Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding the fundamental mechanism of apoptosis is crucial to developing therapeutic strategies for controlling apoptosis in diseased tissues. We are using model systems with relevance to cancer treatment to investigate the mechanism of apoptosis. Subtraction hybridization cloning was used to identify transcripts present at higher levels in regressing vs. normal prostate; these may be important for apoptosis. One of the genes cloned from regressing prostate is also upregulated in the murine W7.2 lymphocyte cell line induced to undergo apoptosis by treatment with the synthetic glucocorticoid, dexamethasone. This gene encodes a mu class glutathione S-transferase (EC 2.5.1.18), a protein that can protect the cell against oxidative stress by repairing oxidized lipids, proteins, and DNA. Glutathione S-transferase expression does not increase with dexamethasone treatment of lymphocyte cell lines expressing nonfunctional glucocorticoid receptors or a mutation in the apoptotic pathway. Other antioxidant defenses, including catalase (EC 1.11.1.6) and superoxide dismutase (EC 1.15.1.1), decline following dexamethasone treatment of W7.2 cells. Overexpression of the bcl-2 oncogene protects these cells against dexamethasone-mediated apoptosis and prevents the decrease in antioxidant enzyme activity. These findings support the hypothesis that control of the cellular redox state is important to the mechanism of glucocorticoid-mediated lymphocyte apoptosis. Another model system we are using is tumor necrosis factor-alpha treatment of MCF-7 human breast cancer cells. Our preliminary results suggest that, in this system, activation of nuclear factor-kappa B and increased expression of manganese superoxide dismutase may afford protection from apoptosis.
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PMID:Modulation of antioxidant defenses during apoptosis. 940 33

We report evidence of a novel mechanism by which polychlorinated biphenyls might act as potent inducers of inflammation. Aroclor 1242 (A1242), a polychlorinated biphenyl mixture, and 2,2',4,4'-tetrachlorobiphenyl (PCB47), a constituent of A1242 that produces the same patterns of effects, impaired the oxidative burst of human neutrophils by inhibiting the antioxidant enzyme superoxide dismutase, which converts O2- to H2O2. Pre-incubation of neutrophils with A1242 or PCB47 before stimulation with phorbol 12-myristate 13-acetate heightened the respiratory burst, producing a significant increase in intracellular O2- production along with a significant decrease in H2O2 production compared with unexposed agonist-stimulated neutrophils. This was also evident in a physiologically relevant situation in which neutrophils pre-incubated with A1242 were subsequently stimulated with a combination of N-formyl-L-methionyl-L-leucyl-L-phenylalanine and tumor necrosis factor-alpha. Incubation of bovine copper-zinc superoxide dismutase (EC 1.15.1.1) with A1242 or PCB47 in a cell-free system reversed the enzyme-mediated inhibition of 6-hydroxydopamine autoxidation, indicating that polychlorinated biphenyls inhibited superoxide dismutase activity. Low superoxide dismutase activity in neutrophils leads to imbalances between production of free radicals and antioxidant defense mechanisms, which can in turn induce tissue damage and hasten the onset of neutrophil apoptosis.
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PMID:Impairment of human neutrophil oxidative burst by polychlorinated biphenyls: inhibition of superoxide dismutase activity. 946 80

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

Asbestos exposure in humans is associated with inflammatory, fibrotic, and malignant diseases in the lung. Increasing evidence supports the hypothesis that the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNFalpha) is an important mediator of the pathologic responses of asbestosis. In this study, we examine the role of nuclear transcription factor-kappaB (NF-kappaB) and free oxygen radicals in asbestos-induced TNFalpha gene and protein expression in lung macrophages. Exposure of the cells to crocidolite asbestos caused a parallel increase in TNFalpha production and NF-kappaB activation, as analyzed by enzyme-linked immunosorbent assay and electrophoretic mobility shift assay. Inhibition of NF-kappaB by SN50, an inhibitor of NF-kappaB nuclear translocation, or by sequence-specific oligonucleotides directed against the NF-kappaB binding site of TNFalpha promoter attenuated the asbestos effect on TNFalpha production. Gene transfection assays using an expression plasmid containing a luciferase reporter gene and a TNFalpha-derived NF-kappaB gene promoter further indicated the dependence of NF-kappaB activation on asbestos-induced gene expression. The effects of asbestos on NF-kappaB and TNFalpha activation were inhibited by oxygen radical scavengers and were enhanced by antioxidant enzyme inhibitors. These results indicate that asbestos-induced TNFalpha gene expression is mediated through a process that involves NF-kappaB activation and free radical reactions.
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PMID:Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages. 1048 38

The transcription factor nuclear factor kappaB (NF-kappaB) is moving to the forefront of the fields of apoptosis and neuronal plasticity because of recent findings showing that activation of NF-kappaB prevents neuronal apoptosis in various cell culture and in vivo models and because NF-kappaB is activated in association with synaptic plasticity. Activation of NF-kappaB was first shown to mediate antiapoptotic actions of tumor necrosis factor in cultured neurons and was subsequently shown to prevent death of various nonneuronal cells. NF-kappaB is activated by several cytokines and neurotrophic factors and in response to various cell stressors. Oxidative stress and elevation of intracellular calcium levels are particularly important inducers of NF-kappaB activation. Activation of NF-kappaB can interrupt apoptotic biochemical cascades at relatively early steps, before mitochondrial dysfunction and oxyradical production. Gene targets for NF-kappaB that may mediate its antiapoptotic actions include the antioxidant enzyme manganese superoxide dismutase, members of the inhibitor of apoptosis family of proteins, and the calcium-binding protein calbindin D28k. NF-kappaB is activated by synaptic activity and may play important roles in the process of learning and memory. The available data identify NF-kappaB as an important regulator of evolutionarily conserved biochemical and molecular cascades designed to prevent cell death and promote neuronal plasticity. Because NF-kappaB may play roles in a range of neurological disorders that involve neuronal degeneration and/or perturbed synaptic function, pharmacological and genetic manipulations of NF-kappaB signaling are being developed that may prove valuable in treating disorders ranging from Alzheimer's disease to schizophrenia.
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PMID:Roles of nuclear factor kappaB in neuronal survival and plasticity. 1064 95

Evidence from a number of studies suggests that the mechanism by which tumor necrosis factor (TNF) kills transformed cells involves oxidative stress. NAD(P)H:(quinone acceptor) oxidoreductase (NQO1) is an antioxidant enzyme with particular relevance to cancer. The MCF-7 breast cancer cell line was stably transfected with rat NQO1 cDNA to determine whether increased NQO1 activity alters sensitivity to TNF-induced apoptosis. Five clones, with a range of NQO1 enzyme activities from 5- to 50-fold greater than the MCF-7 line, and two control transfectants were examined. Northern blot hybridization analyses and reverse transcription-PCR demonstrated that the increase in NQO1 activity in the transfectants was attributable to expression from the transfected rat sequence. Based on sulforhodamine B assays for the number of viable cells, the NQO1 clones showed increased sensitivity to EO9, an indoloquinone that undergoes bioactive reduction by NQO1. Viability studies also demonstrated that the NQO1 transfectants were significantly more sensitive to TNF than the control transfectants or MCF-7 parent. This increased sensitivity could not be explained by changes in superoxide dismutase or catalase activity or to increased sensitivity to oxidative stress in general, as assessed by response to hydrogen peroxide and paraquat treatment. Using dichlorodihydrofluorescein diacetate as a probe, we found that the NQO1 transfectants had no difference in baseline level of oxidative stress compared to the control cells but did exhibit greater intracellular oxidative stress after TNF treatment. We conclude that NQO1 can affect the TNF-mediated pathway to apoptosis.
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PMID:Increased tumor necrosis factor-alpha sensitivity of MCF-7 cells transfected with NAD(P)H:quinone reductase. 1091 79

The life-prolonging effects of calorie restriction (CR) may be due to reduced damage from cumulative oxidative stress. Our goal was to determine the long-term effects of moderate dietary CR on the myocardial response to reperfusion after a single episode of sublethal ischemia. Male Fisher 344 rats were fed either an ad libitum (AL) or CR (40% less calories) diet. At age 12 mo the animals were anaesthetized and subjected to thoracotomy and a 15-min left-anterior descending coronary artery occlusion. The hearts were reperfused for various periods. GSH and GSSG levels, nuclear factor-kappaB (NF-kappaB) DNA binding activity, cytokine, and antioxidant enzyme expression were assessed in the ischemic zones. Sham-operated animals served as controls. Compared with the AL diet, chronic CR limited oxidative stress as seen by rapid recovery in GSH levels in previously ischemic myocardium. CR reduced DNA binding activity of NF-kappaB. The kappaB-responsive cytokines interleukin-1beta and tumor necrosis factor-alpha were transiently expressed in the CR group but persisted longer in the AL group. Furthermore, expression of manganese superoxide dismutase, a key antioxidant enzyme, was significantly delayed in the AL group. Collectively these data indicate that CR significantly attenuates myocardial oxidative stress and the postischemic inflammatory response.
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PMID:Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury. 1129 11

Hydrogen peroxide (H(2)O(2)) is present in the atmosphere at concentrations known to induce cell and tissue damage. However, inhaled H(2)O(2) vapor should not reach the lower lung due to its high water solubility. It has been suggested that hygroscopic components of particulate matter (PM) may transport H(2)O(2) into the lower lung and induce tissue injury and this was investigated. Ammonium sulfate [(NH(4))(2)SO(4)] was selected as a model for fine atmospheric PM. Treatment of female Sprague-Dawley rats with (NH(4))(2)SO(4) (429 or 215 microg/m(3); 0.3-0.4 microm mass median diameter) or H(2)O(2) (10, 20, or 100 ppb) alone or in combination for 2 h had no major effect on bronchoalveolar lavage fluid cell number or viability or on protein content or lactate dehydrogenase levels, either immediately or 24 h after exposure, relative to air-exposed rats. However, electron microscopy revealed increased numbers of neutrophils in pulmonary capillaries adhered to the vascular endothelium in rats treated with the combination of (NH(4))(2)SO(4) + H(2)O(2). Exposure of rats to (NH(4))(2)SO(4) + H(2)O(2) also resulted in tumor necrosis factor-alpha (TNF-alpha) production by alveolar macrophages. This was observed immediately and 24 h after exposure. Immediately after inhalation of (NH(4))(2)SO(4) + H(2)O(2), a transient increase in production of superoxide anion by alveolar macrophages was observed. In contrast, nitric oxide production by cells from rats exposed to (NH(4))(2)SO(4) + H(2)O(2) or H(2)O(2) alone was decreased, and this persisted for 24 h. Decreases in nitric oxide may be due to superoxide anion-driven formation of peroxynitrite. In this regard, nitrotyrosine, an in vivo marker of peroxynitrite, was detected in lung tissue after exposure of rats to (NH(4))(2)SO(4) + H(2)O(2) or H(2)O(2). We also found that expression of the antioxidant enzyme heme oxygenase-1 by stimulated alveolar macrophages was increased following exposure of rats to (NH(4))(2)SO(4) + H(2)O(2). Taken together, these studies demonstrate that the biological effects of inhaled fine PM are augmented by H(2)O(2). Moreover, tissue injury induced by fine PM may be related to altered production of cytotoxic mediators by alveolar macrophages.
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PMID:Tissue injury following inhalation of fine particulate matter and hydrogen peroxide is associated with altered production of inflammatory mediators and antioxidants by alveolar macrophages. 1174 18

Past studies including our own have confirmed that chronic administration of deprenyl can prolong life spans of at least four different animal species. Pretreatment with the drug for several weeks increases activities of superoxide dismutase (SOD) and catalase (CAT) in selective brain regions. An up-regulation of antioxidant enzyme activities can also be induced in organs such as the heart, kidney, spleen, and adrenal gland, and all are accompanied by an increase in mRNA levels for SODs in these organs. The effect of deprenyl on enzyme activities has a dose-effect relationship of a typical inverted U shape. A similar inverted U shape also has emerged for the drug's effect on survival of animals. An apparent parallelism observed between these two effects of the drug seems to support our contention that the up-regulation of antioxidant enzymes is at least partially responsible for the life-prolonging effect on animals. Further, when a clinically applied dose of the drug for patients with Parkinson's disease was given to monkeys, SOD and CAT activities were increased in striatum of these monkeys, which suggests potential for the drug's applicability to humans. The drug was also found to increase concentrations of cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in the above rat organs. Together with past reports demonstrating that deprenyl increases natural killer (NK) cell functions and interferon-gamma, and prevents the occurrence of malignant tumors in rodents and dogs, the mobilization of these humoral factors may therefore be included as possible mechanisms of action of deprenyl for its diverse antiaging and life-prolonging effects. The potentials of propargylamines, (-)deprenyl in particular, for human use as antiaging drugs remain worthy of exploration in the future.
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PMID:Pharmacological interventions in aging and age-associated disorders: potentials of propargylamines for human use. 1197 4


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