Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Large, prospective, clinical trials have confirmed the efficacy of intensive blood-glucose control to prevent the onset and progression of diabetic complications. However, since it is difficult to maintain blood glucose concentrations close to the normal range, the effect of intensive therapy to prevent diabetic complications may be limited. Other approaches are therefore required to prevent the progression of diabetic complications based on the elucidation of the biological mechanisms. In this review, the impacts of mitochondrial reactive oxygen species (ROS) on diabetes-related complications are described. In endothelial cells, high glucose levels increase mitochondrial ROS, and the normalization of mitochondrial ROS production by inhibitors of mitochondrial metabolism, or by the overexpression of UCP-1 or MnSOD, prevents the glucose-induced accumulation of sorbitol, activation of protein kinase C, and formation of advanced glycation end products, all of which are believed to be major molecular mechanisms of diabetic complications. We also demonstrated that 8-hydroxydeoxyguanosine, which represents mitochondrial oxidative damage, was elevated in patients with either retinopathy, albuminuria, or the increased intima-media thickness of carotid arteries compared to patients without diabetic vascular complications. In addition, to investigate the impact of mitochondrial ROS on diabetic retinopathy in vivo, we established a novel transgenic mouse, which specifically expressed MnSOD in endothelial cells. By the introduction of diabetes, levels of urinary 8-hydroxydeoxyguanosine and expressions of VEGF and fibronectin mRNA in retinas were increased in wild type littermates; however, these observations were ameliorated in transgenic mice. Taking the results together, hyperglycemia could induce mitochondrial ROS production, associating it with the pathogenesis of diabetic vascular complications.
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PMID:[Investigation of a novel mechanism of diabetic complications: impacts of mitochondrial reactive oxygen species]. 1880 Jun 28

Intermittent hypoxia (IH), such as occurs in sleep apnea, induces increased oxidative stress and is associated with altered glucose homeostasis. Because pancreatic beta cells are very sensitive to oxidative stress we tested whether they could be affected by IH. The effects of IH exposure (24 h/day, 5.7 and 21% O(2) alternation) in mice on beta-cell proliferation and beta-cell death were tested using Ki67 staining and TUNEL staining, respectively. To assess the role of oxidative stress in these processes, transgenic mice with beta-cell-specific overexpression of the antioxidant protein MnSOD were exposed to IH. After 4 days of IH exposure, beta-cell proliferation was increased almost fourfold. Coinciding with the increase in proliferation, the subcellular localization of the cell cycle regulator cyclin D2 was increased in the nucleus. In addition, beta-cell death was increased approximately fourfold. MnSOD transgene did not alter the effects of IH on beta-cell proliferation, but completely abrogated the IH effects on cell death. Thus, IH exposure that mimics sleep apnea can lead to increased beta-cell proliferation and cell death. Furthermore, the cell death response seems to be due to oxidative stress.
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PMID:Beta-cell death and proliferation after intermittent hypoxia: role of oxidative stress. 1913 26

The impact of chronic excessive energy intake on protein metabolism is still controversial. Male Wistar rats were fed ad libitum during 5 weeks with either a high-fat high-sucrose diet (HF: n = 9) containing 45% of total energy as lipids (protein 14%; carbohydrate 40% with 83.5% sucrose) or a standard diet (controls: n = 10). Energy intake and body weight were recorded. At the end of the experiment, we measured body composition, metabolic parameters (plasma amino acid, lipid, insulin, and glucose levels), inflammatory parameter (plasma alpha2-macroglobulin), oxidative stress parameters (antioxidant enzyme activities, lipoperoxidation (LPO), protein carbonyl content in liver and muscle), and in vivo fed-state fractional protein synthesis rates (FSRs) in muscle and liver. Energy intake was significantly higher in HF compared with control rats (+28%). There were significant increases in body weight (+8%), body fat (+21%), renal (+41%), and epidydimal (+28%) fat pads in HF compared with control rats. No effect was observed in other tissue weights (liver, muscle, spleen, kidneys, intestine). Liver and muscle FSRs, plasma levels of lipids, glucose, insulin and alpha2-macroglobulin, soleus and liver glutathione reductase and peroxidase activities, MnSOD activity, LPO, and protein carbonyl content were not altered by the HF diet. Only soleus muscle and liver Cu/ZnSOD activity and soleus muscle catalase activities were reduced in HF rats compared with control rats. Thus, chronic excessive energy intake and increased adiposity, in the absence of other metabolic alterations, do not stimulate fed-state tissue protein synthesis rates.
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PMID:Excessive energy intake does not modify fed-state tissue protein synthesis rates in adult rats. 1924 70

Autophagy is involved in human diseases and is regulated by reactive oxygen species (ROS) including superoxide (O(2)(*-)) and hydrogen peroxide (H(2)O(2)). However, the relative functions of O(2)(*-) and H(2)O(2) in regulating autophagy are unknown. In this study, autophagy was induced by starvation, mitochondrial electron transport inhibitors, and exogenous H(2)O(2). We found that O(2)(*-) was selectively induced by starvation of glucose, L-glutamine, pyruvate, and serum (GP) whereas starvation of amino acids and serum (AA) induced O(2)(*-) and H(2)O(2). Both types of starvation induced autophagy and autophagy was inhibited by overexpression of SOD2 (manganese superoxide dismutase, Mn-SOD), which reduced O(2)(*-) levels but increased H(2)O(2) levels. Starvation-induced autophagy was also inhibited by the addition of catalase, which reduced both O(2)(*-) and H(2)O(2) levels. Starvation of GP or AA also induced cell death that was increased following treatment with autophagy inhibitors 3-methyladenine, and wortamannin. Mitochondrial electron transport chain (mETC) inhibitors in combination with the SOD inhibitor 2-methoxyestradiol (2-ME) increased O(2)(*-) levels, lowered H(2)O(2) levels, and increased autophagy. In contrast to starvation, cell death induced by mETC inhibitors was increased by 2-ME. Finally, adding exogenous H(2)O(2) induced autophagy and increased intracellular O(2)(*-) but failed to increase intracellular H(2)O(2). Taken together, these findings indicate that O(2)(*-) is the major ROS-regulating autophagy.
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PMID:Superoxide is the major reactive oxygen species regulating autophagy. 1940 26

Apoptosis arises from neuronal damage following an ischemic insult. Apoptosis-inducing factor (AIF) is a protein released from mitochondria in response to pro-apoptotic signals which then translocates to the nucleus and triggers DNA fragmentation. In parallel with this, pro-apoptotic signals cause the release of cytochrome c from mitochondria, activating caspase-dependent apoptosis. During post-ischemic reperfusion, reactive oxygen species (ROS) are formed in excess in mitochondria and can play a role in initiating apoptosis. In cultures, ROS are formed during post oxygen glucose deprivation (OGD) normoxia/normoglycemia that is used as a model for ischemia. In this study, we delivered viral vectors to overexpress antioxidants (GPX, catalase, CuZnSOD, or MnSOD) in mixed cortical cultures, in order to investigate the effects of ROS-reduction on the release of cytochrome c and AIF. Overexpression of MnSOD, CuZnSOD, catalase or GPX all prevented AIF translocation from mitochondria to the nucleus. Potentially, this could reflect broadly non-specific protection due to reducing ROS load. Arguing against this, overexpression of the same antioxidants did not inhibit cytochrome c release. These findings suggest a specific interaction between ROS formation and the caspase-independent route of apoptosis.
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PMID:Effects of overexpression of antioxidants on the release of cytochrome c and apoptosis-inducing factor in the model of ischemia. 1942 31

The production of hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) is a key event in the development of diabetic complications. Because resveratrol, a naturally occurring polyphenol, has been reported to confer vasoprotection, improving endothelial function and preventing complications of diabetes, we investigated the effect of resveratrol on mtROS production in cultured human coronary arterial endothelial cells (CAECs). The measurement of MitoSox fluorescence showed that resveratrol attenuates both steady-state and high glucose (30 mM)-induced mtROS production in CAECs, an effect that was prevented by the knockdown of the protein deacetylase silent information regulator 2/sirtuin 1 (SIRT1), an intracellular target of resveratrol. An overexpression of SIRT1 mimicked the effects of resveratrol, attenuating mtROS production. Similar results were obtained in CAECs transfected with mitochondria-targeted H(2)O(2)-sensitive HyPer-Mito fluorescent sensor. Amplex red assay showed that resveratrol and SIRT1 overexpression significantly reduced cellular H(2)O(2) levels as well. Resveratrol upregulated MnSOD expression and increased cellular GSH content in a concentration-dependent manner (measured by HPLC coulometric analysis). These effects were attenuated by SIRT1 knockdown and mimicked by SIRT1 overexpression. We propose that resveratrol, via a pathway that involves the activation of SIRT1 and the upregulation of antioxidant defense mechanisms, attenuates mtROS production, suggesting the potential for new treatment approaches targeting endothelial mitochondria in metabolic diseases.
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PMID:Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. 1974 57

Hyperglycemia-induced mitochondrial dysfunction contributes to sensory neuron pathology in diabetic neuropathy. Although Schwann cells (SCs) also undergo substantial degeneration in diabetic neuropathy, the effect of hyperglycemia on the SC mitochondrial proteome and mitochondrial function has not been examined. Stable isotope labeling with amino acids in cell culture (SILAC) was used to quantify the temporal effect of hyperglycemia on the mitochondrial proteome of primary SCs isolated from neonatal rats. Of 317 mitochondrial proteins identified, about 78% were quantified and detected at multiple time points. Pathway analysis indicated that proteins associated with mitochondrial dysfunction, oxidative phosphorylation, the TCA cycle, and detoxification were significantly increased in expression and over-represented. Assessing mitochondrial respiration in intact SCs indicated that hyperglycemia increased the overall rate of oxygen consumption but decreased the efficiency of coupled respiration. Although a glucose-dependent increase in superoxide production occurs in embryonic sensory neurons, hyperglycemia did not induce a substantial change in superoxide levels in SCs. This correlated with a 1.9-fold increase in Mn superoxide dismutase expression, which was confirmed by immunoblot and enzymatic activity assays. These data support that hyperglycemia alters mitochondrial respiration and can cause remodeling of the SC mitochondrial proteome independent of significant contributions from glucose-induced superoxide production.
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PMID:Hyperglycemia alters the schwann cell mitochondrial proteome and decreases coupled respiration in the absence of superoxide production. 1990 32

Retinal mitochondria become dysfunctional in diabetes and the production of superoxide radicals is increased; over-expression of MnSOD abrogates mitochondrial dysfunction and prevents the development of diabetic retinopathy. The mitochondrial DNA (mtDNA) is particularly prone to oxidative damage. The aim of this study is to examine the role of MnSOD in the maintenance of mtDNA. The effect of MnSOD mimic, MnTBAP or over-expression of MnSOD on glucose-induced alterations in mtDNA homeostasis and its functional consequence was determined in retinal endothelial cells. Exposure of retinal endothelial cells to high glucose increased mtDNA damage and compromised the DNA repair machinery. The gene expressions of mitochondrial-encoded proteins of the electron transport chain complexes were decreased. Inhibition of superoxide radicals by either MnTBAP or by over-expression of MnSOD prevented mtDNA damage and protected mitochondrial-encoded genes. Thus, the protection of mtDNA from glucose-induced oxidative damage is one of the plausible mechanisms by which MnSOD ameliorates the development of diabetic retinopathy.
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PMID:Oxidative damage of mitochondrial DNA in diabetes and its protection by manganese superoxide dismutase. 2008 10

Our earlier studies have shown that simultaneous inhibition of glycolysis and pentose phosphate pathway using 2-deoxy-d-glucose (2-DG, an inhibitor of glycolysis) and 6-aminonicotinamide (6-AN, an inhibitor of pentose phosphate pathway) lead to metabolic oxidative stress (MOS), resulting in radiosensitization in malignant cells. Present study was carried out to investigate the effects of 2-DG and 6-AN on intricately regulated endogenous antioxidant defense against MOS during radiosensitization by this combination. Two human tumor cell lines {Head and Neck Squamous carcinoma (KB) and Glioma (BMG-1)} and one non-malignantly transformed cell line (human embryonic kidney, HEK) were used in this study. The presence of 2-DG and 6-AN (added just before irradiation) for 4h, significantly decreased the clonogenicity and metabolic viability of KB and BMG-1 cell lines, while no significant change was seen in HEK cells. Accumulation of ROS was observed only in malignant cell lines, which displayed a compromised redox status evident from enhanced NADP(+)/NADPH and GSSG/GSH ratios and a concomitant decrease in glutathione reductase level and activity at 24h following treatment. The levels and activities of Cu, Zn-SOD and Mn-SOD increased with MOS and were accompanied by a decreased GPx and unaltered catalase activity and level. These results suggest that non-coordinated expression of antioxidant defense, besides compromised redox status, led to selective radiosensitization in the malignant cells.
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PMID:Metabolic oxidative stress induced by a combination of 2-DG and 6-AN enhances radiation damage selectively in malignant cells via non-coordinated expression of antioxidant enzymes. 2036 70

Clinical reports suggest close interactions between stressors, particularly those of long duration, and liver diseases, such as hepatic inflammation, that is proposed to occur via reactive oxygen species. In the present study we have used 21-day social isolation of male Wistar rats as a model of chronic stress to investigate protein expression/activity of liver antioxidant enzymes: superoxide dismutases (SODs), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR), and protein expression of their upstream regulators: glucocorticoid receptor (GR) and nuclear factor kappa B (NFkB). We have also characterized these parameters in either naive or chronically stressed animals that were challenged by 30-min acute immobilization. We found that chronic isolation caused decrease in serum corticosterone (CORT) and blood glucose (GLU), increase in NFkB signaling, and disproportion between CuZnSOD, peroxidases (CAT, GPx) and GLR, thus promoting H2O2 accumulation and prooxidative state in liver. The overall results suggested that chronic stress exaggerated responsiveness to subsequent stressor at the level of CORT and GLU, and potentiated GLR response, but compromised the restoration of oxido-reductive balance due to irreversible alterations in MnSOD and GPx.
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PMID:Chronic stress differentially affects antioxidant enzymes and modifies the acute stress response in liver of Wistar rats. 2040 49


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