Levels Of Cellular Oxidative Stress Research Articles

High Levels of Oxidative Stress Globally Inhibit Gene Transcription and Histone Acetylation

Oxidative stress has been shown to induce ubiquitynation of RNA polymerase II, but direct bearing of that phenomenon on global transcription still remains elusive. In this report, we show that high levels of cellular oxidative stress globally inhibit gene transcription, and that this decrease in transcription is only partly attributable to reduced binding of RNA polymerase II to a model gene promoter. Importantly, we show that this decrease in transcription correlates with a significant decrease in histone H3 and H4 acetylation levels both throughout a model gene, and also globally in the nucleus of cells. Our results suggest that high levels of oxidative stress can inhibit transcription by a mechanism, at least in part, that impedes global histone acetylation levels.

Enhancing risk of ethanol on MeIQx-induced rat hepatocarcinogenesis is accompanied with increased levels of cellular proliferation and oxidative stress

We investigated promotion potential of ethanol after initiation of hepatocarcinogenesis in male, 21-day-old, F344 rats by exposure to 10 ppm 2-amino-3, 8-dimethylimidazo[4,5- f]quinoxaline pellet diet for 8 weeks. The rats in group 1 were then fed on liquid control diet for 16 weeks, group 2 receiving the same diet containing 5% ethanol for 8 weeks followed by 8 weeks on the control diet, while group 3 animals were given 5% ethanol containing liquid diet for the entire16 weeks. On sacrifice at the end of week 24, glutathione S-transferase placental form positive foci, putative preneoplastic lesions in the liver, cell proliferation as indicated by proliferating cell nuclear antigen immunohistochemical staining and levels of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, were significantly increased in the liver of group 3 along with non significant alteration of 8-oxoguanine DNA glycosylase mRNA expression. Lack of persistent increase of above parameters was found in transient ethanol exposure group. These results suggest that chronic consumption of ethanol promotes hepatocarcinogenesis by increasing oxidative stress and cell proliferation. It is also evident that abstinence of ethanol during the second stage stops its persistent promotion effect.

PCB-induced oxidative stress in endothelial cells: modulation by nutrients

AbstractThere is an increasing body of evidence suggesting that exposure to Superfund chemicals may have adverse consequences on many organ systems, as well as carcinogenic and atherogenic effects. This is particularly true for polyhalogenated aromatic hydrocarbons such as the polychlorinated biphenyls (PCBs). The vascular endothelium, which is constantly exposed to blood components including environmental contaminants, is extremely vulnerable to chemical insult as well as necrotic and apoptotic injury. Our recent studies suggest that certain PCBs, especially coplanar PCBs, can compromise normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. Our findings suggest that an increase in the level of cellular oxidative stress is a significant event in PCB-mediated endothelial cell dysfunction and that nutrients can modulate PCB-induced oxidative stress and endothelial toxicity. We have demonstrated that the dietary fat linoleic acid, the parent unsaturated fatty acid of the omega-6 family, can increase endothelial dysfunction induced by selected PCBs, probably by contributing to oxidative stress and as the result of the production of toxic metabolites called leukotoxins. The subsequent imbalance in the overall cellular oxidant/antioxidant status can activate oxidative stress- or redox-sensitive transcription factors, which in turn promote gene expression for inflammatory cytokines and adhesion molecules, intensifying the inflammatory response and endothelial cell dysfunction. Our data also suggest that antioxidant nutrients such as vitamin E can protect against endothelial cell damage mediated by PCBs or polyunsaturated dietary fats by interfering with oxidative stress-sensitive and proinflammatory signaling pathways. The concept that nutrition can modify or ameliorate the toxicity of Superfund chemicals is provocative and warrants further study as the implications for human health are significant. The information from such studies could be used to develop dietary recommendations and nutritional interventions for populations at high risk for exposure to PCBs, including communities living near Superfund sites and those exposed via occupation or diet.

Existing data suggest that Alzheimer's disease is preventable.

The ultimate goal of Alzheimer's disease (AD) research is to prevent the onset of the neurodegenerative process and thereby allow successful aging without cognitive decline. Herein I argue that a simple and effective preventative approach for AD may be in hand. AD is a disorder associated with the aging process and is, accordingly, characterized by cellular and molecular changes that occur in age-related diseases in other organ systems. Such changes include increased levels of oxidative stress, perturbed energy metabolism, and accumulation of insoluble (oxidatively modified) proteins (prominent among which are amyloid beta-peptide and tau). The risk of several other prominent age-related disorders, including cardiovascular disease, cancer, and diabetes, is known to be influenced by the level of food intake--high food intake increases risk, and low food intake reduces risk. An overwhelming body of data from studies of rodents and monkeys has documented the profound beneficial effects of dietary restriction (DR) in extending life span and reducing the incidence of age-related diseases. Reduced levels of cellular oxidative stress and enhancement of energy homeostasis contribute to the beneficial effects of DR. Recent findings suggest that DR may enhance resistance of neurons in the brain to metabolic, excitotoxic, and oxidative insults relevant to the pathogenesis of AD and other neurodegenerative disorders. While further studies will be required to establish the extent to which DR will reduce the incidence of AD, it would seem prudent (based on existing data) to recommend DR as widely applicable preventative approach for age-related disorders including neurodegenerative disorders.

Dietary restriction and 2‐deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: Evidence for a preconditioning mechanism

Stroke, an age-related disorder involving degeneration of neurons resulting from cerebral ischemia, is a major cause of disability and mortality. Although dietary restriction (DR) extends lifespan and reduces levels of cellular oxidative stress in several different organ systems including the brain, the impact of DR on ischemic brain injury is unknown. We report that maintenance of adult rats on a DR regimen resulted in reduced brain damage and improved behavioral outcome in a middle cerebral artery occlusion–reperfusion (MCAO-R) stroke model. Administration of 2-deoxyglucose (2-DG), a nonmetabolizable analogue of glucose, to rats fed ad libitum resulted in reduced ischemic brain damage and improved behavioral outcome following MCAO-R. 2-DG protected cultured hippocampal neurons against chemical hypoxia, demonstrating a direct protective action on neurons. DR and 2-DG administration resulted in an increase in the level of the stress protein heat-shock protein 70 (HSP-70) in striatal cells in vivo, and 2-DG treatment induced HSP-70 in cultured neurons suggesting involvement of a preconditioning stress response in the neuroprotective actions of DR and 2-DG. The neuroprotective effect of DR and 2-DG in this focal cerebral ischemia model suggests that outcome following stroke may be improved in individuals who follow a regimen of reduced food intake. J. Neurosci. Res. 57:830–839, 1999. © 1999 Wiley-Liss, Inc.

Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: Evidence for a preconditioning mechanism

Stroke, an age-related disorder involving degeneration of neurons resulting from cerebral ischemia, is a major cause of disability and mortality. Although dietary restriction (DR) extends lifespan and reduces levels of cellular oxidative stress in several different organ systems including the brain, the impact of DR on ischemic brain injury is unknown. We report that maintenance of adult rats on a DR regimen resulted in reduced brain damage and improved behavioral outcome in a middle cerebral artery occlusion-reperfusion (MCAO-R) stroke model. Administration of 2-deoxyglucose (2-DG), a nonmetabolizable analogue of glucose, to rats fed ad libitum resulted in reduced ischemic brain damage and improved behavioral outcome following MCAO-R. 2-DG protected cultured hippocampal neurons against chemical hypoxia, demonstrating a direct protective action on neurons. DR and 2-DG administration resulted in an increase in the level of the stress protein heat-shock protein 70 (HSP-70) in striatal cells in vivo, and 2-DG treatment induced HSP-70 in cultured neurons suggesting involvement of a preconditioning stress response in the neuroprotective actions of DR and 2-DG. The neuroprotective effect of DR and 2-DG in this focal cerebral ischemia model suggests that outcome following stroke may be improved in individuals who follow a regimen of reduced food intake.

Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease.

Parkinson's disease (PD) is an age-related disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN) and corresponding motor deficits. Oxidative stress and mitochondrial dysfunction are implicated in the neurodegenerative process in PD. Although dietary restriction (DR) extends lifespan and reduces levels of cellular oxidative stress in several different organ systems, the impact of DR on age-related neurodegenerative disorders is unknown. We report that DR in adult mice results in resistance of dopaminergic neurons in the SN to the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-induced loss of dopaminergic neurons and deficits in motor function were ameliorated in DR rats. To mimic the beneficial effect of DR on dopaminergic neurons, we administered 2-deoxy-D-glucose (2-DG; a nonmetabolizable analogue of glucose) to mice fed ad libitum. Mice receiving 2-DG exhibited reduced damage to dopaminergic neurons in the SN and improved behavioral outcome following MPTP treatment. The 2-DG treatment suppressed oxidative stress, preserved mitochondrial function, and attenuated cell death in cultured dopaminergic cells exposed to the complex I inhibitor rotenone or Fe2+. 2-DG and DR induced expression of the stress proteins heat-shock protein 70 and glucose-regulated protein 78 in dopaminergic cells, suggesting involvement of these cytoprotective proteins in the neuroprotective actions of 2-DG and DR. The striking beneficial effects of DR and 2-DG in models of PD, when considered in light of recent epidemiological data, suggest that DR may prove beneficial in reducing the incidence of PD in humans.

2-Deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: evidence for the involvement of stress proteins.

Food restriction can extend life span in rodents and was recently reported to increase the resistance of neurons in the brain to excitotoxic and metabolic insults. In principle, administration to ad libitum fed rodents of an agent that reduces glucose availability to cells should mimick certain aspects of food restriction. We now report that administration of 2-deoxy-D-glucose (2DG), a non-metabolizable analog of glucose, to adult rats results in a highly significant reduction in seizure-induced spatial memory deficits and hippocampal neuron loss. Pretreatment of rat hippocampal cell cultures with 2DG decreases the vulnerability of neurons to excitotoxic (glutamate) and oxidative (Fe2+) insults. The protective action of 2DG is associated with decreased levels of cellular oxidative stress and enhanced calcium homeostasis. 2DG treatment increased levels of the stress-responsive proteins GRP78 and HSP70 in hippocampal neurons, without affecting levels of Bcl-2 or GRP75, suggesting that mild reductions in glucose availability can increase neuronal resistance to oxidative and metabolic insults by a mechanism involving induction of stress proteins. Our findings establish cell culture and in vivo models of "chemical food restriction" which may prove useful in elucidating mechanisms of neuroprotection and in developing preventive approaches for neurodegenerative disorders that involve oxidative stress and excitotoxicity.

No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice

Amyotrophic lateral sclerosis (ALS) is a fatal disease in which spinal cord motor neurons degenerate resulting in progressive paralysis. Some cases of ALS are caused by mutations in the antioxidant enzyme Cu/Zn-superoxide dismutase (SOD). Transgenic mice expressing ALS-linked Cu/Zn-SOD mutations (SODMutM) exhibit a phenotype analogous to that of human ALS patients. Dietary restriction (DR) is a well-established means of extending lifespan in rodents. It may act by reducing levels of cellular oxidative stress. We therefore tested the hypothesis that DR will retard the development of the clinical phenotype and extend the lifespan of SODMutM. There was no significant difference in age of disease onset in mice placed on a DR regimen beginning at 6 weeks of age compared to mice fed ad libitum, and disease duration was shortened indicating that DR accelerates the clinical course. Histological analyses indicated a similar extent of lower motor neuron degeneration in SODMutM maintained on DR or ad libitum diets. We conclude that a dietary manipulation known to extend lifespan has no beneficial effect in an animal model of familial ALS.