Oxidants and antioxidants in proliferative senescence.

In terms of the amount of experimental research it has generated the free radical theory of ageing is one of the most popular hypotheses to explain this ubiquitous phenomenon. From the theory two postulates were derived: either cellular defence mechanisms against free radical-dependent oxidants deteriorate during ageing of cells, or essential, unrepairable damages are imparted to the cell by oxidants regardless of the activity of antioxidant defence systems. The many reports dealing with a putative breakdown in antioxidant defence systems failed to positively support this postulate. However, a minor depletion in cellular glutathione by exposure to a model lipophilic peroxide led to a significant decrement in DNA and protein synthesis. In other words, the glutathione redox cycle is intrinsically fallible with respect to defending the cellular DNA replication system against this model lipophilic peroxide. Interestingly, after ageing in culture cells a partial uncoupling of the NADPH-producing and -consuming systems tends to take place. Experiments involving the addition of antioxidants to the culture medium have failed to significantly extend the lifespan of cultured diploid somatic cells. The level of antioxidants appears to be a modulator rather than a primary determinant of cellular ageing in culture. Several lines of evidence suggest that DNA damages accumulate during ageing of the organism, but no oxidant-related DNA damage has been pinpointed in the cultured cell system. Human mutants with defects in antioxidant enzymes have not shown conclusive signs of accelerated ageing. Cells from patients with Werner's syndrome (progeria of the adult), on the other hand, do not suffer from a defect in their antioxidant defence system, nor do they accumulate more than normal amounts of autofluorescent products resulting from lipid peroxidation. The recent finding that Werner's syndrome constitutes a mutator phenotype may prompt the comparison of oxidant- and ageing-related mutation spectra in order to investigate a mutational theory of ageing as a new derivative from the free radical hypothesis.     

Oxidants and antioxidants in aquatic animals.

1. Oxidative stress, potentially, is experienced by all aerobic life when antioxidant defenses are overcome by prooxidant forces, and is the basis of many physiological abberations. 2. Environmental contaminants may enhance oxidative stress in aquatic organisms, e.g. highly elevated rates of ideopathic lesions and neoplasia among fish inhabiting polluted environments is increasingly related to oxidative stress associated with environmental pollution. 3. Metabolism of redox cycling xenobiotics in aquatic organisms is very similar to that of mammals suggesting similarities in the health consequences of exposure to such compounds. 4. The expression of specific lesions known to arise specifically from oxidative stress, e.g. lipid peroxidation, oxidized bases in DNA and accumulation of lipofuscin pigments are present in many aquatic animals exposed to contaminants. 5. Aquatic organisms contain the major antioxidant enzymes SOD, catalase and glutathione peroxidase, albeit there are marked quantitative differences among the various species reported.     

Oxidants and antioxidants in atherosclerosis

The oxidative theory suggests that LDL oxidation contributes to atherogenesis, implying that attenuation of this process by antioxidants should decrease atherosclerosis. However, a causative link between LDL oxidation and atherogenesis is not firmly established. It requires the identification of the oxidants that are responsible for the initiation of LDL oxidation, and an understanding of the modified moieties that are responsible for the proatherogenic activities of oxidized LDL. The present review summarizes recent data on potential biological oxidants for LDL in the vessel wall, and discusses the antiatherogenic role(s) of selected antioxidants.     

Oxidants and antioxidants in aquatic animals

• 1.1. Oxidative stress, potentially, is experienced by all aerobic life when antioxidant defenses are overcome by prooxidant forces, and is the basis of many physiological abberations.
• 2.2. Environmental contaminants may enhance oxidative stress in aquatic organisms, e.g. highly elevated rates of ideopathic lesions and neoplasia among fish inhabiting polluted environments is increasingly related to oxidative stress associated with environmental pollution.
• 3.3. Metabolism of redox cycling xenobiotics in aquatic organisms is very similar to that of mammals suggesting similarities in the health consequences of exposure to such compounds.
• 4.4. The expression of specific lesions known to arise specifically from oxidative stress, e.g. lipid peroxidation, oxidized bases in DNA and accumulation of lipofuscin pigments are present in many aquatic animals exposed to contaminants.
• 5.5. Aquatic organisms contain the major antioxidant enzymes SOD, catalase and glutathione peroxidase, albeit there are marked quantitative differences among the various species reported.

     

Oxidants,antioxidants and carcinogenesis

Reactive oxygen metabolites (ROMs), such as superoxide anions (O2*-) hydrogen peroxide (H2O2), and hydroxyl radical (*OH), malondialdehyde (MDA) and nitric oxide (NO) are directly or indirectly involved in multistage process of carcinogenesis. They are mainly involved in DNA damage leading sometimes to mutations in tumour suppressor genes. They also act as initiator and/or promotor in carcinogenesis. Some of them are mutagenic in mammalian systems. O2*-, H2O2 and *OH are reported to be involved in higher frequencies of sister chromatid exchanges (SCEs) and chromosome breaks and gaps (CBGs). MDA, a bi-product of lipid peroxidation (LPO), is said to be involved in DNA adduct formations, which are believed to be responsible for carcinogenesis. NO, on the other hand, plays a duel role in cancer. At high concentration it kills tumour cells, but at low concentration it promotes tumour growth and metastasis. It causes DNA single and double strand breaks. The metabolites of NO such as peroxynitrite (OONO-) is a potent mutagen that can induce transversion mutations. NO can stimulate O2*-/H2O2/*OH-induced LPO. These deleterious actions of oxidants can be countered by antioxidant defence system in humans. There are first line defense antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). SOD converts O2*- to H2O2, which is further converted to H2O with the help of GPx and CAT. SOD inhibits *OH production. SOD also act as antipoliferative agent, anticarcinogens, and inhibitor at initiation and promotion/transformation stage in carcinogenesis. GPx is another antioxidative enzyme which catalyses to convert H2O2, to H2O. The most potent enzyme is CAT. GPx and CAT are important in the inactivation of many environmental mutagens. CAT is also found to reduce the SCE levels and chromosomal aberrations. Antioxidative vitamins such as vitamin A, E, and C have a number of biological activities such as immune stimulation, inhibition of nitrosamine formation and an alteration of metabolic activations of carcinogens. They can prevent genetic changes by inhibiting DNA damage induced by the ROMs. Therefore, these antioxidants may be helpful in the treatment of human cancer. However, detailed studies are required to draw a definite conclusion.     

Oxidants, antioxidants in physical exercise and relation to thyroid function.

Intensive muscular exercise promotes the production of reactive oxygen species (ROS) in the working muscles and can impair athletic performance, particularly in conjunction with inadequate recovery. Mammals are protected against oxygen toxicity by a system of ROS scavengers composed of enzymatic and non-enzymatic components. Although antioxidant supplementation has recently been considered as a means to diminish or prevent damage from ROS, the specific antioxidant requirements of athletes are not known. Since thyroid function is essential for athletic performance, thyroid control should be undertaken in cases where there is any sign of thyroid dysfunction "of unknown etiology". Hyperthyroidism and hypothyroidism have been associated with increased production of ROS as well as related inflammatory response and myopathy. There is evidence that antioxidant supplementation combined with antithyroid treatment with methimazole could be useful in decreasing the oxidative stress.     

Oxidants and antioxidants affect the expression of glycodelin

Glycodelin is a glycoprotein that has immunosuppressive activity. We have shown that K562 cells, hematopoitic progenitor cells, are capable of synthesizing glycodelin peptide (Gp) and, perhaps, contribute to Gp in tissues. In addition, several reproductive and nonreproductive tissues themselves are capable of synthesis of glycodelin. In this study, we report that lipid peroxides induce the synthesis of Gp. Antioxidants vitamin E and pyrrolidine dithiocarbamate (PDTC) and antioxidizing enzymes catalase and superoxide dismutase (SOD) effectively blocked phorbol myristate acetate- (PMA-) and lyso phosphatidic acid- (LPA-) induced synthesis of Gp. Dioctanoin (a mimic of diacylglycerol) activated Gp synthesis, and an inhibitor of protein kinase C (PKC) downregulated the response. Based on these observations, we postulate that oxidants by way of PKC might potentiate the angiogenic process.     

Oxidants,antioxidants and the current incurability of metastatic cancers

The vast majority of all agents used to directly kill cancer cells (ionizing radiation, most chemotherapeutic agents and some targeted therapies) work through either directly or indirectly generating reactive oxygen species that block key steps in the cell cycle. As mesenchymal cancers evolve from their epithelial cell progenitors, they almost inevitably possess much-heightened amounts of antioxidants that effectively block otherwise highly effective oxidant therapies. Also key to better understanding is why and how the anti-diabetic drug metformin (the world''s most prescribed pharmaceutical product) preferentially kills oxidant-deficient mesenchymal p53^{− −}cells. A much faster timetable should be adopted towards developing more new drugs effective against p53^{− −} cancers.     

On the role of vitamin C and other antioxidants in atherogenesis and vascular dysfunction

Oxidative stress has been implicated as an important etiologic factor in atherosclerosis and vascular dysfunction. Antioxidants may inhibit atherogenesis and improve vascular function by two different mechanisms. First, lipid-soluble antioxidants present in low-density lipoprotein (LDL), including alpha-tocopherol, and water-soluble antioxidants present in the extracellular fluid of the arterial wall, including ascorbic acid (vitamin C), inhibit LDL oxidation through an LDL-specific antioxidant action. Second, antioxidants present in the cells of the vascular wall decrease cellular production and release of reactive oxygen species (ROS), inhibit endothelial activation (i.e., expression of adhesion molecules and monocyte chemoattractants), and improve the biologic activity of endothelium-derived nitric oxide (EDNO) through a cell- or tissue-specific antioxidant action. alpha-Tocopherol and a number of thiol antioxidants have been shown to decrease adhesion molecule expression and monocyte-endothelial interactions. Vitamin C has been demonstrated to potentiate EDNO activity and normalize vascular function in patients with coronary artery disease and associated risk factors, including hypercholesterolemia, hyperhomocysteinemia, hypertension, diabetes, and smoking.     

Thematic review series: the immune system and atherogenesis. Immune function in atherogenesis

In this overview to a new thematic series on the immune system and atherogenesis, I provide a very brief summary of current conceptions of atherogenesis, of the innate and adaptive immune systems, and of the participation of the latter in atherogenesis, with particular emphasis on studies of the involvement of the immune system in atherosclerosis reported in the last 2 years. This is followed by a short outline of the eight reviews that will make up this thematic series. The overview is concluded with some caveats that should be considered in the analysis of atherosclerosis in experimental animals.     

An appraisal of the American and British health-care systems.

1. A dispassionate comparison of the British and American systems of medical care using conventional guidelines (structure, process, and outcomes) as applied to acknowledged national problems in health and medical care (expense, quality, and distribution) has been made. 2. Dissimilarities in the size of the countries, in the attitudes of physicians, and in homogeneity of populations make it unlikely that the two countries should have identical medical-care systems. 3. The "good features" of the NHS, which by implication might benefit the American system if adopted, are seen to be overshadowed by weakness: a) Relative expensiveness or extravagance of American medicine is seen as underfinancing of the British system. b) Quality of care in Britain is threatened by lack of professional stimulation of generalists, inadequate facilities, and rationing of medical care by prolonged waiting times for elective services. c) Distribution of services is a problem in both countries which will not be corrected by administrative controls but "pegged to incentives" as is true in America. 4. Administrative change in NHS in April 1974 is evidence of internal dissatisfaction. It also demonstrates the need for continual revision of the system; a similar need is made evident by recent legislative proposals in America. 5. Dr. Beeson's final recommendation for voluntary organizational effort by the profession in America has merit.     

Calcium and myocardial cell injury. An appraisal in the cardiomyopathic hamster

The heart muscle is very compliant within a wide range of physiologic impulses. The adaptive energy of the myocardium depends, however, upon adequate oxygen supply and the functional state of the plasmalemma. These limitations have been well demonstrated in a number of experimental models with emphasis on the essential role of Ca2+ transmembrane movements for maintenance of heart functions and its viability. This postulate appeared quite important when we found that Ca2+ slow channel blockers could prevent necrotic changes in hamster hereditary cardiomyopathy. However, the effectiveness of beta-adrenoagonists when given in low doses seems more difficult to interpret since these agonists can only promote Ca2+ transmembrane movements. We can only surmise that Ca2+ accumulation in cardiomyopathic hearts does not derive from a primary defect of the plasmalemma but rather from an exhausted hypokinetic state that favours Ca2+ accumulation with progressive deterioration of the structural proteins. It is thus inferred that Ca2+ mediates rather than initiates the degradation process which characterizes this inherited cardiomyopathy.     

Thematic review series: The immune system and atherogenesis. Cytokine regulation of macrophage functions in atherogenesis

This review will focus on the role of cytokines in the behavior of macrophages, a prominent cell type of atherosclerotic lesions. Once these macrophages have immigrated into the vessel wall, they propagate the development of atherosclerosis by modifying lipoproteins, accumulating intracellular lipids, remodeling the extracellular environment, and promoting local coagulation. The numerous cytokines that have been detected in atherosclerosis, combined with the expression of large numbers of cytokine receptors on macrophages, are consistent with this axis being an important contributor to lesion development. Given the vast literature on cytokine-macrophage interactions, this review will be selective, with an emphasis on the major cytokines that have been detected in atherosclerotic lesions and their effects on properties that are relevant to lesion formation and maturation. There will be an emphasis on the role of cytokines in regulating lipid metabolism by macrophages. We will provide an overview of the major findings in cell culture and then put these in the context of in vivo studies.     

Localization of estrogen receptors in uterine cells. An appraisal of translocation.

The nuclear localization of estrogen receptors has been examined under conditions which minimize redistribution and localization artifacts. A procedure is presented which rapidly lyses suspensions of cells from immature rat uteri by using 0.04% Triton X-100 in isotonic buffer. The ‘nuclei’ which are obtained after lysis have a median diameter of 1μm and are devoid of nuclear membranes. There is close agreement between the number of cells before lysis and the number of nuclear particles after lysis. Triton X-100 gave no interference with quantitative binding of estradiol to receptor and no alteration in the sedimentation behavior of receptor on sucrose gradients containing high or low salt. Using this procedure to monitor the dynamics of estrogen receptor distribution within uterine cells after exposure to estradiol, translocation of estrogen receptor to the nucleus was observed to occur at a rate slightly slower than the rate at which estradiol was specifically bound to free cells or receptors. The difference in these rates is compatible with a model in which estradiol must first bind to the receptor before the binding complex moves to the nucleus. The rate of nuclear translocation was temperature-dependent and was observed to occur at 0 °C, provided that enough time was allowed for steroid entry, receptor charging and transit to the nucleus. Two distinct phases were observed to characterize nuclear receptor localization. In the first phase after hormone exposure, estrogen receptor progressively accumulated in the nucleus; afterwards, estrogen receptor was progressively lost from the nucleus but could not be detected in other subcellular compartments in a form still binding hormone. Since high cell viability was maintained during these manipulations, loss of nuclear receptor was not due to cell damage during in vitro incubation. These studies suggest that this decline in nuclear receptor level after hormone interaction, which is known to occur in vivo, may be a normal event during estrogen interaction with target cells.     

Glycoxidation and lipoxidation in atherogenesis

Atherosclerosis may be viewed as an age-related disease initiated by nonenzymatic, chemical reactions in a biological system. The peroxidation of lipids in lipoproteins in the vascular wall leads to local production of reactive carbonyl species that mediate recruitment of macrophages, cellular activation and proliferation, and chemical modification of vascular proteins by advanced lipoxidation end-products (ALEs). The ALEs and their precursors affect the structure and function of the vascular wall, setting the stage for atherogenesis. The increased risk for atherosclerosis in diabetes may result from additional carbonyl production from carbohydrates and additional chemical modification of proteins by advanced glycation end-products (AGEs). Failure to maintain homeostasis and the increase in oxidizable substrate (lipid) alone, rather than oxidative stress, is the likely source of the increase in reactive carbonyl precursors and the resultant ALEs and AGEs in atherosclerosis. Nucleophilic AGE-inhibitors, such as aminoguanidine and pyridoxamine, which trap reactive carbonyls and inhibit the formation of AGEs in diabetes, also trap bioactive lipids and precursors of ALEs in atherosclerosis. These drugs should be effective in retarding the development of atherosclerosis, even in nondiabetic patients.