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)

Dose intensity is emerging as a crucial determinant of success in cytotoxic cancer therapy; however, myelosuppression presents as one of the major complications encountered with increased dose intensity. Therefore, investigators are looking at the use of cytokine administration in combination with cytotoxic therapy to overcome this problem. Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) have been shown to be beneficial in protecting the hematopoietic system from radiation and chemotherapy. In this report, we give an overview of studies using IL-1 and TNF-alpha as protective agents and discuss possible mechanisms involved in their protective action. Mice pretreated with IL-1 and/or TNF-alpha were shown to be protected from the lethal effects of radiation and it has been suggested that the mechanism for this protection may be through the production of the antioxidant enzyme manganese superoxide dismutase. Similarly, aldehyde dehydrogenase, an enzyme important in the metabolic pathway of cyclophosphamide compounds, has been implicated as being important in the protection of hematopoietic cells from 4-hydroperoxycyclophosphamide. While IL-1 and TNF-alpha stimulate both of these enzymes, other mechanisms are probably also operative for other forms of chemotherapy, i.e. IL-1 and TNF-alpha were shown to protect hematopoietic progenitors from phenylketophosphamide, a cyclophosphamide derivative that is not metabolized by the enzyme aldehyde dehydrogenase. Furthermore, malignant as well as normal cells may possess receptors for these cytokines; therefore, IL-1 and TNF-alpha will have to be selective in their protection. They must be capable of protecting normal hematopoietic cells while rendering malignant cells susceptible to the toxic actions of the chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The therapeutic potential of interleukin-1 and tumor necrosis factor on hematopoietic stem cells. 129 Sep 56

Reactive oxygen species have been implicated as mediators of tissue injury in glomerular inflammation. The expression of the antioxidant enzyme, manganese superoxide dismutase (MnSOD), was examined in primary cultures of rat glomerular epithelial cells (GEC) in response to inflammatory mediators. The results demonstrate that GEC respond to interleukin-1 (IL-1) and bacterial lipopolysaccharride (LPS) with an increase in MnSOD steady-state mRNA levels. The IL-1 alpha-mediated induction of MnSOD mRNA levels was both time- and dose-dependent. Maximal levels approximately 40-fold above controls, were observed at 12 hours with 2 ng/ml of IL-1 alpha. MnSOD protein levels were also markedly elevated by IL-1 alpha. The induction of MnSOD mRNA by IL-1 alpha required de novo transcription as well as some degree of protein synthesis. To elucidate the potential intracellular signal that mediates IL-1 alpha-dependent MnSOD expression, three classical signaling pathways were examined. We found no evidence that MnSOD induction by IL-1 alpha is mediated by either the cyclooxygenase or lipoxygenase pathway or via activation of protein kinase C. Based on the presence of IL-1 alpha in several forms of glomerular inflammation, the observed increase in MnSOD expression by this immunoregulatory cytokine must have an important role in the antioxidant defense of glomerular epithelial cells.
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PMID:Regulation of manganese superoxide dismutase in glomerular epithelial cells: mechanisms for interleukin 1 induction. 756 2

To determine whether non-hematologic tumors influence the bone marrow's antioxidant enzyme response to the radioprotective cytokine interleukin 1 alpha (IL-1), studies were undertaken using BDF1 and Balb/c mice bearing small, medium or large Lewis lung carcinoma (LLCa) or EMT6 mammary carcinoma tumors, respectively. Results demonstrated that, similar to nontumor-bearing mice, treatment of tumor-bearing animals with IL-1 was associated with a significant increase in marrow MnSOD activity. However, the duration of this elevated activity was reduced as tumor burden increased, and this reduction may have an impact on IL-1's ability to radioprotect tumor bearing animals, especially when tumor burden is large. In addition to cytokine-mediated responses, significant tumor-related influences on the marrow's antioxidant enzyme status were seen. Notably, it was observed that the presence of tumor was correlated with a marked suppression of antioxidant enzyme activity. Surprisingly, however, the pattern of enzyme suppression was found to differ between the two tumor models studied both in temporal onset and in the number of enzymes involved. In conclusion, the data obtained from these studies on tumor-bearing animals demonstrate that there are both cytokine-related and tumor-related influences which can effect the antioxidant enzyme status of the hematopoietic marrow-influences which may have the potential to alter the marrow's ability to tolerate free radical-generating events, both endogenous (i.e inflammation, infection) and exogenous (i.e. radiation, certain chemotherapeutic drugs) in origin.
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PMID:Antioxidant enzyme activity in murine hematopoietic bone marrow following treatment with interleukin 1 alpha: influence of tumor. 921 82

Inflammatory cytokines have been shown to upregulate secretion of the antioxidant enzyme extracellular superoxide dismutase (EC-SOD) in dermal fibroblasts and, in other cells, to stimulate production of nitric oxide (.NO). Because superoxide rapidly scavenges .NO, forming the injurious peroxynitrite anion (OONO-), we hypothesize that stimulated cells upregulate EC-SOD expression concurrently with .NO release. To test for coregulation of EC-SOD and .NO within the same cell, the timing of inducible nitric oxide synthase (iNOS) and EC-SOD transcription was measured after exposure of a rate type II pneumocyte analog, the L2 cell line, to a combination of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Upregulation of iNOS and EC-SOD transcription occurred after 6 h of exposure, and transcription of both genes was linked by activation of the transcription factor nuclear factor-kappa B. Both EC-SOD and iNOS were elevated in rat lung homogenates 24 h after intratracheal instillation with IFN-gamma and TNF-alpha. The observation that EC-SOD and iNOS are temporally coregulated after cytokine exposure suggests the possibility of a critical mechanism by which cells might protect .NO and avoid the formation of OONO- during inflammation.
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PMID:Extracellular superoxide dismutase is upregulated with inducible nitric oxide synthase after NF-kappa B activation. 937 27

Apoptosis has been documented as a fundamental component of the life cycle of many cell types. One of the characteristics of this process is the cleavage of genomic DNA into oligonucleosomal fragments. The multifunctional cytokine TGF-beta 1 has been described to induce apoptosis in cultured hepatocytes although in this condition DNA fragmentation has not been detected. We investigated whether TGF-beta 1-induced apoptosis was associated with DNA fragmentation and was affected by PMA. Agarose gel electrophoresis of TGF-beta 1-treated hepatocytes shows a typical ladder-like pattern of DNA fragments and PMA, a selective stimulator of protein kinase C, diminishes the DNA fragmentation and cell death. It has been described that the antioxidant enzyme systems play an important role in the control of apoptosis and that the apoptogenic ability of TGF-beta 1 is through the inhibition of antioxidant enzyme expression in cultured hepatocytes [8]. However, PMA does not induce significant changes levels of manganese superoxide dismutase, copper-zinc superoxide dismutase and catalase mRNAs. Our data reveal that the attenuation of TGF-beta 1-induced DNA fragmentation by PMA is not associated with changes in the expression of antioxidant systems and is probably due selectively to the stimulation of protein kinases C.
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PMID:Effect of phorbol ester (PMA) on antioxidant enzyme expression in TGF-beta 1-induced apoptosis in primary cultures of hepatocytes. 969 11

Thioredoxin, thioredoxin reductase and NADPH, the thioredoxin system, is ubiquitous from Archea to man. Thioredoxins, with a dithiol/disulfide active site (CGPC) are the major cellular protein disulfide reductases; they therefore also serve as electron donors for enzymes such as ribonucleotide reductases, thioredoxin peroxidases (peroxiredoxins) and methionine sulfoxide reductases. Glutaredoxins catalyze glutathione-disulfide oxidoreductions overlapping the functions of thioredoxins and using electrons from NADPH via glutathione reductase. Thioredoxin isoforms are present in most organisms and mitochondria have a separate thioredoxin system. Plants have chloroplast thioredoxins, which via ferredoxin-thioredoxin reductase regulates photosynthetic enzymes by light. Thioredoxins are critical for redox regulation of protein function and signaling via thiol redox control. A growing number of transcription factors including NF-kappaB or the Ref-1-dependent AP1 require thioredoxin reduction for DNA binding. The cytosolic mammalian thioredoxin, lack of which is embryonically lethal, has numerous functions in defense against oxidative stress, control of growth and apoptosis, but is also secreted and has co-cytokine and chemokine activities. Thioredoxin reductase is a specific dimeric 70-kDa flavoprotein in bacteria, fungi and plants with a redox active site disulfide/dithiol. In contrast, thioredoxin reductases of higher eukaryotes are larger (112-130 kDa), selenium-dependent dimeric flavoproteins with a broad substrate specificity that also reduce nondisulfide substrates such as hydroperoxides, vitamin C or selenite. All mammalian thioredoxin reductase isozymes are homologous to glutathione reductase and contain a conserved C-terminal elongation with a cysteine-selenocysteine sequence forming a redox-active selenenylsulfide/selenolthiol active site and are inhibited by goldthioglucose (aurothioglucose) and other clinically used drugs.
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PMID:Physiological functions of thioredoxin and thioredoxin reductase. 1101 61

Manganese-superoxide dismutase (Sod2) removes mitochondrially derived superoxide (O(2)) at near-diffusion limiting rates and is the only antioxidant enzyme whose expression is regulated by numerous stimuli. Here it is shown that Sod2 also serves as a source of the intracellular signaling molecule H(2)O(2). Sod2-dependent increases in the steady-state levels of H(2)O(2) led to ERK1/2 activation and subsequent downstream transcriptional increases in matrix metalloproteinase-1 (MMP-1) expression, which were reversed by expression of the H(2)O(2)-detoxifying enzyme, catalase. In addition, a single nucleotide polymorphism has recently been identified (1G/2G) at base pair--1607 that creates an Ets site adjacent to an AP-1 site at base pair --1602 and has been shown to dramatically enhance transcription of the MMP-1 promoter. Luciferase promoter constructs containing either the 1G or 2G variation were 25- or 1000-fold more active when transiently transfected into Sod2-overexpressing cell lines, respectively. The levels of MMP-2, -3, and -7 were also increased in the Sod2-overexpressing cell lines, suggesting that Sod2 may function as a "global" redox regulator of MMP expression. In addition, Sod2(-/+) mouse embryonic fibroblasts failed to respond to the cytokine-mediated induction of the murine functional analog of MMP-1, MMP-13. This study provides evidence that the modulation of Sod2 activity by a wide array of pathogenic and inflammatory stimuli may be utilized by the cell as a primary signaling mechanism leading to matrix metalloproteinase expression.
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PMID:Manganese superoxide dismutase signals matrix metalloproteinase expression via H2O2-dependent ERK1/2 activation. 1129 30

The generation of reactive oxygen species (free radicals) is an important factor in the development and maintenance of rheumatoid arthritis in humans and animal models. One source of free radicals is nitric oxide produced within the synoviocytes and chondrocytes and giving rise to the highly toxic radical peroxynitrite. Several cytokines, including tumour necrosis factor-alpha (TNFalpha) are involved in the formation of free radicals, partly by increasing the activity of nitric oxide synthase. Indeed, nitric oxide may mediate some of the deleterious effects of cytokines on bone resorption. Aspirin, tetracyclines, steroids and methotrexate can suppress nitric oxide synthase. Dietary antioxidants include ascorbate and the tocopherols and beneficial effects of high doses have been reported especially in osteoarthritis. There is also evidence for beneficial effects of beta-carotene and selenium, the latter being a component of the antioxidant enzyme glutathione peroxidase. The polyunsaturated fatty acids (PUFA) include the n-3 compounds, some of which are precursors of eicosanoid synthesis, and the n-6 group which can increase formation of the pro-inflammatory cytokines TNFalpha and interleukin-6, and of reactive oxygen species. Some prostaglandins, however, suppress cytokine formation, so that n-3 PUFA often oppose the inflammatory effects of some n-6-PUFA. gamma-linolenic acid (GLA) is a precursor of prostaglandin E1, a fact which may account for its reported ability to ameliorate arthritic symptoms. Fish oil supplements, rich in n-3 PUFA such as eicosapentaenoic acid have been claimed as beneficial in rheumatoid arthritis, possibly by suppression of the immune system and its cytokine repertoire. Some other oils of marine origin (e.g. from the green-lipped mussel) and a range of vegetable oils (e.g. olive oil and evening primrose oil) have indirect anti-inflammatory actions, probably mediated via prostaglandin E1. Overall, there is a growing scientific rationale for the use of dietary supplements as adjuncts in the treatment of inflammatory disorders such as rheumatoid arthritis and osteoarthritis.
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PMID:Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. 1129 72

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

Reactive oxygen species (ROS) are known mediators of intracellular signaling cascades. Excessive production of ROS may, however, lead to oxidative stress, loss of cell function, and ultimately apoptosis or necrosis. A balance between oxidant and antioxidant intracellular systems is hence vital for cell function, regulation, and adaptation to diverse growth conditions. Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous oxidoreductase system with antioxidant and redox regulatory roles. In mammals, extracellular forms of Trx also have cytokine-like effects. Mammalian TrxR has a highly reactive active site selenocysteine residue resulting in a profound reductive capacity, reducing several substrates in addition to Trx. Due to the reactivity of TrxR, the enzyme is inhibited by many clinically used electrophilic compounds including nitrosoureas, aurothioglucose, platinum compounds, and retinoic acid derivatives. The properties of TrxR in combination with the functions of Trx position this system at the core of cellular thiol redox control and antioxidant defense. In this review, we focus on the reactions of the Trx system with ROS molecules and different cellular antioxidant enzymes. We summarize the TrxR-catalyzed regeneration of several antioxidant compounds, including ascorbic acid (vitamin C), selenium-containing substances, lipoic acid, and ubiquinone (Q10). We also discuss the general cellular effects of TrxR inhibition. Dinitrohalobenzenes constitute a unique class of immunostimulatory TrxR inhibitors and we consider the immunomodulatory effects of dinitrohalobenzene compounds in view of their reactions with the Trx system.
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PMID:Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. 1172 1


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