Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress is believed to be involved in the pathophysiology of a number of chronic diseases including atherosclerosis, diabetes, and cataracts and to accelerate the aging process. The aim of this study was to elucidate the role of various dietary fats in the in vivo modulation of CCl(4) induced oxidative stress using rat as a model. Rats were raised on diets enriched with saturated (Beef Tallow), n-9 (Sunola oil), n-6 (Safflower oil) or n-3 (Flaxseed oil) fatty acids and exposed to elevated oxidative stress by administration of CCl(4.) Plasma concentration of 8-iso-PGF(2alpha), antioxidant micronutrients and antioxidant enzymes were measured to examine changes to oxidative stress subsequent to the administration of CCl(4). The fatty acid profiles of plasma and RBC membranes reflected the fats fed in the different diets. CCl(4) administration had no significant effect on fatty acid composition of plasma or RBC lipids. Plasma 8-iso-PGF(2alpha) concentrations were elevated by CCl(4) administration regardless of the dietary fat fed. Within the induced oxidative groups the 8-iso-PGF(2alpha) concentrations were highest in Safflower oil followed by Sunola oil, Tallow and finally Flaxseed oil. Induction of oxidative stress by CCl(4) administration was associated with a significant reduction in Vitamin A content reaching a significantly lower concentration (P <0.05) in the Tallow and Flaxseed oil groups. Vitamin E concentrations were significantly lower (p = 0.01) in the Safflower oil and the Flaxseed oil than in the Tallow diet group following CCl(4) administration. Superoxide Dismutase (SOD) and Glutathione Peroxidase (GSHPx) activities were not affected by dietary fat manipulation. The results of this study indicate that dietary fat can modulate lipid peroxidation and antioxidant defenses when exposed to a pro-oxidant challenge.
 ...
PMID:Modulation of carbon tetrachloride-induced oxidative stress by dietary fat in rats(open star). 1183 24

Augmentation of superoxide levels has been linked to impaired relaxation in hypertension, diabetes and hypercholesterolaemia. Purified endothelial nitric oxide synthase (eNOS) generates superoxide under limited availability of 5,6,7,8-tetrahydrobiopterin (BH(4)). Thus alterations in endothelial BH(4) levels have been postulated to stimulate superoxide production from eNOS. This possibility was examined by determining the concentration-dependent effects of BH(4), and its analogues, on superoxide formation by eNOS. Superoxide was quantified by EPR spin trapping, which is the only available technique to quantify superoxide from eNOS. Using 5-ethoxycarbonyl-5-methyl-pyrroline N-oxide, we show that only fully reduced BH(4) diminished superoxide release from eNOS, with efficiency BH(4)>6-methyl-BH(4)>5-methyl-BH(4). In contrast, partially oxidized BH(4) analogues, 7,8-dihydrobiopterin (7,8-BH(2)) and sepiapterin had no effect. Neither l-arginine nor N(G)-nitro-l-arginine methyl ester (l-NAME) abolished superoxide formation. Together, BH(4) and l-arginine stimulated .NO production at maximal rates of 148 nmol/min per mg of protein. These results indicate that BH(4) acts as a "redox switch", decreasing superoxide release and enhancing .NO formation. This role was verified by adding 7,8-BH(2) or sepiapterin to fully active eNOS. Both 7,8-BH(2) and sepiapterin enhanced superoxide release while inhibiting (.)NO formation. Collectively, these results indicate that the ratio between oxidized and reduced BH(4) metabolites tightly regulates superoxide formation from eNOS. The pathological significance of this scenario is discussed.
 ...
PMID:The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. 1187 2

The aim of this work was to study the mechanism of free radical formation in type 1 diabetes and its possible prevention. We have found oxidation of blood glutathione and an increase in plasma lipoperoxide levels in both human type 1 diabetes and experimental diabetes. Peroxide production by mitochondria does not increase in diabetes. On the contrary, the activity of xanthine oxidase, a superoxide-generating enzyme, increases in liver and plasma of diabetic animals. The increase in plasma xanthine oxidase activity may be explained by the increase in the hepatic release of this enzyme, which is not due to nonspecific membrane damage: release of other hepatic enzymes, such as the amino transferases, does not increase in diabetes. Superoxide formation by aortic rings of rabbits increases significantly in diabetes. This is completely inhibited by allopurinol, an inhibitor of xanthine oxidase. Heparin, which releases xanthine oxidase from the vessel wall, also decreases superoxide formation by aortic rings of diabetic animals. Treatment with allopurinol decreases oxidative stress in type 1 diabetic patients: hemoglobin glycation, glutathione oxidation, and the increase in lipid peroxidation are prevented. These results may have clinical significance in the prevention of late-onset vascular complications of diabetes.
Diabetes 2002 Apr
PMID:Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. 1191 34

Mice of the nonobese diabetic strain develop a progressive insulitis resulting in beta-cell destruction and diabetes. Superoxide radicals are abundantly formed by leukocytes and other mechanisms in inflammatory reactions. We here aimed to determine whether superoxide radicals contribute to the beta cell destruction in the mouse model. Transgenic nonobese diabetic mice secreting extracellular-superoxide dismutase under control of the insulin promoter were generated and the development of glucosuria monitored. The overexpression of extracellular-superoxide dismutase resulted in a 6-fold increase in the total superoxide dismutase activity of the islets. The incidence of diabetes of the transgenic mice was, however, not modified. The results suggest that superoxide radicals secreted to the extracellular space do not contribute to the beta cell destruction in the nonobese diabetic mouse model.
 ...
PMID:Overexpression of extracellular-SOD in islets of nonobese diabetic mice and development of diabetes. 1208 84

Professional phagocytes, comprising polymorphonuclear neutrophils and monocyte/macrophage cells, play an important role in the host defense. Any defect in their function exposes the organism to microbial intruders terminating in fatal diseases. The functional responses of the phagocytes to bacterial and fungal infections include chemotaxis, actin assembly, migration, adhesion, aggregation, phagocytosis, degranulation, and reactive oxygen species production. Superoxide generation by phagocytic NADPH oxidase is an imperative step toward bacterial killing. Phagocytes participate in inflammatory reactions and exert tumoricidal activity. They are supported by serum factors such as immunoglobulins, cytokines, complement, the acute phase reactant C-reactive protein, production of antibacterial proteins, and others. In addition to their principal task to eliminate bacteria, they are engaged in removing damaged, senescent, and apoptotic cells. Engulfed cell debris, large particles such as latex beads, fat, and oil droplets, are examples of phagocytic activity illustrated in the present review with transmission and scanning electron microscope micrographs. Numerous factors, such as diseases and stressful conditions, affect the engulfing activity of the professional phagocytes. Our experience regarding the impaired phagocytic capacity of cells in patients with diabetes and chronic renal failure is discussed. The results obtained in our laboratory from experiments detecting the effect of strenuous physical exercise, hypothermia, fasting, and abdominal photon irradiation on the phagocytic capacity of human polymorphonuclear neutrophils and rat peritoneal macrophages are hereby summarized and the reports on those subjects in the recent literature are reviewed. A variety of assays are applied for quantifying phagocytosis. Flow cytometry based on incubation of phagocytic cells with fluorescent conjugated particles and measuring the amount of fluorescence as an indicator of the engulfing capacity of the cells is a useful method. A direct visualization of the ingested particles using light or electron microscopy is a valuable tool for estimation of phagocytic function. In our hands, the use of semithin sections of embedded phagocytes following their incubation with latex particles provided satisfactory results for measuring the total number of phagocytic cells, as well as the internalizing capacity of each individual cell. Microbiological assays, the nitroblue tetrazolium test, quantitation of antibody- and antigen-mediated phagocytosis, as well as methods reviewed in detail in other reports are additional applications for determination of this intricate process.
 ...
PMID:Phagocytosis--the mighty weapon of the silent warriors. 1211 25

Endothelial dysfunction has been proposed as an early manifestation of atherosclerosis. The risk for atherosclerosis is increased in patients with diabetes mellitus, but the mechanism of the increased risk in these patients remains to be elucidated. Emerging evidence suggests that postprandial hyperglycaemia and hyperlipidemia are important risk factors in the development of atherosclerosis in patients with diabetes. Using a high-resolution ultrasound technique, we evaluated the acute effects of oral glucose loading on endothelium-dependent flow-mediated dilation (EFMD) and endothelium-independent flow-mediated dilation (EIFMD) of the brachial artery in 11 men (mean age: 59 +/- 5 years) with type 2 diabetes without chronic complications of diabetes. During these examinations, changes in the level of superoxide anion formation in the neutrophils were also measured. In addition, to investigate the relationship between acute hypertriglyceridemia and EFMD, we assessed the effects of high- and low-fat meals on EFMD of the brachial artery in 12 healthy volunteers. EFMD was diminished after glucose loading (13.2% +/- 6.4%, 7.3% +/- 3.3%*, 12.8% +/- 5.6%, in fasting and at 1 and 2 hours, respectively; *P<0.001 vs fasting). Superoxide anion formation by neutrophils (expressed as 10(-7) nmol/10(6) cells/30 min) was increased after glucose loading (4.7 +/- 2.8 and 6.2 +/- 2.2, in fasting and at one hour, respectively; P<0.05). EIFMD and triglyceride concentrations were not significantly affected by glucose loading. EFMD was also decreased by high-fat feeding (13.1% +/- 4.3%, 7.7% +/- 3.7%*, 7.3% +/- 2.2%*, basal, 2 hours, and 4 hours, respectively; *P<0.01 vs basal). These decreases were reversed by vitamin E treatment. These results show that acute hyperglycaemia induced by 75 gm oral glucose intake and acute hypertriglyceridemia induced by high-fat feeding are implicated in endothelial dysfunction. In addition, these results suggest that chronic and repeated hyperglycaemia and hypertriglyceridemia may play important roles in the development and progression of vascular complications in diabetes, probably through increased oxidative stress.
 ...
PMID:Endothelial dysfunction: its relationship with acute hyperglycaemia and hyperlipidemia. 1216 9

Oxygen free radicals have been implicated in beta-cell dysfunction and apoptosis associated with type 1 and type 2 diabetes mellitus. The roles of free radicals in diabetes have thus far been defined indirectly by monitoring oxidative tissue damage and the effects of antioxidants, free radical scavengers, and overexpression of superoxide dismutase. We employed the superoxide-mediated oxidation of hydroethidine to ethidium to dynamically and directly assess the relative rates of mitochondrial superoxide anion generation in isolated islets in response to glucose stimulation. Superoxide content of isolated islets increased in response to glucose stimulation. We next compared the oxyradical levels in Zucker lean control and Zucker diabetic fatty rat islets by digital imaging microfluorometry. The superoxide content of Zucker diabetic fatty islets was significantly higher than Zucker lean control islets under resting conditions, relatively insensitive to elevated glucose concentrations, and correlated temporally with a decrease in glucose-induced hyperpolarization of the mitochondrial membrane. Importantly, superoxide levels were elevated in islets from young, pre-diabetic Zucker diabetic fatty animals. Overproduction of superoxide was associated with perturbed mitochondrial morphology and may contribute to abnormal glucose signaling found in the Zucker diabetic fatty model of type 2 diabetes mellitus.
 ...
PMID:Visualizing superoxide production in normal and diabetic rat islets of Langerhans. 1251 70

Increased vascular permeability and oxidative stress are important in diabetic retinopathy. Because the cerebral microcirculation is much less affected in diabetes, our objectives are to compare: (1) glutathione peroxidase activity, (2) superoxide dismutase levels, (3) superoxide production, and (4) junctional protein (ZO-1) levels between retinal and brain-derived endothelial cells. Bovine brain and retinal endothelial cell cultures are incubated in medium containing either mM or 30 mM glucose for 5 days. Superoxide is measured in the medium and endothelial cells are then lysed and analyzed for glutathione peroxidase activity as well as levels of superoxide dismustase and ZO-1. The results demonstrate that, compared to brain-derived endothelial cells, retinal endothelial cells release high levels of superoxide, have less glutathione peroxidase activity and lower levels of superoxide dismutase, and ZO-1. Also, unlike brain-derived endothelial cells where ZO-1 levels increased in response to glucose, in retinal endothelial cells, ZO-1 levels are unaffected by glucose. These findings suggest that greater oxidative stress and lower junctional protein levels in retinal endothelial cells may contribute to blood/retinal barrier dysfunction in diabetic retinopathy.
 ...
PMID:Retinal endothelial cells are more susceptible to oxidative stress and increased permeability than brain-derived endothelial cells. 1253 67

Superoxide (O2-) is a key risk factor for cardiovascular disease (CVD), including atherogenesis, reperfusion injury, angina, restenosis following balloon angioplasty, and vein graft failure. Axiomatically, O2- reacts with nitric oxide (NO) to form peroxynitrite (ONOO) resulting in a depletion of endogenous vascular NO, which is now firmly associated with CVD. Furthermore, risk factors for CVD, in particular diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are all associated with oxidative stress OS. Antioxidant therapies, including the gene transfer of antioxidant enzymes, are potentially valuable in the treatment of CVD.
 ...
PMID:Oxidative stress, nitric oxide, and vascular disease. 1254 80

Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest new and attractive "causal" antioxidant therapy. New low-molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein kinase beta isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.
Diabetes Care 2003 May
PMID:New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy. 1271 23


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>