.01 % glipizide . IPC was mimicked by injection of K( DB00171 ) channel openers of 0.01 % (-)cromakalim or 0.01 % P1060 72 h before 20-min ischemia . Co-expression of K( DB00171 ) channel subunits Kir6.2/ Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20- or 40-min ischemia , a 3-min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20-min ischemia had a significant improvement of the ERG . (-)Cromakalim and P1060 mimicked the effect of IPC . DB01067 significantly suppressed the protective effects of preconditioning . In conclusion , activation of K( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult . Coadministration of acetaminophen and troglitazone : pharmacokinetics and safety . DB00197 , a P37231 agonist , enhances the actions of insulin on muscle and liver . It is metabolized predominantly in the liver to a sulfate conjugate and a quinone metabolite . Acetaminophen also undergoes metabolism by conjugation . This three-way crossover study in 12 healthy male volunteers was conducted to investigate the effects of acetaminophen on the metabolism of troglitazone and vice versa . No statistically or clinically relevant differences in area under the concentration-time curve extrapolated to infinity ( AUCinfinity ) were observed for troglitazone , its quinone metabolite , or acetaminophen . A statistically significant decrease in troglitazone sulfate conjugate during administration with acetaminophen was not clinically relevant . No statistically or clinically relevant differences were observed in maximum concentration ( Cmax ) , time to Cmax ( tmax ) , or elimination half-life of troglitazone , its two main metabolites , and acetaminophen or in acetaminophen urinary sulfate excretion , although there was a slight decrease in acetaminophen glucuronide excretion during administration with troglitazone . Adverse events were minor and similar between treatments . These findings suggest that troglitazone and acetaminophen can be coadministered without adverse clinical consequences . [ Comparative study of somatic oncogene mutations in normal thyroid tissues and thyroid neoplasms ] . It is established that numerous somatic oncogene mutation ( P15056 , P01111 , P01112 , P01116 ) and gene translocations ( P07949 /PTC , Q06710 / P37231 ) are associated with the development of thyroid cancer . In this study 22 intraoperative thyroid tissue samples ( 11 pathologic and 11 normal ) were examined . Somatic single nucleotide polymorphisms were analyzed by LigthCycler melting method , while translocations were identified by real-time polymerase chain reaction technique . In tumorous sample 3 P15056 , 2 P01111 and one P01112 mutations were found , as well as one P07949 / Q13635 translocation . Results confirm international data showing that these oncogene mutations and translocations are linked to thyroid cancer . Cytological examination completed with genetic data may support the diagnosis of thyroid malignancies . In addition , genetic alterations may indicate malignant transformation and may become prognostic factors in future . Differential regulation by troglitazone of plasminogen activator inhibitor type 1 in human hepatic and vascular cells . DB00197 , a novel oral insulin sensitizer , normalizes increased plasma activity of plasminogen activator inhibitor type 1 ( P05121 ) in hyperinsulinemic patients such as women with polycystic ovary syndrome and patients with type 2 diabetes mellitus . However , underlying mechanisms have not yet been fully elucidated . Human hepatic and vascular cells , the main sources of circulating P05121 , were studied in cell culture . In human hepatic cells , P05121 accumulated in conditioned medium by 23 % within 24 h after exposure to 3 microg/mL troglitazone ( P = 0.001 ) . The accumulation depended on the concentration of troglitazone , but not that of insulin ( known to stimulate P05121 synthesis ) . By contrast , in human aortic smooth muscle cells , 3 microg/mL troglitazone decreased basal P05121 expression by 23 % ( P = 0.037 ) and decreased transforming growth factor-beta-induced expression by 34 % ( P = 0.026 ) . Concomitant insulin had no effect . P00750 was decreased by 38 % ( P = 0.002 ) . In human endothelial cells , P05121 was diminished by 32 % ( P < 0.001 ) , whereas tissue-type plasminogen activator was unaffected . The results suggest that the reduction in plasma activity of P05121 induced by troglitazone in patients may reflect both directly mediated diminution of its elaboration from vessel walls and indirectly mediated reduction of its hepatic synthesis secondary to attenuation of hyperinsulinemia ( known to increase the hepatic synthesis of P05121 ) . Effects of the PPARgamma agonist troglitazone on endothelial cells in vivo and in vitro : differences between human and mouse . P37231 ( PPARgamma ) agonists and PPARgamma/alpha dual agonists have been or are being developed for clinical use in the treatment of type 2 diabetes mellitus and hyperlipidemias . A common tumor finding in rodent carcinogenicity studies for these agonists is hemangioma/hemangiosarcoma in mice but not in rats . We hypothesized that increased endothelial cell proliferation may be involved in the mechanism of Q07869 agonist-induced vascular tumors in mice , and we investigated the effects on endothelial cells utilizing troglitazone , the first clinically used PPARgamma agonist , in vivo and in vitro . DB00197 ( 400 and 800 mg/kg/day ) induced hemangiosarcomas in mice in a 2-year bioassay . We showed that troglitazone increased endothelial cell proliferation in brown and white adipose tissue and liver in mice at sarcomagenic doses after 4 weeks of treatment . DB00197 was cytotoxic both to human dermal microvascular endothelial cells ( HMEC1 ) and mouse mammary fat pad microvascular endothelial cells ( MFP MVEC ) at high concentrations . However , MFP MVEC were more resistant to the cytotoxic effects of troglitazone based on the much lower LC(50) in HMEC1 ( 17.4 muM ) compared to MFP MVEC ( 92.2 muM ) . DB00197 increased the proliferation and survival of MFP MVEC but not HMEC1 in growth factor reduced conditions . Our data demonstrate that troglitazone may induce hemangiosarcomas in mice , at least in part , through enhancement of survival and proliferation of microvascular endothelial cells . Such an effect does not occur with human cells , suggesting that human may react differently to exposure to Q07869 agonists compared with mice . Curcumin : getting back to the roots . The use of turmeric , derived from the root of the plant Curcuma longa , for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years . The active component of turmeric responsible for this activity , curcumin , was identified almost two centuries ago . Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets , including transcription factors ( e.g. , NF-kappaB , AP-1 , Egr-1 , beta-catenin , and P37231 ) , enzymes ( e.g. , P35354 , 5- P28300 , P35228 , and hemeoxygenase-1 ) , cell cycle proteins ( e.g. , cyclin D1 and P38936 ) , cytokines ( e.g. , P01375 , IL-1 , P05231 , and chemokines ) , receptors ( e.g. , P00533 and P04626 ) , and cell surface adhesion molecules . Because it can modulate the expression of these targets , curcumin is now being used to treat cancer , arthritis , diabetes , Crohn 's disease , cardiovascular diseases , osteoporosis , Alzheimer 's disease , psoriasis , and other pathologies . Interestingly , 6-gingerol , a natural analog of curcumin derived from the root of ginger ( Zingiber officinalis ) , exhibits a biologic activity profile similar to that of curcumin . The efficacy , pharmacologic safety , and cost effectiveness of curcuminoids prompt us to " get back to our roots . " Dependence on phosphoinositide 3-kinase and DB01367 -RAF pathways drive the activity of RAF265 , a novel RAF/ P35968 inhibitor , and RAD001 ( DB01590 ) in combination . Activation of phosphatidylinositol-3-kinase ( PI3K ) -AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K-AKT , or both . We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 -RAF and PI3K , possibly through the cross-inhibition of 4E binding protein 1 and S6 protein . Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells . Activation of peroxisome proliferator-activated receptor ( Q07869 ) -gamma by the thiazolidinedione ( TZD ) class of antidiabetic drugs elicits growth inhibition in a variety of malignant tumors . We clarified the effects of TZDs on growth of human non-small cell lung carcinoma ( NSCLC ) cells that express endogenous P37231 . DB00197 and pioglitazone caused inhibition of cellular growth and induced apoptosis of NSCLC cells in a time- and dose-dependent manner . Subtraction cloning analysis identified that troglitazone stimulated expression of the growth arrest and DNA-damage inducible (GADD)153 gene , and the increased expression of P35638 mRNA was also confirmed by an array analysis of the 160 apoptosis-related genes . Western blot analysis revealed that troglitazone also increased P35638 protein levels in a time-dependent manner . DB00197 did not stimulate P35638 mRNA levels in undifferentiated 3T3- Q9NUQ9 cells lacking P37231 expression , whereas its induction was clearly observed in differentiated adipocytes expressing P37231 . Activity of the P35638 promoter occurred in a NSCLC cell line in transient transcription assays and was significantly stimulated by troglitazone , although binding of Q07869 /retinoid X receptor heterodimer was not detected in the promoter region in gel retardation assays . Inhibition of P35638 gene expression by an antisense phosphorothionate oligonucleotide attenuated the troglitazone-induced growth inhibition . These findings collectively indicated that activation of P37231 by TZDs could cause growth inhibition and apoptosis of NSCLC cells and that P35638 might be a candidate factor implicated in these processes . Interleukin 10 blocks matrix metalloproteinase-2 and membrane type 1-matrix metalloproteinase synthesis in primary human prostate tumor lines . P01308 -like growth factor ( IGF ) I has been shown previously to up-regulate matrix metalloproteinase-2 ( P08253 ) production , whereas the interleukin ( IL ) 10/ P22301 receptor axis has been found to down-regulate P08253 synthesis in tumor cells . In this paper , we showed that P22301 activation of the P22301 receptor blocked P08253 and membrane type 1 ( MT1 ) -MMP transcription and protein synthesis in nonimmortalized primary human prostate cell strains ( i.e. , P84074 -10a and P84074 -10c ) derived from high-grade cancer . Northern blots , Western blots , and ELISAs showed that P22301 suppressed P05019 induction of P08253 and P50281 mRNA synthesis in these cell strains ( P < 0.001 ) . Inhibition studies with P22301 and P08069 antibodies plus transfections experiments with P22301 sense , and P08069 antisense constructs confirmed these results . Finally , transient transfection experiments and chloramphenicol acetyltransferase assays with different regions of the 5' promoter region of the P08253 gene ( -1659 to -555 bp ) additionally showed that P05019 stimulated p53-dependent plasmid catecholamine acetyltransferase activity and that P22301 blocked P05019 -induced plasmid catecholamine acetyltransferase activity . Electrophoretic mobility shift assays revealed that P22301 induced protein(s) binding to a putative " silencer element " ( -1309 to -555 fragment ) downstream of the p53 binding site ( -1649 to -1640 ) . The data show that P22301 blocks P05019 activation of P08253 and P50281 mRNA expression and protein synthesis in primary prostate cell strains . Direct attenuation of plasminogen activator inhibitor type-1 expression in human adipose tissue by thiazolidinediones . Adipose tissue produces substantial amounts of plasminogen activator inhibitor type-1 ( P05121 ) , an established cardiovascular risk factor . This study evaluated P05121 expression in human adipose tissue in response to thiazolidinediones , insulin sensitising drugs activating peroxisome proliferator-activated receptor-gamma ( P37231 ) . DB00197 , rosiglitazone , and ciglitazone significantly reduced P05121 protein expression in human preadipocytes under basal conditions and after stimulation of the cells with TGF-beta . Pioglitazone had no effect . In human adipocytes all four thiazolidinediones significantly attenuated P05121 expression . Signalling appeared to be mediated via P37231 and effects reflected , at least in part , changes in transcription . Accordingly , patients with insulin resistance may benefit from treatment with thiazolidinediones with respect to diminution of P05121 expression in adipose tissue and consequent potential reduction of cardiovascular risk . Comparison of low fat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation . Abnormal distribution of plasma fatty acids and increased inflammation are prominent features of metabolic syndrome . We tested whether these components of metabolic syndrome , like dyslipidemia and glycemia , are responsive to carbohydrate restriction . Overweight men and women with atherogenic dyslipidemia consumed ad libitum diets very low in carbohydrate ( VLCKD ) ( 1504 kcal : % CHO:fat:protein = 12:59:28 ) or low in fat ( LFD ) ( 1478 kcal : % CHO:fat:protein = 56:24:20 ) for 12 weeks . In comparison to the LFD , the VLCKD resulted in an increased proportion of serum total n-6 PUFA , mainly attributed to a marked increase in arachidonate ( 20:4n-6 ) , while its biosynthetic metabolic intermediates were decreased . The n-6/n-3 and arachidonic/eicosapentaenoic acid ratio also increased sharply . Total saturated fatty acids and 16:1n-7 were consistently decreased following the VLCKD . Both diets significantly decreased the concentration of several serum inflammatory markers , but there was an overall greater anti-inflammatory effect associated with the VLCKD , as evidenced by greater decreases in P01375 , P05231 , P10145 , P13500 , P16581 , I- P62158 , and P05121 . Increased 20:4n-6 and the ratios of 20:4n-6/20:5n-3 and n-6/n-3 are commonly viewed as pro-inflammatory , but unexpectedly were consistently inversely associated with responses in inflammatory proteins . In summary , a very low carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to a low fat diet . [ Inhibitive effect of troglitazone on TGF-beta(1) and fibronectin expression in human peritoneal mesothelial cells ] . OBJECTIVE : To investigate the effect of the peroxisome proliferator activated receptor-gamma ( P37231 ) agonist troglitazone on TGF-beta(1) and fibronectin ( Fn ) expression in human peritoneal mesothelial cells ( HPMCs ) . METHODS : HPMCs were cultured from human omentum by an enzyme digestion method , growing in medium containing 30 mmol/L D-glucose . TGF-beta(1) and Fn expression were measured in HPMCs in the presence and absence of 15 micromol/L troglitazone . The mRNA expressions of P37231 ,TGF-beta(1) and Fn were determined by semi-quantification reverse transcriptive PCR ( RT-PCR ) . The protein of TGF-beta(1) was determined by enzyme-linked immunosorbent assay ( ELISA ) and proteins of P37231 and Fn were determined by Western blot . RESULTS : The mRNA and protein expression of TGF-beta(1) and Fn were significantly increased in HPMCs stimulated with 30 mmol/L D-glucose compared with the control group with P00748 media ( P < 0.01 ) . Obvious decrease of TGF-beta(1) was found in troglitazone ( 15 micromol/L ) treated group compared with group stimulated with 30 mmol/L D-glucose ( P < 0.05 ) . Exposure of HPMCs to troglitazone reduced the Fn secretion ( P < 0.05 ) . CONCLUSION : DB00197 reduced the expression of TGF-beta(1) in HPMCs stimulated by 30mmol/L D-glucose , and reduced Fn production . P37231 agonists may have a specific role in ameliorating the course of progressive peritoneal fibrosis under long-term peritoneal dialysis states . Diabetes mellitus and macrovascular disease : mechanisms and mediators . Atherosclerosis is a chronic inflammatory condition initiated in the endothelium in response to injury and maintained through the interactions between modified lipoproteins , macrophages , and arterial wall constituents . Risk for macrovascular disease is substantially increased in patients with type 2 diabetes mellitus . Factors underlying the link between insulin resistance/type 2 diabetes and macrovascular disease include reduced adiponectin concentration , increased expression of vascular cell adhesion molecule-1 and consequent adhesion of T-lymphocytes to the coronary endothelium , procoagulability with increased expression of plasminogen activator inhibitor-1 ( P05121 ) -1 , and instability of atherosclerotic plaques resulting from increased expression by macrophages of matrix metalloproteinases ( MMPs ) . Thiazolidinediones ( TZDs ) are agonists of peroxisome proliferator-activated receptor ( Q07869 ) -gamma and increase adiponectin . TZD therapy is associated with decreases in hepatic fat content and glycosylated hemoglobin and an increase in hepatic glucose disposal . TZDs lower circulating free fatty acid concentration and triglyceride content in the liver , but not in skeletal muscle . Effects of P37231 agonists in vitro and in animal models provide evidence for additional potential antiatherosclerotic benefits in patients with diabetes beyond the treatment of hyperglycemia and dyslipidemia , including the reduction of expression of macrophage MMPs and scavenger receptor-1 , and indirect reduction of P05121 and inhibition of vascular smooth muscle cell proliferation , via suppression of type 1 angiotensin-2 receptor expression . Dual Q07869 /gamma agonists , retinoid receptor agonists , and , to a lesser extent , TZDs , also stimulate cholesterol efflux from macrophages in vitro . The ratio of plasminogen activator inhibitor type-1 activity to the concentration of plasminogen activator inhibitor type-1 protein in diabetes : adding insult to injury . BACKGROUND : This study was performed to delineate the relationship between plasminogen activator inhibitor type-1 ( P05121 ) activity and P05121 protein to characterize the functional importance of elevated P05121 in diabetes . METHODS : P05121 activity ( chromogenic substrate kinetic assay ) and protein ( enzyme-linked immunosorbent assay ) were assayed in baseline central venous catheter-acquired samples from 170 patients with type 2 diabetes studied in the DB00197 Atherosclerosis Regression Trial ( TART ) . RESULTS : The data demonstrated that the ratio of P05121 activity to the concentration of P05121 protein is increased as a function of increasing concentrations of P05121 protein in blood . CONCLUSIONS : The results demonstrate that the ratio of P05121 activity to the concentration of P05121 protein is higher when the concentration of P05121 is elevated . The nonlinearity appears to depend on the fact that the rate of disappearance of P05121 activity in blood is a function of the concentration of P05121 protein . The regulation of rotenone-induced inflammatory factor production by DB00171 -sensitive potassium channel expressed in BV-2 cells . Our previous studies have demonstrated that activating DB00171 -sensitive potassium channel ( K( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson 's disease ( PD ) . In this study , it was first shown that the subunits of K( DB00171 ) channels are expressed in BV-2 cells , and then it was investigated whether K( DB00171 ) channel was involved in regulating inflammatory factor production from BV-2 cells activated by rotenone . It was found that K( DB00171 ) channel was expressed in BV-2 cell and formed by the combination of Kir 6.1 and Q09428 2A/2B . K( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone-induced morphological alterations of BV-2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5-hydroxydecanoate acid ( a selective mitochondrial K( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K( DB00171 ) channels , especially mitochondrial DB00171 -sensitive potassium channels ( mitoK( DB00171 ) channels ) , played a crucial role in preventing the activation of BV-2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders . [ Clinical effect and side effect of troglitazone ] . DB00197 , a P37231 agonist , is a new drug for type 2 diabetes . The drug decreases blood glucose via enhancing insulin action . Recently Sankyo pharmaceutical company is warning severe hepatotoxicity by troglitazone . It recommends to examine liver function every month in diabetic patients treated with the drug in order early to find drug-induced hepatitis . In Japan 153 diabetic patients treated with the drug developed severe hepatitis and 8 of them died of drug-side effects . Quinone metabolite of troglitazone predominantly in the liver to a sulfate conjugate and activation of Q07869 gamma and O75469 ( pregnane X receptor ) by troglitazone are supposed to be factors of hepatotoxic mechanism . Pro- P08253 activation by the PPARgamma agonist , ciglitazone , induces cell invasion through the generation of ROS and the activation of P29323 . P37231 ( PPARgamma ) is a nuclear receptor modulating a variety of biological functions including cancer cell proliferation and differentiation . However , the role of PPARgamma and its ligands in tumor invasion is unclear . To evaluate a possible role for PPARgamma ligands in tumor invasion , we examined whether PPARgamma agonists including pioglitazone , troglitazone , rosiglitazone , and ciglitazone could affect the activity of matrix metalloproteinases ( MMPs ) in the HT1080 cell line , a well-studied and well-characterized cell line for MMP research . The gelatin zymography assay showed that ciglitazone activated pro- P08253 significantly . In addition , ciglitazone increased the expression of P08253 , which was accompanied by an increase of membrane type 1-MMP ( P50281 ) expression . The PPARgamma antagonist , GW9662 attenuated the ciglitazone-induced PPARgamma activation but it did not affect the pro- P08253 activation by ciglitazone , suggesting that the action of ciglitazone on the pro- P08253 activation bypassed the PPARgamma pathway . Antioxidants and various inhibitors of signal transduction were used to investigate the mechanism of ciglitazone-induced pro- P08253 activation . We found that the sustained production of reactive oxygen species ( ROS ) was required for pro- P08253 activation by ciglitazone . We also found that PB98059 , an inhibitor of MEK- P29323 , significantly blocked ciglitazone-induced pro- P08253 activation and that extracellular signal-regulated kinase ( P29323 ) was hyperphosphorylated by ciglitazone . Moreover , cell invasion was significantly increased by ciglitazone in the HT1080 cell lines , whereas cell motility was not affected . This study suggests that ciglitazone-induced pro- P08253 activation increases PPARgamma-independent tumor cell invasion through ROS production and P29323 activation in some types of cancer cells . Sequence variation in P37231 may underlie differential response to troglitazone . Thiazolidinediones ( TZDs ) are peroxisome proliferator-activated receptor-gamma ( P37231 ) agonists used to treat type 2 diabetes . TZDs can also be used to reduce rates of type 2 diabetes in at-risk individuals . However , a large fraction of TZD-treated patients ( 30-40 % ) do not respond to TZD treatment with an improvement in insulin sensitivity ( Si ) . We hypothesized that variation within the gene encoding P37231 may underlie this differential response to TZD therapy . We screened approximately 40 kb of P37231 in 93 nondiabetic Hispanic women ( 63 responders and 30 nonresponders ) with previous gestational diabetes who had participated in the DB00197 In the Prevention Of Diabetes study . TZD nonresponse was defined as the lower tertile in change in Si after 3 months of treatment . Baseline demographic and clinical measures were not different between responders and nonresponders . We identified and genotyped 131 variants including 126 single nucleotide polymorphisms and 5 insertion-deletion polymorphisms . Linkage disequilibrium analysis identified five haplotype blocks . Eight variants were associated with TZD response ( P < 0.05 ) . Three variants were also associated with changes in Si as a continuous variable . Our results suggest that P37231 variation may underlie response to TZD therapy in women at risk for type 2 diabetes . Thiazolidinediones : effects on insulin resistance and the cardiovascular system . Thiazolidinediones ( TZDs ) have been used for the treatment of hyperglycaemia in type 2 diabetes for the past 10 years . They may delay the development of type 2 diabetes in individuals at high risk of developing the condition , and have been shown to have potentially beneficial effects on cardiovascular risk factors . TZDs act as agonists of peroxisome proliferator-activated receptor-gamma ( P37231 ) primarily in adipose tissue . P37231 receptor activation by TZDs improves insulin sensitivity by promoting fatty acid uptake into adipose tissue , increasing production of adiponectin and reducing levels of inflammatory mediators such as tumour necrosis factor-alpha ( P01375 ) , plasminogen activator inhibitor-1( P05121 ) and interleukin-6 ( P05231 ) . Clinically , TZDs have been shown to reduce measures of atherosclerosis such as carotid intima-media thickness ( CIMT ) . However , in spite of beneficial effects on markers of cardiovascular risk , TZDs have not been definitively shown to reduce cardiovascular events in patients , and the safety of rosiglitazone in this respect has recently been called into question . Dual Q07869 /gamma agonists may offer superior treatment of insulin resistance and cardioprotection , but their safety has not yet been assured . P37231 ligands inhibit growth of human esophageal adenocarcinoma cells through induction of apoptosis , cell cycle arrest and reduction of ornithine decarboxylase activity . P37231 ( P37231 ) , a member of the nuclear hormone receptor superfamily , is involved in suppression of growth of several types of tumors such as liposarcoma , breast cancer , prostate cancer , and colon cancer , possibly through induction of cell cycle arrest and/or apoptosis . In this study , we demonstrated expression of P37231 mRNA and protein in human esophageal carcinoma cells . Expression of P37231 protein was higher in an adenocarcinoma cell line ( TE-7 cells ) than in a squamous cell carcinoma cell line ( TE-1 cells ) . P37231 ligands such as 15-deoxy-Delta12,14-prostaglandin J2 and troglitazone significantly inhibited the growth of TE-7 cells but had less or no effect on growth of TE-1 cells . 15d-PGJ2 and troglitazone induced apoptosis in TE-7 cells but not in TE-1 cells . DB00197 caused P55008 cell cycle arrest and reduced ornithine decarboxylase activity ( ODC ) in TE-7 cells but not in TE-1 cells . Inhibition by P37231 ligands of growth of esophageal adenocarcinoma cells may thus be due to induction of apoptosis , P55008 cell cycle arrest and reduction of ODC activity . DB00197 antagonizes tumor necrosis factor-alpha-induced reprogramming of adipocyte gene expression by inhibiting the transcriptional regulatory functions of NF-kappaB . DB00197 ( Q96PF1 ) , a member of the thiazolidinedione class of anti-diabetic compounds and a peroxisome proliferator activator receptor-gamma ( P37231 ) agonist , restores systemic insulin sensitivity and improves the full insulin resistance syndrome in vivo . The mechanisms underlying its in vivo function are not understood . Here we investigated the potential functional interaction between P37231 and NF-kappaB in adipocytes . We show that Q96PF1 selectively blocked tumor necrosis factor-alpha-induced and NF-kappaB-dependent repression of multiple adipocyte-specific genes and induction of growth phase and other genes . This occurs without interfering with NF-kappaB expression , activation , nuclear translocation , or DNA binding and without suppressing NF-kappaB-dependent survival signals . Notably , the expressions of some tumor necrosis factor-alpha-induced genes in adipocytes were unaffected by P37231 activation . In reporter gene assays in HeLa cells , ectopic expression of P37231 abolished induction of a NF-kappaB-responsive reporter gene by the p65 subunit ( RelA ) of NF-kappaB , and the inhibition was further enhanced in the presence of Q96PF1 . Conversely , overexpression of p65 inhibited induction of a P37231 -responsive reporter gene by activated P37231 in a dose-dependent manner . The inhibitory effect was independent of the presence of NF-kappaB-binding sites in the promoter region . Other NF-kappaB family members , p50 and c-Rel as well as the S276A mutant of p65 , blocked P37231 -mediated gene transcription less effectively . Thus , p65 antagonizes the transcriptional regulatory activity of P37231 in adipocytes , and P37231 activation can at least partially override the inhibitory effects of p65 on the expression of key adipocyte genes . Our data suggest that inhibition of NF-kappaB activity is a mechanism by which P37231 agonists improve insulin sensitivity in vivo and that adipocyte NF-kappaB is a potential therapeutic target for obesity-linked type 2 diabetes . 15-Deoxy-delta(12,14)-prostaglandin J(2) inhibits IL-1beta-induced IKK enzymatic activity and P25963 degradation in rat chondrocytes through a PPARgamma-independent pathway . P37231 ( PPARgamma ) ligands have been shown to inhibit the effects of proinflammatory cytokines such as interleukin-1beta ( IL-1beta ) . This cytokine plays a key role in articular pathophysiologies by inducing the production of inflammatory mediators such as nitric oxide ( NO ) and prostaglandin E(2) ( PGE(2) ) . We previously demonstrated that 15d-PGJ(2) was more potent than troglitazone to counteract IL-1beta effects on chondrocytes . Here , we studied the action of 15d-PGJ(2) on intracellular targets in nuclear factor-kappaB ( NF-kappaB ) signalling pathway in IL-1beta treated rat chondrocytes . We found that 15d-PGJ(2) decreased inhibitor kappaBalpha ( P25963 ) degradation but not its phosphorylation by specifically inhibiting O15111 beta ( IKKbeta ) , but not IKKalpha , enzymatic activity . We further evaluated the involvement of PPARgamma in the anti-inflammatory action of its ligands . In chondrocytes overexpressing functional PPARgamma protein , 15d-PGJ(2) pre-treatment inhibited inducible NO synthase and P35354 mRNA expression , nitrite and PGE(2) production , p65 translocation and NF-kappaB activation . DB00197 or rosiglitazone pre-treatment had no effect . 15d-PGJ(2) exhibited the same effect in chondrocytes overexpressing mutated PPARgamma protein . These results suggest that 15d-PGJ(2) exerts its anti-inflammatory effect in rat chondrocytes by a PPARgamma-independent mechanism , which can be conferred to a partial inhibition of P25963 degradation . P01308 -like growth factor-1 receptor signaling increases the invasive potential of human epidermal growth factor receptor 2-overexpressing breast cancer cells via Src-focal adhesion kinase and forkhead box protein M1 . Resistance to the human epidermal growth factor receptor ( P04626 ) -targeted antibody trastuzumab is a major clinical concern in the treatment of P04626 -positive metastatic breast cancer . Increased expression or signaling from the insulin-like growth factor-1 receptor ( IGF-1R ) has been reported to be associated with trastuzumab resistance . However , the specific molecular and biologic mechanisms through which IGF-1R promotes resistance or disease progression remain poorly defined . In this study , we found that the major biologic effect promoted by IGF-1R was invasion , which was mediated by both Src-focal adhesion kinase ( Q05397 ) signaling and Q08050 ( FoxM1 ) . Cotargeting IGF-1R and P04626 using either IGF-1R antibodies or IGF-1R short hairpin RNA in combination with trastuzumab resulted in significant but modest growth inhibition . Reduced invasion was the most significant biologic effect achieved by cotargeting IGF-1R and P04626 in trastuzumab-resistant cells . Constitutively active Src blocked the anti-invasive effect of IGF-1R/ P04626 cotargeted therapy . Furthermore , knockdown of FoxM1 blocked DB01277 -mediated invasion , and dual targeting of IGF-1R and P04626 reduced expression of FoxM1 . Re-expression of FoxM1 restored the invasive potential of IGF-1R knockdown cells treated with trastuzumab . Overall , our results strongly indicate that therapeutic combinations that cotarget IGF-1R and P04626 may reduce the invasive potential of cancer cells that are resistant to trastuzumab through mechanisms that depend in part on Src and FoxM1 . Pervanadate-induced shedding of the intercellular adhesion molecule ( ICAM ) -1 ectodomain is mediated by membrane type-1 matrix metalloproteinase ( P50281 ) . In several vascular diseases , the ectodomain of intercellular adhesion molecule ( ICAM ) -1 is shed by the proteolytic activity of a zinc-dependent endopeptidase , releasing a soluble form of the protein ( sICAM-1 ) , a common marker for inflammatory diseases . Since reactive oxygen species ( ROS ) generated during prolonged inflammation are known to induce shedding or cleavage of several transmembrane proteins , we sought to explore the cleavage and enzymatic effects that the pervanadate , via oxidation and subsequent inactivation of protein tyrosine phosphatase , has on P05362 cleavage . In these studies , we used endothelial cells ( ECs ) and 293 human embryonic kidney ( P29320 ) cells expressing high-levels of surface P05362 . In addition , use of specific tissue inhibitors of metalloproteinases ( TIMPs ) , small interfering (si)RNA designed to knockdown endopeptidase activity , and an immunocolocalization assay were employed to determine the identity of a specific metalloproteinase mediating pervanadate-induced sICAM-1 shedding . Our data indicate that membrane type-1 matrix metalloproteinase ( P50281 ) is involved in pervanadate-mediated shedding of the sICAM-1 ectodomain in both cell types . Immunostaining and confocal microscopy provide visual evidence that P05362 and P50281 colocalize at the cellular surface following pervanadate treatment , further implicating the involvement of P50281 activity in this mode of P05362 shedding . Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients . The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation . Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis . Selected up-regulated genes were further validated by quantitative real-time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis ( n=5 ) . Selected genes up-regulated before transplantation were : Q07011 ( tumor necrosis factor [ P01375 ] receptor superfamily , member 9 ) ; P14784 ( interleukin-2 receptor beta ) ; Q92843 ( P10415 -like 2 ) ; Q96PH1 ( NADPH ) oxidase , EF-hand calcium binding domain 5 ) ; P50542 ( peroxisomal biogenesis factor 5 ) ; P37231 ( peroxisome proliferator-activated receptor gamma ) ; Q96Q05 ( O14920 binding protein ) ; Q9NYR9 ( NFKappaBeta inhibitor interacting Ras-like 2 ) ; P05112 ( interleukin-4 ) ; IL-4R ( interleukin 4 receptor ) ; P07327 ( alcohol dehydrogenase 1A , class 1 ) ; O75891 ( aldehyde dehydrogenase 1 family , member Q9NUQ9 ) ; P05164 ( myeloperoxidase ) ; P01160 ( natriuretic peptide precursor A ) ; Q16548 ( P10415 -related protein A1 ) ; P24522 ( growth arrest and DNA-damage-inducible alpha ) ; P55061 ( P55061 ) ; P42336 ( phosphoinositide-3-kinase , catalytic , alpha polypeptide ) ; P38484 ( interferon gamma receptor 2 ) ; O60674 ( Janus Kinase 2 ) ; FAS ( Fas , P01375 receptor superfamily , member 6 ) ; Q92844 ( TRAF family member-associated NFKB activator ) ; O95551 ( O95551 ) ; and P08758 ( annexin A5 ) . Thiazolidinediones : a comparative review of approved uses . Thiazolidinediones are a powerful and clinically important new class of oral antidiabetic agents that act by improving insulin sensitivity . DB00197 is the prototype drug in this class but was withdrawn from the market in March 2000 due to its association with idiosyncratic hepatotoxicity . Currently two thiazolidinediones , rosiglitazone and pioglitazone , are U.S . Food and Drug Administration ( FDA ) approved for treatment of type 2 diabetes . These agents bind to and activate peroxisome proliferator-activator receptor gamma ( P37231 ) and work by altering the expression of genes involved in glucose uptake , glucose disposal , and lipid metabolism . The drugs differ in receptor binding and potency due to differences in their side chain moieties . These agents are rapidly absorbed from the gastrointestinal tract and are metabolized mainly in the liver . Rosiglitazone is FDA approved for monotherapy and for use in combination therapy with metformin or sulfonylureas . Pioglitazone is FDA approved for monotherapy as well as for use in combination therapy with metformin , insulin , or sulfonylureas . These drugs may also cause significant changes in plasma lipid concentrations , and improved insulin sensitivity may improve ovulatory function and fertility in women with polycystic ovary syndrome . The most serious side effect of the thiazolidinediones is hepatotoxicity . Although rosiglitazone and pioglitazone were not associated with hepatotoxicity in premarketing clinical trials , there were two recent case reports of idiosyncratic hepatotoxicity in patients treated with rosiglitazone . In addition , these agents may be associated with edema and some hematological changes . The purpose of this review is to provide an overview of the two currently approved thiazolidinediones and to suggest an approach for their safe and rational use . Disruption of ERalpha signalling pathway by PPARgamma agonists : evidences of PPARgamma-independent events in two hormone-dependent breast cancer cell lines . P37231 ( PPARgamma ) is a nuclear receptor that can be activated by natural ligands such as 15-deoxy-delta(12,14)-prostaglandin J2 ( 15d-PGJ(2) ) as well as synthetic drugs such as thiazolidinediones . The treatment of human breast cancer cell lines with PPARgamma agonists is known to have antiproliferative effects but the role of PPARgamma activation in the process remains unclear . In the present study , we investigated the effects of four PPARgamma agonists , Rosiglitazone ( RGZ ) , DB09201 ( CGZ ) , DB00197 ( Q96PF1 ) and the natural agonist 15d-PGJ(2) , on estrogen receptor alpha ( ERalpha ) signalling pathway in two hormone-dependent breast cancer cell lines , MCF-7 and ZR-75-1 . In both of them , Q96PF1 , CGZ and 15d-PGJ(2) induced an inhibition of ERalpha signalling associated with the proteasomal degradation of ERalpha . ZR-75-1 cells were more sensitive than MCF-7 cells to these compounds . Treatments that induced ERalpha degradation inhibited cell proliferation after 24 h . In contrast , 24 h exposure to RGZ , the most potent activator of PPARgamma disrupted neither ERalpha signalling nor cell proliferation . 9-cis retinoic acid never potentiated the proteasomal degradation of ERalpha . PPARgamma antagonists ( T0070907 , BADGE and GW 9662 ) did not block the proteolysis of ERalpha in MCF-7 and ZR-75-1 cells treated with Q96PF1 . ERalpha proteolysis still occurred in case of PPARgamma silencing as well as in case of treatment with the PPARgamma-inactive compound Delta2- Q96PF1 , demonstrating a PPARgamma-independent mechanism . The use of thiazolidinedione derivatives able to trigger ERalpha degradation by a PPARgamma-independent pathway could be an interesting tool for breast cancer therapy . Cyclooxygenase-independent inhibition of H2O2-induced cell death by S-ketoprofen in renal cells . The stress response of the distal tubule to oxidative attack may be relevant to recovery from acute renal failure . In distal tubular Madin-Darby cells ( MDCK ) , H(2)O(2) induced up-regulation of cyclooxygenases ( P23219 and P35354 ) , prostaglandin-E(2) production and caspase-independent cell death . Cell death was inhibited by S-ketoprofen , but not by the much weaker P36551 inhibitor R-ketoprofen . Interestingly , we identified 15-deoxy-Delta(12,14)-prostaglandin-J(2) ( 15d-PGJ(2) ) , a peroxisome-proliferator activated receptor-gamma agonist , as a lethal prostaglandin whose effect was reproduced by the P37231 agonist ciglitazone . Nevertheless , H(2)O(2)-induced cell death was unaffected by other non-steroidal anti-inflammatory drugs ( NSAIDs ) or all-trans-retinoic acid . Moreover , c-Jun-N-terminal kinase inhibitor SP600125 prevented 15-deoxy-Delta(12,14)-PGJ(2)-induced cell death , but not H(2)O(2)-induced cell death . P37231 antagonist GW9662 showed no affect on the cell death . These results indicated that protection by S-ketoprofen was P36551 -independent and PPARgamma independent . Moreover , the IC(50) value of the action of S-ketoprofen for the inhibition of H(2)O(2)-induced MDCK cell death ( approximately equal 140microM ) was much higher than the IC(50) value for the inhibition of P23219 and P35354 activities ( approximately equal 1microM ) . Further design of S-ketoprofen derivatives devoid of P36551 inhibitory activity will give opportunity to protect the kidney against oxidative attack while avoiding unwanted effects of NSAID . DB00197 suppresses transforming growth factor-beta1-induced collagen type I expression in keloid fibroblasts . BACKGROUND : Peroxisome proliferator-activated receptor ( Q07869 ) -gamma agonists are increasingly used in patients with diabetes and some studies have suggested a beneficial effect on organ fibrosis . However their effects on dermal fibrosis in keloids are unknown . OBJECTIVE : To investigate the effect of the P37231 agonist troglitazone on transforming growth factor ( TGF ) -beta1-induced collagen type I expression in keloid fibroblasts . METHODS : Keloid fibroblasts were cultured and exposed to different concentrations of troglitazone in the presence of TGF-beta1 . The mRNA expression of P37231 was determined by semiquantitative reverse transcriptase-polymerase chain reaction . The protein of P37231 , Q15796 , P84022 , phoshpo- Q15796 /3 and collagen type I was determined by Western blotting and collagen synthesis was evaluated by measuring (3)H-proline incorporation . The effect of troglitazone on cell viability was evaluated by the colorimetric conversion of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide . RESULTS : P37231 was expressed at a moderate level in keloid fibroblasts . DB00197 depressed TGF-beta1-stimulated collagen type I expression and collagen synthesis in keloid fibroblasts in a concentration-dependent manner . Moreover , troglitazone inhibited expression and phosphorylation of TGF-beta1-induced Q15796 /3 . Cell viability was unaffected . These inhibitory effects of troglitazone were reversed by the P37231 -specific antagonist GW9662 . CONCLUSIONS : Our data suggest that P37231 is present in keloid fibroblasts and P37231 activation inhibits TGF-beta1-induced collagen type I expression at least in part by decreasing collagen synthesis . P37231 may be a promising therapeutic target for keloids .