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NITRIC OXIDE, AND REACTIVE OXYGEN IN HEALTH DISEASE AND INDUSTRY Humanity is (to varying extents) under chronic exposure to nitric oxide (NO) and reactive oxygen species (ROS), as well as related substances. These come from exogenous pollutants (cigarette smoke, factory and automobile exhaust gases, etc), and from endogenous sources (neuronal and cardiovascular NO synthases form low levels of NO for regulatory events; at sites of inflammation and infection, and around cancerous cells, phagocytes and other immune/inflammatory cells form copious amounts of NO and ROS in response to the same chemical and particulate stimuli; our normal aerobic metabolic activities, including oxidative electron transport chronically produce ROS; etc). ROS include superoxide (O2–), hydrogen peroxide (H2O2), hypochlorite (OCl–), etc. An oxidative stress is imposed on the cell by the presence of ROS and NO. Some chemotherapeutic agents may impose oxidative stress in the cell as part of their mode of action [e.g., artemisinine against malaria]. Some of the physiological roles of NO are mediated by products formed from the reaction of NO and ROS, e.g., peroxynitrite (ONOO–) from superoxide (O2–) and NO. Via oxidation, nitrosation and nitration reactions often involving free radicals, ONOO–modifies and/or damages cellular molecules, e.g., proteins, DNA, RNA, carbohydrates, and lipids. NO may also interact with heme-iron and iron-sulfur clusters
Cellular antioxidants, including thiols [glutathione (GSH), and cysteine (CySH)], beta-carotene, enzymes [superoxide dismutase (SOD), and catalase], and vitamins A, C, and E (tocopherols), detoxify the free radicals and restore homeostasis. If the antioxidants are inadequate, inflammatory, degenerative and other diseases (e.g., cardiovascular disease, arthritis, cataracts, Alzeimer’s disease, etc) as well as cancer may result. Thus, NO and ROS may cause a spectrum of effects from beneficial to adverse. The specific products formed, and the particular physiological events triggered depend on levels of NO, ROS and other chemical components, the cellular location, and redox state. Generally, at low levels, NO serves salutary cellular regulatory functions. We are interested in the consequences of the interactions of antibiotic, anti-neoplastic and other chemotherapeutic agents with NO, ROS, thiyl and/or other free radicals that may be formed by the myriad of combinations of potential chemical events at specific cellular microenvironments, especially during pathogenesis. How are these interactions related to: (a) the outcome of a therapeutic intervention, for instance (efficacy, drug resistance, etc.)? (b) the choice of therapeutic agents for specific individuals in specific pathological conditions At the present time, using an in vitro model, we are studying the susceptibility of Escherichia coli and Azotobacter vinelandii to the antibiotic/antineoplastic agent, Cerulenin. We relate the efficacy of cerulenin with; (i) its inhibition of fatty acid synthesis; and (ii) homeoviscous adaptation in these organisms. Our goal is to unravel, at the molecular level, how NO and ROS may modulate these events; and the potential consequences to treatment outcome in real life antibiotic/anti-neoplastic intervention. For Azotobacter vinelandii we further aim to discover how this bacterium could be managed to perform its nitrogen fixation and bioremediation functions optimally, for greater crop yields, and a cleaner environment. Methods and Techniques: Microbial Culture; Wet assays for oxidative stress; Differential Scanning Calorimetry for membrane lipid phase transitions; HPLC and Thin Layer Chromatography for lipid classes; Gas Liquid Chromatography for fatty acid profiles; SDS-PAGE and Western Blotting for protein modifications. 1. UNDERGRADUATE CCOURSES: A. Lectures: 08.3502/3-002 Intermediate Biochemistry I Fall 2005 C. Labs: 08.3502/3 Fall 2005 08.3503/3 Winter 2006 08.4506/3 Fall 2005 2. GRADUATE COURSE: [For Chemistry Dept., University of Manitoba] 002.740 Topics in Biochemistry Winter 2005; 2006 Redox Chemistry in Health and Disease (microbes, humans/animals and plants)” [Oxidation-reduction reactions in the cell intimately associated with the biological intricacies of life, aging, and death, in all living systems, as well as their direct relationship with the Oxygen Paradox] 3. RESEARCH PROJECT STUDENTS & RESEARCH ASSISTANTS:
Some Selected Publications:
1. Larsen, A., Sliskovic, I., Juric, D., Pinnock, C., Kullman, H., Segstro, E., Reinfelds, G. and Eze, M.O. (2005). “The Fatty Acid Profile of Vegetative Azotobacter vinelandii ATCC 12837: Growth Phase-Dependence” Applied Microbiology and Biotechnology. Published online 2005 Feb 2; [Epub ahead of print]. 2. Eze, M.O., Yuan, L., Crawford, R.M., Paranavitana, J. A., Hadfield, T.L., Bhattacharjee, A.K. Warren, R.L. and Hoover, D.L. (2000). “Effects of Opsonization and Gamma-Interferon on Growth of Brucella melitensis 16M in Mouse Peritoneal Macrophages in Vitro”. Infection and Immunity, 68, 257-263. 3. Onwurah, I.N.E. and Eze, M.O., (2000). “Superoxide Dismutase Activity in Azotobacter vinelandii in the Disposition of Environmental Toxicants Exemplified by Fenton Reagent and Crude Oil”. Toxic Substance Mechanisms, 19, 111-123. 4. Nwanguma, B.C. and Eze, M.O. (1996). “Changes in the Concentrations of the Polyphenolic Constituents of Sorghum during Malting and Mashing”. J. Science of Food and Agric. (UK.) 70, 162-166. 5. Nwanguma, B.C. and Eze, M.O. (1995). “Heat Sensitivity, Optimum pH and Changes in Activity of Sorghum Peroxidase during Malting and Mashing”. J. Institute of Brewing (UK.). 101, 275-276. 6. Eze, M.O., Hunting, D.J. and Ogan, A.U. (1993). “Reactive Oxygen Associated with Parasitic and Other Tropical Infections: Carcinogenic Potential”. Chapter 6, in Free Radicals in Tropical Diseases. O.I. Aruoma (editor). Harwood Academic Publishers, UK. pp 111-136. 7. Eze, M.O. (1992). “Membrane Fluidity, Reactive Oxygen Species and Cell-M ediated Immunity: Implication in Nutrition and Disease”. Medical Hypotheses 37, 220-224. 8. Eze, M.O. (1991). “Production of Superoxide by Macrophages from Plasmodium chabaudi Infected Mice”. CYTOBIOS 66, 93-104. 9. Eze, M.O. (1990). “Consequences of the Lipid Bilayer to Membrane-Associated Reactions”. Journal of Chemical Education, 67, 17-20.