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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxide-producing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases.
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PMID:Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. 1587 5

Metal-induced toxicity and carcinogenicity, with an emphasis on the generation and role of reactive oxygen and nitrogen species, is reviewed. Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid peroxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). Whilst iron (Fe), copper (Cu), chromium (Cr), vanadium (V) and cobalt (Co) undergo redox-cycling reactions, for a second group of metals, mercury (Hg), cadmium (Cd) and nickel (Ni), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. Arsenic (As) is thought to bind directly to critical thiols, however, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. However, a recent discovery that the upper limit of "free pools" of copper is far less than a single atom per cell casts serious doubt on the in vivo role of copper in Fenton-like generation of free radicals. Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition. Various studies have confirmed that metals activate signalling pathways and the carcinogenic effect of metals has been related to activation of mainly redox-sensitive transcription factors, involving NF-kappaB, AP-1 and p53. Antioxidants (both enzymatic and non-enzymatic) provide protection against deleterious metal-mediated free radical attacks. Vitamin E and melatonin can prevent the majority of metal-mediated (iron, copper, cadmium) damage both in vitro systems and in metal-loaded animals. Toxicity studies involving chromium have shown that the protective effect of vitamin E against lipid peroxidation may be associated rather with the level of non-enzymatic antioxidants than the activity of enzymatic antioxidants. However, a very recent epidemiological study has shown that a daily intake of vitamin E of more than 400 IU increases the risk of death and should be avoided. While previous studies have proposed a deleterious pro-oxidant effect of vitamin C (ascorbate) in the presence of iron (or copper), recent results have shown that even in the presence of redox-active iron (or copper) and hydrogen peroxide, ascorbate acts as an antioxidant that prevents lipid peroxidation and does not promote protein oxidation in humans in vitro. Experimental results have also shown a link between vanadium and oxidative stress in the etiology of diabetes. The impact of zinc (Zn) on the immune system, the ability of zinc to act as an antioxidant in order to reduce oxidative stress and the neuroprotective and neurodegenerative role of zinc (and copper) in the etiology of Alzheimer's disease is also discussed. This review summarizes recent findings in the metal-induced formation of free radicals and the role of oxidative stress in the carcinogenicity and toxicity of metals.
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PMID:Metals, toxicity and oxidative stress. 1589 31

Diabetes induces oxidative stress and leads to attenuation of cardiac K+ currents. We investigated the role of superoxide ions and angiotensin II (ANG II) in generating and linking oxidative stress to the modulation of K+ currents under diabetic conditions. K+ currents were measured using patch-clamp methods in ventricular myocytes from streptozotocin (STZ)-induced diabetic rats. Superoxide ion levels, indicating oxidative stress, were measured by fluorescent labelling with dihydroethidium (DHE). ANG II content was measured using enzyme-linked immunosorbent asssay (ELISA). The results showed DHE fluorescence to be significantly higher in cells from diabetic males, compared to controls. Relief of stress by the NADPH oxidase inhibitor apocynin or by superoxide dismutase (SOD) but not by catalase reversed the attenuation of K+ currents and reduced DHE fluorescence. In cells from diabetic females, neither apocynin nor SOD augmented K+ currents, ANG II was not elevated and DHE fluorescence was significantly weaker than in cells from males. Reduced glutathione (GSH) also augmented K+ currents in cells from diabetic males but not females. In ovariectomized diabetic females K+ currents were augmented by GSH and apocynin. Current augmentation and the attenuation of DHE fluorescence by apocynin were significantly blunted by excess ANG II (300 nm). Diabetic male rats pretreated with the angiotensin-converting enzyme (ACE) inhibitor quinapril were hyperglycaemic, but their cellular ANG II levels and DHE fluorescence were significantly decreased. In cells from these rats, K+ currents were insensitive to apocynin. In conclusion, diabetes-related oxidative stress attenuates K+ currents through ANG II-generated increased superoxide ion levels. When ANG II levels are lower, as in diabetic females or following ACE inhibition in males, oxidative stress is reduced, with blunted alterations in K+ currents.
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PMID:Modulation of potassium currents by angiotensin and oxidative stress in cardiac cells from the diabetic rat. 1594 65

Vascular dysfunction is a hallmark of many diseases, including coronary heart disease, stroke, and diabetes. The underlying mechanisms of these disorders are intimately associated with an increase in oxidative stress and excess generation of reactive oxygen species. Here, we report that the anionic free radical, superoxide (O2*- ), directly affects the function of ion channels in vascular endothelial cells. Vascular endothelial cells were exposed to O2*- under physiological, symmetrical chloride and chloride-free conditions. Superoxide was generated from the reaction of xanthine (0.2 mM) and xanthine oxidase (0.1, 1, and 10 mU/ml) while its effects were determined with the whole cell mode of the patch-clamp technique. Inhibitors of K+ and Cl- channels were used to determine the role of these ion channels in mediating the electrophysiological effects of superoxide. The addition of O2*- caused a dose-dependent depolarization of endothelial cells and activation of the whole cell current. Activation of superoxide-dependent current was observed in the presence of inhibitors of K+ channels, Ba2+ (100 microM) or iberiotoxin (100 nM), and was not affected by inhibitors of nonselective cation channels, La3+, or by inhibition of the Cl-/HCO3- transporter by bumetanide. The inhibitors of the Cl- channel, NPPB (0.1 mM) or DIDS (100 microM), partially prevented activation of superoxide-dependent current but were unable to reverse it. The effects of superoxide on the amplitude of whole cell current were prevented and reversed by superoxide dismutase. Taken together, these results suggest that superoxide directly affects the function of ion channels in vascular endothelium but the mechanisms of its modulatory effects remain unresolved.
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PMID:Electrophysiological effects of O2*- on the plasma membrane in vascular endothelial cells. 1596 27

Oxidative stress has been implicated in pancreatic beta-cell damage, insulin resistance and vascular function in diabetic patients and the dysfunction of antioxidant enzymes may be associated with the pathogenesis of diabetes. Extracellular superoxide dismutase (EC-SOD) is found in the extracellular matrix of tissues and the major scavenger of superoxide radical. To investigate the role of genetic variability for the pathogenesis of type 2 diabetes, we scanned the protein coding exon and flanking introns of EC-SOD gene for mutation in Japanese type 2 diabetic patients. We identified two missense mutations, Ala40Thr (GCG-->ACG) and Arg213Gly (CGG-->GGG), and a silent mutation, Leu53Leu (CTG-->TTG). For one of these variants, the Ala40Thr polymorphism, the frequency of Thr allele and the number of subjects with Thr allele (Ala/Thr+Thr/Thr) were higher in type 2 diabetic patients (n=205) than those in non-diabetic subjects (n=220) (33.2% versus 24.1%, p=0.003 and 55.6% versus 42.7%, p=0.008, respectively). The patients with Thr allele also showed earlier age at diagnosis of diabetes (42.2+/-7.8 years versus 44.4+/-6.9 years, p=0.037) and higher prevalence of hypertension (53.5% versus 38.5%, p=0.032) than those without the allele. Insulin sensitivity, furthermore, was evaluated in 71 type 2 diabetic patients with short insulin tolerance test (SITT). The patients with Thr allele showed lower insulin sensitivity (Kitt value of SITT) than those without the allele (1.78+/-0.78%/min versus 2.33+/-1.02%/min, p=0.012), although no significant differences in other clinical and biochemical characteristics were observed between two groups. These results suggest that the genetic variant of EC-SOD gene is associated with insulin resistance and the susceptibility to type 2 diabetes.
Diabetes Res Clin Pract 2006 Feb
PMID:Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes. 1599 Jan 93

Oxidative stress is suggested to have an important role in the development of complications in diabetes. Because ozone therapy can activate the antioxidant system, influencing the level of glycemia and some markers of endothelial cell damage, the aim of this study was to investigate the therapeutic efficacy of ozone in the treatment of patients with type 2 diabetes and diabetic feet and to compare ozone with antibiotic therapy. A randomized controlled clinical trial was performed with 101 patients divided into two groups: one (n = 52) treated with ozone (local and rectal insufflation of the gas) and the other (n = 49) treated with topical and systemic antibiotics. The efficacy of the treatments was evaluated by comparing the glycemic index, the area and perimeter of the lesions and biochemical markers of oxidative stress and endothelial damage in both groups after 20 days of treatment. Ozone treatment improved glycemic control, prevented oxidative stress, normalized levels of organic peroxides, and activated superoxide dismutase. The pharmacodynamic effect of ozone in the treatment of patients with neuroinfectious diabetic foot can be ascribed to the possibility of it being a superoxide scavenger. Superoxide is considered a link between the four metabolic routes associated with diabetes pathology and its complications. Furthermore, the healing of the lesions improved, resulting in fewer amputations than in control group. There were no side effects. These results show that medical ozone treatment could be an alternative therapy in the treatment of diabetes and its complications.
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PMID:Therapeutic efficacy of ozone in patients with diabetic foot. 1619 34

Measurement of antioxidant enzyme activities is of great importance in the evaluation of oxidative stress in human metabolism. Sialic acids are also vital bio-markers for some diseases such as acute myocardial infarction and diabetes. In the present study, antioxidant enzyme activities (SOD, CAT, GSH-Px) and free sialic acid (FSA) levels in saliva were determined before and after training in the elite Turkish judoists (ETJ). According to the results, antioxidant enzyme activities in post-exercise values were significantly (p < 0.05) higher than those of pre-exercise values. A major finding of this study was that FSA levels also increased significantly (p < 0.05). Superoxide radical anion might have been effectively dismutated to hydrogen peroxide by elevated SOD activity. Accordingly, it suggests that CAT, having a higher increasing rate, was more efficient than GSH-Px in decomposition of hydrogen peroxide. In conclusion, the increase in antioxidant enzyme activities might have caused the elevation of FSA levels after training. Over-excreted sialic acids to saliva might have an important role in the removal of hydrogen peroxide. Since the increase in FSA levels in saliva has been found to be in well accordance with antioxidant enzymes, FSA may be concluded as an alternative oxidative stress marker in athletes.
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PMID:Possible interactions between antioxidant enzymes and free sialic acids in saliva: a preliminary study on elite judoists. 1632 Jan 66

The aim of this study was to evaluate the effect of single melatonin injection on plasma oxidative stress in rats with streptozotocin induced diabetes. Diabetes was induced after a single intraperitoneal dose of streptozotocin (60 mg/kg), while hyperglycemia was determined 10 days upon injection. Diabetic rats were divided into two groups. In the first group the injection of melatonin was applied intraperitoneally (20 mg/kg), while the second group received physiological solution. Twenty-four hours later the rats were killed and their blood was centrifuged. In the rat plasma the following parameters were evaluated: the glucose level, superoxide radical, lipid peroxidation, reduced glutathione, total antioxidant capacity, antioxidant enzymes and the aldose reductase activity. The injected melatonin decreased the superoxide radical in the rat plasma. Moreover, melatonin increased the total antioxidative capacity and the activity of antioxidative enzymes superoxide dismutase and glutathione peroxidase. These results indicate that melatonin is a strong scavenger, which may diminish negative effects of oxidative stress in diabetic rats 24 hours after its application The findings suggest that melatonin is also a strong antioxidant. It increases the antioxidant enzymes activity, inhibiting the release of superoxide radicals. A high total antioxidative capacity and the lower activity of aldose reductase enlarge melatonin scavenger capacity against reactive oxygen species in diabetic rats.
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PMID:Effects of melatonin on plasma oxidative stress in rats with streptozotocin induced diabetes. 1633 28

Statins may have favorable effects on endothelial barrier function, possibly through reduction of oxidative stress and modulation of expression of vasoactive proteins. The permeability of human umbilical endothelial cells in culture to a group of fluorescein isothiocyanate dextrans of different molecular weights were studied under various experimental conditions. Superoxide anion production was measured with an ethidium bromide fluorescence method. Cellular endothelin 1 mRNA and endothelin 1 in culture media were measured with Northern blots and enzyme immunoassays, respectively. Rosuvastatin (10 nmol/l) normalized the 500 mg/dl dextrose-induced permeability changes. Superoxide anion production induced by 500 mg/dl dextrose was inhibited by therapeutic concentrations of rosuvastatin or simvastatin (10 nmol/l), whereas the increased levels of cellular endothelin 1 mRNA and endothelin 1 in culture media was inhibited by supratherapeutic concentrations of statins (> or =0.1 micromol/l). In conclusion, 1) endothelial cell barrier dysfunction occurs in cells treated with high concentrations of dextrose, 2) statin treatment of endothelial cells normalizes barrier permeability, and 3) the favorable effects of statins may be attributed to the inhibition of the dextrose-induced increase in superoxide anions, whereas inhibition of endothelin expression was observed only at supratherapeutic concentrations.
Diabetes 2006 Feb
PMID:Statins prevent dextrose-induced endothelial barrier dysfunction, possibly through inhibition of superoxide formation. 1644 83

Blockade of the renin-angiotensin system (RAS) reduces cardiovascular morbidity and mortality in diabetic patients. Ang II-mediated generation of reactive oxygen species (ROS) has been suggested to be involved in several diabetic complications. We investigated whether the inhibition of Ang II production with an ACE inhibitor (ACEi) reduces oxidative stress and limits structural cardiovascular remodeling in a rat model of streptozotocin (STZ)-induced diabetes. Diabetic rats were treated for 7 weeks with an ACEi (lisinopril, 5 mg/kg/d), an antioxidant (N-acetyl-l-cysteine (NAC), 0.5 g/kg/d) and their combination. At sacrifice, ROS in the myocardium and thoracic aorta, LV myocyte number and size and aorta morphology were determined by quantitative histological methods. Superoxide and hydroxyl radical content, detected by dihydroethidium (DHE) and 8-hydroxydeoxyguanosine (8-OHdG), were 6.7 and 4.5-fold, respectively, higher in diabetic myocardium than in non-diabetic controls (p<0.001). The amount of superoxide was 5-fold higher in the thoracic aorta of diabetic rats compared to controls (p<0.001). Diabetes caused a modest increase in myocyte volume (+13%, p<0.01), a reduction of LV myocyte number (-43%, p<0.001), an accumulation of collagen around coronary arterioles (1.9-fold increase, p<0.01) and a decrease in arterial elastin/collagen ratio (-63%, p<0.001) compared to controls. Treatment with the ACEi attenuated ROS formation and prevented phenotypic changes in the heart (cardiomyocyte hypertrophy, perivascular fibrosis) and in the aorta of diabetic rats to the same extent as NAC. The absence of an additive effect, suggests a common mechanism of action, through the reduction of oxidative stress.
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PMID:Cardiovascular oxidative stress is reduced by an ACE inhibitor in a rat model of streptozotocin-induced diabetes. 1644 48


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