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Showing papers on "Oxidative stress published in 2009"


Journal ArticleDOI
TL;DR: It is argued that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
Abstract: Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.

4,369 citations


Journal ArticleDOI
24 Feb 2009-ACS Nano
TL;DR: A possible mechanism of toxicity is proposed which involves disruption of the mitochondrial respiratory chain by Ag-np leading to production of ROS and interruption of ATP synthesis, which in turn cause DNA damage.
Abstract: Silver nanoparticles (Ag-np) are being used increasingly in wound dressings, catheters, and various household products due to their antimicrobial activity. The toxicity of starch-coated silver nanoparticles was studied using normal human lung fibroblast cells (IMR-90) and human glioblastoma cells (U251). The toxicity was evaluated using changes in cell morphology, cell viability, metabolic activity, and oxidative stress. Ag-np reduced ATP content of the cell caused damage to mitochondria and increased production of reactive oxygen species (ROS) in a dose-dependent manner. DNA damage, as measured by single cell gel electrophoresis (SCGE) and cytokinesis blocked micronucleus assay (CBMN), was also dose-dependent and more prominent in the cancer cells. The nanoparticle treatment caused cell cycle arrest in G2/M phase possibly due to repair of damaged DNA. Annexin-V propidium iodide (PI) staining showed no massive apoptosis or necrosis. The transmission electron microscopic (TEM) analysis indicated the presen...

3,261 citations


Journal ArticleDOI
TL;DR: Recognition of upstream and downstream antioxidant therapy to oxidative stress has been proved an effective tool in alteration of any neuronal damage as well as free radical scavenging.
Abstract: Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism of antioxidants, overproduction or incorporation of free radicals from environment to living system leads to serious penalty leading to neuro-degeneration. Neural cells suffer functional or sensory loss in neurodegenerative diseases. Apart from several other environmental or genetic factors, oxidative stress (OS) leading to free radical attack on neural cells contributes calamitous role to neuro-degeneration. Though, oxygen is imperative for life, imbalanced metabolism and excess reactive oxygen species (ROS) generation end into a range of disorders such as Alzheimer's disease, Parkinson's disease, aging and many other neural disorders. Toxicity of free radicals contributes to proteins and DNA injury, inflammation, tissue damage and subsequent cellular apoptosis. Antioxidants are now being looked upon as persuasive therapeutic against solemn neuronal loss, as they have capability to combat by neutralizing free radicals. Diet is major source of antioxidants, as well as medicinal herbs are catching attention to be commercial source of antioxidants at present. Recognition of upstream and downstream antioxidant therapy to oxidative stress has been proved an effective tool in alteration of any neuronal damage as well as free radical scavenging. Antioxidants have a wide scope to sequester metal ions involved in neuronal plaque formation to prevent oxidative stress. In addition, antioxidant therapy is vital in scavenging free radicals and ROS preventing neuronal degeneration in post-oxidative stress scenario.

2,874 citations


Journal ArticleDOI
TL;DR: The biomarker 8-OHdG or 8-oxodG has been a pivotal marker for measuring the effect of endogenous oxidative damage to DNA and as a factor of initiation and promotion of carcinogenesis and has been used to estimate the DNA damage in humans after exposure to cancer-causing agents.
Abstract: There is extensive experimental evidence that oxidative damage permanently occurs to lipids of cellular membranes, proteins, and DNA. In nuclear and mitochondrial DNA, 8-hydroxy-2' -deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2' -deoxyguanosine (8-oxodG) is one of the predominant forms of free radical-induced oxidative lesions, and has therefore been widely used as a biomarker for oxidative stress and carcinogenesis. Studies showed that urinary 8-OHdG is a good biomarker for risk assessment of various cancers and degenerative diseases. The most widely used method of quantitative analysis is high-performance liquid chromatography (HPLC) with electrochemical detection (EC), gas chromatography-mass spectrometry (GC-MS), and HPLC tandem mass spectrometry. In order to resolve the methodological problems encountered in measuring quantitatively 8-OHdG, the European Standards Committee for Oxidative DNA Damage was set up in 1997 to resolve the artifactual oxidation problems during the procedures of isolation and purification of oxidative DNA products. The biomarker 8-OHdG or 8-oxodG has been a pivotal marker for measuring the effect of endogenous oxidative damage to DNA and as a factor of initiation and promotion of carcinogenesis. The biomarker has been used to estimate the DNA damage in humans after exposure to cancer-causing agents, such as tobacco smoke, asbestos fibers, heavy metals, and polycyclic aromatic hydrocarbons. In recent years, 8-OHdG has been used widely in many studies not only as a biomarker for the measurement of endogenous oxidative DNA damage but also as a risk factor for many diseases including cancer.

1,538 citations


Journal ArticleDOI
TL;DR: Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity and supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.
Abstract: Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species (ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisome-proliferator-activated receptor gamma (PPARγ), and PPARγ coactivators PGC1α and PGC1β only in the absence of antioxidants (P < 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.

1,376 citations


Journal ArticleDOI
TL;DR: This review focuses on current knowledge of the pathways of redox regulation, with discussion of the somewhat juxtaposed hypotheses of "oxidative damage" versus "Oxidative signaling," within the wider context of physiological function, from plant cell biology to potential applications.
Abstract: Reactive oxygen species (ROS) have multifaceted roles in the orchestration of plant gene expression and gene-product regulation. Cellular redox homeostasis is considered to be an “integrator” of information from metabolism and the environment controlling plant growth and acclimation responses, as well as cell suicide events. The different ROS forms influence gene expression in specific and sometimes antagonistic ways. Low molecular antioxidants (e.g., ascorbate, glutathione) serve not only to limit the lifetime of the ROS signals but also to participate in an extensive range of other redox signaling and regulatory functions. In contrast to the low molecular weight antioxidants, the “redox” states of components involved in photosynthesis such as plastoquinone show rapid and often transient shifts in response to changes in light and other environmental signals. Whereas both types of “redox regulation” are intimately linked through the thioredoxin, peroxiredoxin, and pyridine nucleotide pools, they ...

1,280 citations


Journal ArticleDOI
TL;DR: This article showed that spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells.
Abstract: Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.

1,230 citations


Journal ArticleDOI
TL;DR: It is shown that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function.
Abstract: High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H2O2-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H2O2 emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H2O2 emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

1,129 citations


Journal ArticleDOI
TL;DR: Diet-derived antioxidants may be particularly important in diminishing cumulative oxidative damage and helping us to stay healthier for longer.
Abstract: Free radicals and other oxygen-derived species are constantly generated in vivo, both by “accidents of chemistry” and for specific metabolic purposes. The reactivity of different free radicals varies, but some can cause severe damage to biological molecules, especially to DNA, lipids, and proteins. Antioxidant defense systems scavenge and minimize the formation of oxygen-derived species, but they are not 100% effective. Hence, diet-derived antioxidants may be particularly important in diminishing cumulative oxidative damage and helping us to stay healthier for longer. Repair systems exist to deal with molecules that have been oxidatively damaged. Damage to DNA by hydroxyl radicals appears to occur in all aerobic cells, and might be a significant contributor to the age-dependent development of cancer. Lipid peroxidation probably contributes significantly to the development of atherosclerosis.

1,067 citations


Journal ArticleDOI
TL;DR: The role of different antioxidants as potential selection criteria for improving plant salt tolerance has been critically discussed and the potential of this approach in counteracting stress-induced oxidative stress has been discussed at length in this review.

1,025 citations


Journal ArticleDOI
TL;DR: The sources and metabolism of ROS in this organelle are reviewed, including the conditions that regulate the production of these species, such as mild uncoupling, oxygen tension, respiratory inhibition, Ca2+ and K+ transport, and mitochondrial content and morphology.

Journal ArticleDOI
TL;DR: The comparative analysis demonstrated that particle composition probably played a primary role in the cytotoxic effects of different nanoparticles, however, the potential genotoxicity might be mostly attributed to particle shape.
Abstract: Although the biological effects of some nanomaterials have already been assessed, information on toxicity and possible mechanisms of various particle types are insufficient. Moreover, the role of particle properties in the toxic reaction remains to be fully understood. In this paper, we aimed to explore the interrelationship between particle size, shape, chemical composition and toxicological effects of four typical nanomaterials with comparable properties: carbon black (CB), single wall carbon nanotube, silicon dioxide (SiO(2)) and zinc dioxide (ZnO) nanoparticles. We investigated the cytotoxicity, genotoxicity and oxidative effects of particles on primary mouse embryo fibroblast cells. As observed in the methyl thiazolyl tetrazolium (MTT) and water-soluble tetrazolium (WST) assays, ZnO induced much greater cytotoxicity than non-metal nanoparticles. This was significantly in accordance with intracellular oxidative stress levels measured by glutathione depletion, malondialdehyde production, superoxide dismutase inhibition as well as reactive oxygen species generation. The results indicated that oxidative stress may be a key route in inducing the cytotoxicity of nanoparticles. Compared with ZnO nanoparticles, carbon nanotubes were moderately cytotoxic but induced more DNA damage determined by the comet assay. CB and SiO(2) seemed to be less effective. The comparative analysis demonstrated that particle composition probably played a primary role in the cytotoxic effects of different nanoparticles. However, the potential genotoxicity might be mostly attributed to particle shape.

Journal ArticleDOI
TL;DR: Analysis of plants expressing targeted modifications of components of the antioxidant system and comparison of closely related plant species with different degrees of toxic metal sensitivity have established a link between the degree of plant tolerance to metals and the level of antioxidants.

Journal ArticleDOI
TL;DR: The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases and suggests the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment.
Abstract: Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Owing to the pleiotropic effects of GSH on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates, and/or oxidation state can be compromised by inherited or acquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases, such as cancer, Parkinson's disease, and Alzheimer's disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases.

Journal ArticleDOI
TL;DR: The results of numerous studies show that LPO, and probably oxidative stress in general, may exert both deleterious and beneficial effects in vivo, and it appears difficult to regulate the formation of free radical-mediated LPO products.

Journal ArticleDOI
TL;DR: From the evaluation ofmGSH influence on different pathologic settings such as hypoxia, ischemia/reperfusion injury, aging, liver diseases, and neurologic disorders, it is becoming evident that it has an important role in the pathophysiology and biomedical strategies aimed to boost mGSH levels.
Abstract: Mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain Among the arsenal of antioxidants and detoxifying enzymes existing in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death mGSH importance is based not only on its abundance, but also on its versatility to counteract hydrogen peroxide, lipid hydroperoxides, or xenobiotics, mainly as a cofactor of enzymes such as glutathione peroxidase or glutathione-S-transferase (GST) Many death-inducing stimuli interact with mitochondria, causing oxidative stress; in addition, numerous pathologies are characterized by a consistent decrease in mGSH levels, which may sensitize to additional insults From the evaluation of mGSH inf

Journal ArticleDOI
TL;DR: The findings suggest that AgNP cytotoxicity is primarily the result of oxidative stress and is independent of the toxicity of Ag(+) ions.

Journal ArticleDOI
TL;DR: Significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model and provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.
Abstract: Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (Aβ) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of Aβ binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.

Journal ArticleDOI
TL;DR: This review discusses the targeting of the elevated copper levels and oxidative stress levels in cancer with the aid of a copper chelator d-penicillamine (d-pen) for potential cancer treatment.

Journal ArticleDOI
TL;DR: The purpose of this review is to discuss the role of oxidative stress in metabolic syndrome and its major clinical manifestations (namely coronary artery disease, hypertension and diabetes), and to highlight the effects of lifestyle modification in ameliorating oxidative stress.

Journal ArticleDOI
TL;DR: The results show that TiO(2) nanoparticles induced 8-hydroxy-2'-deoxyguanosine, gamma-H2AX foci, micronuclei, and DNA deletions, and inflammation was present as characterized by a moderate inflammatory response, and these findings raise concern about potential health hazards associated with TiO('s nanoparticles exposure.
Abstract: Titanium dioxide (TiO2) nanoparticles are manufactured worldwide in large quantities for use in a wide range of applications including pigment and cosmetic manufacturing. Although TiO2 is chemically inert, TiO2 nanoparticles can cause negative health effects, such as respiratory tract cancer in rats. However, the mechanisms involved in TiO2-induced genotoxicity and carcinogenicity have not been clearly defined and are poorly studied in vivo. The present study investigates TiO2 nanoparticles–induced genotoxicity, oxidative DNA damage, and inflammation in a mice model. We treated wild-type mice with TiO2 nanoparticles in drinking water and determined the extent of DNA damage using the comet assay, the micronuclei assay, and the γ-H2AX immunostaining assay and by measuring 8-hydroxy-2′-deoxyguanosine levels and, as a genetic instability endpoint, DNA deletions. We also determined mRNA levels of inflammatory cytokines in the peripheral blood. Our results show that TiO2 nanoparticles induced 8-hydroxy-2′-deoxyguanosine, γ-H2AX foci, micronuclei, and DNA deletions. The formation of γ-H2AX foci, indicative of DNA double-strand breaks, was the most sensitive parameter. Inflammation was also present as characterized by a moderate inflammatory response. Together, these results describe the first comprehensive study of TiO2 nanoparticles–induced genotoxicity in vivo in mice possibly caused by a secondary genotoxic mechanism associated with inflammation and/or oxidative stress. Given the growing use of TiO2 nanoparticles, these findings raise concern about potential health hazards associated with TiO2 nanoparticles exposure. [Cancer Res

Journal ArticleDOI
TL;DR: The cellular and vascular aspects of reactive oxygen and nitrogen species generation and their role in the pathogenesis of ischaemia–reperfusion phenomena and the proposed mechanisms of oxidative stress-related neuronal death will be reflected upon.
Abstract: Stroke is one of the leading causes of mortality and morbidity, with astronomical financial repercussions on health systems worldwide. Ischaemic stroke accounts for approximately 80-85% of all cases and is characterised by the disruption of cerebral blood flow and lack of oxygen to the affected area. Oxidative stress culminates due to an imbalance between pro-oxidants and antioxidants and consequent excessive production of reactive oxygen species. Reactive oxygen species are biphasic, playing a role in normal physiological processes and are also implicated in a number of disease processes, whereby they mediate damage to cell structures, including lipids, membranes, proteins, and DNA. The cerebral vasculature is a major target of oxidative stress playing a critical role in the pathogenesis of ischaemic brain injury following a cerebrovascular attack. Superoxide, the primary reactive oxygen species, and its derivatives have been shown to cause vasodilatation via the opening of potassium channels and altered vascular reactivity, breakdown of the blood-brain barrier and focal destructive lesions in animal models of ischaemic stroke. However, reactive oxygen species are involved in normal physiological processes including cell signalling, induction of mitogenesis, and immune defence. Primarily, this review will focus on the cellular and vascular aspects of reactive oxygen and nitrogen species generation and their role in the pathogenesis of ischaemia-reperfusion phenomena. Secondly, the proposed mechanisms of oxidative stress-related neuronal death will be reflected upon and in summation specific targeted neuroprotective therapies targetting oxidative stress and their role in the pathogenesis of stroke will be discussed.

Journal ArticleDOI
TL;DR: The antioxidant defense systems, free radicals production and their role in cancer and age related diseases and also some of the recent patent relevant to the field are reviewed.
Abstract: Chronic inflammation is a pathological condition characterized by continued active inflammation response and tissue destruction. Many of the immune cells including macrophages, neutrophils and eosinophils are involved directly or by production of inflammatory cytokine production in pathology of chronic inflammation. From literatures, it is appear that there is a general concept that chronic inflammation can be a major cause of cancers and express aging processes. Moreover, many studies suggest that chronic inflammation could have serious role in wide variety of age-related diseases including diabetes, cardiovascular and autoimmune diseases. Inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor for cancer and age-related disorders. This article reviews the antioxidant defense systems, free radicals production and their role in cancer and age related diseases and also some of the recent patent relevant to the field. Study of the role of free radicals in human diseases can help the investigators to consider the antioxidants as proper agents in preventive medicine, especially for cancer and aging processes.

Journal ArticleDOI
18 Sep 2009-Small
TL;DR: Gold nanoparticles (AuNPs) are generally considered nontoxic, similar to bulk gold, which is inert and biocompatible, but here, ligand chemistry is a critical parameter determining the degree of cytotoxicity.
Abstract: Gold nanoparticles (AuNPs) are generally considered nontoxic, similar to bulk gold, which is inert and biocompatible. AuNPs of diameter 1.4 nm capped with triphenylphosphine monosulfonate (TPPMS), Au1.4MS, are much more cytotoxic than 15-nm nanoparticles (Au15MS) of similar chemical composition. Here, major cell-death pathways are studied and it is determined that the cytotoxicity is caused by oxidative stress. Indicators of oxidative stress, reactive oxygen species (ROS), mitochondrial potential and integrity, and mitochondrial substrate reduction are all compromised. Genome-wide expression profiling using DNA gene arrays indicates robust upregulation of stress-related genes after 6 and 12 h of incubation with a 2 x IC50 concentration of Au1.4MS but not with Au15MS nanoparticles. The caspase inhibitor Z-VAD-fmk does not rescue the cells, which suggests that necrosis, not apoptosis, is the predominant pathway at this concentration. Pretreatment of the nanoparticles with reducing agents/antioxidants N-acetylcysteine, glutathione, and TPPMS reduces the toxicity of Au1.4MS. AuNPs of similar size but capped with glutathione (Au1.1GSH) likewise do not induce oxidative stress. Besides the size dependency of AuNP toxicity, ligand chemistry is a critical parameter determining the degree of cytotoxicity. AuNP exposure most likely causes oxidative stress that is amplified by mitochondrial damage. Au1.4MS nanoparticle cytotoxicity is associated with oxidative stress, endogenous ROS production, and depletion of the intracellular antioxidant pool.

Journal ArticleDOI
TL;DR: Evidence of organ-specific antioxidant responses elicited by environmental pollutants in humans and animal models is reviewed and it is suggested that in complex organisms such as mammals, organs and tissues contain distinct antioxidant systems, and this may form the basis for differential susceptibility to environmental toxic agents.
Abstract: In aerobic organisms, oxygen is essential for efficient energy production but paradoxically, produces chronic toxic stress in cells. Diverse protective systems must exist to enable adaptation to oxidative environments. Oxidative stress (OS) results when production of reactive oxidative species (ROS) exceeds the capacity of cellular antioxidant defenses to remove these toxic species. Epidemiological and clinical studies have linked environmental factors such as diet and lifestyle to cancer, diabetes, atherosclerosis, and neurodegenerative disorders. All of these conditions, as well as the aging process, are associated with OS due to elevation of ROS or insufficient ROS detoxification. Many environmental pollutants engage signaling pathways that are activated in response to OS. The same sequences of events are also associated with the etiology and early pathology of many chronic diseases. Investigations of oxidative responses in different in vivo models suggest that, in complex organisms such as mammals, organs and tissues contain distinct antioxidant systems, and this may form the basis for differential susceptibility to environmental toxic agents Thus, understanding the pathways leading to the induction of antioxidant responses will enable development of strategies to protect against oxidative damage. We shall review evidence of organ-specific antioxidant responses elicited by environmental pollutants in humans and animal models.

Journal ArticleDOI
TL;DR: An overview of the roles ROS and autophagy play in cell survival and cell death, and their importance to cancer is given.
Abstract: Reactive oxygen species (ROS) have been identified as signaling molecules in various pathways regulating both cell survival and cell death. Autophagy, a self-digestion process that degrades intracellular structures in response to stress, such as nutrient starvation, is also involved in both cell survival and cell death. Alterations in both ROS and autophagy regulation contribute to cancer initiation and progression, and both are targets for developing therapies to induce cell death selectively in cancer cells. Many stimuli that induce ROS generation also induce autophagy, including nutrient starvation, mitochondrial toxins, hypoxia, and oxidative stress. Some of these stimuli are under clinical investigation as cancer treatments, such as 2-methoxyestrodial and arsenic trioxide. Recently, it was demonstrated that ROS can induce autophagy through several distinct mechanisms involving Atg4, catalase, and the mitochondrial electron transport chain (mETC). This leads to both cell-survival and cell-dea...

Journal ArticleDOI
TL;DR: This minireview focused on direct evidence for the generation of free radicals in intact animals following acute Cd overload and discussed the association of ROS in chronic Cd toxicity and carcinogenesis.

Journal ArticleDOI
TL;DR: This review focuses on recent findings and interaction between endothelium-dependent vasodilation and oxidative stress in cardiovascular diseases.
Abstract: The vascular endothelium is involved in the release of various vasodilators, including nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor, as well as vasoconstrictors. NO plays an important role in the regulation of vascular tone, inhibition of platelet aggregation, and suppression of smooth muscle cell proliferation. Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis. Cardiovascular diseases are associated with endothelial dysfunction. It is well known that the grade of endothelial function is a predictor of cardiovascular outcomes. Oxidative stress plays an important role in the pathogenesis and development of cardiovascular diseases. Several mechanisms contribute to impairment of endothelial function. An imbalance of reduced production of NO or increased production of reactive oxygen species, mainly superoxide, may promote endothelial dysfunction. One mechanism by which endothelium-dependent vasodilation is impaired is an increase in oxidative stress that inactivates NO. This review focuses on recent findings and interaction between endothelial function and oxidative stress in cardiovascular diseases. (Circ J 2009; 73: 411 - 418)

Journal ArticleDOI
TL;DR: These aldehydes exhibit great reactivity with biomolecules, such as proteins, DNA, and phospholipids, generating a variety of intra and intermolecular covalent adducts, which can diffuse within or even escape from the cell and attack targets far from the site of the original event.

Journal ArticleDOI
TL;DR: Results reveal that the cardioprotective effects of H2S are mediated in large part by a combination of antioxidant and antiapoptotic signaling.
Abstract: Rationale: The recent emergence of hydrogen sulfide (H2S) as a potent cardioprotective signaling molecule necessitates the elucidation of its cytoprotective mechanisms. Objective: The present study evaluated potential mechanisms of H2S-mediated cardioprotection using an in vivo model of pharmacological preconditioning. Methods and Results: H2S (100 μg/kg) or vehicle was administered to mice via an intravenous injection 24 hours before myocardial ischemia. Treated and untreated mice were then subjected to 45 minutes of myocardial ischemia followed by reperfusion for up to 24 hours, during which time the extent of myocardial infarction was evaluated, circulating troponin I levels were measured, and the degree of oxidative stress was evaluated. In separate studies, myocardial tissue was collected from treated and untreated mice during the early (30 minutes and 2 hours) and late (24 hours) preconditioning periods to evaluate potential cellular targets of H2S. Initial studies revealed that H2S provided profound protection against ischemic injury as evidenced by significant decreases in infarct size, circulating troponin I levels, and oxidative stress. During the early preconditioning period, H2S increased the nuclear localization of Nrf2, a transcription factor that regulates the gene expression of a number of antioxidants and increased the phosphorylation of protein kinase Ce and STAT-3. During the late preconditioning period, H2S increased the expression of antioxidants (heme oxygenase-1 and thioredoxin 1), increased the expression of heat shock protein 90, heat shock protein 70, Bcl-2, Bcl-xL, and cyclooxygenase-2 and also inactivated the proapoptogen Bad. Conclusions: These results reveal that the cardioprotective effects of H2S are mediated in large part by a combination of antioxidant and antiapoptotic signaling.