Advances in Free Radical Biology & Medicine最新文献

The vertebrate retina has several features that make it vulnerable to damage from autoxidation. The photoreceptor membranes contain high levels of polyunsaturated fatty acids; abundant mitochondria are present which may leak activated oxygen species; and light exposure of the retina may cause photoxidation. These features are analyzed in detail, and the various antioxidant mechanisms of the vertebrate retina are surveyed. The interplay among oxidant stress and antioxidant defenses is illustrated by review of situations where these variables are either artificially manipulated or changed naturally. Vitamin E deficiency damages the retina in a number of well-defined vertebrate model systems, and a lipid autoxidation mechanism for this damage is widely assumed. The retina is quite sensitive to damage by elevated or prolonged light exposure; however, a free-radical role in light damage to the retina has not been established. An alternative mechanism for damage due to vitamin E deficiency and light is considered, which involves elevated vitamin A levels and vitamin A toxicity. Evidence is reviewed that the primate retina requires both vitamin E and selenium. The puzzling role of ocular melanin in light damage and protection is reviewed. Possible contributions of autoxidative damage to aging of the human retina are discussed.

Ascorbate has been demonstrated to be an effective antioxidant. It can act both directly, by reaction with aqueous peroxyl radicals, and indirectly, by restoring the antioxidant properties of fat-soluble vitamin E. The overall consequence of these antioxidant activities is the beneficial control of lipid peroxidation of cellular membranes including those surrounding as well as within intracellular organelles. Intracellular free radical attack on non-lipid nuclear material may also be diminished.

In addition to reviewing the chemical basis of the antioxidant function of vitamin C, this report will focus on the importance of vitamin C as an antioxidant component of plasma as well as the extracellular fluids surrounding the lung, lens and retina. The protection by vitamin C of phagocytic cells involved in the defense against pathogen invasion will also be discussed.

This review presents evidence which supports the importance of vitamin C as a component of the overall antioxidant protective mechanisms found in cells and tissues. The data are consistent and form a strong consensus for investigating the importance of the antioxidant function of vitamin C in the maintenance of human health.

The induction of cancer by chemicals proceeds through a series of stages as a normal cell transforms into a malignant neoplasm. Free radicals, particularly those derived from molecular oxygen, may participate throughout these transitions. In this article the evidence for the involvement of free radicals in some of the later events associated with carcinogenesis, namely, tumor promotion, are reviewed. Tumor promoters elicit the production of radicals by direct chemical generation and through the indirect activation of cellular metabolic sources. Both pathways may lead to the formation of a cellular prooxidant state. Studies with free radical scavengers demonstrate inhibition of biochemical and biological sequelae of tumor promoter exposure. Potential biological targets of radical attack include nucleic acids, proteins, and lipids and the possible role of radical-mediated modification of these biomolecules in tumor promotion is discussed.

Cigarette smoke, either directly or indirectly, causes alpha-1-proteinase inhibitor (a1PI) to lose elastase inhibitory capacity (EIC), leaving lung connective tissues susceptible to proteolytic degradation. This paper discusses possible mechanisms for inactivation by cigarette smoke (CS) and by a model system [NO, isoprene, and air] that duplicates much of CS free radical chemistry. Inactivation of a1PI by either CS or the model is biphasic; a fast inactivation is followed by a slower one. With pre-prepared extracts, only the slow inactivation is observed. Apparently short-lived species in the smoke itself and the model system cause the fast inactivation; they may be peroxynitrates, which form in smoke from nitrogen dioxide and peroxyl radicals. The slower inactivation appears to involve hydrogen peroxide and/or organic hydroperoxides or species produced by them. Incubation of a1PI with linoleic acid produces a slow loss of EIC, prevented by the presence of vitamin E, which supports the hypothesis of a route involving lipid hydroperoxides. Protection of a1PI by various types of compounds shows that unprotonated amines and amino acids protect, but the protonated or acylated compounds do not. Ascorbate and glutathione provide the strongest protection.

Classical pathology demonstrated that fluorescent lipofuscin granules developed in the aging cells. Age-related fluorescent substances increase with lipid oxidation of tissues. The fluorophores of these substances have been considered to be conjugated Schiff bases between primary amines or proteins and malonaldehyde. Our recent studies showed that the fluorophores produced in the in vitro reaction of primary amines or proteins with malonaldehyde are 1,4-dihydropyridine-3,5-dicarbaldehydes, whose fluorescence characteristics are similar to but not always the same as those of the age-related fluorescent substances. The in vitro reaction of primary amines or proteins with oxidized lipids produces fluorescent substances similar to those in the aging cells or tissues. Monofunctional aldehydes can also participate in the formation of the fluorescent substances. The fluorescent substances produced from the reaction of primary amines or proteins with monofunctional aldehydes showed spectra close to those of the age-related fluorescent substances.

Biological membranes are complex mixtures of lipids that aggregate to form the lipid bilayer structure. Phospholipids are key architectural components of membranes and these phospholipids are themselves highly oxidizable if they have significant polyunsaturation. Autoxidation of phospholipids proceeds to give many different peroxide products by a mechanism that is essentially the same as the mechanism for autoxidation of fatty acids or esters in the bulk phase or in inert organic solvents. This mechanism is understood reasonably well and products isolated from phospholipid autoxidation may be described based upon this general autoxidation mechanism. High pressure liquid chromatography methods for separation of complex phospholipid mixtures, including their oxidation products, have been developed and kinetic methods long used to study autoxidation in organic solvents have been translated to study autoxidation of micelles or phospholipid aggregates such as liposomes. The current status of research in this field is reviewed.

Evidence concerning the involvement of metabolic rate, prooxidants and antioxidants in processes of aging and development of animals is examined. Life span of poikilotherms and homeotherms is apparently dependent on a genetically-determined metabolic potential (i.e., total amount of energy expended during life per unit weight) and the rate of metabolic expenditure. Metabolic potential may vary in different species and under different environmental conditions. The relationship between metabolic potential, metabolic rate and duration of life is most demonstrable in organisms with a variable basal metabolic rate, such as poikilotherms and mammalian hibernators. Experimental regimes which reduce metabolic rate prolong life span and tend to retard the rate of age-related physiological and biochemical changes and vice versa. Effects of metabolic rate on aging may be mediated by oxygen free radicals. Antioxidant defenses tend to decline during aging, whereas, free radical induced damage seems to increase with age. Intracellular environment becomes progressively less reducing during the course of development and aging. We have postulated that such a shift in redox potential may play a role in the modulation of gene activity during development and aging.

Pulmonary oxgen toxicity results in intraalveolar hemorrhage and edema following the breakdown of the alveolar-capillary barrier. Hyperoxia causes increased production of partially reduced species of oxygen in lung cells critical for maintaining the integrity of the alveolar-capillary barrier, the capillary endothelial cell and the alveolar epithelium. $\text{In}$ $\text{vitro}$ studies of subcellular organelles isolated from lung including mitochondria, microsomes and nuclei show that oxygen radical production by these organelles increases as a function of oxygen tension. Morphological alterations of lung cell organelles in early stages of oxygen toxicity probably reflect cell injury induced by toxic reactions of relatively high local concentrations of reactive oxygen species. Cell injury and secondary inflammatory responses will occur when edogenous antioxidant defenses are overwhelmed. Oxygen-injured lung cells release paracrine mediators which effect the growth and differentiation of other lung cells. A number of factors can modify pulmonary oxygen toxicity, including the maturational state of the lung, infiltration of phagocytic cells, liposome-mediated augmentation of lung cell antioxidant enzyme activities and commonly prescribed medications.