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Reactive species of oxygen, nitrogen and transition metals: interactions and relevance in physiological and pathological processes


Reactive oxygen and nitrogen intermediates are now widely recognized to play important roles in a variety of physiological and pathological processes. Excessive production of superoxide anion and nitric oxide individually has been associated with several pathologies but only recently has it been hypothesized that interactions between them may also be important in the etiology of many human diseases including atherosclerosis, neurodegenerative diseases and cancer. Also overlooked in the past have been the addition reactions between free radicals and oxidizing intermediates with biomolecules. It is becoming increasingly recognized, however, that the stable products of these reactions, named adducts, may be important mediators of the biological effects of free radicals and oxidizing species. The present project is based on the hypothesis that the understanding of the physiological and pathological roles of free radicals, an essential step to the ultimate goal of therapeutic intervention in those clinical conditions associated with oxidative damage, requires a better knowledge of the interactions between free radicals, oxidants and transition metal ions under physiological conditions and also, of the addition reactions between free radicals and biomolecules. Three general problems are being studied. First, reactions of nitric oxide and its derived oxidants (particularly, peroxynitrite) with biomolecules and their potential role in microbicidal and deleterious processes. The reactions are being studied in vitro; to learn about their significance in vivo, we are using Leishmania amazonensis murine infection as a model. Second, addition reactions between free radicals (particularly, carbon-centered radical metabolites) with nucleic acids in vitro and in vivo; the adducts are being characterized and their mutagenic and mitogenic properties are being examined. The third project focus on the mechanisms by which transition metal ion complexes modulates the reactivity of nitrogen-derived oxidants (Previous work and employed methodologies are found in the cited references). (AU)

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