Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8IXL6 (RNS)
 1,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhaled fibres with certain physico-chemical properties are known to induce mesothelioma in humans. The induction of reactive oxygen (ROS) or nitrogen species (RNS) have been suggested as molecular mechanism of fibre induced carcinogenesis. In earlier studies we were able to demonstrate that crocidolite asbestos in vivo induces mutations in transgenic rats with a specific molecular spectrum that indicates the involvement of 8-hydroxydeoxyguanosine (8-OHdG) as pre-mutagenic adduct. 8-OHdG may be induced by primary (direct) and/or secondary (cellular mediated) mechanisms. Therefore, the induction of 8-OHdG as well as the inflammatory response of animals treated with fibre samples significantly differing in their physico-chemical characteristics was investigated. As appropriate system to study mesothelioma carcinogenesis, intraperitoneal injection in rats was used with samples of UICC crocidolite, crocidolite with reduced iron content, and a vitreous fibre (MMVF 11). Equal numbers of carcinogenic fibres from each sample revealed significant comparable increases in 8-OHdG induction. Parameters of inflammation (percentage of macrophages and TNF-alpha secretion) correlated significantly with the induction of 8-OHdG, 10 weeks after treatment.
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PMID:Induction of 8-hydroxydeoxyguanosine by man made vitreous fibres and crocidolite asbestos administered intraperitoneally in rats. 1528 33

Persistent inflammation and associated excessive oxidative stress have been crucially implicated in quartz-induced pulmonary diseases, including fibrosis and cancer. We have investigated the significance of the particle surface reactivity of respirable quartz dust in relation to the in vivo generation of reactive oxygen and nitrogen species (ROS/RNS) and the associated induction of oxidative stress responses in the lung. Therefore, rats were intratracheally instilled with 2 mg quartz (DQ12) or quartz whose surface was modified by either polyvinylpyridine-N-oxide (PVNO) or aluminium lactate (AL). Seven days after instillation, the bronchoalveolar lavage fluid (BALF) was analysed for markers of inflammation (total/differential cell counts), levels of pulmonary oxidants (H2O2, nitrite), antioxidant status (trolox equivalent antioxidant capacity), as well as for markers of lung tissue damage, e.g. total protein, lactate dehydrogenase and alkaline phosphatase. Lung homogenates as well as sections were investigated regarding the induction of the oxidative DNA-lesion/oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) using HPLC/ECD analysis and immunohistochemistry, respectively. Homogenates and sections were also investigated for the expression of the bifunctional apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) by Western blotting and immunohistochemistry. Significantly increased levels of H2O2 and nitrite were observed in rats treated with non-coated quartz, when compared to rats that were treated with either saline or the surface-modified quartz preparations. In the BALF, there was a strong correlation between the number of macrophages and ROS, as well as total cells and RNS. Although enhanced oxidant generation in non-coated DQ12-treated rats was paralleled with an increased total antioxidant capacity in the BALF, these animals also showed significantly enhanced lung tissue damage. Remarkably however, elevated ROS levels were not associated with an increase in 8-OHdG, whereas the lung tissue expression of APE/Ref-1 protein was clearly up-regulated. The present data provide further in vivo evidence for the crucial role of particle surface properties in quartz dust-induced ROS/RNS generation by recruited inflammatory phagocytes. Our results also demonstrate that quartz dust can fail to show steady-state enhanced oxidative DNA damage in the respiratory tract, in conditions were it elicits a marked and persistent inflammation with associated generation of ROS/RNS, and indicate that this may relate to compensatory induction of APE/Ref-1 mediated base excision repair.
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PMID:The crucial role of particle surface reactivity in respirable quartz-induced reactive oxygen/nitrogen species formation and APE/Ref-1 induction in rat lung. 1626 28

Although production of reactive nitrogen and reactive oxygen species (RNS and ROS) is a component of innate defense against viral infection, their overproduction in the brain may also lead to deleterious consequences. To investigate potential immunopathologic roles of oxidative stress during herpes encephalitis, the authors examined the expression kinetics of inducible nitric oxide synthase (iNOS) as well as heme oxygenase-1 (HO-1), a marker of oxidative stress, and evaluated infection-induced oxidative brain damage. Results from these studies showed that both iNOS and HO-1 gene expression were highly elevated in the brain within 7 days post infection (d.p.i.) and remained elevated through 21 d.p.i. Real-time bioluminescence imaging of HO-1 promoter-luciferase transgenic mice confirmed HO-1 promoter activity in the brains of HSV-1-infected animals within 3 d.p.i., which peaked between 5 and 7 d.p.i. Immunohistochemical staining for both 3-nitrotyrosine and 8-hydroxydeoxyguanosine (8-OH-dG), as well as quantitative assessment of 8-isoprostane levels, demonstrated the presence of viral infection-induced oxidative brain damage. In addition, when brain leukocytes obtained from animals with experimental herpes encephalitis were sorted using fluorescence-activated cell sorting (FACS) and the individual cell populations analyzed, CD45(int)/CD11b(+) resident microglia were found to be the major cellular source of iNOS expression.
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PMID:Microglia are the major cellular source of inducible nitric oxide synthase during experimental herpes encephalitis. 1856 57

MnTE-2-PyP(5+) is a potent catalytic scavenger of reactive oxygen and nitrogen species, primarily superoxide and peroxynitrite. It therefore not only attenuates primary oxidative damage, but was found to modulate redox-based signaling pathways (HIF-1alpha, NF-kappaB, SP-1, and AP-1) and thus, in turn, secondary oxidative injury also. Cancer has been widely considered an oxidative stress condition. The goal of this study was to prove if and why a catalytic SOD mimic/peroxynitrite scavenger would exert anti-cancer effects, i.e., to evaluate whether the attenuation of the oxidative stress by MnTE-2-PyP(5+) could suppress tumor growth in a 4T1 mouse breast tumor model. Tumor cells were implanted into Balb/C mouse flanks. Three groups of mice (n=25) were studied: control (PBS) and 2 and 15 mg/kg/day of MnTE-2-PyP(5+) given subcutaneously twice daily starting when the tumors averaged 200 mm(3) (until they reached approximately 5-fold the initial volume). Intratumoral hypoxia (pimonidazole, carbonic anhydrase), HIF-1alpha, VEGF, proliferating capillary index (CD105), microvessel density (CD31), protein nitration, DNA oxidation (8-OHdG), NADPH oxidase (Nox-4), apoptosis (CD31), macrophage infiltration (CD68), and tumor drug levels were assessed. With 2 mg/kg/day a trend toward tumor growth delay was observed, and a significant trend was observed with 15 mg/kg/day. The 7.5-fold increase in drug dose was accompanied by a similar (6-fold) increase in tumor drug levels. Oxidative stress was largely attenuated as observed through the decreased levels of DNA damage, protein 3-nitrotyrosine, macrophage infiltration, and NADPH oxidase. Further, hypoxia was significantly decreased as were the levels of HIF-1alpha and VEGF. Consequently, suppression of angiogenesis was observed; both the microvessel density and the endothelial cell proliferation were markedly decreased. Our study indicates for the first time that MnTE-2-PyP(5+) has anti-cancer activity in its own right. The anti-cancer activity via HIF/VEGF pathways probably arises from the impact of the drug on the oxidative stress. Therefore, the catalytic scavenging of ROS/RNS by antioxidants, which in turn suppresses cellular transcriptional activity, could be an appropriate strategy for anti-cancer therapy. Enhancement of the anti-cancer effects may be achieved by optimizing the dosing regime, utilizing more bioavailable Mn porphyrins (MnP), and combining MnP treatment with irradiation, hyperthermia, and chemotherapy. Mn porphyrins may be advantageous compared to other anti-cancer drugs, owing to their radioprotection of normal tissue and the ability to afford pain management in cancer patients via prevention of chronic morphine tolerance.
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PMID:Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress in a mouse model of breast tumor. 1959 20

In the present study, the role of ROS and RNS in activation of inflammatory response and associated molecular events during apoptosis of polymorphonuclear leucocytes (PMNs) in patients from an outbreak of argemone oil (AO) poisoning leading to epidemic dropsy in Lucknow, India was undertaken. It was observed that generation of superoxide radical, nitrite formation and phagocytosis (103-429%) were significantly increased in PMNs of dropsy patients. Furthermore, activities of superoxide dismutase and glutathione peroxidase (GPx) (47-79%) were found to be increased while that of catalase and glutathione reductase (GR) (56-57%) were decreased. Lipid and protein oxidation, nitrotyrosine formation and 8-hydroxydeoxyguanosine (8-OHdG) excretion were significantly enhanced with concomitant depletion of GSH levels (67%) in dropsy patients. In addition, significant elevation of IL-6, IL-8 and TNF-alpha (68-406%) in plasma was observed. Apoptosis was enhanced (1.5 folds) with increased (2.0-3.6 folds) caspases 3, 8 and 9 activities along with DNA fragmentation (119%). The results suggest that generation of ROS and RNS along with enhancement of secretion of inflammatory mediators leading to DNA damage followed by apoptosis may have an effect on immune system, which in turn may be responsible for histopathological changes in target organs of dropsy patients.
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PMID:Activation of inflammatory response and apoptosis of polymorphonuclear leukocytes in patients with argemone oil poisoning. 1987 8

Diabetic mellitus, a chronic metabolic disorder, is one of the most important health problems in the world, especially in developing countries. Our earlier investigations reported the beneficial action of arjunolic acid (AA) against streptozotocin-mediated type 1 hyperglycemia. We have demonstrated that AA possesses protective roles against drug- and chemical- (environmental toxins) induced hepatotoxicity. Liver is the main organ of detoxification. The purpose of this study was to explore whether AA plays any protective role against hyperglycemic hepatic dysfunctions and, if so, what molecular pathways it utilizes for the mechanism of its protective action. In experimental rats, type 1 hyperglycemia was induced by streptozotocin. AA was administered orally at a dose of 20mg/kg body wt both before and after diabetic induction. An insulin-treated group was included in the study as a positive control for type 1 diabetes. Hyperglycemia caused a loss in body weight, reduction in serum insulin level, and increased formation of HbA(1C) as well as advanced glycation end products (AGEs). Elevated levels of serum ALT and ALP, increased production of ROS and RNS, increased lipid peroxidation, increased 8-OHdG/2-dG ratio, and decreased GSH content and cellular antioxidant defense established the hyperglycemic liver dysfunction. Activation of iNOS, IkappaBalpha/NF-kappaB, and MAPK pathways as well as signals from mitochondria were found to be involved in initiating apoptotic cell death. Hyperglycemia caused overexpression of PARP, reduction in intracellular NAD as well as ATP level, and increased DNA fragmentation in the liver tissue of the diabetic animals. Results of immunofluorescence (using anti-caspase-3 and anti-Apaf-1 antibodies), DAPI/PI staining, and DNA ladder formation and information obtained from FACS analysis confirmed the apoptotic cell death in diabetic liver tissue. Histological studies also support the experimental findings. AA treatment prevented or ameliorated the diabetic liver complications and apoptotic cell death. The effectiveness of AA in preventing the formation of ROS, RNS, HbA(1C), AGEs, and oxidative stress signaling cascades and protecting against PARP-mediated DNA fragmentation can speak about its potential uses for diabetic patients.
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PMID:Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: Prophylactic role of arjunolic acid. 2018 23

2-chloroethyl ethyl sulphide (CEES), a monofunctional analogue of sulfur mustard, is a strong vesicant and an alkylating chemical warfare agent. We studied the molecular mechanism of oxidative stress triggered signaling cascades in murine macrophages exposed to CEES with lipopolysaccharide (LPS). Exposure of CEES with specific dose of LPS stimulates oxidative stress caused increasing level of intracellular ROS and RNS, decreased antioxidant enzymes, increasing bimolecular damage, reduced cell viability, and cell cycle arrest. Synergistic exposure of CEES and LPS provoked significant increase in phosphorylation of MAPKs, Akt, tuberin, that down regulate OGG1 expression and 8-OHdG accumulations. Treatment with Akt and ERK1/2 inhibitors, the cells with constitutively active inhibiting activity of Akt and ERK1/2MAPK significant reduce CEES and LPS challenge tuberin but not the OGG1. In addition, the N-acetylcysteine inhibited ROS/RNS generation, elevation of antioxidants level, expression of ERK1/2, Akt, tuberin phosphorylation, resulted in deceased 8-OHdG accumulation and upregulation of OGG1 protein expression suggesting no involvement of Akt and ERK1/2MAPK pathways after CEES and LPS challenge. Collectively, our results indicate that exposure of CEES and LPS induces oxidative stress and the activation of tuberin, and 8-OHdG accumulation via upstream signaling pathways including Akt and ERK1/2MAPK pathway in macrophages but not the down regulation of OGG1.
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PMID:Effects of CEES and LPS synergistically stimulate oxidative stress inactivates OGG1 signaling in macrophage cells. 2497 29

High glucose-induced increase in production of reactive oxygen/nitrogen species (ROS/RNS) is recognized as a major cause of the clinical complications associated with diabetes. ROS/RNS apart from being redox agents, cause an unwanted severe physiological load to cells, also act as cellular messengers, and play a key role in activation of circulating macrophages. However, the molecular mechanisms of activation of macrophages by hyperglycemic conditions are currently unclear. In the present study, we report that high glucose (HG) causes a dramatic increase in the production of inflammatory cytokines and chemokines, at least in part through enhanced mRNA transcription. The increase in levels of inflammatory cytokines/chemokines corresponds to increased levels of ROS/RNS, which is accompanied by increased activities of Akt, ERK1/2, tuberin, down regulation of 8-oxoG-DNA glycosylase (OGG1), and increase in 8-hydroxydeoxyguanosine (8-OHdG) accumulation in DNA. Elevated levels of ROS/RNS are triggering alteration in antioxidants level, biomolecules damage, cell cycle dysregulation, and apoptosis in macrophage cells. Pretreatment of antioxidants caused decrease in the levels of ROS/RNS leads to an increase in the levels of antioxidants, decrease in biomolecules damage, alterations in Akt, ERK1/2, tuberin, upregulation of OGG1, and decrease in 8-OHdG accumulations in DNA. Further, antioxidants treatments inhibit the effects of HG on the transcriptional activity of cytokines and chemokines. Our results demonstrate that intracellular signaling pathways mediated by ROS/RNS are linked to each other by elevated glucose in macrophages activation leading to inflammation. These findings provide a mechanistic explanation of how ROS/RNS cooperate to conduct inflammatory intracellular signals in macrophages related complications in hyperglycemic conditions.
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PMID:Hyperglycemia-induced inflammation caused down-regulation of 8-oxoG-DNA glycosylase levels in murine macrophages is mediated by oxidative-nitrosative stress-dependent pathways. 2686 Sep 57

Reactive oxygen and nitrogen species (ROS/RNS) play a crucial role in inflammatory bowel disease (IBD) exacerbating the chronic inflammatory process. Endogenous and diet antioxidants can neutralize these compounds. The apple is widely consumed, with several antioxidant activity compounds. The present study evaluated the effects of concentrated apple extract (CAE) in acetic acid induced colitis. 29 Wistar male rats were randomized into 5 groups. G1-Sham/saline solution, G2-CAE/control, G3-acetic acid/control, G4-curative- CAE treatment and G5-preventive-CAE treatment. Eight days later, the animals were euthanized and the colonic segment resected for macroscopic and histological analysis. Gene expression was evaluated for inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), catalase and copper and zinc superoxide dismutase (CuZnSOD) by quantitative real time PCR, while protein expression was assessed for iNOS, COX-2 and 8-hydroxy-20-deoxyguanosine (8-OHdG) via immunohistochemistry. The groups G3, G4 and G5 had weight loss, while G5 had weight increase at the end of the experiment. The treatment with CAE reduced the macroscopic and microscopic injury, decreased iNOS mRNA expression and increased CuZnSOD mRNA expression in animals with induced acetic acid-colitis. The findings of the present study suggest that CAE treatment exerts an antioxidant role by downregulating iNOS and upregulating CuZnSOD.
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PMID:Effect of Concentrated Apple Extract on Experimental Colitis Induced by Acetic Acid. 2886 68

Oxidative stress increases with age in multiple organ systems and is implicated in the development of age-related pathologies in them. Studies from our laboratory show that the intrinsic pathway proapoptotic proteins BAX and caspase-3 (CASP3) lie upstream of mitochondrial production of oxidative stress-inducing reactive species (RS) such as reactive oxygen and reactive nitrogen species (ROS and RNS) in apoptotic and nonapoptotic neurons in cell culture. Our objective in this study was to determine if these findings could be generalized to the development of oxidative stress in nonneuronal tissues in vivo. We first investigated the effect of genetic deletion of Bax on DNA damage in the liver, heart and kidneys of female mice of increasing ages (5, 14, 22 months). The organs of the aged mice showed increased oxidative DNA strand breaks compared to young animals (5 month). Ablation of Bax greatly reduced this damage. We next assessed lipid peroxidation, DNA oxidation, and protein tyrosine nitration to determine whether Casp3 deletion reduces oxidative stress in the hearts, livers, and kidneys of 12-month-old female mice. Lipid peroxides and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were much lower in organs from mice with depleted Casp3 than in those of wild type animals. Nitration of protein tyrosine residues, caused by RNS, was also significantly suppressed in the tissues of Casp3 null mice compared to those in wild type mice. Our findings indicate that BAX and CASP3 have a vital role in the generation of oxidative stress in organs of aged mice.
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PMID:The intrinsic apoptotic pathway lies upstream of oxidative stress in multiple organs. 3265 46


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