Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pioglitazone, a thiazolidinedione derivative, was developed from our basic research on diabetic animal models and our chemical research on lipid-lowering agents. In clinical studies, pioglitazone at doses of 15-45 mg/man/day produced 1.0-1.6% reduction in HbA1c for 6 months. Moreover, pioglitazone produced about 14% reduction in plasma triglyceride levels and 4-11% increase in HDL-cholesterol(HDL-C) levels without the significant changes in total cholesterol and LDL-C levels. Although the exact molecular mechanism of reducing insulin resistance still remains obscure, pioglitazone normalizes abnormalities in the cellular insulin signal transduction. This effect seems to be due to the inhibitory action of pioglitazone on TNF-alpha production, which is one of the factors responsible for insulin resistance. Pioglitazone is a potent agonist for the peroxisome proliferator activated receptor(PPAR)-gamma, that is related to differentiation of adipocytes, and the relationship between TNF-alpha production and PPAR-gamma has been reported. Therefore, the agonistic activity of pioglitazone on PPAR-gamma may be involved in the mechanism for reducing insulin resistance. Recently, it was demonstrated that pioglitazone is also an agonist of PPAR-alpha, which plays a central role in lipid metabolism through enhancing the synthesis of apo AI, apo AII and reverse cholesterol transporters, such as fatty acid transporter molecules, and SR-B1 and ABCA1 reverse cholesterol transport receptors. Therefore, these findings suggest that pioglitazone has a benefit for prevention of both diabetic micro-angiopathy and macro-angiopathy.
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PMID:[Pharmacological effects of a thiazolidinedione derivative, pioglitazone]. 1171 6

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.
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PMID:The regulation of EN-RAGE (S100A12) gene expression in human THP-1 macrophages. 1464 89

BACKGROUND: The over-expression of transforming growth factor beta-1(TGF-beta1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidbeta (Abeta) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-beta1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-beta1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Abeta-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-beta1-induced pathology. METHODS: Two-month-old TGF-beta1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Abeta precursor protein (APP) by western blot analysis; Abeta deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means +/- SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed. RESULTS: Animals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Abeta or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Abeta42- with no change in APP contents - while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits. CONCLUSIONS: i) TGF-beta1 over-expressing mice may not be an appropriate model of Abeta-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-beta1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-beta1 actions in brain.
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PMID:Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised. 1528 4

Thiazolidinediones (TZDs) are peroxisomal proliferator-activated receptor (PPAR)-gamma agonists. They increase insulin action through several mechanisms including: stimulation of the expression of genes that increase fat oxidation and lower plasma free fatty acid levels; increased expression, synthesis and release of adiponectin; and stimulation of adipocyte differentiation resulting in more and smaller fat cells. TZDs lower blood sugar comparably to sulfonylureas and metformin. The clinical use of TZDs is limited due to the long duration of time required before they reach their full blood sugar-lowering action (3-4 months) and adverse effects such as fluid retention, resulting in excessive weight gain and occasionally in peripheral and/or pulmonary oedema and congestive heart failure. Troglitazone, a TZD that has since been removed from the market because of hepatoxicity, has been demonstrated to decrease the progression from normal or impaired glucose tolerance to overt Type 2 diabetes mellitus. Pioglitazone, another TZD, marginally decreased the incidence of cardiovascular complications in patients with Type 2 diabetes mellitus (PROactive trial). Other, as yet, unapproved uses of TZDs include: non-alcoholic fatty liver disease, in which TZDs reduced hepatic fat accumulation and improved liver function tests; polycystic ovary syndrome, where TZDs improved ovulation, hirsutism and endothelial dysfunction; and lipodystrophies, where TZDs increased body fat (marginally) and decrease liver size. Lastly, because PPAR-alpha and -gamma agonists improve atherosclerotic vascular disease and insulin sensitivity, respectively, dual PPAR-alpha/gamma agonists, which are currently undergoing clinical trials, may be useful in treating patients with the metabolic syndrome.
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PMID:Recent findings concerning thiazolidinediones in the treatment of diabetes. 1650 61

Ragaglitazar is a novel and potent dual peroxisome proliferators activated receptor (PPAR) alpha and gamma activator. The aim of this study is to investigate the effect of ragaglitazar on blood pressure and endothelial function in insulin resistant animal model and non-insulin resistant hypertensive models. The effects ragaglitazar were tested in Zucker fa/fa, spontaneously hypertensive rats (SHR), 2 kidney 1clip rat (2K1C) and Wistar Kyoto rats (WKY). Pioglitazone was taken as a comparative standard. Ragaglitazar showed significant reduction (P<0.001) of systolic blood pressure (SBP) in insulin resistant fa/fa rats, with concomitant reduction in plasma triglycerides (TG) and insulin levels while pioglitazone (10 mg kg(-1)) showed significant (P<0.05) but comparatively less reduction. Ragaglitazar in contrast to pioglitazone showed significant reduction (P<0.05) of SBP in SHR, 2K1C while the same dose did not have any effect on normotensive WKY. Ragaglitazar also showed significant improvement in acetylcholine-induced relaxation in isolated aorta of Zucker fa/fa, SHR, 2K1C and also potentiated the insulin-induced vasorelaxation in Zucker fa/fa rats. These findings summarize that ragaglitazar shows significant reduction of BP and improvement in endothelial function not only in insulin resistant but also in non-insulin resistant hypertensive models where standard thiazolidinediones are ineffective. These data indicates that dual PPARalpha and gamma activator ragaglitazar can be beneficial for the treatment of hypertension and vascular disease commonly associated with type 2 diabetes.
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PMID:Antihypertensive effect of ragaglitazar: a novel PPARalpha and gamma dual activator. 1665 Oct 4

Endothelial progenitor cell (EPC) dysfunction is an important mediator of vascular disease in diabetes. We aimed to elucidate the mechanism of adhesion of EPC to diabetic and non-diabetic arteries and to study the effect of the anti-diabetic drug pioglitazone. Peripheral blood mononuclear cells were isolated from healthy donors. Human internal mammary arteries (HIMA) were isolated from patients who underwent coronary artery bypass surgery. EPC were labelled with 111In-oxine and perfused to HIMA in a perfusion chamber. Stromal derived factor-1 (SDF-1) and cyclooxygenase-2 (COX-2) were assessed by immunohistochemical analysis. CXCR-4 expression was assessed by flow cytometry. Adhesion of EPC was increased in HIMA from diabetic patients and was reduced after preincubation with 15 mM glucose for 72 h. EPC adhesion and CXCR-4 expression were inversely correlated. COX-2 and SDF-1 immunostaining in HIMA were positively correlated. Pioglitazone (1 microM) increased the adhesion of EPC to HIMA and the expression of CXCR-4 in EPC. Therefore, EPC-recruiting capability is increased in diabetic arteries, although EPC adhesion is notably impaired by high glucose concentrations. Interestingly, pioglitazone treatment enhances EPC adhesiveness.
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PMID:EPC adhesion to arteries from diabetic and non-diabetic patients: effect of pioglitazone. 1927 97

Individuals with systemic lupus erythematosus (SLE) have a striking increase in the risk of premature atherosclerosis, a complication preceded by significant subclinical vascular damage. A proposed mechanism leading to accelerated vascular disease in SLE is an imbalance between vascular damage and repair, as patients with this disease display significant abnormalities in phenotype and function of endothelial progenitor cells. In addition, individuals with SLE have a higher incidence of insulin resistance which may further contribute to the increased cardiovascular risk. This study examined the role of the peroxisome proliferator activated receptor gamma agonist pioglitazone in improving endothelial function, endothelial progenitor cell numbers and functional capacity, metabolic parameters, and disease activity in the lupus-prone murine model New Zealand Black/New Zealand White (NZB x NZW)F(1). Ten-week-old prenephritic female NZB/NZW F(1) mice were exposed to 10 or 25 mg/kg/day of oral pioglitazone or vehicle for 15 or 24 wk. Mice exposed to pioglitazone exhibited pronounced enhancement in endothelial-dependent vasorelaxation of thoracic aortas and in endothelial progenitor cell function, as assessed by the capacity of bone marrow-derived endothelial progenitor cells to differentiate into mature endothelial cells. Pioglitazone-treated mice showed improvement in insulin resistance, adipokine, and lipid profile. Kidneys from pioglitazone-treated mice showed significant decreases in immune complex deposition, renal inflammation, T cell glomerular infiltration, and intrarenal synthesis of TNF-alpha, IL-1beta, and VCAM-1. These results indicate that peroxisome proliferator-activated receptor gamma agonists could serve as important tools in the prevention of premature cardiovascular disease and organ damage in SLE.
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PMID:The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves cardiometabolic risk and renal inflammation in murine lupus. 1962 Mar