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Oxidative Stress and Health

Oxidative Stress and Health. Arnold Stern, MD, PhD Professor of Pharmacology Assistant Dean for Extramural Education Programs New York University School of Medicine. NEW YORK UNIVERSITY. IN EXISTENCE FOR OVER 150 YEARS

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Oxidative Stress and Health

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  1. Oxidative Stress and Health Arnold Stern, MD, PhD Professor of Pharmacology Assistant Dean for Extramural Education Programs New York University School of Medicine

  2. NEW YORK UNIVERSITY • IN EXISTENCE FOR OVER 150 YEARS • INTERNATIONAL DISTINCTION IN LIBERAL ARTS, SCIENCE, EDUCATION, THE HEALTH PROFESSIONS, LAW, THE ARTS, COMMUNICATIONS, PUBLIC SERVICE • HOME TO 33 GLOBAL PROGRAMS AND DEPARTMENTS AND 18 INTERNATIONAL CENTERS AND INSTITUTES • STUDENTS COME FROM ALL OVER THE WORLD • ALUMNI ARE LEADERS IN HEALTH CARE, GOVERNMENT, LAW, GLOBAL ORGANIZATIONS AND BUSINESSES • OUR PRESIDENT SEES US AS AN ENTERPRISE UNIVERSITY, THAT DEFINES ITS MISSION THROUGH THE LENS OF AN URBAN AND GLOBAL PERSPECTIVE

  3. NEW YORK CITY • ECLECTIC MIX OF VIBRANT CULTURES, LANGUAGES AND ETHNICITIES • THREE MILLION OF THE EIGHT MILLION RESIDENTS WERE BORN OUTSIDE OF THE USA • FORTY SIX PERCENT SPEAK A LANGUAGE OTHER THAN ENGLISH IN THEIR HOMES • FORTY PERCENT OF CHILDREN BORN IN 2005 HAD A LEAST ONE PARENT THAT WAS AN IMMIGRANT • FIVE PERCENT OF THE POPULATION ARE OF CHINESE ANCESTRY WITH THREE AREAS OF THE CITY SPECIFICALLY INHABITED BY CHINESE-AMERICANS • HOME TO THE UNITED NATIONS, INTERNATIONAL FOUNDATIONS AND GLOBAL NON-PROFIT ORGANIZATIONS

  4. Information About Medical Schools in the USA • Over 130 medical schools with the greatest number state supported • Approximately 40,000 applicants and 17,000 new admissions per year • Four year curriculum with the first two years primarily in the basic sciences and the second two years in the clinical sciences • Post-graduate programs in specialties are a minimum of three years followed by sub-specialty training and fellowships of an additional three years or more

  5. Education Prior to Entering Medical School • 4 year college degree • Sufficient science preparation (inorganic and organic chemistry, basic biology, physics) • Students are considered for admission with other backgrounds than science • Need to take standardized national test (Medical College Admissions Test-MCAT)

  6. New York University School of Medicine • A private medical school in the public interest • 400+ basic research scientists • Over 3000 part time and full time clinical faculty • Over 600 medical students, over 200 graduate students and over 70 MD, PhD students • 6 major teaching hospitals including Bellevue Hospital, the Hospital for Joint Diseases and the Rusk Institute for Rehabilitation Medicine

  7. What is Oxidative Stress • In biological systems utilizing oxygen, highly reactive species are formed in the normal process of metabolism • Working definitions of oxidative stress: 1) a perturbation of the balance between pro-oxidant and antioxidant behavior (Sies) 2) an absolute level of oxidative stress and not an imbalance (a constant free-radical flux) (Cutler) • Pro-oxidant reactions contribute to a number of physiological and pathological phenomena (ex. Inflammation, ageing, carcinogenesis, drug metabolism, blood pressure regulation, male potency)

  8. What Causes Oxidative Stress Free radicals--generally highly reactive species formed during metabolism (contain an unpaired electron making it potentially highly reactive) Free radical species are generally regulated by a number of physiological mechanisms Free radicals formed in biological systems generally react with oxygen to form reactive oxygen (ROS) Reactive nitrogen species (RNS) are formed endogenously

  9. Reactive Oxygen Species (ROS) • Energy production generally requires the reaction of oxygen • In these reactions oxygen is ultimately converted to water • The conversion of oxygen to water can occur by a number of steps (enzymes exist that either directly convert the oxygen to water or convert the intermediate products of oxygen metabolism)

  10. Reactive Intermediates of Oxygen Oxygen---->superoxide (a free radical)---> hydrogen peroxide--->hydroxyl radical--->water • Each step is a one electron reduction, therefore superoxide and hydroxyl radical are free radicals because they have an unpaired electron • An enzyme exists that regulates cellular respiration and directly converts oxygen to water and avoids the intermediate ROS (cytochrome c oxidase) • Regulation of ROS involve enzymes and anti-oxidants that ultimately result in their conversion to water (superoxide dismutase, catalase, glutathione peroxidase)

  11. ENDOGENOUS AND EXOGENOUS SOURCES OF NITRIC OXIDE • Additional exogenous sources * NO-donors - S-Nitrosoglutathione

  12. Biological Functions of RNS Regulation of blood pressure Control of male potency Modulate cellular functions Destroy pathological bacteria and parasites

  13. THE CHEMICAL BIOLOGY OF NITRIC OXIDE

  14. ROS/RNS and Organism Dysfunction Destruction of essential and structural components Are all components of a cell equally important as sensitive targets or are there particular targets that when damaged produce the most serious and far-reaching dysfunctional effects? Most important targets are DNA and mitochondrial DNA Two hypotheses are highly considered Free radicals are mutagenic With time, free radical damage results in accumulation of non-repairable damage to the cell

  15. Processes Evolved to Reduce Destruction by ROS/RNS Reduction of endogenous production (decrease of inflammation) Reduction of specific metabolic rate (correlation of long life span with relatively small body size) Increase resistance of key targets to oxidative damage (diminish peroxidation by nature of membrane lipids) Increase protection by antioxidants (vitamin E, polyphenols, glutathione) Repair, turnover and remodeling (cell division, DNA replication) Repair processes for nucleic acids, proteins and lipids

  16. Diseases and Oxidative Stress • 250 human diseases are known to be associated with oxidative stress • Association with oxidative stress is not necessarily a cause-and-effect relationship • Ageing, accelerated ageing (Progeria) • Heart and cardiovascular disease (atherosclerosis) • Cancer • Nervous System (Stroke, Alzheimer’s, Parkinsonism) • Muscle Diseases (muscular dystrophy, multiple sclerosis) • Eye (macular degeneration, cataracts) • Kidney (chronic renal disease) • Gastro-intestinal (diabetes, inflammatory bowel disease) • Lung (asthma, asbestosis) • Hemopoietic (malaria, HIV) • Liver (alcohol-induced cirrhosis, hepatitis B) • Skin (porphyria) • Pregnancy (pre-eclampsia) • Radiation-mediated dysfunctions • Age-related diseases associated with long term chronic inflammation

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