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)

Studies of marginal zinc deficiency in rhesus monkeys have demonstrated that plasma Zn levels are often a poor indication of Zn status. To better assess the Zn status of these animals, we examined their liver concentration of Zn as well as of other minerals, metallothionein (MT), and superoxide dismutase (SOD). Liver-wedge biopsies were obtained from adult rhesus monkeys fed for 15 mo, either a control (100 micrograms Zn/g) or a marginally Zn deficient diet (4 micrograms/g; ZD). Liver Zn and MT concentrations were lower in ZD monkeys than in controls whereas iron concentration was higher in ZD monkeys than in controls. Liver copper, manganese, and magnesium concentrations and activities of CuZnSOD and MnSOD were similar in the two groups. Data from the groups were pooled for regression analysis. Measurement of liver Zn and MT concentrations are useful in the assessment of the effects of long-term Zn deprivation in primates.
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PMID:Studies of marginal zinc deprivation in rhesus monkeys. III. Use of liver biopsy in the assessment of zinc status. 337 2

Changes in zinc (Zn) metabolism and interleukin-1 beta (IL-1 beta) release occur as part of the physiological response to tissue injury and trauma. In the present study, the influence of Zn status on the response to continuous low-dose IL-1 beta administration was evaluated. Rats were fed 50 micrograms Zn/g (adequate zinc; AZn) or 5 micrograms Zn/g (marginal zinc; MZn) diets for 14 days. On day 15, rats were infused via osmotic minipumps, with IL-1 beta (2.3 ng/hr) or saline (control, C) and euthanized 1, 3, or 7 days later. In the AZn rats, IL-1 beta infusion resulted in increased plasma copper (Cu) concentrations and ceruloplasmin (Cp) activity, and decreased iron (Fe) concentrations throughout the 7d period. These effects were most pronounced on d1 and d3. A similar trend was observed in the MZn rats, but IL-1 beta-induced increases in plasma Cu and Cp activity were less than in the AZn fed rats. In MZn and AZn IL-1 beta infused rats, plasma Zn was decreased on Day 1, and Day 3, respectively, compared with their respective controls. AZn IL-1 beta-infused rats were characterized by high liver Fe, Zn, and metallothionein (MT) concentrations on Day 1; by Day 7, only MT concentrations remained elevated. Liver MnSOD activity was 13%-29% higher in both the AZn- and MZn-IL-1 beta-infused rats than their respective controls on Day 3 and Day 7, with most significant increase observed on Day 7. These data show that Zn status can influence the response to low-dose IL-1 beta; this influence of Zn should be considered when IL-1 beta is given therapeutically.
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PMID:Zinc status and interleukin-1 beta-induced alterations in mineral metabolism in rats. 807 54

Previous reports have shown that exposure of vascular endothelial and smooth muscle cells to exogenous amyloid beta (Abeta) peptide results in cell damage and toxicity via oxidative injury. In this study we demonstrate that overexpression of the amyloid precursor protein (APP) is toxic to bovine aortic endothelial cells but not to bovine aortic smooth muscle cells. Intracellular coexpression of the free radical scavenger proteins metallothionein or MnSOD abolished the toxic effect of APP overexpression in endothelial cells. Our results demonstrate that endothelial cells are specifically susceptible to intracellular overexpression of APP and free radical generation is the likely mechanism of cell damage due to APP overexpression.
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PMID:Endothelial cell dysfunction in response to intracellular overexpression of amyloid precursor protein. 985 67

In order to determine the role of the neuropoietic cytokine interleukin-6 (IL-6) during the first 3 weeks after a focal brain injury, we examined the inflammatory response, oxidative stress and neuronal survival in normal and interleukin-6-deficient (knockout, IL-6KO) mice subjected to a cortical freeze lesion. In normal mice, the brain injury was followed by reactive astrogliosis and recruitment of macrophages from 1 day postlesion (dpl), peaking at 3-10 dpl, and by 20 dpl the transient immunoreactions were decreased, and a glial scar was present. In IL-6KO mice, the reactive astrogliosis and recruitment of macrophages were decreased throughout the experimental period. The expression of the antioxidant and anti-apoptotic factors metallothionein I+II (MT-I+II) was increased prominently by the freeze lesion, but this response was significantly reduced in the IL-6 KO mice. By contrast, the expression of the antioxidants Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-SOD, and catalase remained unaffected by the IL-6 deficiency. The lesioned mice showed increased oxidative stress, as judged by malondialdehyde (MDA) and nitrotyrosine (NITT) levels and by formation of inducible nitric oxide synthase (iNOS). IL-6KO mice showed higher levels of MDA, NITT, and iNOS than did normal mice. Concomitantly, in IL-6KO mice the number of apoptotic neurons was significantly increased as judged by TUNEL staining, and regeneration of the tissue was delayed relative to normal mice. The changes in neuronal tissue damage and in brain regeneration observed in IL-6KO mice are likely caused by the IL-6-dependent decrease in MT-I+II expression, indicating IL-6 and MT-I+II as neuroprotective factors during brain injury.
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PMID:Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice. 1110 68

Zinc has been shown to have antioxidant actions, which may be due, in part, to induction of metallothionein (MT). Such induction can protect tissues against various forms of oxidative injury because MT can function as an antioxidant. The objective of this study was to investigate if zinc or MT induction by zinc could afford protection against CYP2E1-dependent toxicity. HepG2 cells overexpressing CYP2E1 (E47cells) were treated with 60 microM arachidonic acid (AA), which is known to be toxic to these cells by a mechanism dependent on CYP2E1, oxidative stress, and lipid peroxidation. E47 cells were preincubated overnight in the absence or presence of metals such as zinc or cadmium that can induce MT. The culture medium containing the metals was removed, AA was added, and cell viability determined after 24 h incubation. Preincubation overnight with 150 microM zinc sulfate or 5 microM cadmium chloride induced a 20- to 30-fold increase of MT2A mRNA; high levels of MT2A mRNA were maintained during the subsequent challenge period with AA, even after the zinc was removed. MT protein levels were increased about 4- to 5-fold during the overnight preincubation with zinc and a 20- to 30-fold increase was observed 24 h after zinc removal during the AA challenge. The treatment with zinc was associated with significant protection against the loss of cell viability caused by AA in E47 cells. The zinc pretreatment protected about 50% against the DNA fragmentation, cell necrosis, the enhanced lipid peroxidation and increased generation of reactive oxygen species, and the loss of mitochondrial membrane potential induced by AA treatment in E47 cells. CYP2E1 catalytic activity and components of the cell antioxidant defense system such as glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPX), catalase, Cu,Zn superoxide dismutase (SOD), and MnSOD were not altered under these conditions. Zinc preincubation also protected the E47 cells against BSO-dependent toxicity. When E47 cells were coincubated with zinc plus AA for 24 h (i.e., zinc was not removed, nor was there a preincubation period prior to challenge with AA), AA toxicity was increased. Thus, zinc had a direct pro-oxidant effect in this model and an indirect antioxidant effect, perhaps via induction of MT. MT may have potential clinical utility for the prevention or improvement of liver injury produced by agents known to be metabolized by CYP2E1 to reactive intermediates and to cause oxidative stress.
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PMID:Metallothionein 2A induction by zinc protects HEPG2 cells against CYP2E1-dependent toxicity. 1256 70

To identify molecular events occurring during the early response to hyperoxia, we measured changes over time in total lung gene expression in C57BL/6 mice during prolonged exposure to > 95% O2. Specifically, differential gene expression of > 8,734 sequence-verified murine complementary DNAs was analyzed after 0, 8, 24, and 48 h of O2 exposure, with additional genes of interest analyzed at 24 h. Of the 385 genes differentially expressed, hyperoxia increased expression of 175 genes (2.0%) and decreased expression of 210 genes (2.3%). The majority of "classic" antioxidant enzymes, including catalase, MnSOD, and Cu-Zn SOD, showed no change in expression during hyperoxia, with a number of other antioxidant enzymes, including glutathione peroxidase, glutathione-S-Transferase (GST) Pi1, GST mu2, and heme oxygenase-1 showing relatively moderate increases. The exception was the heavy metal-binding protein metallothionein, which increased expression over 7-fold after 48 h of O2. We found no change in the expression of a number of known proinflammatory genes after 24 or 48 h of hyperoxia. A large increase in p21 expression was demonstrated, suggesting overall inhibition of cell cycle progression. Increases of the antiapoptotic gene Bcl-XL were counterbalanced by similar increases of the proapoptotic gene BAX. New findings included significant increases in expression of cysteine-rich protein 61(cyr61) at 48 h, suggesting a potential role for this factor in angiogenesis or remodeling of the extra cellular matrix during recovery from hyperoxia. In addition, downregulation of thrombomodulin expression occurred by 24 h and was further decreased at 48 h. Given the importance of thrombomodulin/thrombin interaction in regulating protein C activity, decreases in thrombomodulin may contribute to activation of the coagulation and inflammatory cascades and development of lung injury with hyperoxia.
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PMID:Gene expression profiling of the early pulmonary response to hyperoxia in mice. 1276 Sep 66

Intestinal mucosal damage in the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC) involves reactive oxygen metabolites (ROMs). ROMs are neutralized by endogenous antioxidant enzymes in a carefully balanced two-step pathway. Superoxide dismutases (SODs) convert superoxide anion to hydrogen peroxide (H(2)O(2)), which is subsequently neutralized to water by catalase (CAT) or glutathione peroxidase (GPO). Remarkably changed expression levels of the three isoforms of SOD in paired non-inflamed and inflamed mucosae from CD and UC patients have been previously reported in comparison to normal control mucosa. Most notable was the strong up-regulation of Mn-SOD in inflamed epithelium. It was hypothesized that in order to provide optimal protection against ROM-mediated damage, these changes should be coordinately counterbalanced by an increased H(2)O(2)-neutralizing capacity. Therefore, the same tissue samples were used to assess the levels, activities, and/or localization of the most prominent mucosal H(2)O(2)-related antioxidants CAT, GPO, glutathione (GSH), myeloperoxidase (MPO), and metallothionein (MT). Quantitative measurements showed that in both CD and UC patients, intestinal inflammation was associated with increased activities of CAT, GPO, and MPO, whereas the mucosal GSH content was unaffected and the concentration of MT was decreased. Despite this overall increase in mucosal H(2)O(2)-metabolizing enzyme capacity, immunohistochemical analysis revealed a differentially disturbed antioxidant balance in IBD epithelium and lamina propria. In the lamina propria, the risk of direct H(2)O(2)-mediated damage seemed to be restrained by the increasing numbers of CAT- and MPO-positive monocytes/macrophages and neutrophils that infiltrated the inflamed areas. On the other hand, MPO overexpression might increase the lamina propria levels of hypochlorous acid, a stable ROM with multiple pro-inflammatory effects. In the epithelium, the number of cells that expressed CAT remained unchanged during inflammation and GPO was found in only a very low and constant number of epithelial cells. In addition, the inflamed epithelium displayed decreased expression of the hydroxyl radical (OH(*)) scavenger MT. In view of the high epithelial SOD levels in inflamed IBD epithelium, it is speculated that the efficient removal of excess H(2)O(2) is hampered in these cells, thereby increasing not only the risk of detrimental effects of H(2)O(2) directly, but also those of its extremely reactive derivatives such as OH(*). Taken together, the results suggest an imbalanced and inefficient endogenous antioxidant response in the intestinal mucosa of IBD patients, which may contribute to both the pathogenesis and the perpetuation of the inflammatory processes.
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PMID:Imbalanced secondary mucosal antioxidant response in inflammatory bowel disease. 1295 13

Reactive oxygen species (ROS) cause macromolecular damage and may play an important role in tumor development. Superoxide dismutase (SOD) and metallothionein (MT) serve as initial and final defense mechanisms, respectively, against ROS. We hypothesized that the inducibility of Mn-SOD and MT mRNA by paraquat, an intracellular superoxide generator, might be altered in lymphocytes of gastric cancer patients. The inducibility of Mn-SOD mRNA by paraquat in lymphocytes of 19 normal subjects and the 14 gastric cancer patients was 162.4 +/- 16.7% and 87.9 +/- 9.5%, respectively (P = 0.001). The inducibility of MT mRNA by paraquat in the normal subjects and the gastric cancer patients was 126.7 +/- 15.8% and 115.4 +/- 12.9%, respectively. This suggests that the failure of Mn-SOD mRNA induction by oxidative stress in peripheral lymphocytes may be involved in the development of gastric cancer and may be of value in predicting the future occurrence of gastric cancer. In addition, the wide variation in Mn-SOD and MT mRNA levels among normal subjects may reflect different susceptibilities to diseases including cancer.
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PMID:Differential induction of Mn-containing superoxide dismutase by paraquat in peripheral lymphocytes of normal subjects and gastric cancer patients. 1450 39

Three populations of brown trout (Salmo trutta) exposed to different metal levels in their natural environments, were studied with respect to antioxidants metallothionein (MT), superoxide dismutase (SOD) and catalase (CAT) as well as for corresponding mRNA levels. In addition, mRNA levels were studied for glutathione peroxidase (GPx) and glutathione reductase (GR). The Cd/Zn-exposed trout (Naustebekken River) had higher accumulated levels of Cd, Cu and Zn in gills, and higher levels of MT (both protein and mRNA) in liver and kidney as well as in gills compared to the Cu-exposed trout (Rugla River) and trout from an uncontaminated reference river (Stribekken River). Less MT found in the Cu-exposed trout may increase susceptibility to oxidative stress, but no higher levels of antioxidant mRNAs were found in gills of these trouts. The data indicated that chronic exposures of brown trout to Cd, Zn and/or Cu did not involve maintenance of high activities of SOD and CAT enzymes in gills, although SOD mRNA levels were higher in the Cd/Zn-exposed trout. In livers, mRNA levels of SOD, CAT and GPx were higher in the metal-exposed trout, but in the case of GR this was only seen in kidneys of Cd/Zn-exposed trout. However, both metal-exposed groups had higher activities of SOD enzyme in liver compared to the unexposed reference trout, and CAT activity was found to be higher in kidneys of Cu-exposed trout. The Cu-exposed trout did not seem to rely on MT production to avoid Cu toxicity in gills, but rather by keeping the Cu uptake at a low level. A coordinated expression of different stress genes may also be important in chronic metal exposure. It may be concluded that the observed metal effects relies on acclimation rather than on genetic adaptation in the metal exposed populations.
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PMID:Antioxidative stress proteins and their gene expression in brown trout (Salmo trutta) from three rivers with different heavy metal levels. 1661 85

Manganese (Mn) is a ubiquitous and essential element that can be toxic at high doses. In individuals exposed to high levels of this metal, Mn can accumulate in various brain regions, leading to neurotoxicity. In particular, Mn accumulation in the mid-brain structures, such as the globus pallidus and striatum, can lead to a Parkinson's-like movement disorder known as manganism. While the mechanism of this toxicity is currently unknown, it has been postulated that Mn may be involved in the generation of reactive oxygen species (ROS) through interaction with intracellular molecules, such as superoxide and hydrogen peroxide, produced within mitochondria. Conversely, Mn is a required component of an important antioxidant enzyme, Mn superoxide dismutase (MnSOD), while glutamine synthetase (GS), a Mn-containing astrocyte-specific enzyme, is exquisitely sensitive to oxidative stress. To investigate the possible role of oxidative stress in Mn-induced neurotoxicity, a series of inhalation studies was performed in neonatal and adult male and female rats as well as senescent male rats exposed to various levels of airborne-Mn for periods of time ranging from 14 to 90 days. Oxidative stress was then indirectly assessed by measuring glutathione (GSH), metallothionein (MT), and GS levels in several brain regions. MT and GS mRNA levels and regional brain Mn concentrations were also determined. The collective results of these studies argue against extensive involvement of ROS in Mn neurotoxicity in rats of differing genders and ages. There are, however, instances of changes in individual endpoints consistent with oxidative stress in certain brain tissues.
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PMID:Effects of inhaled manganese on biomarkers of oxidative stress in the rat brain. 1684 51


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