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)

Because reactive oxygen species have been implicated in the pathogenesis of various hyperproliferative and inflammatory diseases, the mRNA expression of the antioxidant enzyme superoxide dismutase was studied in psoriatic skin tissue. By using reverse transcription-PCR we found similar expression of copper, zinc superoxide dismutase (CuZnSOD) in the involved vs. uninvolved psoriatic skin. In contrast, the level of the manganese superoxide dismutase (MnSOD) mRNA message was consistently higher in lesional psoriatic skin as compared to adjacent uninvolved skin and healthy control skin. Parallel investigation of those cytokines that are thought to be direct or indirect inducers of the MnSOD activity revealed an increased mRNA expression of IL-1 beta, TNF-alpha, and GM-CSF in lesional psoriatic skin. To study if these cytokines exert a direct effect on dismutase expression in epidermal cells, human keratinocytes in culture were challenged with IL-1 beta, TNF-alpha, and GM-CSF. It was found that IL-1 beta and TNF-alpha, but not GM-CSF, induced the mRNA expression of MnSOD, and an additive effect was demonstrated for the two former cytokines. Further, the expression of both CuZnSOD and MnSOD transcripts was similar in cultured keratinocytes maintained at low differentiation (low Ca2+ medium) and cells forced to terminal differentiation (by high Ca2+ medium). Our results indicate that the abnormal expression of MnSOD mRNA in lesional psoriatic skin is not directly linked to the pathologic state of keratinocyte differentiation in the skin. It seems more likely that the cutaneous overexpression of MnSOD in psoriatic epidermis represents a protective cellular response evoked by cytokines released from inflammatory cells invading the diseased skin.
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PMID:Increased mRNA expression of manganese superoxide dismutase in psoriasis skin lesions and in cultured human keratinocytes exposed to IL-1 beta and TNF-alpha. 774 20

This review addresses the general hypothesis that the pathogenesis of preeclampsia is related to an imbalance of increased oxidative stress and lipid peroxidation coupled to a deficiency of antioxidant protection. Evidence will be presented that this imbalance is present in both the maternal compartment and the placental compartment and that interactions between these two compartments result in the clinical manifestations of this disorder. We suggest the following as a scenario for the development of preeclampsia: Oxidative stress in the maternal compartment affects the placenta in such a way as to bring about a decrease in placental antioxidant enzyme protection. The oxidative stress in the maternal compartment may be preexisting (e.g., obesity, diabetes, hyperlipidemia) or may be caused by placental secretion of lipid peroxides. Decreased placental antioxidant enzyme protection leads to a cascade of events in the placenta of uncontrolled lipid peroxidation with increased thromboxane production and increased tumor necrosis factor (TNF-alpha) production. Increased placental secretion of lipid peroxides and/or TNF-alpha results in activation of leukocytes as they circulate through the intervillous space. The activated leukocytes serve as circulating mediators that link the increased oxidative stress of the placenta with a widespread increase in oxidative stress and endothelial dysfunction in the mother. In the third trimester, when the placenta is growing rapidly, the mother's antioxidant capacity is no longer able to compensate, and the clinical symptoms of preeclampsia appear.
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PMID:Maternal-placental interactions of oxidative stress and antioxidants in preeclampsia. 965 11

Tumor necrosis factor-alpha is assumed to play a role in toxic liver damage. We examined whether exogenous tumor necrosis factor-alpha must be present for alpha-amanitin cytotoxicity in rat hepatocyte culture. alpha-Amanitin at a concentration of 0.1 microM, which is close to that found in intoxicated patients, inhibits RNA and protein synthesis within 12 h but cytotoxicity only occurs after a latency period and is pronounced at 36 h after the start of treatment. Tumor necrosis factor-alpha is not indispensable for the development of cytotoxicity but aggravates it and leads to a time shift towards earlier times. Lipid peroxidation is low with alpha-amanitin alone even at 36 h but markedly increased by cotreatment with tumor necrosis factor-alpha. The antioxidant silibin prevents the effect of tumor necrosis factor-alpha, indicating an involvement of reactive oxygen species. alpha-Amanitin alone does not increase but dose-dependently inhibits the expression of the antioxidant enzyme manganous superoxide dismutase and decreases the inducing effect of TNF-alpha on the expression of this enzyme. The gene expression of endogenous tumor necrosis factor-alpha in the hepatocytes is not increased but rather inhibited by alpha-amanitin treatment. The results suggest that alpha-amanitin causes delayed cytotoxicity following rapid inhibition of RNA and protein synthesis and that tumor necrosis factor-alpha shortens the latency period and aggravates the cytotoxicity by a mechanism which may involve reactive oxygen species.
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PMID:Influence of tumor necrosis factor-alpha and silibin on the cytotoxic action of alpha-amanitin in rat hepatocyte culture. 1043 58

It has previously been shown that hyperoxia induces nonapoptotic cell death in cultured lung epithelial cells, whereas hydrogen peroxide (H(2)O(2)) and paraquat cause apoptosis. To test whether pathways leading to oxidative apoptosis in epithelial cells are sensitive to molecular O(2), A549 cells were exposed to 95% O(2) prior to exposure to lethal concentrations of H(2)O(2). The extent of H(2)O(2)-induced apoptosis was significantly reduced in cells preexposed to hyperoxia compared with room-air controls. Preexposure of the hyperoxia-resistant HeLa-80 cell line to 80% O(2) also inhibited oxidant-induced apoptosis, suggesting that this inhibition is not due to O(2) toxicity. Because hyperoxia generates reactive oxygen species and activates the redox-sensitive transcription factor nuclear factor kappa B (NF-kappa B), the role of antioxidant enzymes and NF-kappa B were examined in this inhibitory process. The onset of inhibition appeared to be directly related to the degradation of I kappa B and subsequent activation of NF-kappa B (either by hyperoxia or TNF-alpha), whereas no significant up-regulation of endogenous antioxidant enzyme activities was found. In addition, suppression of NF-kappa B activities by transfecting A549 cells with a dominant-negative mutant construct of I kappa B significantly augmented the extent of H(2)O(2)-induced apoptosis. These data suggest that hyperoxia inhibits oxidant-induced apoptosis and that this inhibition is mediated by NF-kappa B.
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PMID:Hyperoxia inhibits oxidant-induced apoptosis in lung epithelial cells. 1103 97

Molecular hydrogen reacts with the hydroxyl radical, a highly cytotoxic species produced in inflamed tissues. It has been suggested therefore to use gaseous hydrogen in a new anti-inflammatory strategy. We tested this idea, with the aid of the equipment and skills of COMEX SA in Marseille, a group who experiments with oxygen-hydrogen breathing mixtures for professional deep-sea diving. The model used was schistosomiasis-associated chronic liver inflammation. Infected animals stayed 2 weeks in an hyperbaric chamber in a normal atmosphere supplemented with 0.7 MPa hydrogen. The treatment had significant protective effects towards liver injury, namely decreased fibrosis, improvement of hemodynamics, increased NOSII activity, increased antioxidant enzyme activity, decreased lipid peroxide levels and decreased circulating TNF-alpha levels. Under the same conditions, helium exerted also some protective effects, indicating that hydroxyl radical scavenging is not the only protective mechanism. These findings indicate that the proposed anti-inflammatory strategy deserves further attention.
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PMID:Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. 1151 Apr 17

NF-kappaB is known to exert a cytoprotective action against TNF-alpha-induced apoptosis. To study the role of NF-kappaB in various TNF-alpha-treated epithelial cell lines, we generated stable transfectants overexpressing a mutated unresponsive form of the IkappaBalpha inhibitor (MT cells). As NF-kappaB prevented TNF-alpha-induced apoptosis in various epithelial cancer cell lines, we searched for NF-kappaB target gene products responsible for this difference of sensitivity. We observed an increased Bcl-X(L) expression level in OVCAR-3 cells compared with OVCAR-3 cells expressing a mutated IkappaBalpha inhibitor (MT cells). Induction of the antioxidant enzyme MnSOD was detected only in TNF-alpha-treated OVCAR, MCF7A/Z and HCT116 cells but not in MT cells. Moreover, reactive oxygen species were involved in TNF-alpha-induced apoptosis, as various antioxidants partially protected these cells from apoptosis. At last, transfection of the MnSOD cDNA in MT cells, which do not express this protein after TNF-alpha stimulation, partially restored resistance to TNF-alpha-induced cell death, as observed by clonogenic assays. However, transfection of the Bcl-X(L) cDNA did not induce any protective effect. Therefore, MnSOD expression is induced by NF-kappaB in epithelial cancer cells in response to TNF-alpha, and is at least partially responsible for their resistance to TNF-alpha-induced apoptosis, presumably through the clearance of death-inducing ROS.
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PMID:NF-kappaB-dependent MnSOD expression protects adenocarcinoma cells from TNF-alpha-induced apoptosis. 1203 30

Manganese superoxide dismutase (MnSOD) has been shown to suppress the development of cancer. Tamoxifen (TAM), a nonsteroidal anti-estrogen that is widely used in chemotherapy, is known to be a modulator of antioxidant status. However, the mechanism by which TAM mediates antioxidant enzyme induction remains unclear. In this study we investigated TAM enhancement of MnSOD induction by TNF-alpha. The results show that co-treatment with TAM and TNF-alpha increases the MnSOD promoter/enhancer driven luciferase activity, MnSOD mRNA and protein levels. Interestingly, co-treatment with TAM and TNF-alpha drastically decreases the binding activity of the p50/p50 homodimer and increases that of the p50/p65 heterodimer compared to TNF-alpha alone. This change in DNA binding could not be attributed to a decrease in the level of p50, its precursor, p105, or its inhibitors. Furthermore, TAM did not enhance degradation of IkappaB-alpha. These results suggest that p50/p50 homodimer may act as an inhibitory complex of MnSOD expression. Modulation of the DNA binding activity in favor of the p50/p65 complex may enhance NF-kappaB mediated induction of MnSOD by TAM. These findings reveal a potential novel mechanism for the induction of the human MnSOD gene.
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PMID:Tamoxifen enhancement of TNF-alpha induced MnSOD expression: modulation of NF-kappaB dimerization. 1203 62

Calorie restriction (CR) is known to delay the aging process in rodents and is postulated to act by decreasing free radical generation and increasing antioxidant enzyme activity. The present study was designed to investigate the effect of CR and age on oxidative stress-induced apoptosis and associated changes in the levels of TNF-alpha, and Bcl-2 in splenic T lymphocytes. Ad libitum (AL)- or CR-fed C57BL/6J mice were sacrificed either at 6 (young) or 18 (old) months and splenic lymphocytes were incubated with or without 25 micro M H2O2 to induce apoptosis. Apoptosis increased with age in cells of AL-fed mice incubated with H2O2. CR prevented this rise in apoptosis in total splenic lymphocytes and in CD4(+) and CD8(+) T lymphocyte subsets either with or without H2O2. Free radicals increased and mitochondrial membrane potential decreased in aged mice. CR prevented these changes and also prevented the age-associated increase in TNF-alpha and loss of Bcl-2 in total splenic lymphocytes and in CD4(+) and CD8(+) lymphocyte subsets. In summary, lymphocytes in aged AL-fed mice were much more susceptible to oxidative stress-induced apoptosis whereas CR normalized apoptosis by preventing the increase in TNF-alpha and the decrease in Bcl-2 associated with aging.
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PMID:Inhibition of H2O2-induced apoptosis of lymphocytes by calorie restriction during aging. 1242 90

Astrocytes play an important role in the homeostasis of the CNS both in normal conditions and after ischemic injury. The swelling of astrocytes is observed during and several seconds after brain ischemia. Then ischemia stimulates sequential morphological and biochemical changes in glia and induces its proliferation. Reactive astrocytes demonstrate stellate morphology, increased glial fibrillary acidic protein (GFAP) immunoreactivity, increased number of mitochondria as well as elevated enzymatic and non-enzymatic antioxidant activities. Astrocytes can re-uptake and metabolize glutamate and in this way they control its extracellular concentration. The ability of astrocytes to protect neurons against the toxic action of free radicals depends on their specific energy metabolism, high glutathione level, increased antioxidant enzyme activity (catalase, superoxide dismutase, glutathione peroxidase) and overexpression of antiapoptotic bcl-2 gene. Astrocytes produce cytokines (TNF-alpha, IL-1, IL-6) involved in the initiation and maintaining of immunological response in the CNS. In astrocytes, like in neurones, ischemia induces the expression of immediate early genes: c-fos, c-jun, fos B, jun B, jun D, Krox-24, NGFI-B and others. The protein products of these genes modulate the expression of different proteins, both destructive ones and those involved in the neuroprotective processes.
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PMID:Role of astrocytes in pathogenesis of ischemic brain injury. 1471 74

Results are presented which support the hypothesis that adequate steady-state levels of hydrogen peroxide (H2O2) are required to overcome the effects of high catalase and glutathione peroxidase (GPx) expression for p38 mitogen-activated protein (MAP) kinase activation and tumor necrosis factor (TNF)-alpha gene expression in human alveolar macrophages stimulated with asbestos. We found significant differences in the types and amounts of reactive oxygen species generated in human blood monocytes compared with human alveolar macrophages. This difference in reactive oxygen species production is related, in part, to the differences in antioxidant enzyme expression and activity. Most importantly, catalase and GPx activities were significantly increased in alveolar macrophages compared with blood monocytes. Asbestos activated the p38 MAP kinase and induced TNF-alpha gene expression only in blood monocytes. Increasing the steady-state levels of H2O2 by using polyethylene glycol superoxide dismutase, an antioxidant that crosses the cell membrane, or aminotriazole, an irreversible inhibitor of catalase, allowed the p38 MAP kinase to be activated in alveolar macrophages. In addition, asbestos-stimulated macrophages cultured with polyethylene glycol superoxide dismutase had a significant increase in gene expression mediated by the TNF-alpha promoter. These results demonstrate that high catalase and GPx activity in human alveolar macrophages limits the effectiveness of H2O2 to act as a mediator of inflammatory gene expression.
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PMID:High levels of catalase and glutathione peroxidase activity dampen H2O2 signaling in human alveolar macrophages. 1496 75


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