The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration

Aging is the progressive accumulation of changes with time that are associated with or responsible for the ever-increasing susceptibility to disease and death which accompanies advancing age. These time-related changes are attributed to the aging process. The nature of the aging process has been the subject of considerable speculation. Accumulating evidence now indicates that the sum of the deleterious free radical reactions going on continuously throughout the cells and tissues constitutes the aging process or is a major contributor to it. In mammalian systems the free radical reactions are largely those involving oxygen. Dietary manipulations expected to lower the rate of production of free radical reaction damage have been shown (i) to increase the life span of mice, rats, fruit flies, nematodes, and rotifers, as well as the "life span" of neurospora; (ii) to inhibit development of some forms of cancer; (iii) to enhance humoral and cell-mediated immune responses; and (iv) to slow development of amyloidosis and the autoimmune disorders of NZB and NZB/NZW mice. In addition, studies strongly suggest that free radical reactions play a significant role in the deterioration of the cardiovascular and central nervous systems with age. The free radical theory of aging provides reasonable explanations for age-associated phenomena, including (i) the relationship of the average life spans of mammalian species to their basal metabolic rates, (ii) the clustering of degenerative diseases in the terminal part of the life span, (iii) the beneficial effect of food restriction on life span, (iv) the greater longevity of females, and (v) the increase in autoimmune manifestations with age. It is not unreasonable to expect on the basis of present data that the healthy life span can be increased by 5-10 or more years by keeping body weight down, at a level compatible with a sense of well-being, while ingesting diets adequate in essential nutrients but designed to minimize random free radical reactions in the body.

https://www.pnas.org/content/pnas/78/11/7124.full.pdf

The aging process

Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues.

The discovery of the adventitious formation of the potential cancer-causing agent acrylamide in a variety of foods during cooking has raised much concern, but the chemical mechanism(s) governing its production are unclear. Here we show that acrylamide can be released by the thermal treatment of certain amino acids (asparagine, for example), particularly in combination with reducing sugars, and of early Maillard reaction products (N-glycosides). Our findings indicate that the Maillard-driven generation of flavour and colour in thermally processed foods can -- under particular conditions -- be linked to the formation of acrylamide.

Acrylamide from Maillard reaction products

Lyophilization and development of solid protein pharmaceuticals

The Carbohydrates: Chemistry and Biochemistry

The visco-elastic properties of salivary secretions are due to high molecular-weight glycoproteins, known as mucins. Mucins are composed of numerous oligosaccharide side-chains O-glycosidically linked through 2-acetamido-2-deoxy-alpha-D-galactose to the hydroxyl groups of seryl and threonyl residues of the protein core; on the average, every fourth amino acid residue is involved in such a bond. This work conveys their isolation and purification, compiles the compositional analysis of several mammalian submaxillary and sublingual mucins; defines the conditions of the alkaline beta-elimination reaction, its mechanism, and importance in structural studies of glycoprotens, and briefly discusses the influence of stimuli on mucous secretions, as well as biosynthesis, structural diversity, and physiological role of salivary mucous glycoproteins.

Current concepts of the structure and nature of mammalian salivary mucous glycoproteins.

Hyaluronic acid, a linear polymer of alternating N-acetyl-D-glucosamine and D-glucuronic acid units with a molecular weight of 105 to 107, is known to be degraded by X-rays, ultraviolet radiation, and ultrasonic waves (1-6). This substance and other natural and synthetic polymers are also degraded by autoxidants such as ascorbic acid or ferrous or cuprous ions in the presence of oxygen (7), by mechanisms probably involving free radicals (5, 8, 9) similar to those involved in their degradation by radiations. This latter reaction has been described as the oxidativereductive depolymerization (ORD) reaction (10). Alexander et al. (8, 11) noted degradations of polymethacrylic acid by both X-rays and several autoxidants such as cysteine, but the present study is the first formal comparison of the effects of radiations and autoxidants on hyaluronic acid. The present work was carried out in order to compare the effects of radiation on hyaluronic acid with those produced by autoxidants under closely similar conditions. A semiquantitative comparison of the effects of X-rays, ,B-rays (P32, internally), and autoxidants is reported. The effect of visible light with riboflavin as sensitizer was also studied. For the ORD reaction, the results of a survey of possible autoxidants and antioxidants are included. Viscometric measurements were used as the criterion of the degree of degradation of hyaluronic acid.

Depolymerization of Hyaluronic Acid by Autoxidants and Radiations

Severe protein-calorie malnutrition is common in patients with AIDS and could contribute to the progressive deterioration characteristic of that disease. Selenium deficiency could also have a negative impact on immune function and other organ functions vital for recovery from infectious diseases. Therefore, to assess any role for selenium in AIDS we determined plasma and erythrocyte selenium levels and glutathione peroxidase activity in 13 patients with AIDS compared to 8 patients with AIDS-related complex (ARC) and 14 healthy controls. Plasma selenium levels were significantly reduced in AIDS patients compared to controls (p less than .0001) and to ARC (p less than .02). Erythrocyte selenium levels in both AIDS and ARC were also reduced compared to controls (p less than .02), but not to each other. Glutathione peroxidase activity in AIDS was 28.9 +/- 1.4 U/g Hb vs 38.4 +/- 6.9 in ARC (p = NS) and 52.3 +/- 1.7 in controls (p less than .0001 vs AIDS; p less than .02 vs ARC). When all groups were combined, there were significant correlations between total lymphocyte count and both plasma selenium (r = .53; p less than .002) and erythrocyte glutathione peroxidase activity (r = .65; p less than .0001). In addition, strong correlations were noted between plasma selenium and serum albumin (r = .68; p less than .0001), plasma selenium and glutathione peroxidase (r = .77; p less than .0001), and glutathione peroxidase and hematocrit (r = .66; p less than .0001). In AIDS or ARC, no correlations between selenium with disease duration or weight loss were present. We conclude that, in comparison to normals, patients manifesting infection with human immunodeficiency virus have evidence of selenium deficiency as determined by diminished plasma and erythrocyte levels and glutathione peroxidase activity. These abnormalities are most marked in patients with AIDS, but are also present in patients with AIDS-related complex. Selenium deficiency has important implications for the progression and pathogenesis of clinical disease in AIDS.

Anthony Herp

Papers

The Carbohydrates: Chemistry and Biochemistry

Current concepts of the structure and nature of mammalian salivary mucous glycoproteins.

Depolymerization of Hyaluronic Acid by Autoxidants and Radiations

Abnormalities of blood selenium and glutathione peroxidase activity in patients with acquired immunodeficiency syndrome and aids-related complex

Lipid composition of tracheobronchial secretions from normal individuals and patients with cystic fibrosis.