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At least 19 recordsLinked to original sources

PubMedDate not supplied

Mitochondrial ROS metabolism: modulation by uncoupling proteins.

Most of the oxygen consumed by aerobic organisms is reduced to water by the enzyme cytochrome c oxidase in the terminal reaction of the mitochondrial respiratory chain. A significant proportion of the oxygen molecules are converted to superoxide anion radicals by complexes I and III via a nonenzymatic process. A cascade of enzymes, some of them inside the mitochondria themselves, scavenges superoxide anions in order to protect cells from oxidative damage induced by reactive oxygen species (ROS). Unfortunately, the quantification of the fluxes of mitochondrial ROS inside living cells is currently almost impossible, and this in turn limits our knowledge. Presently, the involvement of mitochondrial ROS can only be demonstrated by indirect strategies and among them knockout techniques are the most convincing. The yield of superoxide generation and subsequently ROS production depend mostly on oxygen concentration but can be efficiently modulated by mitochondrial uncoupling. This role could be assumed in part by one of the Uncoupling Proteins (UCPs). These proteins have coenzyme Q as an obligatory partner and we present here the hypothesis of UCPs as a crucial element of the respiratory chain. ROS have been mostly involved in degenerative processes including ageing. More recently, numerous studies point out the role of ROS as true intracellular second messengers. A putative role of mitochondrial ROS as the sensing element of energy metabolism is discussed here. We propose that UCPs could play a central role in modulation of ROS-dependent signalling pathways and metabolic sensing via the modulation of ROS generation.

Animals↗

PubMed2004

Regulatory role of dADAR in ROS metabolism in Drosophila CNS.

Pre-mRNA adenosine deaminase (ADAR) is involved in many physiological processes by either directly converting adenosine to inosine in certain pre-mRNAs or indirectly regulating expression of certain genes. Mutations of Drosophila ADAR (dADAR) results in neuronal dysfunction and hypersensitivity to oxygen deprivation. Recently, we found that the mutant flies were very resistant to paraquat, a compound that generates free radicals. In order to further characterize the neuronal role of dADAR and understand the basis for the resistance to the oxidative stress, we investigated the effect of dADAR on the expression of genes encoding scavengers of cellular reactive oxygen species (ROS) in both dADAR mutant and overexpression flies. Our data show that the expression of the genes encoding known ROS scavengers [superoxide dismutase (SOD) and catalase] is not regulated by dADAR. However, the transcripts of genes encoding two potential ROS scavengers (dhd and Cyp4g1) were robustly increased in dADAR mutant flies, and conversely both were significantly decreased in dADAR overexpressing flies. Using dhd [encoding a Drosophila homolog of the mammalian protein thioredoxin (Trx)] transgenic flies, we confirmed that the resistance of dADAR mutant flies to paraquat resulted, at least partially, from the up-regulation of dhd gene in dADAR mutant flies. Our data not only confirm the importance of ADAR in maintenance of neuronal function but also reveal its regulatory role in the expression of genes encoding ROS scavengers.

Adenosine Deaminase↗

PubMed2002

Nitric oxide acts as an antioxidant and delays programmed cell death in barley aleurone layers.

Nitric oxide (NO) is a freely diffusible, gaseous free radical and an important signaling molecule in animals. In plants, NO influences aspects of growth and development, and can affect plant responses to stress. In some cases, the effects of NO are the result of its interaction with reactive oxygen species (ROS). These interactions can be cytotoxic or protective. Because gibberellin (GA)-induced programmed cell death (PCD) in barley (Hordeum vulgare cv Himalaya) aleurone layers is mediated by ROS, we examined the effects of NO donors on PCD and ROS-metabolizing enzymes in this system. NO donors delay PCD in layers treated with GA, but do not inhibit metabolism in general, or the GA-induced synthesis and secretion of alpha-amylase. alpha-Amylase secretion is stimulated slightly by NO donors. The effects of NO donors are specific for NO, because they can be blocked completely by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. The antioxidant butylated hydroxy toluene also slowed PCD, and these data support our hypothesis that NO is a protective antioxidant in aleurone cells. The amounts of CAT and SOD, two enzymes that metabolize ROS, are greatly reduced in aleurone layers treated with GA. Treatment with GA in the presence of NO donors delays the loss of CAT and SOD. We speculate that NO may be an endogenous modulator of PCD in barley aleurone cells.

Abscisic Acid↗

PubMed1991

Enhanced reactive oxygen species metabolism of air space cells in hypersensitivity pneumonitis.

Reactive oxygen species (ROS) are produced by phagocytic cells as part of host defense mechanisms, but these same products released by air space cells have been shown to contribute to pulmonary inflammation in interstitial lung diseases and likely represent a general mechanism of lung injury. However, the possible contribution of these compounds to lung inflammation in hypersensitivity pneumonitis (HP) has yet to be reported. We performed 11 bronchoalveolar lavage (BAL) studies in six patients with HP and compared the results with results from studies in 21 healthy normal volunteers. In patients with HP, spontaneous and stimulated measures of ROS metabolism by air space cells were significantly higher than those seen in normal volunteers. When alveolar macrophages were purified by depleting neutrophils and eosinophils on density gradients of Percoll (specific gravity 1.075 gm/ml), ROS metabolism remained elevated when compared with that in cells obtained from healthy controls, confirming that alveolar macrophage ROS metabolism is enhanced in patients with HP. Further, we found significant elevations in BAL total protein, lymphocytes, eosinophils, and neutrophils in patients with HP when they were compared with normal volunteers, with an increased proportion of BAL T lymphocytes expressing CD8 and natural killer surface antigens, consistent with previous work. Lavage samples from patients with HP with clinically active disease had higher proportions of BAL eosinophils and concentrations of total protein, lower forced expiratory volume in 1 second, lower forced vital capacity, and lower arterial oxygen tensions, and higher indices of ROS metabolism than samples from patients with HP with inactive disease. HP is associated with evidence of air space inflammation, to which alveolar macrophage-derived ROS may contribute.

Adolescent↗

PubMed1989

Heterogeneity in cell recovery and superoxide production in buoyant, density-defined subpopulations of human alveolar macrophages from healthy volunteers and sarcoidosis patients.

Reactive oxygen species (ROS) are ubiquitous compounds produced by phagocytes with important roles in both host defense and pulmonary inflammation. Enhanced ROS metabolism by alveolar macrophages (AM) has been previously demonstrated in various interstitial lung diseases including sarcoidosis. We studied 17 healthy, nonsmoking volunteers and 10 patients with sarcoidosis by bronchoalveolar lavage, and separated AM on discontinuous Percoll gradients to determine patterns of airspace cell recovery and the corresponding ROS metabolism of density-defined AM subpopulations. AM subpopulations were largely purified from contaminating granulocytes, thereby allowing more accurate estimation of ROS metabolism by AM. In bronchoalveolar lavage material from sarcoidosis patients, increased recovery of cells of high (1.075 gm/ml) density was found, which contrasted with the pattern seen in the volunteers in whom cells of lowest density (1.045 gm/ml) predominated. In addition, dense cells from sarcoidosis patients exhibited enhanced stimulated ROS metabolism compared with cells of similar density obtained from the volunteers or with sarcoid cells of lower density. At least three mechanisms may contribute to increased lung oxidative burden in sarcoidosis. The combination of increased bronchoalveolar lavage cell counts, increased cell recovery at high density, and increased cell function produced substantial increases in the total oxidative burden imposed on the lungs of sarcoidosis patients by airspace cells. We conclude that AM metabolism of ROS is dependent on the density and, by implication, the maturity of the cells and that regulation of AM ROS metabolism differs markedly between sarcoidosis patients and healthy volunteers.

Analysis of Variance↗

PubMed1994

The pentachlorophenol metabolite tetrachloro-p-hydroquinone induces the formation of 8-hydroxy-2-deoxyguanosine in liver DNA of male B6C3F1 mice.

Tetrachloro-p-hydroquinone (TCHQ), the major metabolite of pentachlorophenol (PCP) in mammalian systems, is known to autoxidize to its semiquinone radical under physiological conditions. In this way, PCP could present a potent source of reactive oxygen species (ROS) during metabolization. ROS contribute to numerous modifications of DNA. Formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG), a product of hydroxyl radical attack on DNA, is monitored as a marker of a major genetic lesion induced by agents which produce oxygen radicals. We studied the properties of TCHQ for the induction of oxidative DNA damage in vivo. Male B6C3F1 mice were fed a diet containing TCHQ for 2 and 4 weeks. These experiments resulted in an enhancement of about 50% of the 8-OH-dG portion in liver DNA after administration of 300 mg TCHQ/kg body wt./day for 2 weeks. Control levels did not change over the periods of 2 and 4 weeks, respectively. In contrast to these results, a single i.p. injection of 20 or 50 mg/kg body wt. did not affect the 8-OH-dG content after 6 and 24 h, respectively. These data may support a possible contribution of ROS to the carcinogenicity of PCP.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1988

Increased alveolar macrophage chemiluminescence and airspace cell superoxide production in active pulmonary sarcoidosis.

Alveolar macrophages (AMs) and lymphocytes are activated in pulmonary sarcoidosis. Mediators from these cells are potentially important in the pathophysiology and pathogenesis of this disease. To determine whether the enhanced release of reactive oxygen species (ROS) participates in inflammatory events in sarcoidosis, and to explore the relationship between ROS release and clinical parameters, we studied ROS metabolism of AMs and other airspace cells by luminol-enhanced chemiluminescence and by direct biochemical measurement of superoxide anion production. Ten of 17 patients with sarcoidosis were prospectively found to have active disease by objective radiographic, functional, and laboratory criteria. In these subjects, ROS metabolism by AMs was significantly enhanced compared either with healthy control subjects or with patients with inactive sarcoidosis. Abnormalities in ROS metabolism were not seen in peripheral blood monocytes, suggesting that this increased metabolic activity is compartmentalized to the lung. Enhanced ROS metabolism by AMs was associated with recent adverse chest radiographic changes, recent decline in forced vital capacity, and more advanced radiographic type. These data support the hypothesis that ROS generated by airspace cells can promote parenchymal inflammation in sarcoidosis, are associated with physiologic and radiologic changes, and may thereby contribute to the pathogenesis of sarcoidosis.

Adult↗

PubMed2000

Targeted neuronal gene expression and longevity in Drosophila.

Earlier studies from this laboratory have shown that in the insect, Drosophila melanogaster, the motorneuron is an important cellular nexus between the metabolism of reactive oxygen species (ROS) and adult lifespan. This was demonstrated by experiments in which expression of CuZn SOD (SOD1) specifically in motorneurons was shown to extend the mean and maximum adult lifespans to 140% of normal, and to rescue the majority of deliterious phenotypes displayed by SOD1-null mutants. We have interpreted these results to mean either that the lifespan of the organism is normally limited by the functional lifespan of this post-mitotic cell type, or that ROS metabolism in motorneurons affects organismic lifespan via a systemic, perhaps neuroendocrine, signaling mechanism. We have now extended these studies to ask: (i) whether expression of catalase (CAT) or of the mitochondrially-localized Mn SOD (SOD2) in motorneurons, either singly or in combination with SOD1, have similar effects on lifespan; (ii) if expression of SOD2 can rescue SOD1-null mutant phenotypes; and (iii) if ROS metabolism in cell types other than motorneurons has significant impact on aging and lifespan determination.

Aging↗

PubMed1990

Enhanced reactive oxygen species metabolism of airspace cells and airway inflammation follow antigen challenge in human asthma.

Airflow limitation and airway inflammation follow antigen bronchoprovocation in sensitized individuals. Inflammation likely results from the interplay of several previously demonstrated factors, but the participation and persistence of enhanced reactive oxygen species (ROS) metabolism of airspace cells after antigen challenge have received more limited attention. We studied nine subjects with mild asthma by bronchoalveolar lavage before and 48 (one subject) to 72 (eight subjects) hours after antigen bronchoprovocation and compared airspace cell numbers and types, cell function, and bronchoalveolar lavage fluid protein, albumin, and immunoglobulins. Mild, but significant, airflow limitation persisted at the time of the second lavage. Eosinophil influx was a notable component of the increased airspace cells in postchallenge lavages. Airspace cells demonstrated significantly enhanced ROS metabolism, and total protein, albumin, and IgM levels were higher in postchallenge lavage specimens. Antigen bronchial challenge produces airspace inflammation, which may develop, in part, as a consequence of enhanced ROS metabolism of airspace cells.

Adult↗

PubMed2004

Peripheral parameters of oxidative stress in patients with infiltrative Graves' ophthalmopathy treated with corticosteroids.

Infiltrative ophthalmopathy, which may develop in patients with Graves' disease, is considered an inflammatory disorder of autoimmune background. There is growing evidence that changed reactive oxygen species (ROS) metabolism plays an important role in pathogenesis of autoimmune diseases. Corticotherapy is a principal method of ophthalmopathy treatment, and its therapeutic effect is partially connected with influence on ROS generation systems. This study was undertaken to investigate corticosteroids treatment influence on blood extracellular indices of ROS metabolism in Graves' ophthalmopathy patients. Plasma indices of free radical generation and scavenging were determined in 22 euthyroid patients with active infiltrative Graves' ophthalmopathy initially, after intensive corticotherapy and after completing of steroid treatment. Age- and sex-matched 24 healthy volunteers and 25 euthyroid Graves' patients without overt ophthalmopathy served as controls. In the ophthalmopathy patients hydrogen peroxide (H(2)O(2)), lipid hydroperoxides (ROOH), thiobarbituric acid-reacting substances (TBARS) and ceruloplasmin (CP) levels and superoxide dismutase (SOD) and catalase (CAT) activities were increased, whereas glutathione peroxidase (GPx) and glutathione reductase (GR) activities were reduced. Intensive corticotherapy resulted in normalization (partial for ROOH) of ROS metabolism peripheral markers. After the withdrawal of corticosteroids a reduction of ophthalmopathy clinical activity was present, yet a marked restoration of increased oxidative stress indices was observed, along with activation of antioxidant defence systems (not significant for CAT activity). These data demonstrate that corticosteroids are effective in reduction of peripheral oxidative stress present in infiltrative Graves' ophthalmopathy, but this effect tends to be transient.

Adrenal Cortex Hormones↗

PubMed2005

Mitochondrial metabolism of reactive oxygen species.

Oxidative stress is considered a major contributor to etiology of both "normal" senescence and severe pathologies with serious public health implications. Mitochondria generate reactive oxygen species (ROS) that are thought to augment intracellular oxidative stress. Mitochondria possess at least nine known sites that are capable of generating superoxide anion, a progenitor ROS. Mitochondria also possess numerous ROS defense systems that are much less studied. Studies of the last three decades shed light on many important mechanistic details of mitochondrial ROS production, but the bigger picture remains obscure. This review summarizes the current knowledge about major components involved in mitochondrial ROS metabolism and factors that regulate ROS generation and removal. An integrative, systemic approach is applied to analysis of mitochondrial ROS metabolism, which is now dissected into mitochondrial ROS production, mitochondrial ROS removal, and mitochondrial ROS emission. It is suggested that mitochondria augment intracellular oxidative stress due primarily to failure of their ROS removal systems, whereas the role of mitochondrial ROS emission is yet to be determined and a net increase in mitochondrial ROS production in situ remains to be demonstrated.

Animals↗

PubMed2004

Redox signaling by ionizing radiation in mouse liver.

Since radiation treatment has been reappraised in the treatment of hepatic tumors, radiation response in the liver is emerging as an interesting new area of investigation. In this study, identification of the repertoire of signaling proteins was performed using a proteomics approach involving cellular responses of liver tissue to ionizing radiation. Approximately 800 protein spots were detected. Among them, at least 28 proteins showed significant quantitative alterations after radiation. The significantly altered proteins were categorized as those related to reactive oxygen species (ROS) metabolism, metabolic pathway proteins, and G-type proteins. Particularly, the expression levels of proteins related to ROS metabolism, including cytochrome c, glutathione S-transferase Pi, NADH dehydrogenase, and peroxiredoxin VI, were increased after radiation. It is suggested that although radiation initiates cytotoxic effects, it can also induce a radioprotective antioxidant system.

Animals↗

PubMed1998

Nonsteroidal anti-inflammatory drugs, short-chain fatty acids, and reactive oxygen metabolism in human colorectal cancer cells.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and short-chain fatty acids are effective suppressors of colorectal cancer that may work in part by accentuating apoptosis of transformed cells. Since reactive oxygen species (ROS) can play an important role in regulating cell growth and cell death, we determined the effect of the NSAIDs indomethacin and salicylic acid, and the short-chain fatty acids butyrate and propionate on ROS metabolism in the HT-29 human colorectal carcinoma cell line. We find that all of these agents increase cellular peroxide generation, as determined by two independent assays. Arachidonic acid was also found to increase ROS generation, and could synergize with indomethacin in this reaction. The NSAIDs and short-chain fatty acids under study all possess a carboxyl group, and this carboxyl group is essential for salicylic acid's ability to increase ROS production. Although the two NSAIDs examined increase peroxide production, they were both found to suppress superoxide generation by vitamin K3 (menadione), a redox cycling compound similar to those found in the colon. The short-chain fatty acids did not have this activity. The ability of these NSAIDs and short-chain fatty acids to alter cellular ROS metabolism may contribute to their chemopreventive activity.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

Melatonin prevents disruption of hepatic reactive oxygen species metabolism in rats treated with carbon tetrachloride.

We reported that melatonin prevents the progression of carbon tetrachloride (CCl4)-induced acute liver injury in rats possibly by attenuating enhanced lipid peroxidation and reduced glutathione depletion. Herein, we examined the effect of melatonin on the changes in hepatic reactive oxygen species (ROS) metabolism in rats with a single intraperitoneal injection of CCl4 (1.6 g/kg body weight); the intent was to clarify the therapeutic mechanism of the indoleamine on CCl4-induced acute liver injury. Rats with and without CCl4 treatment received a single oral dose of melatonin (10, 50 or 100 mg/kg body weight) 6 hr after CCl4 treatment. Hepatic concentrations of ascorbic acid (ASC) and vitamin E (VE) and hepatic activities of superoxide dismutase (SOD), catalase (CAT), Se-glutathione peroxidase (Se-GSH-Px), glutathione reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PDH), and xanthine oxidase (XO) were determined 6 and 24 hr after CCl4 treatment. The liver of CCl4-treated rats showed reductions in ASC concentrations, and SOD activity and an increase in G-6-PDH activity at 6 hr after treatment and further decreases in ACS concentrations and SOD activity and also further increase in G-6-PDH activity in addition to decreases in CAT and GSSG-R activities and increases in VE concentrations and XO activity at 24 hr after treatment. Melatonin attenuated the reductions in hepatic ASC concentrations and SOD, CAT and GSSG-R activities and the increase in hepatic XO activity in a dose-dependent manner without affecting either hepatic Se-GSH-Px activity or the increased hepatic VE concentration and G-6-PDH activity at 24 hr after CCl4 treatment. No dose of melatonin influenced hepatic ACS and VE concentrations and SOD, CAT, Se-GSH-Px, G-6-PDH, and XO activities in CCl4-untreated rats. These results indicate that melatonin postadministered at pharmacological doses prevents the disruption of hepatic ROS metabolism associated with ASC, SOD, CAT, GSSG-R, and XO, in addition to reduced glutathione, in CCl4-treated rats.

Animals↗

PubMed1999

Signals controlling the expression of cytosolic ascorbate peroxidase during pathogen-induced programmed cell death in tobacco.

In plants ascorbate peroxidase (APX) is an important H2O2-detoxifying enzyme. The expression of APX is rapidly induced in response to stresses that result in the accumulation of reactive oxygen species (ROS). We have recently reported that the steady-state level of transcripts encoding cytosolic APX (cAPX) is dramatically induced during the hypersensitive response (HR) of tobacco plants infected with tobacco mosaic virus (TMV). Because cAPX expression is closely linked to the production of ROS in plant cells, studying the regulation cAPX mRNA can reveal some of the signal transduction events associated with ROS metabolism during the HR. Analysis of cAPX mRNA induction during the HR suggested that the expression of cAPX is under the control of the HR signal transduction pathway. The activation of cAPX expression followed signaling events such as changes in protein phosphorylation and induction of ion fluxes. Expression of cAPX was suppressed under conditions of low oxygen pressure, and could only be mimicked by enhancing the intracellular generation of ROS. Interestingly, salicylic acid (SA), which is thought to be involved in ROS metabolism during the HR, did not affect the induction of cAPX mRNA during TMV-induced HR. Using cAPX expression as a marker for the production of ROS, it is suggested that SA may not be involved in the formation of ROS during the HR of tobacco to TMV, and that ROS may not be involved in the induction of the pathogenesis-related protein, PR-1, during this process.

Anti-Infective Agents↗

PubMed1996

Capacity of circulating neutrophils to produce reactive oxygen species after exhaustive exercise.

To investigate the cause of disagreement within the large body of literature concerning the effect of exercise on the capacity of circulating neutrophils to produce reactive oxygen species (ROS), 10 male endurance-trained athletes underwent maximal exercise. The generation of superoxide radical (O2-.) by neutrophils was first detected on a cell-by-cell basis by using histochemical nitro blue tetrazolium tests performed directly on fresh unseparated blood, which showed that responsive neutrophils under several stimulatory conditions relatively decreased after exercise. Similarly, O2-. detected with bis-N-methylacridinium nitrate (lucigenin)-dependent chemiluminescence (CL) of a fixed number of purified neutrophils on stimulation with opsonized zymosan was decreased slightly after exercise. In contrast, the 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol)-dependent CL response of the neutrophils indicative of the myeloperoxidase (MPO)-mediated formation of highly reactive oxidants was significantly enhanced after exercise. It therefore suggests that the pathway of neutrophil ROS metabolism might be forwarded from the precursor O2-. production to the stages of more reactive oxidant formation due to the facilitation of MPO degranulation. In addition, these phenomena were closely associated with the exercise-induced mobilization of neutrophils from the marginated pool into the circulation, which was mediated by the overshooting of catecholamines during exercise. These findings indicate that the use of different techniques for detecting ROS or the different stages of neutrophil ROS metabolism could explain some of the disparate findings of the previous studies.

Adult↗

PubMed1997

Targeted overexpression of Cu/Zn superoxide dismutase protects pancreatic beta-cells against oxidative stress.

Current evidence suggests that reactive oxygen species (ROS) may participate in the destruction of pancreatic beta-cells leading to type 1 diabetes. Genetic factors pre-disposing individual susceptibility to type 1 diabetes might therefore include those affecting the efficacy of ROS metabolism. In a direct in vivo test of this hypothesis, we have generated strains of mice carrying transgenes that supplement basal levels of the radical-scavenging enzyme Cu/Zn superoxide dismutase in the pancreas via directed expression in beta-cells. Expression of these transgenes significantly enhances resistance to alloxan-induced diabetogenesis above that of control animals, thereby providing direct in vivo evidence that genetic variation in ROS metabolism can affect susceptibility to oxidative stress-mediated diabetogenesis.

Animals↗

PubMed1992

Effect of 2,2'-dicarbomethoxylamino-5,5'-dibenzimidazolyl ketone on antioxidant defenses of Acanthocheilonema viteae and its laboratory host Mastomys natalensis.

The effect of the macrofilaricidal agent of 2,2'-dicarbomethoxylamino-5,5'-dibenzimidazolyl ketone (C.D.R.I. compound 82/437), on the metabolism of reactive oxygen species (ROs) in Acanthocheilonema viteae and Mastomys natalensis was measured following intraperitoneal administration at therapeutic doses. The recovered worms possessed substantially reduced levels of catalase and glutathione peroxidase (GPx), and thus were less able to detoxify H2O2. Nonetheless, the subcutaneous and adjoining muscle tissues, in which the parasites were lodged, exhibited elevated levels of antioxidant enzymes and reduced glutathione. It is concluded that compound 82/437 kills the filariid by paralysing its H2O2 detoxifying capacity without altering ROs metabolism in the tissue in which the parasite resides. Furthermore, since catalase and GPx of the liver and lungs do not show sign of inhibition, a difference appears to exist in the enzymes of the parasite and the host.

Animals↗