Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress has been proposed as the pathogenic mechanism linking insulin resistance with endothelial dysfunction during diabetes. The present study investigated the attenuation of plasma dyslipidemia and oxidative damage by caloric restriction in experimental diabetes. Forty male Wistar rats were divided into ad libitum and calorie-restricted groups. The calorie-restricted group was subjected to 30% caloric restriction for 63 days before induction of diabetes to 50% of both groups. Caloric restriction significantly (p<0.01) reduced the body weights, reactive oxygen species (ROS), catalase, total cholesterol levels and non-significantly reduced SOD activities in non-diabetic and diabetic rats. Caloric restriction was also found to improve blood glucose levels, glycated hemoglobin, malondialdehyde, triglyceride, oxidized glutathione and reduced glutathione levels and significantly (p<0.05) increased GPx and GR activities in the experimental animals. The non-diabetic rats fed ad libitum had the most significant increases in body weight which could be due to dyslipidemia. These results indicate that dietary caloric restriction attenuates the oxidative damage and dyslipidemia exacerbated during diabetes as evidenced by the significant reduction in their body weights, ROS, total cholesterol levels and the increases in GPx activity and redox status.
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PMID:Attenuation of plasma dyslipidemia and oxidative damage by dietary caloric restriction in streptozotocin-induced diabetic rats. 1758 83

Accelerated cardiovascular disease is a frequent complication of renal disease. Chronic kidney disease promotes hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. Furthermore, diabetic nephropathy is the leading cause of renal failure in developed countries. Together, hypertension, dyslipidemia, and diabetes are major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Inflammatory mediators are often elevated and the renin-angiotensin system is frequently activated in chronic kidney disease, which likely contributes through enhanced production of reactive oxygen species to the accelerated atherosclerosis observed in chronic kidney disease. Promoters of calcification are increased and inhibitors of calcification are reduced, which favors metastatic vascular calcification, an important participant in vascular injury associated with end-stage renal disease. Accelerated atherosclerosis will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Consequently, subjects with chronic renal failure are exposed to increased morbidity and mortality as a result of cardiovascular events. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with chronic kidney disease.
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PMID:Chronic kidney disease: effects on the cardiovascular system. 1760 56

Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates currently used to treat dyslipidemia. PPARalpha regulates the expression of genes encoding proteins that are involved in lipid metabolism, fatty acid oxidation, and glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance. In addition, PPARalpha exerts anti-inflammatory effects both in the vascular wall and the liver. Here we provide an overview of the mechanisms through which PPARalpha affects the initiation and progression of atherosclerosis, with emphasis on the modulation of atherosclerosis-associated inflammatory responses. PPARalpha activation interferes with early steps in atherosclerosis by reducing leukocyte adhesion to activated endothelial cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte migration. In later stages of atherosclerosis, evidence suggests activation of PPARalpha inhibits the formation of macrophage foam cells by regulating expression of genes involved in reverse cholesterol transport, formation of reactive oxygen species (ROS), and associated lipoprotein oxidative modification among others. Furthermore, PPARalpha may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity. These various effects may be linked to the generation of PPARalpha ligands by endogenous mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate PPARalpha in responses such as hypertension and diabetic cardiomyopathy. Although some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular events, other studies have been less clear, in terms of benefit. Independent of the clinical effects of currently used drugs purported to achieve PPARalpha, extensive data establish the importance of PPARalpha in the transcriptional regulation of lipid metabolism, atherosclerosis, and inflammation.
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PMID:PPARalpha in atherosclerosis and inflammation. 1763 13

Accelerated formation of advanced glycation/lipoxidation and endproducts (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and tested as inhibitors of AGE/ALE formation. We have previously reported the therapeutic effects of several new AGE/ALE inhibitors on the prevention of nephropathy and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the effects of various concentrations of a compound, LR-90, on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of diabetic STZ-rats. Diabetic male Sprague-Dawley rats were treated with or without LR-90 (0, 5, 20, 25, and 50 mg/l of drinking water). After 32 weeks, body weight, glycemic status, renal function, and plasma lipids were measured. Kidney histopathology and AGE/ALE accumulation and RAGE protein expression in tissues were also determined. In vitro studies were also performed to determine the possible mechanism of action of LR-90 in inhibiting AGE formation and AGE-protein cross-linking. LR-90 protected the diabetic kidneys by inhibiting the increase in urinary albumin-to-creatinine ratio and ameliorated hyperlipidemia in diabetic rats in a concentration-dependent fashion without any effects on hyperglycemia. LR-90 treatment also reduced kidney AGE/ALE accumulation and RAGE protein expression in a concentration-dependent manner. In vitro, LR-90 exhibited general antioxidant properties by inhibiting metal-catalyzed reactions and reactive oxygen species (OH radical) and reactive carbonyl species (methlyglyoxal, glyoxal) generations without any effect on pyridoxal 5' phosphate. The compound also prevents AGE-protein cross-linking reactions. These findings demonstrate the bioefficacy of LR-90 in treating nephropathy and hyperlipidemia in diabetic animals by inhibiting AGE accumulation, RAGE protein expression, and protein oxidation in the diabetic kidney. Additionally, our study suggests that LR-90 may be useful also to delay the onset and progression of diabetic atherosclerosis as the compound can inhibit the expression of RAGE and inflammation-related pathology, as well as prevent lipid peroxidation reactions.
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PMID:Novel inhibitors of glycation and AGE formation. 1770 84

The metabolic syndrome (MetS) phenotype is typically characterized by visceral obesity, insulin resistance, atherogenic dyslipidemia involving hypertriglyceridemia and subnormal levels of high density lipoprotein-cholesterol (HDL-C), oxidative stress and elevated cardiovascular risk. The potent antioxidative activity of small HDL3 is defective in MetS [Hansel B, et al. J Clin Endocrinol Metab 2004;89:4963-71]. We evaluated the functional capacity of small HDL3 particles from MetS subjects to protect endothelial cells from apoptosis induced by mildly oxidized low-density lipoprotein (oxLDL). MetS subjects presented an insulin-resistant obese phenotype, with hypertriglyceridemia, elevated apolipoprotein B and insulin levels, but subnormal HDL-C concentrations and chronic low grade inflammation (threefold elevation of C-reactive protein). When human microvascular endothelial cells (HMEC-1) were incubated with oxLDL (200 microg apolipoprotein B/ml) in the presence or absence of control HDL subfractions (25 microg protein/ml), small, dense HDL3b and 3c significantly inhibited cellular annexin V binding and intracellular generation of reactive oxygen species. The potent anti-apoptotic activity of small HDL3c particles was reduced (-35%; p<0.05) in MetS subjects (n=16) relative to normolipidemic controls (n=7). The attenuated anti-apoptotic activity of HDL3c correlated with abdominal obesity, atherogenic dyslipidemia and systemic oxidative stress (p<0.05), and was intimately associated with altered physicochemical properties of apolipoprotein A-I (apoA-I)-poor HDL3c, involving core cholesteryl ester depletion and triglyceride enrichment. We conclude that in MetS, apoA-I-poor, small, dense HDL3c exert defective protection of endothelial cells from oxLDL-induced apoptosis, potentially reflecting functional anomalies intimately associated with abnormal neutral lipid core content.
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PMID:Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity. 1786 79

Insulin resistance is characteristic of obesity, type 2 diabetes, and components of the cardiometabolic syndrome, including hypertension and dyslipidemia, that collectively contribute to a substantial risk for cardiovascular disease. Metabolic actions of insulin in classic insulin target tissues (eg, skeletal muscle, fat, and liver), as well as actions in nonclassic targets (eg, cardiovascular tissue), help to explain why insulin resistance and metabolic dysregulation are central in the pathogenesis of the cardiometabolic syndrome and cardiovascular disease. Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. Thereby, when nutrient oxidation is inefficient, the ratio of ATP production/oxygen consumption is low, leading to an increased production of superoxide anions. Reactive oxygen species formation may have maladaptive consequences that increase the rate of mutagenesis and stimulate proinflammatory processes. In addition to reactive oxygen species formation, genetic factors, aging, and reduced mitochondrial biogenesis all contribute to mitochondrial dysfunction. These factors also contribute to insulin resistance in classic and nonclassic insulin target tissues. Insulin resistance emanating from mitochondrial dysfunction may contribute to metabolic and cardiovascular abnormalities and subsequent increases in cardiovascular disease. Furthermore, interventions that improve mitochondrial function also improve insulin resistance. Collectively, these observations suggest that mitochondrial dysfunction may be a central cause of insulin resistance and associated complications. In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue.
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PMID:Role of mitochondrial dysfunction in insulin resistance. 1830 8

NAD(P)H oxidase is a prominent source of reactive oxygen species in the vasculature. Vascular NAD(P)H oxidase is comprised of several subunits, one of which, p22phox, is encoded by a gene exhibiting several allelic variants. Here the C(242)T nucleotide transition has been found to alter superoxide anion production and associated with an altered risk of coronary artery disease (CAD). We assessed the role of this variant in two case-control studies, and performed a meta-analysis of previously reported investigations relating it to vascular risk. Population I was comprised of 492 subjects with type 2 diabetes, with or without macrovascular disease, matched for age, sex, and duration of diabetes. Population II was comprised of 158 subjects with or without either CAD or cerebro-vascular disease, and matched for age, sex, smoking status, weight category and the presence of hypertension, dyslipidemia, and diabetes. Our findings were meta-analyzed together with additional studies retrieved from the literature. The C(242)T polymorphism distribution did not differ between cases and controls in populations I and II both at univariate and multivariate analyses, and this was confirmed in a meta-analysis with 11 previously published populations. The meta-analysis, however, suggested a protective role of the T allele on CAD as an end point in Asian populations. In conclusion, these data suggest a significant heterogeneity for a modulating role of the T allele in the C(242)T polymorphism of p22-phox for the occurrence of CAD across ethnicities, with the absence of a significant effect in Caucasians.
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PMID:The C242T polymorphism of the p22phox component of NAD(P)H oxidase and vascular risk. Two case-control studies and a meta-analysis. 1832 9

Atherosclerosis is an example of an inflammatory disorder. During the acute phase and under inflammatory conditions, high-density lipoprotein (HDL), which is normally anti-inflammatory, can become proinflammatory. Reactive oxygen species generated by several enzyme systems can modify phospholipids and sterols, producing oxidized phospholipids and oxidized sterols that reduce the capacity of HDL to protect against undesirable oxidative modifications of molecules. In animal models of dyslipidemia, diabetes, vascular inflammation, and chronic rejection, it is observed that reducing oxidative and inflammatory pressure will help HDL regain its protective role. One way to accomplish this is through the use of apolipoprotein A-I mimetic peptides, which remove oxidation products from lipoproteins and cell membranes, returning normal structure and function to low-density lipoprotein and HDL. These mimetic peptides markedly reduce atherosclerosis in animal models. Published studies of apolipoprotein mimetic peptides in models of inflammatory disorders other than atherosclerosis suggest that they have efficacy in a wide range of inflammatory conditions.
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PMID:Proatherogenic high-density lipoprotein, vascular inflammation, and mimetic peptides. 1841 73

Although a change in lifestyle is the first choice in controlling cardiovascular risk, lipid-lowering drugs are effective in normalizing different forms of atherogenic dyslipidemia. Although statins are a class of drugs which primarily lower low-density lipoprotein cholesterol, fibrates decrease triglycerides, normalize the low-density lipoprotein cholesterol profile, and increase high-density lipoprotein cholesterol. As lipids are important determinants for cardiovascular diseases, these drugs reduce cardiovascular morbidity. However, a number of recent studies indicate that, in addition to their lipid-normalizing activities, statins and fibrates exhibit pleiotropic actions, such as inhibit inflammation, improve endothelial function, suppress the production of reactive oxygen species, etc. Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis, whereas fibrates are activators of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). The similarity between the pleiotropic effects of statins and fibrates is remarkable and suggests a mechanistic link between these two classes of drugs. Here we discuss recent data on the cross-talk between statins and PPARalpha agonists and the mechanisms behind these actions.
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PMID:Cross-talk between statins and PPARalpha in cardiovascular diseases: clinical evidence and basic mechanisms. 1843 44

Non-alcoholic fatty liver disease, defined as the presence of macrovascular steatosis in the presence of less than 20 gm of alcohol ingestion per day, is the most common liver disease in the USA. It is most commonly associated with insulin resistance/type 2 diabetes mellitus and obesity. It is manifested by steatosis, steatohepatitis, cirrhosis, and, rarely, hepatocellular carcinoma.Hepatic steatosis results from an imbalance between the uptake of fat and its oxidation and export. Insulin resistance, predisposing to lipolysis of peripheral fat with mobilization to and uptake of fatty acids by the liver, is the most consistent underlying pathogenic factor. It is not known why some patients progress to cirrhosis; however, the induction of CYP 2E1 with generation of reactive oxygen species appears to be important.Treatment is directed at weight loss plus pharmacologic therapy targeted toward insulin resistance or dyslipidemia. Bariatric surgery has proved effective. While no pharmacologic therapy has been approved, emerging data on thiazolidinediones have demonstrated improvement in both liver enzymes and histology. There are fewer, but promising data, with statins which have been shown to be hepatoprotective in other liver diseases. The initial enthusiasm for ursodeoxycholic acid has not been supported by histologic studies.
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PMID:Treatment of non-alcoholic fatty liver disease. 1851 64


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