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)

In this study, we provide evidence that the muscarinic M1 receptor targets NF-E2-related factor-2 (Nrf2), a transcription factor that regulates the expression of genes containing antioxidant response elements (AREs) in their promoters and that collectively constitute the phase II antioxidant response. In hippocampal primary and cerebellar granule neuron cultures expressing endogenous M1 receptor, carbachol increased the levels of a prototypical phase II antioxidant enzyme, heme oxygenase-1. Moreover, in a heterologous system, based on lentiviral expression of M1 receptor in PC12 pheochromocytoma cells, we found that M1 increased total and nuclear Nrf2 protein levels and heme oxygenase-1 messenger RNA and protein levels. Luciferase reporter constructs for AREs and the use of two inhibitors of protein kinase C (PKC), chelerythrine and 2-aminoethyl diphenylborinate, or transfection with relevant expression vectors allowed us to identify Galphaq, phospholipase C-beta and the classical PKC-gamma isoenzyme, as responsible for the regulation of Nrf2. A PKC-insensitive Nrf2S40A single-point mutant partially channeled M1 signaling to AREs, therefore suggesting the participation of additional intermediates. Inhibition of glycogen synthase kinase-3beta (GSK-3beta) augmented M1-dependent activation of AREs while a PKC-insensitive mutant of GSK-3beta (GSK-3beta-Delta9) blocked this effect and prevented M1-induced accumulation of Nrf2 in the nucleus. Our results demonstrate a previously unidentified role of the Galphaq/phospholipase C-beta/PKC/GSK-3beta axis in regulation of Nrf2 by M1. Such role provides additional conceptual support for the use of cholinemimetics in the treatment of pathologies that, like Alzheimer's disease, require a reinforcement of the cell antioxidant capacity.
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PMID:The muscarinic M1 receptor activates Nrf2 through a signaling cascade that involves protein kinase C and inhibition of GSK-3beta: connecting neurotransmission with neuroprotection. 1955 56

Melatonin has potent hepatoprotective effects as an antioxidant. However, the signaling pathway of melatonin in the induction of antioxidant enzymes against acute liver injury is not fully understood. The study aimed to determine whether melatonin could prevent dimethylnitrosamine (DMN)-induced liver injury through nuclear erythroid 2-related factor 2 (Nrf2) and inflammation. Liver injury was induced in rats by a single injection of DMN (30 mg/kg, i.p.). Melatonin treatment (50 mg/kg/daily, i.p.) was initiated 24 hr after DMN injection for 14 days, after which the rats were killed and samples were collected. Serum and antioxidant enzyme activities improved in melatonin-treated rats, compared with DMN-induced liver injury group (P < 0.01). Melatonin reduced the infiltration of inflammatory cells and necrosis in the liver, and increased the expression of NADPH: quinone oxidoreductase-1, heme oxygenase-1, and superoxide dismutase-2, which were decreased by DMN. Melatonin increased expression of novel transcription factor, Nrf2, and decreased expression of inflammatory mediators including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and inducible nitric oxide synthase. The increased nuclear binding of nuclear factor-kappa B (NF-kappaB) in the DMN-induced liver injury group was inhibited by melatonin. Our results show that melatonin increases antioxidant enzymes and Nrf2 expression in parallel with the decrease of inflammatory mediators in DMN-induced liver injury, suggesting that melatonin may play a role of antioxidant defense via the Nrf2 pathway, by reducing inflammation by NF-kappaB inhibition.
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PMID:Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model. 1962 59

Salicornia herbacea has been used as a folk medicine for disorders such as constipation, obesity, diabetes, and cancer. Recent studies have shown that S. herbacea has antioxidative, anti-inflammatory, immunomodulatory, antihyperglycemic, and antihyperlipidemic activities. In the present work, we investigated the protective effects of the chlorogenic acid derivative, 3-caffeoyl, 4-dihydrocaffeoyl quinic acid (CDCQ), which was isolated from S. herbacea, against tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity in Hepa1c1c7 cells. Pretreatment of Hepa1c1c7 cells with CDCQ significantly reduced t-BHP-induced generation of ROS, caspase-3 activation, and subsequent cell death. Also, CDCQ up-regulated heme oxygenase-1 (HO-1) expression, which conferred cytoprotection against oxidative injury induced by t-BHP. Moreover, CDCQ-induced nuclear translocation of the transcription factor NF-E2-related factor 2 (Nrf2), which is upstream of CDCQ-induced HO-1 expression, and PI3K/Akt activation, a pathway that is involved in induced Nrf2 nuclear translocation. Taken together, these results suggest that the protective effects of CDCQ against t-BHP-induced hepatotoxicity may be due, at least in part, to its ability to scavenge ROS and to regulate the antioxidant enzyme HO-1 via the PI3K/Akt-Nrf2 signaling pathways.
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PMID:Protective mechanisms of 3-caffeoyl, 4-dihydrocaffeoyl quinic acid from Salicornia herbacea against tert-butyl hydroperoxide-induced oxidative damage. 1964 27

The anti-inflammatory properties of transforming growth factor-beta(1) (TGF-beta(1)) account for its protection against atherosclerotic plaque rupture. This study investigates whether activation of the Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) transcription pathway is involved in TGF-beta(1) mediated induction of the antioxidant enzyme heme oxygenase-1 (HO-1) in smooth muscle cells (SMC). Human aortic smooth muscle cells (HAoSMC) or wild-type and Nrf2-deficient mouse (MAoSMC) aortic SMC were treated with TGF-beta(1) (2.5-10 ng/ml, 0-24 hrs). We report the first evidence that TGF-beta(1) induces Nrf2 mediated HO-1 expression and antioxidant response element activity, which was paralleled by enhanced superoxide production and expression of the NAD(P)H oxidase subunit p22(phox). TGF-beta(1) failed to induce HO-1 expression in MAoSMC derived from Nrf2-deficient mice, and HO-1 induction by TGF-beta(1) in HAoSMC was attenuated by inhibition of extracellular signal regulated kinase or c-jun-N-terminal kinase but not p38 mitogen activated protein kinase. Inhibition of NAD(P)H oxidase or scavenging of superoxide diminished HO-1 induction in response to TGF-beta(1). The oxidative stress agents glucose oxidase (GOx) and diethylmaleate enhanced TGF-beta(1) generation and HO-1 expression in HAoSMC, while antagonism of TGF-beta(1) signalling by adenoviral Smad7 overexpression attenuated their induction of HO-1. Pre-treatment of HAoSMC with TGF-beta(1) reduced nuclear translocation of the pro-apoptotic mediator p53 elicited by GOx. Our findings demonstrate that Nrf2 is a new target of TGF-beta(1) signalling in the vasculature which may contribute to the atheroprotective properties attributed to this growth factor.
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PMID:Transforming growth factor-beta1 elicits Nrf2-mediated antioxidant responses in aortic smooth muscle cells. 1967 92

We have previously reported that age-associated oxidative stress via protein kinase C (PKC) increases D1 receptor (D1R) phosphorylation and causes D1R-G protein uncoupling in renal proximal tubules (RPTs) of old Fischer 344 rats. This results in reduced ability of D1R agonist SKF-38393 to inhibit Na+-K+-ATPase in RPTs of old rats. Here, we studied the effect of treadmill exercise on markers of oxidative stress, PKC, D1R phosphorylation, D1R-G protein coupling, and Na+-K+-ATPase activity in RPTs of adult and old rats. We found increased levels of malondialdehyde, a marker of oxidative stress, in RPTs of old rats, which decreased during exercise. Nuclear levels of nuclear erythroid-related factor (Nrf)-2 and nuclear factor (NF)-kappaB in RPTs, transcription factors involved in antioxidant enzyme gene transcription, increased in exercised old rats. This was accompanied by an increase in the activity and expression of antioxidant enzymes, superoxide dismutase and heme oxygenase-1. Age-related decrease in the levels of D1R mRNAs and proteins was attenuated during exercise. Furthermore, exercise in old rats decreased PKC activity and D1R phosphorylation and increased SKF-38393-mediated [35S]guanosine 5'-O-(3-thiotriphosphate) binding (an index of D1R-G protein coupling). SKF-38393 also caused inhibition of Na+-K+-ATPase in these animals. Also, exercise caused a decrease in proteinuria and increase in phosphaturia in old rats. These results suggest beneficial effects of exercise in terms of increasing antioxidant defenses, decreasing oxidative stress, and improving kidney function in general and D1R function in particular in aging. Both Nrf-2 and NF-kappaB seem to play key role in this phenomenon.
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PMID:Exercise activates redox-sensitive transcription factors and restores renal D1 receptor function in old rats. 1975 68

Soluble oligomeric amyloid beta (oAbeta) 1-42 causes synaptic dysfunction and neuronal injury in Alzheimer's disease (AD). Although accumulation of microglia around senile plaques is a hallmark of AD pathology, the role of microglia in oAbeta1-42 neurotoxicity is not fully understood. Here, we showed that oAbeta but not fibrillar Abeta was neurotoxic, and microglia activated with unmethylated DNA CpG motif (CpG), a ligand for Toll-like receptor 9, attenuated oAbeta1-42 neurotoxicity in primary neuron-microglia co-cultures. CpG enhanced microglial clearance of oAbeta1-42 and induced higher levels of the antioxidant enzyme heme oxygenase-1 in microglia without producing neurotoxic molecules such as nitric oxide and glutamate. Among subclasses of CpGs, class B and class C activated microglia to promote neuroprotection. Moreover, intracerebroventricular administration of CpG ameliorated both the cognitive impairments induced by oAbeta1-42 and the impairment of associative learning in Tg2576 mouse model of AD. We propose that CpG may be an effective therapeutic strategy for limiting oAbeta1-42 neurotoxicity in AD.
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PMID:Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer's disease. 1983 64

With the recognition that chronic exposure to oxidative stress occurs in many disease states and can be deleterious to the human health, great interest has emerged in understanding the mechanisms by which mammalian cells develop resistance to chronic oxidative stress. In order to study the mechanisms of development of resistance to chronic oxidative stress, a model system where Chinese hamster fibroblasts (HA1) are chronically exposed to progressively increasing concentrations of H(2)O(2) (50-800 muM) or hyperoxia (80-95% O(2)) has been developed. Following >200 d of exposure to H(2)O(2) (or 18 months of exposure to hyperoxia), the cells developed stable H(2)O(2)-resistant (or O(2)-resistant) phenotypes that are characterized by increases in total glutathione, antioxidant enzyme activity, heme oxygenase activity, stress protein gene expression, DNA repair pathways, and resistance to a wide variety of other toxic stress known to cause oxidant injury. In addition, these oxidant-resistant cells exhibited amplification of the gene for catalase and constitutively elevated AP-1 DNA binding activity. Further, beyond 240 d genomic instability as evidenced by chromosomal rearrangements and alterations in ploidy was stably maintained upon removal from the chronic oxidative stress conditions. These results demonstrate the capability of mammalian cells to develop stable oxidative stress-resistant phenotypes in response to both exogenous (H(2)O(2)) as well as endogenous (95% O(2)) oxidative stress. The understanding of mechanisms of resistance to oxidative stress and its possible relevance in various disease states are discussed.
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PMID:The generation of stable oxidative stress-resistant phenotypes in Chinese hamster fibroblasts chronically exposed to hydrogen peroxide or hyperoxia. 2001 79

Oxidative stress is a key factor involved in the development and progression of Alzheimer disease (AD), and it is well documented that free radical oxidative damage, particularly of neuronal lipids, proteins, nucleic acids, and sugars, is extensive in brains of AD patients. The complex chemistry of peroxynitrite has been the subject of intense study and is now evident that there are two principal pathways for protein modification: the first one involves homolytic hydroxyl radical-like chemistry that results in protein-based carbonyls and the second involves electrophilic nitration of vulnerable side chains, in particular the electron-rich aromatic rings of Tyr and Trp. In the presence of buffering bicarbonate, peroxynitrite forms a CO(2) adduct, which augments its reactivity. Formation of 3-nitrotyrosine by this route has become the classical protein marker specifically for the presence of peroxynitrite. Protein-based carbonyls can be detected by two methods: (i) derivatization with 2,4-dinitrophenylhydrazine (DNPH) and detection of the protein-bound hydrazones using an enzyme-linked anti-2,4-dinitrophenyl antibody and (ii) derivatization with biotin-hydrazide and detection of the protein-bound acyl hydrazone with enzyme-linked avidin or streptavidin. Glycation of proteins by reducing sugars (Maillard reaction) results in a profile of time-dependent adduct evolution rendering susceptibility to oxidative elaboration. In addition, oxidative stress can result in oxidized sugar derivatives which can subsequently modify protein through a process known as glycoxidation. Of more general importance, oxidative stress results in lipid peroxidation and the production of a range of electrophilic and mostly bifunctional aldehydes that modify numerous proteins. The more important protein modifications are referred to as advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs). Protein modification can result in both non-cross-link and cross-link AGEs and ALEs, the latter arising from the potential bifunctional reactivity, such as that of the lipid-derived modifiers 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA). Oxidative damage to nucleic acids results in base modification, substitutions, and deletions. Among the most common modifications, 8-hydroxyguanosine (8OHG) is considered a signature of oxidative damage to nucleic acid.Cells are not passive to increased oxygen radical production but rather upregulate protective responses. In neurodegenerative diseases, heme oxygenase-1 (HO-1) induction is coincident with the formation of neurofibrillary tangles. This enzyme that converts heme, a prooxidant, to biliverdin/bilirubin (antioxidants) and free iron has been considered an antioxidant enzyme. But seen in the context of arresting apoptosis, HO-1 and tau may play a role in maintaining the neurons free from the apoptotic signal (cytochrome c), since tau has strong iron-binding sites. Given the importance of iron as a catalyst for the generation of reactive oxygen species, changes in proteins associated with iron homeostasis can be used as an index of cellular responses. One such class of proteins is the iron regulatory proteins (IRPs) that respond to cellular iron concentrations by regulating the translation of proteins involved in iron uptake, storage, and utilization. Therefore, IRPs are considered to be the central control components of cellular iron concentration.
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PMID:Detection and localization of markers of oxidative stress by in situ methods: application in the study of Alzheimer disease. 2001 93

Reactive oxygen species (ROS) produce damage to all major cellular constituents. The antioxidant properties of the ethyl acetate fraction of Empetrum nigrum was assessed against hydrogen peroxide (H(2)O(2))-induced cell damage. Empetrum extract was found to scavenge (1) intracellular ROS in cell system, (2) hydroxyl radicals generated by the Fenton reaction (FeSO(4) + H(2)O(2)), and (3) superoxide radicals generated by xanthine/xanthine oxidase in a cell-free system as detected by electron spin resonance (ESR) spectrometry. Cell damage was produced by H(2)O(2) treatment as evidenced by DNA damage, lipid peroxidation, and increased protein carbonyl formation; however, Empetrum extract prevented H(2)O(2)-induced damage to these parameters. Empetrum extract increased viability of Chinese hamster lung fibroblast (V79-4) cells exposed to H(2)O(2), as evidenced by decreased apoptotic nuclear fragmentation, and lower sub G(1) cell population. Further, Empetrum extract restored the cellular antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1), which were reduced by H(2)O(2) treatment. In conclusion, Empetrum extract protected cells against H(2)O(2)-induced cell damage via antioxidant properties by scavenging ROS and enhancing antioxidant enzyme activities.
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PMID:Risk reduction of ethyl acetate fraction of Empetrum nigrum var. japonicum via antioxidant properties against hydrogen peroxide-induced cell damage. 2007 24

The organic nitrate pentaerythritol tetranitrate is devoid of nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetranitrate can improve angiotensin II-induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 mononitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetranitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase), as assessed by dihydroethidine staining, lucigenin-enhanced chemiluminescence, and quantification of dihydroethidine oxidation products in angiotensin II (1 mg/kg per day for 7 days)-treated rats. The antioxidant features of pentaerythritol tetranitrate were recapitulated in spontaneously hypertensive rats. In addition to an increase in HO-1 protein expression, pentaerythritol tetranitrate but not isosorbide-5 mononitrate normalized vascular reactive oxygen species formation and augmented aortic protein levels of the tetrahydrobiopterin-synthesizing enzymes GTP-cyclohydrolase I and dihydrofolate reductase in angiotensin II-treated rats, thereby preventing endothelial NO synthase uncoupling. Haploinsufficiency of HO-1 completely abolished the beneficial effects of pentaerythritol tetranitrate in angiotensin II-treated mice, whereas HO-1 induction by hemin (25 mg/kg) mimicked the effect of pentaerythritol tetranitrate. Improvement of vascular function in this particular model of arterial hypertension by pentaerythritol tetranitrate largely depends on the induction of the antioxidant enzyme HO-1 and identifies pentaerythritol tetranitrate, in contrast to isosorbide-5 mononitrate, as an organic nitrate able to improve rather than to worsen endothelial function.
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PMID:Pentaerythritol tetranitrate improves angiotensin II-induced vascular dysfunction via induction of heme oxygenase-1. 2015 49


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