The Experts below are selected from a list of 171825 Experts worldwide ranked by ideXlab platform
Flint M Beal - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial dysfunction and Oxidative Damage in alzheimer s and parkinson s diseases and coenzyme q10 as a potential treatment
Journal of Bioenergetics and Biomembranes, 2004Co-Authors: Flint M BealAbstract:There is substantial evidence that mitochondrial dysfunction and Oxidative Damage may play a key role in the pathogenesis of neurodegenerative disease. Evidence supporting this in both Alzheimer's and Parkinson's diseases is continuing to accumulate. This review discusses the increasing evidence for a role of both mitochondrial dysfunction and Oxidative Damage in contributing to beta-amyloid deposition in Alzheimer's disease. I also discuss the increasing evidence that Parkinson's disease is associated with abnormalities in the electron transport gene as well as Oxidative Damage. Lastly, I reviewed the potential efficacy of coenzyme Q as well as a number of other antioxidants in the treatment of both Parkinson's and Alzheimer's diseases.
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Oxidative Damage to mitochondrial dna shows marked age dependent increases in human brain
Annals of Neurology, 1993Co-Authors: Patrizia Mecocci, Usha Macgarvey, Allan Kaufman, Deborah A Koontz, John M Shoffner, Douglas C Wallace, Flint M BealAbstract:A major theory of aging is that Oxidative Damage may accumulate in DNA and contribute to physiological changes associated with aging. We examined age-related accumulation of Oxidative Damage to both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in human brain tissue. We measured the oxidized nucleoside, 8-hydroxy-2′-deoxyguanosine (OH8dG), in DNA isolated from 3 regions of cerebral cortex and cerebellum from 10 normal humans aged 42 to 97 years. The amount of OH8dG, expressed as a ratio of the amount of deoxyguanosine (dG) or as fmol/μg of DNA, increased progressively with normal aging in both nDNA and mtDNA; however, the rate of increase with age was much greater in mtDNA. There was a significant 10-fold increase in the amount of OH8dG in mtDNA as compared with nDNA in the entire group of samples, and a 15-fold significant increase in patients older than 70 years. These results show for the first time that there is a progressive age-related accumulation in Oxidative Damage to DNA in human brain, and that the mtDNA is preferentially affected. It is possible that such Damage may contribute to age-dependent increases in incidence of neurodegenerative diseases.
Michael P Murphy - One of the best experts on this subject based on the ideXlab platform.
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prevention of mitochondrial Oxidative Damage as a therapeutic strategy in diabetes
Diabetes, 2004Co-Authors: Katherine Green, Martin D Brand, Michael P MurphyAbstract:Hyperglycemia causes many of the pathological consequences of both type 1 and type 2 diabetes. Much of this Damage is suggested to be a consequence of elevated production of reactive oxygen species by the mitochondrial respiratory chain during hyperglycemia. Mitochondrial radical production associated with hyperglycemia will also disrupt glucose-stimulated insulin secretion by pancreatic β-cells, because pancreatic β-cells are particularly susceptible to Oxidative Damage. Therefore, mitochondrial radical production in response to hyperglycemia contributes to both the progression and pathological complications of diabetes. Consequently, strategies to decrease mitochondrial radical production and Oxidative Damage may have therapeutic potential. This could be achieved by the use of antioxidants or by decreasing the mitochondrial membrane potential. Here, we outline the background to these strategies and discuss how antioxidants targeted to mitochondria, or selective mitochondrial uncoupling, may be potential therapies for diabetes.
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prevention of mitochondrial Oxidative Damage using targeted antioxidants
Annals of the New York Academy of Sciences, 2002Co-Authors: Geoffrey F Kelso, Carolyn M Porteous, Gillian Hughes, Elizabeth C Ledgerwood, Alison M Gane, Robin A J Smith, Michael P MurphyAbstract:: Mitochondrial-targeted antioxidants that selectively block mitochondrial Oxidative Damage and prevent some types of cell death have been developed. These antioxidants are ubiquinone and tocopherol derivatives and are targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation. Because of the large mitochondrial membrane potential, these cations accumulated within mitochondria inside cells, where the antioxidant moiety prevents lipid peroxidation and protects mitochondria from Oxidative Damage. The mitochondrially localized ubiquinone also protected mammalian cells from hydrogen peroxide-induced apoptosis while an untargeted ubiquinone analogue was ineffective against apoptosis. When fed to mice these compounds accumulated within the brain, heart, and liver; therefore, using these mitochondrial-targeted antioxidants may help investigations of the role of mitochondrial Oxidative Damage in animal models of aging.
Bruce N Ames - One of the best experts on this subject based on the ideXlab platform.
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Oxidative Damage increases with age in a canine model of human brain aging
Journal of Neurochemistry, 2002Co-Authors: Elizabeth Head, Bruce N Ames, Tory M Hagen, B A Muggenburg, Norton W Milgram, Carl W CotmanAbstract:We assayed levels of lipid peroxidation, protein carbonyl formation, glutamine synthetase (GS) activity and both oxidized and reduced glutathione to study the link between Oxidative Damage, aging and β-amyloid (Aβ) in the canine brain. The aged canine brain, a model of human brain aging, naturally develops extensive diffuse deposits of human-type Aβ. Aβ was measured in immunostained prefrontal cortex from 19 beagle dogs (4–15 years). Increased malondialdehyde (MDA), which indicates increased lipid peroxidation, was observed in the prefrontal cortex and serum but not in cerebrospinal fluid (CSF). Oxidative Damage to proteins (carbonyl formation) also increased in brain. An age-dependent decline in GS activity, an enzyme vulnerable to Oxidative Damage, and in the level of glutathione (GSH) was observed in the prefrontal cortex. MDA level in serum correlated with MDA accumulation in the prefrontal cortex. Although 11/19 animals exhibited Aβ, the extent of deposition did not correlate with any of the Oxidative Damage measures, suggesting that each form of neuropathology accumulates in parallel with age. This evidence of widespread Oxidative Damage and Aβ deposition is further justification for using the canine model for studying human brain aging and neurodegenerative diseases.
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adrenalectomy causes Oxidative Damage and monoamine increase in the brain of rats and enhances immobilization stress induced Oxidative Damage and neurotransmitter changes
International Journal of Stress Management, 1998Co-Authors: Jiankang Liu, Isao Yokoi, Stephanie J Doniger, Hideaki Kabuto, Akitane Mori, Bruce N AmesAbstract:The paradox that increased levels of glucocorticoids can either enhance or suppress the organism's defense against stress, has been an obstacle to formulating a unified picture of glucocorticoid function. To clarify the glucocorticoid paradox, we examined male Sprague-Dawley rats exposed to immobilization stress and/or bilateral adrenalectomy (ADX), and measured Oxidative Damage to lipid, protein, and DNA, as well as monoamine neurotransmitter turnover. ADX, which is similar to stress, induces an increase in lipid peroxidation and protein oxidation, accompanied by increased monoamine neurotransmitter turnover in several regions of the brain of rats. The effect of ADX is greater than that induced by short-term immobilization stress. In addition, ADX enhances stress-induced Oxidative Damage and increase of monoamine neurotransmitter turnover. These results, together with our previous finding that long-term stress causes Oxidative Damage to the brain, suggest that stress levels of glucocorticoids, or levels lower than basal, cause Oxidative Damage. However, basal levels of glucocorticoids appear to buffer against Oxidative Damage. These findings provide possible mechanisms to understand the glucocorticoid paradox, and support the stress-Oxidative hypothesis of aging acceleration.
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Oxidative Damage and mitochondrial decay in aging
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Mark K Shigenaga, Tory M Hagen, Bruce N AmesAbstract:We argue for the critical role of Oxidative Damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the Oxidative lesions that accumulate with age. Several mitochondrial functions decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function, in part by increasing cellular ATP production. Such evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to Oxidative Damage is likely to be a major contributor to cellular, tissue, and organismal aging.
Arlan Richardson - One of the best experts on this subject based on the ideXlab platform.
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the role of Oxidative Damage and stress in aging
Mechanisms of Ageing and Development, 2004Co-Authors: Alex Bokov, Asish R Chaudhuri, Arlan RichardsonAbstract:The Free Radical/Oxidative Stress Theory of Aging, which was first proposed in 1956, is currently one of the most popular explanations for how aging occurs at the biochemical/molecular level. However, most of the evidence in support of this theory is correlative, e.g., Oxidative Damage to various biomolecules increases with age, and caloric restriction, which increases life span and retards aging, reduces the age-related increase in Oxidative Damage to biomolecules. The most direct test of the Free Radical/Oxidative Stress Theory of Aging is to specifically alter the age-related increase in Oxidative Damage and determine how this alteration affects life span. For the first time, investigators can use genetically altered animals to test directly the role of Oxidative Damage in aging. In this manuscript, we critically review the past research in this area and discuss potential future research directions in testing the Free Radical/Oxidative Theory of Aging.
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increased Oxidative Damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice
Journal of Biological Chemistry, 1998Co-Authors: Melissa D Williams, Holly Van Remmen, Craig C Conrad, Tingting Huang, Charles J Epstein, Arlan RichardsonAbstract:This study characterizes mitochondria isolated from livers of Sod2 −/+ and Sod2 +/+ mice. A 50% decrease in manganese superoxide dismutase (MnSOD) activity was observed in mitochondria isolated from Sod2 −/+ mice compared withSod2 +/+ mice, with no change in the activities of either glutathione peroxidase or copper/zinc superoxide dismutase. However, the level of total glutathione was 30% less in liver mitochondria of the Sod2 −/+ mice. The reduction in MnSOD activity in Sod2 −/+ mice was correlated to an increase in Oxidative Damage to mitochondria: decreased activities of the Fe-S proteins (aconitase and NADH oxidoreductase), increased carbonyl groups in proteins, and increased levels of 8-hydroxydeoxyguanosine in mitochondrial DNA. In contrast, there were no significant changes in Oxidative Damage in the cytosolic proteins or nuclear DNA. The increase in Oxidative Damage in mitochondria was correlated to altered mitochondrial function. A significant decrease in the respiratory control ratio was observed in mitochondria isolated from Sod2 −/+ mice compared with Sod2 +/+ mice for substrates metabolized by complexes I, II, and III. In addition, mitochondria isolated from Sod2 −/+ mice showed an increased rate of induction of the permeability transition. Therefore, this study provides direct evidence correlating reduced MnSOD activity in vivo to increased Oxidative Damage in mitochondria and alterations in mitochondrial function.
Fli M Eal - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial dysfunction and Oxidative Damage in alzheimer s and parkinson s diseases and coenzyme q10 as a potential treatment
Journal of Bioenergetics and Biomembranes, 2004Co-Authors: Fli M EalAbstract:There is substantial evidence that mitochondrial dysfunction and Oxidative Damage may play a key role in the pathogenesis of neurodegenerative disease. Evidence supporting this in both Alzheimer's and Parkinson's diseases is continuing to accumulate. This review discusses the increasing evidence for a role of both mitochondrial dysfunction and Oxidative Damage in contributing to β-amyloid deposition in Alzheimer's disease. I also discuss the increasing evidence that Parkinson's disease is associated with abnormalities in the electron transport gene as well as Oxidative Damage. Lastly, I reviewed the potential efficacy of coenzyme Q as well as a number of other antioxidants in the treatment of both Parkinson's and Alzheimer's diseases.