Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxynitrite (ONOO-) is a strong oxidant derived from nitric oxide ('NO) and superoxide (O2.-), reactive nitrogen (RNS) and oxygen species (ROS) present in inflamed tissue. Other oxidant stresses, e.g., TNF-alpha and hyperoxia, induce mitochondrial, manganese-containing superoxide dismutase (MnSOD) gene expression. These experiments tested whether ONOO regulated MnSOD gene expression in human lung epithelial (A549) cells. 3-morpholinosydnonimine HCI (SIN-1) (10 or 1000 microM) increased MnSOD mRNA, but did not change hypoxanthine guanine phosphoribosyl transferase (HPRT) mRNA. Authentic peroxynitrite (ONOO ) (100-500 microM) also increased MnSOD mRNA but did not change constitutive HPRT mRNA expression. ONOO stimulated luciferase gene expression driven by a 2.5 kb fragment of the rat MnSOD gene 5' promoter region. MnSOD gene induction due to ONOO- was inhibited effectively by L-cysteine (10 mM) and partially inhibited by N-acetyl cysteine (50 mM) or pyrrole dithiocarbamate (10 mM). .NO from 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA NONOate) (100 or 1000 microM) did not change MnSOD or HPRT mRNA. Neither H202 nor NO2-, breakdown products of SIN-1 and ONOO , had any effect on MnSOD mRNA expression; however, ONOO- and SIN-1 did not increase MnSOD protein content detectable by western blots, nor did they increase MnSOD enzymatic activity. Increased steady state [O2.-] in the presence of .NO yields ONOO , and ONOO has direct, stimulatory effects on MnSOD transcript expression.
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PMID:Peroxynitrite modulates MnSOD gene expression in lung epithelial cells. 974 82

Apoptosis has been hypothesized to be mediated through the induction of free radicals via oxidative pathway. In this study, we demonstrated the induction of cellular apoptosis by anoxia-hyperoxia shift, but not by anoxia or hyperoxia alone in NIH3T3 cells. The decrement of ROS by anoxia thus appears to be an essential early event leading to apoptosis. G1 arrest was detected in anoxia-treated cells, and postanoxic oxygen recovery could reverse this effect, and induce apoptosis. On analysis of the binding activity of AP-1, we found biphasic induction of binding ability in cells undergoing anoxia-hyperoxia shift. In the early stage of anoxia, a transitional increase of AP-1 binding activity was detected, which was reduced to the minimal levels after 24 h of anoxia. During the period of postanoxic hyperoxia treatment, the binding activity of AP-1 was reinduced and increased remarkably with time up to 24 h. These results were in accordance with the expressions of c-jun and c-fos proteins. Enhancement of poly(ADP-ribosyl)ation activities, especially ADP-ribosylation of histone H1 was detected in post-anoxic hyperoxia-treated cells, and cleavage of PARP and activation of caspase 3 were also observed in post-anoxic hyperoxia (recovery) treated cells, but not in anoxia-treated cells. We propose that the differential induction of c-jun/c-fos (AP-1) gene expressions and sequential activation of PARP activity are essential in anoxia/hyperoxia-induced apoptosis.
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PMID:Elevation of apoptotic potential by anoxia hyperoxia shift in NIH3T3 cells. 1048 34

Free radicals are an integral part of metabolism and are formed continuously in the body. Many sources of stress heat, irradiation, hyperoxia, inflammation and any increases in metabolism including exercise, injury, and even repair processes lead to increased production of free radicals and associated reactive oxygen or nitrogen species (ROS/RNS). Evidence is accumulating that free radicals have important functions in the signal network of cells, including induction of growth and apoptosis and as killing tools of immunocompetent cells. Endogenous and nutritional antioxidant systems have to be adjusted to ensure adequate removal of radicals during stress to prevent damage to membranes, proteins, or nucleic acids. Excessive stress will induce DNA damage in the form of oxidized nucleosides, strand breaks, or DNA-protein crosslinks. Possible consequences of DNA damage are repair, apoptosis/necrosis, or defective repair leading to DNA sequence alterations and possibly to the development of cancer or, in case of mitochondrial DNA, to metabolic dysfunction. Excessive exercise will also induce DNA damage in peripheral leukocytes. The good message is that moderate stress in form of regular exercise/training may have protective effects against exercise-induced DNA damage. Up-regulation of endogenous antioxidant defense systems and complex regulation of repair systems such as heat shock proteins (HSP 70, HSP 27, HO 1) are seen in response to training and exercise. Up-regulation of antioxidants and modulation of the repair response may be mechanisms by which exercise can beneficially influence our health. Massive intervention into the redox state by pharmaceutical doses of exogenous antioxidants should be regarded with caution due to the ambiguous role of free radicals in regulation of growth, apoptosis, and cytotoxicity by immunocompetent cells.
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PMID:Free radicals, exercise, apoptosis, and heat shock proteins. 1157 49

Although oxygen is required for normal aerobic respiration, hyperoxia (95% O(2)/5% CO(2)) damages DNA, inhibits proliferation in G1, S and G2 phases of the cell cycle, and induces necrosis. The current study examines whether growth arrest in G1 protects pulmonary epithelial cells from oxidative DNA damage and cell death. Mv1Lu pulmonary adenocarcinoma cells were chosen for studies because hyperoxia inhibits their proliferation in S and G2 phase, while they can be induced to arrest in G1 by altering culture conditions. Hyperoxia inhibited proliferation, increased intracellular redox, and rapidly reduced clonogenic survival. In contrast, Mv1Lu cells treated with transforming growth factor (TGF)-beta1, deprived of serum or grown to confluency, arrested and remained predominantly in G1 even during exposure. Growth arrest in G1 significantly enhanced clonogenic survival by 10-50-fold. Enhanced survival was not due to reduction in the intracellular redox-state of the cells, but instead was associated with reduced DNA strand breaks and p53 expression. Our findings suggest that the protective effects of G1 is mediated not simply by a reduction in intracellular ROS, but rather through an enhanced ability to limit or rapidly recognize and repair damaged DNA.
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PMID:Growth arrest in G1 protects against oxygen-induced DNA damage and cell death. 1220 77

We previously reported that hyperoxia (95% O(2)) induces an S-phase cell cycle arrest in glutathione peroxidase-deficient human carcinoma cells T47D-H3 (Exp. Cell Res. 256:347-357; 2000). Here, we investigated whether increasing the peroxide scavenging capacity via glutathione peroxidase-1 (GPx1) expression can prevent cell cycle alterations induced by oxidative stress. We show that GPx1-proficient T47D-GPx-2 transfectant cells, in which GPx1 concentration is most elevated in mitochondria (Biochem. Biophys. Res. Commun. 272:416-422; 2000), are partially resistant to cell cycle inhibition induced by hyperoxia or menadione exposure. Transient cell growth resistance was observed at the level of cell cycle phase distribution, Cdk2 activity, and DNA synthesis after 40 h hyperoxia. This differential resistance was associated with an inhibition of ROS production and lipid peroxidation induced by hyperoxia. After 64 h hyperoxic exposure, cell growth was completely abolished in both cell lines, despite elevated glutathione levels. However, in contrast to the GPx1-deficient cells, T47D-GPx-2 cells showed an increased capacity to recover from a cell cycle arrest mediated by a 64 h hyperoxic stress. Differential recovery was also observed at the ultrastructural level between Gpx1-proficient and -deficient cells. These data indicate that GPx1 played an important role in the cell capacity to recover from hyperoxic insults. The limited protection conferred by GPx1 during hyperoxia suggests that the deleterious effects were partially mediated by peroxide-derived free radicals, but also involved the action of nonperoxide-derived reactive species.
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PMID:Glutathione peroxidase-1 expression enhances recovery of human breast carcinoma cells from hyperoxic cell cycle arrest. 1239 36

In an investigation of the antitumor effects of 2-methoxyestradiol (2-ME) in combination with other reactive oxygen generating treatments, 2-ME (0.5 microM) was found to completely inhibit cell proliferation of rat DS-sarcoma cells in vitro, with 71% of cells dying after exposure to 5 microM 2-ME. Concentration-dependent increases in ROS-formation, lipid peroxidation and mitochondrial changes were also observed, and an elevation in caspase-3 activity resulted in DNA fragmentation and apoptosis. Combination of 2-ME with hypoxanthine and xanthine oxidase enhanced in vitro cytotoxicity. In vivo, 2-ME caused a slight inhibition of tumor growth, with no tumors cured. Combination of 2-ME treatment with localized 44 degrees C hyperthermia, respiratory hyperoxia and xanthine oxidase caused a tumor growth delay with 51% of tumors cured. These results suggest that amplifying the levels of reactive oxygen species within tumor tissue with substances such as 2-ME may prove to be a promising strategy for adjuvant treatment of solid tumors.
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PMID:2-Methoxyestradiol enhances reactive oxygen species formation and increases the efficacy of oxygen radical generating tumor treatment. 1243 19

Cu,Zn-superoxide dismutase (SOD1) represents along with catalase the first coordinated line of defense against ROS and is found in all aerobic organisms. The dissection of the regulatory controls that drive the expression of SOD1 may provide further insight into the functional significance of this enzyme. The aim of this study was to elucidate temporal and spatial patterns of SOD1 expression, as well as to identify gene domains that govern its expression. Immunostaining analysis was used to delineate marked tissue and stage-specific expression patterns during the course of development and aging. By and large, there were no significant alterations in SOD1 mRNA and protein levels in response to the stress that accompanies aging, nor in response to different environmental insults, such as heat and hyperoxia. Expression of SOD1 seems to be largely determined by intrinsic factors. By histochemical analysis of transgenics carrying various sod1-reporter gene fusions, it was also possible to identify sequence domains, governing SOD1 expression. In particular a 1140 base pair region, composed of the single sod1 intron along with exon 2, was found to be essential for permitting spatial and temporal expression patterns that approximate normal endogenous expression.
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PMID:Profiling Cu,Zn-superoxide dismutase expression in Drosophila melanogaster--a critical regulatory role for intron/exon sequence within the coding domain. 1501 82

Although the actin cytoskeleton has been implicated in the control of NADPH oxidase in phagocytosis, very little is known about the cytoskeletal regulation of endothelial NADPH oxidase assembly and activation. Here, we report a role for cortactin and the tyrosine phosphorylation of cortactin in hyperoxia-induced NADPH oxidase activation and ROS production in human pulmonary artery ECs (HPAECs). Exposure of HPAECs to hyperoxia for 3 h induced NADPH oxidase activation, as demonstrated by enhanced superoxide production. Hyperoxia also caused a thickening of the subcortical dense peripheral F-actin band and increased the localization of cortactin in the cortical regions and lamellipodia at cell-cell borders that protruded under neighboring cells. Pretreatment of HPAECs with the actin-stabilizing agent phallacidin attenuated hyperoxia-induced cortical actin thickening and ROS production, whereas cytochalasin D and latrunculin A enhanced basal and hyperoxia-induced ROS formation. In HPAECs, a 3-h hyperoxic exposure enhanced the tyrosine phosphorylation of cortactin and interaction between cortactin and p47(phox), a subcomponent of the EC NADPH oxidase, when compared with normoxic cells. Furthermore, transfection of HPAECs with cortactin small interfering RNA or myristoylated cortactin Src homology domain 3 blocking peptide attenuated ROS production and the hyperoxia-induced translocation of p47(phox) to the cell periphery. Similarly, down-regulation of Src with Src small interfering RNA attenuated the hyperoxia-mediated phosphorylation of cortactin tyrosines and blocked the association of cortactin with actin and p47(phox). In addition, the hyperoxia-induced generation of ROS was significantly lower in ECs expressing a tyrosine-deficient mutant of cortactin than in vector control or wild-type cells. These data demonstrate a novel function for cortactin and actin in hyperoxia-induced activation of NADPH oxidase and ROS generation in human lung endothelial cells.
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PMID:Regulation of hyperoxia-induced NADPH oxidase activation in human lung endothelial cells by the actin cytoskeleton and cortactin. 1756 3

Oxygen-based therapies expose lung to elevated levels of ROS and induce lung cell damage and inflammation. Injured cells are replaced through increased proliferation and differentiation of epithelial cells and fibroblasts. Failure to modulate these processes leads to excessive cell proliferation, collagen deposition, fibrosis, and chronic lung disease. Poly(ADP-ribose) polymerase-1 (PARP-1) is activated in response to DNA damage and participates in DNA repair, genomic integrity, and cell death. In this study, we evaluated the role of PARP-1 in lung repair during recovery after acute hyperoxia exposure. We exposed PARP-1 -/- and wild-type mice for 64 h to 100% hyperoxia and let them recover in air for 5-21 days. PARP-1-deficient mice exhibited significantly higher lung cell hyperplasia and proliferation than PARP-1 +/+ animals after 5 and 10 days of recovery. This was accompanied by an increased inflammatory response in PARP-1 -/- compared with wild-type animals, characterized by neutrophil infiltration and increased IL-6 levels in bronchoalveolar lavages. These lesions were reversible, since the extent of the hyperplastic regions was reduced after 21 days of recovery and did not result in fibrosis. In vitro, lung primary fibroblasts derived from PARP-1 -/- mice showed a higher proliferative response than PARP-1 +/+ cells during air recovery after hyperoxia-induced growth arrest. Altogether, these results reveal an essential role of PARP-1 in the control of cell repair and tissue remodeling after hyperoxia-induced lung injury.
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PMID:Poly(ADP-ribose) polymerase-1 (PARP-1) controls lung cell proliferation and repair after hyperoxia-induced lung damage. 1757 13

Cytotoxic reactive oxygen species are constantly formed as a by-product of aerobic respiration and are thought to contribute to aging and disease. Cells respond to oxidative stress by activating various pathways, whose balance is important for adaptation or induction of cell death. Our lab recently reported that BiP (GRP78), a proposed negative regulator of the unfolded protein response (UPR), declines during hyperoxia, a model of chronic oxidative stress. Here, we investigate whether exposure to hyperoxia, and consequent loss of BiP, activates the UPR or sensitizes cells to ER stress. Evidence is provided that hyperoxia does not activate the three ER stress receptors IRE1, PERK, and ATF6. Although hyperoxia alone did not activate the UPR, it sensitized cells to tunicamycin-induced cell death. Conversely, overexpression of BiP did not block hyperoxia-induced ROS production or increased sensitivity to tunicamycin. These findings demonstrate that hyperoxia and loss of BiP alone are insufficient to activate the UPR. However, hyperoxia can sensitize cells to toxicity from unfolded proteins, implying that chronic ROS, such as that seen throughout aging, could augment the UPR and, moreover, suggesting that the therapeutic use of hyperoxia may be detrimental for lung diseases associated with ER stress.
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PMID:Hyperoxia augments ER-stress-induced cell death independent of BiP loss. 1978 88


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