Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A direct involvement of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1) in neuroprotection has not yet been shown. The aim of this study was to examine changes, localization and role of NQO1 after different neuronal injury paradigms. In primary cultures of rat cortex the activity of NQO1 was measured after treatment with ethylcholine aziridinium (AF64A; 40 micro m), inducing mainly apoptotic cell death, or oxygen-glucose deprivation (OGD; 120 min), which combines features of apoptotic and necrotic cell death. After treatment with AF64A a significant NQO1 activation started after 24 h. Sixty minutes after OGD a significant early induction of the enzyme was observed, followed by a second increase 24 h later. Enzyme activity was preferentially localized in glial cells in control and injured cultures, however, expression also occurred in injured neuronal cells. Inhibition of the NQO1 activity by dicoumarol, cibacron blue or chrysin (1-100 nM) protected the cells both after exposure to AF64A or OGD as assessed by the decreased release of lactate dehydrogenase. Comparable results were obtained in vivo using a mouse model of focal cerebral ischaemia. Dicoumarol treatment (30 nmol intracerebroventricular) reduced the infarct volume by 29% (p = 0.005) 48 h after the insult. After chemical induction of NQO1 activity by t-butylhydroquinone in vitro neuronal damage was exaggerated. Our data suggest that the activity of NQO1 is a deteriorating rather than a protective factor in neuronal cell death.
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PMID:Role of NAD(P)H:quinone oxidoreductase in the progression of neuronal cell death in vitro and following cerebral ischaemia in vivo. 1260 27

Chronic exposure to hyperglycemia can lead to cellular dysfunction that may become irreversible over time, a process that is termed glucose toxicity. Our perspective about glucose toxicity as it pertains to the pancreatic beta-cell is that the characteristic decreases in insulin synthesis and secretion are caused by decreased insulin gene expression. The responsible metabolic lesion appears to involve a posttranscriptional defect in pancreas duodenum homeobox-1 (PDX-1) mRNA maturation. PDX-1 is a critically important transcription factor for the insulin promoter, is absent in glucotoxic islets, and, when transfected into glucotoxic beta-cells, improves insulin promoter activity. Because reactive oxygen species are produced via oxidative phosphorylation during anaerobic glycolysis, via the Schiff reaction during glycation, via glucose autoxidation, and via hexosamine metabolism under supraphysiological glucose concentrations, we hypothesize that chronic oxidative stress is an important mechanism for glucose toxicity. Support for this hypothesis is found in the observations that high glucose concentrations increase intraislet peroxide levels, that islets contain very low levels of antioxidant enzyme activities, and that adenoviral overexpression of antioxidant enzymes in vitro in islets, as well as exogenous treatment with antioxidants in vivo in animals, protect the islet from the toxic effects of excessive glucose levels. Clinically, consideration of antioxidants as adjunct therapy in type 2 diabetes is warranted because of the many reports of elevated markers of oxidative stress in patients with this disease, which is characterized by imperfect management of glycemia, consequent chronic hyperglycemia, and relentless deterioration of beta-cell function.
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PMID:Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. 1260 96

During experimental hypertensive cardiac hypertrophy, the heart energy metabolism reverts from the normal adult type that obtains the majority of its requirement for adenosine triphosphate (ATP) from metabolism of fatty acids and oxidative phosphorylation (OXPHOS), to the fetal form, which metabolizes glucose and lactate. Mitochondrial synthesis and function require an estimated 1000 polypeptides, 37 of which are encoded by mitochondrial (mt) DNA, the rest by nuclear (n) DNA. Inherited or acquired aberrations of either mtDNA or nDNA mitochondrial genes cause mitochondrial dysfunction. Tissue expression of OXPHOS enzyme defects is often heterogeneous. As a result, cardiomyopathy and cardiac failure are frequent but unpredictable complications of mitochondrial encephalopathy, neuropathy, and myopathy. Several nuclear genes that encode mitochondrial proteins have been sequenced and specific defects associated with nuclear genes that affect mitochondrial structure and function have been linked to hypertrophic and dilated cardiomyopathies and to cardiac conduction defects. Thyroid hormone and exercise stimulate expression of a nuclear respiratory factor (NRF) that induces the nuclear gene TFAM, which encodes the mitochondrial transcription factor A that controls mitochondrial replication and transcription. TFAM-null mouse embryos lack mitochondria and fail to develop a heart. Mitochondrial dysfunction enhances the generation of radical oxygen species (ROS), which damage mtDNA, nDNA, proteins, and lipid membranes. Mice lacking the mitochondrial antioxidant enzyme manganese-superoxide dismutase (SOD) develop dilated cardiomyopathy. Palliative mitochondrial therapy with L-acetyl-carnitine and coenzyme Q10 improves cardiac function in patients with cardiomyopathy. Cure is only achievable by mitochondrial gene therapy. Experimental direct gene therapy uses vectors or targeting signal sequences to insert genes into mtDNA; indirect gene therapy employs viral or non-viral vectors to introduce genes into nDNA. Clinical repair of damaged somatic and germline genes that encode mitochondrial proteins may soon be within reach.
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PMID:Review: Mitochondrial medicine--cardiomyopathy caused by defective oxidative phosphorylation. 1458 51

In this study, the effects of L-carnitine treatment on lipids, lipid peroxidation of plasma, reactivity and antioxidant enzyme activity of aorta were evaluated in streptozotocin (STZ)-diabetic rats. Treatment with L-carnitine (0.6 g kg(-1) daily, i.p.) was started 8 weeks after the induction of diabetes and continued for 2 weeks. Diabetes was induced by a single injection of streptozotocin (45 mg kg(-1), i.p.). Plasma cholesterol, triglyceride and thiobarbituric acid reactive substance (TBARS) levels and blood glucose levels were significantly increased, although free carnitine levels were markedly decreased in diabetic rats. L-Carnitine treatment completely normalized plasma cholesterol, triglyceride, free carnitine and TBARS levels but partially restored blood glucose levels of diabetic rats. STZ-diabetes caused a significant reduction in the endothelium-dependent relaxation response to acetylcholine (ACh). In diabetic aorta, TBARS levels and catalase (CAT) activity were significantly increased but glutathione peroxidase (GSH-Px) activity was unchanged. Treatment of diabetic rats with L-carnitine resulted in partial restoration of the endothelium-dependent relaxation response to ACh and completely normalized the oxidant/antioxidant state. These results suggested that the beneficial effects of L-carnitine treatment partially improve vascular reactivity and antioxidant property beyond its reduction of plasma lipids and it may have an important therapeutic approach in the treatment of diabetic vascular complications.
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PMID:Effects of L-carnitine treatment on oxidant/antioxidant state and vascular reactivity of streptozotocin-diabetic rat aorta. 1460 21

The relentless decline in beta-cell function frequently observed in type 2 diabetic patients, despite optimal drug management, has variously been attributed to glucose toxicity and lipotoxicity. The former theory posits hyperglycemia, an outcome of the disease, as a secondary force that further damages beta-cells. The latter theory suggests that the often-associated defect of hyperlipidemia is a primary cause of beta-cell dysfunction. We review evidence that patients with type 2 diabetes continually undergo oxidative stress, that elevated glucose concentrations increase levels of reactive oxygen species in beta-cells, that islets have intrinsically low antioxidant enzyme defenses, that antioxidant drugs and overexpression of antioxidant enzymes protect beta-cells from glucose toxicity, and that lipotoxicity, to the extent it can be attributable to hyperlipidemia, occurs only in the context of preexisting hyperglycemia, whereas glucose toxicity can occur in the absence of hyperlipidemia.
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PMID:Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. 1474 76

Recent data indicate that the oxidative stress plays an important role in the pathogenesis of diabetes and its complications such as retinopathy, nephropathy and accelerated atherosclerosis. In diabetic retinopathy, it was demonstrated a selective loss of pericytes accompanied by capillary basement membrane thickening, increased permeability and neovascularization. This study was designed to investigate the role of diabetic conditions such as high glucose, AGE-Lysine, and angiotensin II in the modulation of antioxidant enzymes activities, glutathione level and reactive oxygen species (ROS) production in pericytes. The activity of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) was measured spectrophotometrically. The production of ROS was detected by spectrofluorimetry and fluorescence microscopy after loading the cells with 2'-7' dichlorofluoresceine diacetate; as positive control H2O2 was used. Intracellular calcium was determined using Fura 2 AM assay. The results showed that the cells cultured in high glucose alone, do not exhibit major changes in the antioxidant enzyme activities. The presence of AGE-Lys or Ang II induced the increase of SOD activity. Their combination decreased significantly GPx activity and GSH level. A three times increase in ROS production and a significant impairment of intracellular calcium homeostasis was detected in cells cultured in the presence of the three pro-diabetic agents used. In conclusion, our data indicate that diabetic conditions induce in pericytes: (i) an increase of ROS and SOD activity, (ii) a decrease in GPx activity and GSH level, (iii) a major perturbation of the intracellular calcium homeostasis. The data may explain the structural and functional abnormalities of pericytes characteristic for diabetic retinopathy.
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PMID:Changes in oxidative balance in rat pericytes exposed to diabetic conditions. 1509 Feb 67

Paraoxonase 1 (PON1) is an antioxidant enzyme that inhibits the oxidative modification of LDL. Since PON1 has been shown to express in pancreatic islets and oxidative stress plays a role in beta-cell dysfunction, we investigated the impact of the PON1 polymorphisms on beta-cell function. This study included 84 healthy and glucose-tolerant white subjects who underwent an oral glucose tolerance test. Beta-cell function (1stPHS and 2ndPHS) was estimated according to the formulae published by Stumvoll et al. The relationship of the L55M and Q192R polymorphisms to beta-cell function was examined. Allelic frequency in this population was 0.37 for the M allele and 0.30 for the R allele. For the L55M polymorphism, the LM genotype had the lowest 1stPHS (P = 0.009) and 2ndPHS (P = 0.007), indicating molecular heterosis. Multivariate analyses confirmed that the L55M polymorphism was an independent determinant for 1stPHS (P = 0.016) and 2ndPHS (P = 0.009), after adjustment for covariates. For the Q192M polymorphism, no difference was noted in 1stPHS and 2ndPHS. We observed the L55M polymorphism of the PON1 gene as an independent determinant for beta-cell function in glucose-tolerant whites. Our observations suggest that this polymorphism could play a role in beta-cell dysfunction.
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PMID:Association of paraoxonase 1 polymorphism with beta-cell function: a case of molecular heterosis. 1509 70

In the present study we investigated the effects of simvastatin treatment on lipid metabolism and peroxidation, antioxidant enzyme activities and ultrastructure of the diabetic rat myocardium. Diabetes was induced by single injection of streptozotocin (45 mg/kg i.p.). Eight weeks after induction of diabetes, a subgroup of control and of diabetic rats was treated with simvastatin for 4 weeks (10 mg/kg/day, orally). Blood glucose, plasma cholesterol and triacylglycerol, as well as levels of cardiac thiobarbituric acid reactive substances (TBARS) were significantly increased in diabetic rats. The activities of antioxidant enzymes, catalase (CAT) and glutathione peroxidase (GSHPx), were also elevated in the diabetic myocardium. Treatment with simvastatin markedly reduced serum triacylglycerol and cholesterol, and partially controlled hyperglycemia in diabetic animals. The increased activation of antioxidant enzymes and the excess of lipid peroxidation measured by TBARS were completely reversed by simvastatin treatment. Diabetic rats displayed ultrastructural ischemia-like alterations of cardiomyocytes and capillaries, which support oxidative stress-induced tissue remodelling. In the diabetic myocardium simvastatin treatment partly attenuated angiopathic and atherogenic processes, detected by electron microscopy. These results suggest that simvastatin, known as a lipid-lowering drug, may positively affect diabetes induced cardiovascular complications via reducing risks of atherosclerotic pathological processes, such as imbalance between oxidant and antioxidant state.
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PMID:Effects of simvastatin treatment on oxidant/antioxidant state and ultrastructure of diabetic rat myocardium. 1511 25

Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic beta-cell dysfunction found in diabetes. Possibly caused by low levels of antioxidant enzyme expressions, pancreatic beta-cells are vulnerable to oxidative stress. When beta-cell-derived HIT-T15 cells or isolated rat islets were exposed to oxidative stress, insulin gene expression was markedly decreased. To investigate the significance of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes, we evaluated the effects of antioxidants in diabetic C57BL/KsJ-db/db mice. According to an intraperitoneal glucose tolerance test, the treatment with antioxidants retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Histological analyses of the pancreata revealed that the beta-cell mass was significantly larger in the mice treated with the antioxidants, and the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. As possible mechanism underlying the phenomena, expression of pancreatic and duodenal homeobox factor-1 (also known as IDX-1/STF-1/IPF1), an important transcription factor for the insulin gene, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. Under diabetic conditions, JNK is activated by oxidative stress and involved in the suppression of insulin gene expression. This JNK effect appears to be mediated in part by nucleocytoplasmic translocation of PDX-1, which is also downstream of JNK activation. Taken together, oxidative stress and consequent activation of the JNK pathway are involved in progression of beta-cell dysfunction found in diabetes. Antioxidants may serve as a novel mechanism-based therapy for type 2 diabetes.
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PMID:Role of oxidative stress in pancreatic beta-cell dysfunction. 1512 94

Sugar-casein glycation products (GPs) were generated by Maillard reaction (MR) with different monosaccharide sources [e.g., glucose (Glc), fructose (Fru), and ribose (Rib)] and prolonged heating (e.g., 27 days at 55 degrees C) to produce Maillard reaction products (MRPs) that varied in opponent (L, a, b) color measurement and changes in pH, available lysine, and amino-sugar ratio. Theses results signified different rates of three sugar and casein glycation. Sugar-casein GPs from aldohexose, ketohexose, and aldopentose sugar sources were recovered on day 18 of heating and compared for bioactive properties using human embryonic intestinal cell (Int-407) and adenocarcinoma cell (Caco-2) lines. Glu- and Fru-casein GPs produced significant (p < 0.05) decreases in antioxidant superoxide dismutase (SOD), glutathione peroxidase, and glutathione reductase enzyme activities in the Int-407 cell line, whereas no effect on antioxidant enzymes was obtained from Rib-casein GP. Moreover, the Caco-2 cell antioxidant enzyme status was not affected by the presence of sugar-casein GPs, regardless of sugar source. The reduction in antioxidant enzyme activity of Int-407 cells by Glu and Fru- casein GPs corresponded to a significant (p < 0.05) reduction in Int-407 cell viability. In contrast, no change in Caco-2 cell viability was observed with sugar-casein GP. This finding demonstrates that the noted variable cytotoxic, sugar specific effects of casein GP were related to reductions in critical antioxidant enzyme activities. Moreover, the source of intestinal cell line was an important factor to show the effect of sugar-casein GPs on redox-related cytotoxicity.
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PMID:Redox-related cytotoxic responses to different casein glycation products in Caco-2 and int-407 cells. 1516 Dec 33


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