UNIPROT:P30044 - FACTA Search

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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

Bacterial endotoxin has been shown to protect rats from lethal hyperoxia. The structure of endotoxin contains diphosphoryl lipid A (DPL) as the lipid backbone stripped of protein and polysaccharides. DPL is the component of the endotoxin molecule that has been demonstrated (in previous studies) to be responsible for the immunologic, mitogenic, pyrogenic, and lethal properties of endotoxin. Monophosphoryl lipid A (MPL) is a nonpyrogenic, nontoxic modification of the DPL molecule that retains its immunostimulatory and mitogenic properties. We hypothesized that DPL may be the actual active component of endotoxin that protects rats from lethal hyperoxia. We also hypothesized that the protection from hyperoxia that is afforded by the DPL component may be related to endogenous release of tumor necrosis factor alpha which should allow MPL to also be protective. To test these hypotheses, we performed a series of experiments in which rats were treated with endotoxin, DPL, MPL or vehicle and exposed to room air or hyperoxia. We found that DPL and endotoxin both protected rats from lethal hyperoxia, but MPL alone was not protective. Even though MPL was not protective, DPL and MPL both increased endogenous release of tumor necrosis factor alpha early after injection (peak DPL level, 3619 +/- 1500 pg/ml, peak MPL level, 4038 +/- 500 pg/ml). Protection in both the endotoxin- and DPL-treated animals was associated with increases in lung antioxidant enzyme activities. We concluded that DPL protect rats from hyperoxia but that MPL is not protective in spite of its immunostimulatory and mitogenic effects.
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PMID:Diphosphoryl lipid A protects rats from lethal hyperoxia. 151 89

The levels of the antioxidant enzyme manganese superoxide dismutase (Mn-SOD) are frequently decreased in tumor cells and increased in normal cells upon treatment with ionizing radiation. We studied Mn-SOD at different stages during the neoplastic conversion of radiation-initiated Syrian hamster embryo HDR-3 cells. Mn-SOD activity and the concentration of Mn-SOD protein and mRNA increased gradually during the malignant transformation of HDR-3 cells after radiation exposure; fully neoplastic cells showed greater Mn-SOD levels than preneoplastic and normal 84-3 cells. Inhibitors of superoxide (SO) anion production (thenoyltrifluoroacetone and rotenone) decreased the concentration of Mn-SOD mRNA, raising the possibility that the generation of SO radicals participated in the upregulation of Mn-SOD in cells transformed by exposure to radiation. We observed an increase in the concentration of tumor necrosis factor alpha (TNF alpha) in HDR-3 cells relative to mock-irradiated cells. Together with the observation that TNF alpha stimulates the production of SO by mitochondria and increases the level of Mn-SOD mRNA in other experimental systems, our results suggest that as normal 84-3 cells undergo malignant transformation induced by ionizing radiation they produce TNF alpha, to which the cells respond by increasing the concentration of Mn-SOD mRNA and protein and the activity of the enzyme.
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PMID:Increased manganese superoxide dismutase activity, protein, and mRNA levels and concurrent induction of tumor necrosis factor alpha in radiation-initiated Syrian hamster cells. 898 10

Leukocyte aggregation and activation on endothelial cells (EC) are important preliminary events in leukocyte migration into tissue and subsequent inflammation. Thus, an increase in leukocyte adherence has the potential to affect inflammatory disease outcome. Selenium (Se) is an integral part of the antioxidant enzyme glutathione peroxidase (GSH-Px) and plays an important role in the maintenance of the redox state of a cell. Se supplementation in the bovine has been shown to improve the outcome of acute mastitis caused by coliform bacteria, in part by enhancing the speed of neutrophil migration into the affected mammary gland. However, the mechanisms by which Se modulates neutrophil migration have not been elucidated. Therefore, an in vitro model of Se deficiency in primary bovine mammary artery EC was used to examine the impact of Se status on the adhesive properties of EC. The effect of Se on functional activities was examined by measuring neutrophil adherence to Se-deficient and Se-supplemented EC. Se-deficient EC showed significantly enhanced neutrophil adherence when stimulated with tumor necrosis factor alpha (TNF-alpha) for 4 or 24 h, interleukin-1 for 12 h, or H2O2 for 20 min (P < 0.05). To determine the mechanisms underlying these changes in neutrophil adherence, the expression of EC adhesion molecules, ICAM-1, E-selectin, and P-selectin were examined at the molecular level by a competitive reverse transcription-polymerase chain reaction. Results revealed higher mRNA expression for E-selectin and ICAM-1 in Se-deficient EC stimulated with TNF-alpha for 3 and 6 h, and greater expression of P-selectin mRNA in Se-supplemented EC with 3-h TNF-alpha stimulation. These studies provide new information to establish the role of Se nutrition in the initiation of leukocyte adherence to endothelium.
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PMID:Increased neutrophil adherence and adhesion molecule mRNA expression in endothelial cells during selenium deficiency. 1033 95

15-deoxy-Delta(12,14)-PGJ(2), a cyclopentenone derivative of PGD(2), was recently reported [Petrova et al., Proc. Natl. Acad. Sci. USA 96 (1999) 4668-4673] to suppress inducible nitric oxide synthase (iNOS) production in microglia and mixed glial cultures stimulated with lipopolysaccharide (LPS). We report here that in addition to suppressing iNOS production, 15d-PGJ(2) also decreases the production of tumor necrosis factor alpha (TNFalpha), interleukin-1 beta (IL-1beta) and cyclooxygenase-2 (COX-2) in LPS-stimulated BV-2 microglial cells, thereby acting as a general inhibitor of microglial activation. Concomitantly, 15d-PGJ(2) itself up-regulates the production of the antioxidant enzyme heme oxygenase-1 (HO-1) and increases intracellular total glutathione levels. To test if increased HO-1 levels were involved in the ability of 15d-PGJ(2) to block microglial activation, we used a HO-1 inhibitor that could block the activity of HO-1. The presence of the HO-1 inhibitor did not alter the 15d-PGJ(2)-induced inhibition of LPS-stimulated iNOS and TNFalpha protein levels, and led to only a partial reduction in the protection offered by 15d-PGJ(2) against LPS-induced nitrite production. These results suggest that HO-1 upregulation by 15d-PGJ(2) is not the primary pathway responsible for the anti-inflammatory action of 15d-PGJ(2) in microglial cells.
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PMID:Cyclopentenone prostaglandin 15-deoxy-Delta(12,14)-prostaglandin J(2) acts as a general inhibitor of inflammatory responses in activated BV-2 microglial cells. 1083 4

Evidence has accumulated for a role of toxic oxygen radicals in the pathogenesis of ischemia-reperfusion injury in the kidney. The aim of this study was to evaluate the hypothesis that reducing postischemic renal injury is possible by delivery of the gene for the antioxidant enzyme superoxide dismutase (SOD). Female Sprague-Dawley rats received intravenous injections of recombinant adenovirus (1 x 10(9) pfu) containing the transgenes for Escherichia coli beta-galactosidase (Ad-LacZ, as control) or human Cu/Zn-SOD (Ad-SOD). Three days later, renal ischemia was produced by cross-clamping the left renal vessels for 60 min. The right kidney was removed before reperfusion and processed for the transgene. Renal SOD protein and activity in rats given Ad-SOD was 2.5-fold higher than from the animals receiving Ad-LACZ: Urinary lactate dehydrogenase concentrations were elevated by ischemia-reperfusion in the Ad-LacZ group (1403 +/- 112 U/L), yet values were 50% lower in Ad-SOD-treated rats. Free radical production was elevated by ischemia-reperfusion but was significantly lower in SOD-treated animals. Importantly, on postischemic day 1, glomerular filtration rates were reduced to 0.21 ml/min per 100 g in the Ad-LacZ group, whereas values remained significantly higher (0.39) in the Ad-SOD group. Two weeks after ischemia-reperfusion, inflammation, interstitial fibrosis, tubular atrophy and tissue levels of tumor necrosis factor alpha and interleukin-1 were significantly higher in the Ad-LacZ-treated than in Ad-SOD-treated rats. In conclusion, these results indicate that SOD expression can be increased by delivery of the sod gene to the kidney by intravenous injection and that sod gene transduction minimized ischemia-reperfusion-induced acute renal failure.
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PMID:Cu/Zn-superoxide dismutase gene attenuates ischemia-reperfusion injury in the rat kidney. 1172 38

Epidemiologists have observed a positive association between human morbidity and mortality and the atmospheric concentrations of fine particulate matter (PM), but the mechanisms underlying the toxic effects of PM have not been elucidated. Various components of ambient PM have been implicated in toxicity (including ultrafine particles, transition metals, organics and oxidants). Our research focused on hydrogen peroxide (H2O2). We speculated that fine PM transports H2O2 into the lower lung, leading to tissue injury and to accumulation and activation of macrophages in these regions. The macrophages release cytotoxic mediators and proinflammatory cytokines that contribute to the pathogenesis of tissue injury. To test this hypothesis, we conducted studies to determine (1) whether tissue injury induced by aerosols is mediated by cytotoxic H2O2 carried into the lower lung by fine particles and (2) whether exposure of rats to fine PM leads to accumulation of activated macrophages in the lung. For our studies, systems were designed to generate model atmospheric fine PM and atmospheric peroxides consisting of an ammonium sulfate [(NH4)2SO4] aerosol (mass median diameter, 0.46 +/- 0.14 microm) and H2O2. We also constructed a 6-port nose-only exposure chamber. Female Sprague Dawley rats were exposed for 2 hours to aerosols consisting of (NH4)2SO4 (430 microg/m3), (NH4)2SO4 + 10, 20 or 100 ppb H2O2, vapor-phase H2O2 (10, 20 or 100 ppb), or particle-free air. Studies using oxygen-18 (18O)-labeled H2O2 were conducted to validate the transport of H2O2 into the lower lung with (NH4)2SO4. Rats were killed immediately (0 hours) or 24 hours after exposure. Compared with control animals, inhalation of (NH4)2SO4 and H2O2, alone or in combination, had no major effect on cell number or viability, protein content, or lactate dehydrogenase (LDH) levels in bronchoalveolar lavage (BAL) fluid collected either immediately or 24 hours after exposure. However, electron microscopy revealed that a larger number of neutrophils in pulmonary capillaries adhered to the vascular endothelium, especially in lungs of rats exposed to (NH4)2SO4 + H2O2. Inhalation of (NH4)2SO4 + H2O2 was also found to be associated with altered macrophage functional activity. Thus, exposing rats to (NH4)2SO4 + 20 ppb H2O2 or 20 ppb H2O2 alone caused a level of tumor necrosis factor alpha (TNF-alpha) production by lung macrophages that was higher than in controls. This higher level was observed immediately after exposure and persisted for at least 24 hours. Greater TNF-alpha production was also detected 24 hours after exposure to (NH4)2SO4 + 10 ppb H2O2. Immediately after rats inhaled (NH4)2SO4 + 10 ppb H2O2 or 20 ppb H2O2 alone, we also observed a transiently higher production of superoxide anion (O2-) by alveolar macrophages. Macrophages isolated 24 hours after exposure to 20 ppb H2O2 also produced larger quantities of superoxide anion. In contrast, immediately after exposure, macrophages from rats exposed to (NH4)2SO4 + 10 ppb H2O2 or to 20 ppb H2O2 alone generated less nitric oxide (NO). Reduced nitric oxide production was also observed 24 hours after exposure to (NH4)2SO4 + 10 ppb H2O2 or to 10 or 20 ppb H2O2 alone. Reduced nitric oxide production may have been due to superoxide anion-driven formation of peroxynitrite (ONOO-) anions. In this regard, nitrotyrosine, an in vivo marker of peroxynitrite, was detected in lung tissue immediately after rats were exposed to (NH4)2SO4 + H2O2 or to H2O2 alone (10 or 20 ppb). We also found that alveolar macrophages from rats exposed to (NH4)2SO4 + H2O2 showed a greater expression of the antioxidant enzyme heme oxygenase-1 (HO-1) when stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Similar results were observed after exposure of rats to an organic peroxide aerosol (cumene hydroperoxide). Taken together, the results of our studies demonstrate that biological effects of inhaled H2O2 are augmented by fine PM. Moreover, tissue injury induced by (NH4)2SO4 + H2O2 may be related to altered production of cytotoxic mediators by alveolar macrophages. Determining the relevance of these toxicologic results to human health will be important in future studies for evaluating the risk of exposure.
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PMID:Peroxides and macrophages in the toxicity of fine particulate matter in rats. 1503 94

Thioredoxin reductase (TrxR) is a selenoprotein that catalyzes the reduction of the active site disulfide of thioredoxin (Trx), which regulates the redox status of the cells. In the present study, we found that TrxR1, one of the three TrxR isozymes, was induced by cadmium as well as tumor necrosis factor alpha (TNFalpha) in bovine arterial endothelial cells (BAEC), and investigated the mechanism of cadmium-induced TrxR1 expression. We here showed that cadmium, differently from TNFalpha, enhanced the promoter activity of the 5'-flanking region of human TrxR1 gene (nucleotides -1692 to +49). Deletion and site-directed mutation of antioxidant responsive element (ARE) (nucleotides -62 to -48) in this region abolished the response to cadmium. Overexpression of NF-E2-related factor-2 (Nrf2) augmented the TrxR1 promoter activity. In contrast, overexpression of the dominant negative mutant of Nrf2 suppressed cadmium-induced activation of TrxR1 promoter through the ARE. Chromatin immunoprecipitation (ChIP) assays showed that anti-Nrf2 antibody precipitated ARE from the chromatin of the cadmium-treated cells. These results indicated that cadmium-induced TrxR1 gene expression is mediated by the activation of Nrf2 transcription factor and its binding to ARE in the TrxR1 gene promoter. We further found that in addition to cadmium, the activators of Nrf2, such as diethyl maleate (DEM) and arsenite, induced both TrxR1 and Trx gene expression in BAEC. Nrf2 might play an important role in the regulation of the cellular Trx system consisting of Trx and TrxR.
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PMID:Transcriptional regulation of thioredoxin reductase 1 expression by cadmium in vascular endothelial cells: role of NF-E2-related factor-2. 1552 Oct 73

Expression of manganese superoxide dismutase (MnSOD), a nuclear-encoded mitochondrial primary antioxidant enzyme, is protective against various paradigms of oxidative stress-induced brain injury. We have shown previously that the presence of an intronic nuclear factor site, kappaB (NF-kappaB), in the MnSOD gene is essential for the induction of MnSOD by tumor necrosis factor alpha (TNF-alpha). However, whether activation of NF-kappaB is protective against oxidative stress-induced neuronal injury is unclear. In the present study, we demonstrate that TNF-alpha activates NF-kappaB activity in neuronal, SH-SY5Y, cells and preferentially enhances the binding of p50 and p65 to the promoter/enhancer regions of the MnSOD gene. Binding of NF-kappaB members to the MnSOD gene leads to the induction of MnSOD mRNA and protein levels. Consequently, induction of MnSOD by TNF-alpha primes neuronal cells to develop resistance against subsequent exposure to beta-amyloid and FeSO(4). Taken together, these results suggest that NF-kappaB might exert its protective function by induction of MnSOD leading to subsequent protection against oxidative stress-induced neuronal injury.
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PMID:NF-kappaB-associated MnSOD induction protects against beta-amyloid-induced neuronal apoptosis. 1708 85

Cadmium (Cd) exposure has been recognized to result in a wide variety of cellular responses, including oxidative stress and body weight loss. The aim of the present study was to examine the effect of lycopene supplementation on the antioxidant defense system, lipid peroxidation (LPO) level, nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha) production, and body weight in Cd-exposed rats. Animals were divided into four groups (n = 7): control, Cd-treated, Cd plus lycopene-treated, and lycopene-treated. Cadmium (as CdCl2) was administrated orally for 20 days (6.6 mg kg(-1) day(-1)), and lycopene (10 mg kg(-1) day(-1)) was similarly administered. Lycopene administration significantly suppressed Cd-induced LPO in plasma and kidney homogenates. Lycopene also reversed Cd-decreased body weight compared to the control. Cadmium treatment had diverse effects on the antioxidant enzyme activities. Although antioxidant superoxide dismutase activity was unchanged, glutathione peroxidase activity was decreased, and catalase activity was elevated in kidney homogenates of Cd-administrated group. However, lycopene treatment reversed Cd-changed enzyme activities to the control level. Xanthine oxidase activity and TNF-alpha concentration were not altered by Cd administration, indicating that superoxide anion production and inflammation were not stimulated. Cadmium did not change NO levels in kidney homogenates but decreased those in plasma, and this effect was not prevented by lycopene supplementation. The result suggests that consumption of adequate levels of lycopene may be useful to prevent heavy-metal-induced LPO and body weight loss.
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PMID:Oral administration of lycopene reverses cadmium-suppressed body weight loss and lipid peroxidation in rats. 1787 60

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