Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00403 (Rosiglitazone)
 810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adipocytokine adiponectin is released by adipocytes upon activation of the peroxisome proliferator-activated receptor gamma (PPAR gamma). PPAR gamma has binding sites for thiazolidinediones and free fatty acids (FFAs). To evaluate if adiponectin serum concentrations are synergistically regulated by FFAs and thiazolidinediones IN VIVO plasma FFAs were acutely elevated in healthy subjects pre-treated with rosiglitazone or placebo. Sixteen healthy male subjects (23-37 years) were included in this double-blind, randomized, placebo-controlled parallel-group study. Rosiglitazone 8 mg or placebo was administered daily for 21 days. On the last day plasma FFA concentrations were increased by an intravenous triglyceride/heparin infusion. Blood for determination of adiponectin, C-reactive protein (CRP), leptin, resistin, FFAs, glucose, and insulin was drawn at baseline and on day 21 before and after 5 hours of triglyceride/heparin infusion. Adiponectin concentrations increased and FFA levels decreased in subjects receiving rosiglitazone (all p<0.05 VS. baseline). Lipid infusion significantly increased FFA plasma concentrations, with an attenuated elevation in rosiglitazone-treated subjects. However, adiponectin concentrations were only increased in subjects on rosiglitazone (p=0.018 VS. before lipid infusion), but not in controls. Leptin increased during lipid infusion in subjects receiving placebo but not in those on rosiglitazone. CRP and resistin were not affected by rosiglitazone or FFAs. The acute increase in circulating adiponectin concentrations during acutely elevated FFA depends on PPAR gamma activation in healthy subjects.
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PMID:Adiponectin concentrations increase during acute FFA elevation in humans treated with rosiglitazone. 1795 42

Ligands for peroxisome proliferator-activated receptor gamma (PPAR gamma) possess anticancer properties. However, the efficacy of PPAR gamma ligands varies in different cancers. In colon cancer, the role of PPAR gamma and its ligands is controversial. We recently showed that downregulation of X-linked inhibitor of apoptosis protein (XIAP) could sensitize colon cancer cells to troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether rosiglitazone, another more clinically relevant PPAR gamma ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP(+/+) cells and HCT116-XIAP(-/-) cells were treated with various concentrations of rosiglitazone. The effects of rosiglitazone on cell proliferation, apoptosis and growth of xenograft colon cancers were studied. Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that rosiglitazone strongly suppressed the growth of xenograft colon cancer, especially tumors derived from HCT116-XIAP(-/-) cells. The rosiglitazone-treated tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of PPAR gamma by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP(-/-) cells, as well as in xenograft tumors derived from HCT116-XIAP(-/-) cells. We concluded that rosiglitazone significantly suppresses the growth of xenograft colon cancer, and downregulation of XIAP sensitizes the xenograft tumors to rosiglitazone-induced tumor suppression in vivo via upregulation of PTEN.
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PMID:Loss of XIAP sensitizes rosiglitazone-induced growth inhibition of colon cancer in vivo. 1835 48

There is accumulating evidence that omega-3 fatty acids may modulate immune responses. When monocytes were differentiated to dendritic cells (DCs) in the presence of docosahexaenoic acid (DHA), the expression of costimulatory and antigen presentation markers was altered in a concentration-dependent way, positively or negatively, depending on the markers tested and the maturation stage of the DCs. Changes induced by eicosapentaenoic acid and linoleic acid were similar but less intense than those of DHA, whereas oleic acid had almost no effect. DHA-treated, mature DCs showed inhibition of IL-6 expression and IL-10 and IL-12 secretion, and their lymphoproliferative stimulation capacity was impaired. The phenotypic alterations of DCs induced by DHA were similar to those already reported for Rosiglitazone (Rosi), a peroxisome proliferator-activated receptor gamma (PPAR gamma) activator, and the retinoid 9-cis-retinoic acid (9cRA), a retinoid X receptor (RXR) activator. Moreover, DHA induced the expression of PPAR gamma target genes pyruvate dehydrogenase kinase-4 and aP-2 in immature DCs. The combination of DHA with Rosi or 9cRA produced additive effects. Furthermore, when DCs were cultured in the presence of a specific PPAR gamma inhibitor, all of the changes induced by DHA were blocked. Together, these results strongly suggest that the PPAR gamma:RXR heterodimer is the pathway component activated by DHA to induce its immunomodulatory effect on DCs.
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PMID:Human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through PPAR(gamma):RXR heterodimers: comparison with other polyunsaturated fatty acids. 1892 99

In an initial study to determine if rosiglitazone had chemopreventive activity, Fischer-344 female rats were administered twice weekly doses of hydroxybutyl(butyl)nitrosamine (OH-BBN), a urinary bladder specific carcinogen, for 8 weeks. Two weeks following the last dose of OH-BBN, rats were administered rosiglitazone (50 mg/kg BW) daily by gavage for the remainder of the study (7 months). Only 57% of OH-BBN-treated animals developed palpable urinary bladder cancers during the course of the study, while all of the OH-BBN plus rosiglitazone treated rats developed large cancers (p < 0.01). Surprisingly, examination for PPAR gamma by immunohistochemistry in the urinary bladders of rats showed that while untreated bladder urothelium and preneoplastic lesions clearly expressed PPAR gamma, frank carcinomas exhibited significantly lower levels. This was confirmed by employing microarray studies of the same samples. In additional studies, lower doses of rosiglitazone (10, 2 and 0.4 mg/kg BW/day) were administered. The 10 mg/kg BW/day dose greatly enhanced bladder cancer incidence (p < 0.01). The dose of 2 mg/kg BW/day, which is roughly equivalent to a standard human dose, also significantly increased bladder cancer incidence (controls, 48%; rosiglitazone-treated, 84%). The lowest dose did not significantly increase tumor incidence (rosiglitazone at 0.4 mg/kg BW/day, 64%) or tumor weight in the rats, although there was a trend in that direction. Rosiglitazone alone (10 mg/kg BW/day) given in the absence of OH-BBN did not result in bladder cancer formation when given for 10 months. In summary, rosiglitazone over a wide dose range enhanced urinary bladder carcinogenesis in the OH-BBN model in rats.
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PMID:Rosiglitazone, a PPAR gamma agonist: potent promoter of hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers. 1871 22

In macrophages, the accumulation of cholesteryl esters synthesized by acyl-coenzyme A: cholesterol acyltransferase 1(ACAT1) plays a crucial role in foam cell formation, a hallmark of early atherosclerotic lesions. It is suggested that Chlamydia pneumoniae (C. pneumoniae) induces foam cell formation. However, the mechanism of foam cell formation induced by C. pneumoniae has not been fully elucidated. In this study, we found that C. pneumoniae increased the expression of acyl-coenzyme A: cholesterol acyltransferase 1(ACAT1) mRNA and protein in a dose-dependent manner in THP-1-derived macrophages exposed to low density lipoprotein (LDL). In addition, C. pneumoniae dose-dependently suppressed the expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) mRNA and protein. Rosiglitazone, a specific PPAR gamma agonist, not only dose-dependently alleviated the down-regulation of PPAR gamma expression by C. pneumoniae infection, but also dose-dependently inhibited the C. pneumoniae-induced ACAT1 expression. Furthermore, higher doses of rosiglitazone (10 and 20 microM) suppressed the C. pneumoniae-induced foam cell formation from morphological (Oil red O staining) and biochemical (zymochemistry method) criteria. These results first demonstrate that C. pneumoniae induces macrophage-derived foam cell formation by up-regulating ACAT1 expression via PPAR gamma-dependent pathway, which may contribute to its pro-atherogenic properties.
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PMID:Chlamydia pneumoniae induces macrophage-derived foam cell formation by up-regulating acyl-coenzyme A: cholesterol acyltransferase 1. 1904 99

Indenone KR-62776 acts as an agonist of PPAR gamma without inducing obesity in animal models and cells. X-ray crystallography reveals that the indenone occupies the binding pocket in a different manner than rosiglitazone. 2-Dimensional gel-electrophoresis showed that the expression of 42 proteins was altered more than 2.0-fold between KR-62776- or rosiglitazone-treated adipocyte cells and control cells. Rosiglitazone down-regulated the expression of ERK1/2 and suppressed the phosphorylation of ERK1/2 in these cells. However, the expression of ERK1/2 was up-regulated in KR-62776-treated cells. Phosphorylated ERK1/2, activated by indenone, affects the localization of PPAR gamma, suggesting a mechanism for indenone-inhibition of adipogenesis in 3T3-L1 preadipocyte cells. The preadipocyte cells are treated with ERK1/2 inhibitor PD98059, a large amount of the cells are converted to adipocyte cells. These results support the conclusion that the localization of PPAR gamma is one of the key factors explaining the biological responses of the ligands.
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PMID:PPAR gamma partial agonist, KR-62776, inhibits adipocyte differentiation via activation of ERK. 1934 70

The present study was designed to investigate the ameliorative potential of rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, in tibial and sural nerve transection-induced neuropathic pain in rats. The pinprick, cold immersion, hot plate and hot immersion tests were performed to assess the degree of mechanical and cold hyperalgesia; heat hyperalgesia and allodynia, respectively. The tissue thio-barbituric acid reactive species and reduced glutathione were measured as the markers of oxidative stress. Furthermore, the myeloperoxidase activity (a specific marker of inflammation) was also measured along with the determination of the calcium levels. Rosiglitazone (2.5, 5 and 10 mg/kg p.o.), was administered for 28 days after tibial and sural nerve transection. Administration of rosiglitazone (5 and 10 mg/kg p.o.) attenuated tibial and sural nerve transection-induced mechanical and cold hyperalgesia without modulating heat hyperalgesia. Rosiglitazone also attenuated tibial and sural nerve transection-induced increase in oxidative stress, myeloperoxidase activity and calcium levels. It may be concluded that rosiglitazone has ameliorative potential in attenuating the painful state associated with tibial and sural nerve transection, which may further be attributed to anti-inflammatory actions with subsequent decrease in oxidative stress and calcium levels.
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PMID:Ameliorative potential of rosiglitazone in tibial and sural nerve transection-induced painful neuropathy in rats. 1942 70

This work aimed at characterizing the role of peroxisome proliferator-activated receptors (PPAR)alpha in human white adipocyte metabolism and at comparing PPAR alpha and PPAR gamma actions in these cells. Primary cultures of human fat cells were treated with the PPAR alpha agonist GW7647 or the PPAR gamma agonist rosiglitazone. Changes in gene expression were determined using DNA microarrays and quantitative RT-PCR. Western blot and metabolic studies were performed to identify the biological effects elicited by PPAR agonist treatments. GW7647 induced an up-regulation of beta-oxidation gene expression and increased palmitate oxidation. Unexpectedly, glycolysis was strongly reduced at transcriptional and functional levels by GW7647 leading to a decrease in pyruvate and lactate production. Glucose oxidation was decreased. Triglyceride esterification and de novo lipogenesis were inhibited by the PPAR alpha agonist. GW7647-induced alterations were abolished by a treatment with a PPAR alpha antagonist. Small interfering RNA-mediated extinction of PPAR alpha gene expression in hMADS adipocytes attenuated GW7647 induction of palmitate oxidation. Rosiglitazone had no major impact on glycolysis and beta-oxidation. Altogether these results show that PPAR alpha can selectively up-regulate beta-oxidation and decrease glucose utilization in human white adipocytes.
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PMID:Peroxisome proliferator-activated receptor-alpha control of lipid and glucose metabolism in human white adipocytes. 1988 68

Rosiglitazone, a PPAR gamma agonist, is an antidiabetic drug that shows secondary beneficial actions on cardiovascular system. Our study is centered on myocardial remodeling in maternal protein restriction offspring, focusing on fibrosis and vascularization. Wistar rat dams received one of the two diets: normal (19% protein; NP) or low protein (5% protein; LP) during gestation and lactation. Three-month-old male offspring were divided into four groups: NP treated with rosiglitazone (NPR, 5 mg/kg/day); untreated NP (NP); LP treated (LPR); untreated LP (LP) until six months. Blood pressure (BP) was higher in LP, but rosiglitazone reduced BP at the first week of treatment in LPR. Rosiglitazone had beneficial effects on fibrosis (less than 23%, P<0.05) and vascularization (plus 57% of capillary/cardiomyocyte ratio, P<0.01) compared with LP offspring, independently of blood glucose. Multivariate analysis classified 95% of groups, and LPR offspring showed values close to those of NP offspring. Rosiglitazone showed beneficial effects on rat offspring programmed by low protein diet during gestation decreasing cardiac fibrosis and enhancing myocardial vascularization. These results are significant in translational medicine for patients with chronic diseases in adult life and increased cardiovascular risk.
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PMID:Rosiglitazone reverses cardiac adverse remodeling (fibrosis and vascularization) in perinatal low protein rat offspring. 2044 73

Rosiglitazone (RSG) has a variety of actions on both insulin sensitization and anti-atherogenic effects. The molecular effect of RSG on monocyte/macrophage function in terms of de novo synthesis of adiponectin is not fully understood. Here, we examined the regulation of adiponectin expression in human monocytes/macrophages by RSG and its function on monocyte adhesion during initiation of atherosclerosis. Adiponectin expression in monocytes and macrophages was studied by RT-PCR, quantitative real-time PCR, Western blot, and immunocytochemistry. Signal transduction and adhesion molecules were studied in order to describe the function of de novo synthesized adiponectin in monocyte adhesion. Adiponectin was expressed and upregulated during monocyte differentiation. The expression of adiponectin was enhanced, albeit at a much lesser degree, by a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist RSG, which was similar to what was found in adipocytes. Monocyte adhesion was remarkably reduced when the cells were treated with RSG for 12 h. This inhibitory effect of RSG was abolished by specific anti-adiponectin antibodies but not by non-immune immunoglobulin G in a serum-free condition. Adiponectin-induced suppression on monocyte adhesion was inhibited by a selective AMP-activated protein kinase (AMPK) inhibitor compound C. The reduced expression and/or function of adhesion molecule integrins may underlie the mechanism contributing to reduced monocyte adhesion upon AMPK activation. Our data suggest that the inhibitory effect of RSG on monocyte adhesion might be at least in part through de novo adiponectin expression and activation of an AMPK-dependent pathway, which might play an important role in atherogenesis.
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PMID:Rosiglitazone inhibits monocyte/macrophage adhesion through de novo adiponectin production in human monocytes. 2050 17


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