At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

N epsilon-(carboxymethyl)lysine, N epsilon-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.

Role of Oxidative Stress in Development of Complications in Diabetes

Emerging infectious diseases (EIDs) of free-living wild animals can be classified into three major groups on the basis of key epizootiological criteria: (i) EIDs associated with “spill-over” from domestic animals to wildlife populations living in proximity; (ii) EIDs related directly to human intervention, via host or parasite translocations; and (iii) EIDs with no overt human or domestic animal involvement. These phenomena have two major biological implications: first, many wildlife species are reservoirs of pathogens that threaten domestic animal and human health; second, wildlife EIDs pose a substantial threat to the conservation of global biodiversity.

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Emerging Infectious Diseases of Wildlife-- Threats to Biodiversity and Human Health

Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. Free radicals are formed disproportionately in diabetes by glucose oxidation, nonenzymatic glycation of proteins, and the subsequent oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the simultaneous decline of antioxidant defense mechanisms can lead to damage of cellular organelles and enzymes, increased lipid peroxidation, and development of insulin resistance. These consequences of oxidative stress can promote the development of complications of diabetes mellitus. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins, and hyperglycemia in diabetes, and their consequences, are discussed in this review. In vivo studies of the effects of various conventional and alternative drugs on these biomarkers are surveyed. There is a need to continue to explore the relationship between free radicals, diabetes, and its complications, and to elucidate the mechanisms by which increased oxidative stress accelerates the development of diabetic complications, in an effort to expand treatment options.

Diabetes, oxidative stress, and antioxidants: a review

Oxidative stress and oxidative damage to tissues are common end points of chronic diseases, such as atherosclerosis, diabetes, and rheumatoid arthritis. The question addressed in this review is whether increased oxidative stress has a primary role in the pathogenesis of diabetic complications or whether it is a secondary indicator of end-stage tissue damage in diabetes. The increase in glycoxidation and lipoxidation products in plasma and tissue proteins suggests that oxidative stress is increased in diabetes. However, some of these products, such as 3-deoxyglucosone adducts to lysine and arginine residues, are formed independent of oxidation chemistry. Elevated levels of oxidizable substrates may also explain the increase in glycoxidation and lipoxidation products in tissue proteins, without the necessity of invoking an increase in oxidative stress. Further, age-adjusted levels of oxidized amino acids, a more direct indicator of oxidative stress, are not increased in skin collagen in diabetes. We propose that the increased chemical modification of proteins by carbohydrates and lipids in diabetes is the result of overload on metabolic pathways involved in detoxification of reactive carbonyl species, leading to a general increase in steady-state levels of reactive carbonyl compounds formed by both oxidative and nonoxidative reactions. The increase in glycoxidation and lipoxidation of tissue proteins in diabetes may therefore be viewed as the result of increased carbonyl stress. The distinction between oxidative and carbonyl stress is discussed along with the therapeutic implications of this difference.

Role of oxidative stress in diabetic complications: a new perspective on an old paradigm.

Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxide in low density lipoprotein.

Protein glycation and oxidative stress in diabetes mellitus and ageing

It has been postulated that the etiology of the complications of diabetes involves oxidative stress, perhaps as a result of hyperglycemia. Consistent with this hypothesis, it has been shown that glucose, under physiological conditions, produces oxidants that possess reactivity similar to the hydroxyl free radical. These oxidants hydroxylate benzoic acid, fragment protein, and induce peroxidation in phosphatidylcholine liposomes and low-density lipoprotein (LDL) when LDL is incubated with hyperglycemic levels of glucose in vitro. These reactions are accelerated by transition metals and inhibited by a metal-chelating agent. The atherosclerotic potential of LDL in diabetes mellitus is often discussed in terms of protein glycosylation, which may affect cellular interactions. Our studies demonstrate, however, that peroxidative reactions also accompany LDL glycosylation in vitro. Peroxidative modification of LDL has also been implicated in LDL atherogenicity. Our studies indicate that glycosylation and peroxidation occur concomitantly in LDL modified by glucose in vitro and may both contribute to the behavioral changes of this lipoprotein.

Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose.

Glucose may oxidise under physiological conditions and lead to the production of protein reactive ketoaldehydes, hydrogen peroxide and highly reactive oxidants. Glucose is thus able to modify proteins by the attachment of its oxidation derived aldehydes, leading to the development of novel protein fluoro-phores, as well as fragment protein via free radical mechanisms.The fragmentation of protein by glucose is inhibitable by metal chelators such as diethylenetriamine pentaacetic acid (DETAPAC) and free radical scavengers such as benzoic acid, and sorbitol. The enzymic antioxidant, catalase, also inhibits protein fragmentation.Protein glycation and protein oxidation are inextricably linked. Indeed, using boronate affinity chromatography to separate glycated from non-glycated material, we demonstrate that proteins which arc glycated exhibit an enhanced tryptophan oxidation. Our observation that both glycation and oxidation occur simultaneously further supports the hypothesis that tissue damage associated wit...

James V. Hunt

Papers

Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxide in low density lipoprotein.

Protein glycation and oxidative stress in diabetes mellitus and ageing

Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose.

Oxidative Glycation and Free Radical Production: A Causal Mechanism of Diabetic Complications

Free radical damage to proteins: The influence of the relative localization of radical generation, antioxidants, and target proteins