Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pioglitazone is the second thiazolidinedione derivative to be clinically used for type 2 diabetes in Japan. It is ten times more potent than troglitazone in glucose-lowering effect. Favourable effects against abnormal lipid levels including decreasing blood triglyceride levels, free fatty acid levels and increasing HDL-cholesterol is advantage to treat obese diabetic patient who may develop atherosclerosis. Up to now, there has been no report of severe hepatic dysfunction due to pioglitazone treatment. Pioglitazone should be carefully monitored in its clinical treatment regarding possible its side effect of hepatic dysfunction.
 ...
PMID:[Clinical evaluation of pioglitazone]. 1070 64

EN-RAGE is a ligand for the receptor for advanced glycation end products (RAGE) and may be involved in the development of diabetic macro- and micro-angiopathy. This study is designed to investigate the regulation of EN-RAGE gene expression in human macrophages. The amounts of EN-RAGE mRNA were measured in cultured human THP-1 macrophages after treatment with various stimuli known to modulate atherosclerosis. First, interleukin-6 (IL-6), a proinflammatory cytokine, increased the level of EN-RAGE mRNA by approximately 2-fold in a time- and a dose-dependent fashion. EN-RAGE protein was detected in the cultured medium and increased significantly by the addition of IL-6. The induction was abolished by pretreatment with the JAK kinase inhibitor and cycloheximide, but not with the MEK kinase inhibitor. Second, pioglitazone (PIO), a thiazolidinedione, decreased the level of EN-RAGE mRNA by approximately 25% of the basal in a time- and a dose-dependent fashion. Pioglitazone also inhibited the induction of EN-RAGE mRNA by IL-6. These results indicate the production of EN-RAGE is induced by IL-6 through de novo protein synthesis via the JAK-STAT kinase pathway and inhibited by the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) in human macrophages.
Atherosclerosis 2003 Dec
PMID:The regulation of EN-RAGE (S100A12) gene expression in human THP-1 macrophages. 1464 89

Atherosclerosis is the major cause of morbidity and mortality in patients with type 2 diabetes, and pioglitazone has been reported to have anti-inflammatory and potential antiatherogenic effects. The aim of the present study was to determine whether pioglitazone, glibenclamide, or voglibose affects carotid intima-media thickness (IMT), pulse wave velocity (PWV), and urinary albumin excretion (UAE) in normotensive type 2 diabetic nephropathy patients. Forty-five normotensive type 2 diabetes patients with microalbuminuria were randomized to 12-month treatment with pioglitazone (30 mg/d, n = 15), glibenclamide (5 mg/d, n = 15), or voglibose (0.6 mg/d, n = 15). Pre- and posttreatment UAE, PWV, and IMT values were compared between treatment groups and a group of age-matched healthy control subjects (n = 30). Pretreatment PWV, IMT, and UAE values differed little between the 3 groups, but UAE was greater in the 45 type 2 diabetes patients (132.5 +/- 36.4 microg/min) than in the control subjects (6.2 +/- 1.8 microg/min, P < .001). IMT (0.76 +/- 0.12 mm) was significantly greater in the diabetics than in the controls (0.60 +/- 0.08 mm, P < .01). PWV (1,840 +/- 320 cm/s) was also significantly greater in the diabetics than in the controls (1,350 +/- 225 cm/s, P < .01). After 6 and 12 months, UAE, IMT, and PWV in the pioglitazone treatment group were significantly lower than those in the glibenclamide treatment group and voglibose treatment group (UAE: 6 months, P < .05 and 12 months, P < .01; IMT and PWV: 6 months, P < .05 and 12 months, P < .05). Pioglitazone, but not glibenclamide or voglibose, appears to be effective in reducing UAE, IMT, and PWV in normotensive type 2 diabetes patients with microalbuminuria.
 ...
PMID:Effect of pioglitazone on carotid intima-media thickness and arterial stiffness in type 2 diabetic nephropathy patients. 1537 99

Thiazolidinediones (TZD) [Troglitazone (TRO), Pioglitazone (PGZ), Rosiglitazone, (RGZ)] are a novel class of antidiabetic drugs for patients with Type-2 diabetes mellitus (T2DM) able to decrease blood glucose, working through a reduction of insulin resistance. The family of TZD exerts its effect specifically bound to peroxisome proliferator-activated receptor y (PPARy). This is a member of the nuclear hormone receptor superfamily of ligand-dependent transcription factors, together with PPARalpha and deltabeta. Although PPARgamma is essentially expressed in adipose tissue, it has also been found in endothelial cells, macrophages, vascular smooth muscle cells, glomerular mesangial cells, hepatic stellate cells and in several cancer cell lines. In these cells, the PPARgamma activation by TZD determines modulatory effects on growth factor release, production of cytokine, cell proliferation and migration, extracellular matrix remodeling and control on cell cycle progression and differentiation. In addition, TZD have been shown to have a potent antioxidant effect. This review, taking a quick look beyond the antidiabetic activity of PPARgamma, shows the dramatic ranging of medical implications that the use of TZD could have modulating the PPARgamma activity in several diseases with a strong social impact, such as insulin resistance syndrome, chronic inflammation, atherosclerosis and cancer.
 ...
PMID:Pleiotropic effects of thiazolidinediones: taking a look beyond antidiabetic activity. 1576 51

Pioglitazone is an agonist of the peroxisome proliferator-activated receptor gamma (PPARgamma) that raises HDL-cholesterol plasma in humans. Whether pioglitazone-mediated modifications in HDL-apolipoprotein AI (apo AI) turnover in vivo contribute to this effect has not been completely elucidated. Therefore, we performed kinetic studies of HDL-apo AI radiolabeled with 125I in male New Zealand White rabbits after 6 weeks of 0.6 (n = 8), 1.75 (n = 8), and 2.6 mg/kg/day (n = 7) pioglitazone and vehicle (n = 12) treatment. Fractional catabolic rate (FCR) of HDL-apo AI was significantly higher in 1.75 and 2.6 mg/kg pioglitazone-treated animals, as compared with control rabbits (0.057+/-0.014 and 0.049+/-0.01 versus 0.025+/-0.005 pools/h, respectively); these changes were associated to a similar increase in apo AI production rates (PR) (1.24+/-0.62 and 1.14+/-0.40 versus 0.53+/-0.17 mg/kg/h, p < 0.01). Consequently, apo AI plasma levels in pioglitazone-treated animals were similar to those of controls. The apo AI-FRC and -PR correlated with the relative proportion of the HDL3c subclass, as determined by polyacrylamide gradient electrophoresis. Our data demonstrate that pioglitazone markedly modifies apo AI kinetics and enhances the proportion of small HDL3c particles, despite the unchanged apo AI concentration. Whether or not the pioglitazone-induced structural changes of HDL contribute to the anti-atherosclerotic effects of the drug remains to be determined.
Atherosclerosis 2005 Aug
PMID:Pioglitazone increases the fractional catabolic and production rates of high-density lipoproteins apo AI in the New Zealand White Rabbit. 1603 76

Pioglitazone is an antidiabetic drug known to decrease peripheral, hepatic and vascular insulin resistance by the stimulation of PPARgamma. In clinical trials, pioglitazone as monotherapy or in combination with other oral antidiabetic drugs or insulin has demonstrated to effectively improve blood glucose levels, long-term glucose control and the lipid profile. The vascular effects of pioglitazone include improvement of endothelial function and microcirculation, reduction of blood pressure and inflammatory surrogate markers of atherosclerosis, and a reduction of a composite measure of macrovascular events (death, stroke and myocardial infarctions). The drug is well tolerated and has an acceptable side effect profile. Because of its additional microvascular and macrovascular effects, pioglitazone is an attractive and effective treatment option for the management of Type 2 diabetes mellitus.
 ...
PMID:Pioglitazone: an antidiabetic drug with the potency to reduce cardiovascular mortality. 1650 18

PPAR-gamma agonists (thiazolidinediones, TZDs) may improve endothelial function independently of insulin sensitizing. Bone marrow-derived endothelial progenitor cells (EPC) contribute to neoangiogenesis. Mice were treated with pioglitazone, 20mg/kg/day for 10 days. Treatment with TZD upregulated circulating Sca-1/VEGFR-2 positive EPC in the blood (235+/-60%) and the bone marrow (166+/-30%), cultured spleen-derived DiLDL/lectin positive EPC increased to 231+/-21% (n=24 per group). Upregulation of EPC was persistent after 20 days. TZD increased SDF-1-induced migratory capacity per number of EPC by 246+/-73% and increased expression of telomere repeat-binding factor 2 by 320+/-50%. In vivo neoangiogenesis was increased two-fold (214+/-42%, 20 days). The NOS inhibitor L-NAME did not inhibit the TZD-induced upregulation of EPC. EPC from TZD-treated animals showed reduced in vivo apoptosis (65+/-2.8% of vehicle). In cultured human EPC, pre-treatment with pioglitazone prevented H(2)O(2)-induced apoptosis. Inhibition of EPC apoptosis by TZD was abolished in the presence of wortmannin but not by LNMA. In summary, TZD upregulates both number and functional capacity of endothelial progenitor cells. Pioglitazone prevents apoptosis of EPC in mice as well as in human EPC in a PI3K-dependent but NO-independent manner. Reduction of EPC apoptosis by TZD may be a potentially beneficial mechanism for patients with vascular diseases.
Atherosclerosis 2007 May
PMID:The PPAR-gamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. 1687 72

This study investigates lipoprotein composition in diabetes before and after treatment with insulin or pioglitazone and its relationship to gene expression of five genes found in liver and intestine which are involved in cholesterol homeostasis. Thirty zucker diabetic fatty fa/fa and 10 lean rats were examined. mRNA for 3-hydroxy3-methylglutaryl coenzyme A reductase (HMGCoA), microsomal triglyceride transfer protein (MTTP), Niemann Pick C1-like 1 (NPC1L1) and ATP binding cassette transporters (ABC) G5 and G8 was determined using real-time, reverse transcriptase (RT-PCR). Cholesterol, triglyceride, apo B48 and apo B100 were elevated in chylomicrons and very low density lipoproteins (VLDL) of untreated diabetic animals (p<0.02). For similar blood glucose pioglitazone was more effective than insulin in normalising the lipoproteins. In diabetic animals, HMGCoA reductase, MTTP and NPC1L1 mRNA were significantly elevated (p<0.02) and ABCG5 and ABCG8 were significantly reduced (p<0.02) in the liver. Pioglitazone significantly reduced hepatic MTTP and NPC1L1 mRNA (p<0.0001) and significantly increased ABCG5 and G8 mRNA (p<0.0001) as compared to insulin. In conclusion diabetes was associated with major changes in mRNA levels of proteins involved in the regulation of post-prandial lipoproteins. Pioglitazone and insulin have different effects on post-prandial lipoprotein metabolism in part due their effect on genes regulating cholesterol synthesis and lipoprotein assembly.
Atherosclerosis 2007 Aug
PMID:The different effect of pioglitazone as compared to insulin on expression of hepatic and intestinal genes regulating post-prandial lipoproteins in diabetes. 1710 65

Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk. We conducted a randomised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist (fenofibrate) and a PPAR gamma agonist (pioglitazone) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity (PWV). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function. Insulin sensitivity improved with pioglitazone treatment (p=0.001) and, in keeping with this, adiponectin increased by 85.2% (p<0.001). Pro-inflammatory cytokine levels (TNFalpha, IL-6 and IL-1 beta) fell with both treatments (p<0.01 for TNFalpha and IL-1 beta, p<0.001 for IL-6). VCAM-1 and ICAM-1 were reduced with both treatments (p<0.001 for VCAM-1, p<0.05 for ICAM-1) and E-selectin improved with pioglitazone treatment (p=0.05). Both treatments resulted in a fall in augmentation index. PWV fell by 17.4% with fenofibrate treatment (p<0.001) and 16.3% with pioglitazone treatment (p<0.001). Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity.
Atherosclerosis 2007 Oct
PMID:Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men. 1714 61

A new concept has been proposed to capture the flow of events and chain reactions associated with cardiovascular risk: the metabolic domino. The metabolic domino differs for each individual based on their genetic predisposition. Lifestyle changes are the first dominoes to fall, which lead to obesity and insulin resistance, followed by postprandial hyperglycemia, hypertension, and hyperlipidemia. Atherosclerosis then begins, and diabetes occurs once the domino for impairment of insulin secretion has toppled. Progression of the atherosclerotic process can lead to cardiovascular events such as ischemic heart diseases or cerebrovascular disorders. Preclinical and clinical data indicate that treatments which inhibit the renin angiotensin system, such as angiotensin receptor blockers, can suppress the onset of diabetes and, when administered even earlier in the metabolic domino, reduce the development of hypertension in at-risk individuals. The inhibition of inflammation with thiazolidinedione can also block the sequence of events leading to cardiovascular outcomes, as was shown with pioglitazone in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive).
 ...
PMID:Metabolic domino: new concept in lifestyle medicine. 1724 76


1 2 3 4 Next >>