OXIDATIVE STRESS IN HEALTH AND DISEASE

In Cells, oxidation process uses oxygen to produce energy for biochemical reactions. During these reactions, the free radicals/Reactive oxygen species(ROS) are produced as byproducts of metabolic process.The overproduction of free radicals and reactive oxygen species (ROS) is a common underlying mechanism of many neuropathology’s, as they have been shown to damage various cellular components, including proteins, lipids and DNA. Oxidative stress occurs when the production of these potentially destructive reactive oxygen species (ROS) exceeds the bodies own natural antioxidant defenses, resulting in cellular damage. The higher and frequent consumption of protective food like fruit, vegetables, vegetable oils, nuts, seeds and cereal grains is recommended in prevention of free radical disease.
2.1.1OXIDATIVE STRESS:

Oxidative stress is a state characterized by an excess of reactive oxygen species (ROS) in the body, which creates a potentially unstable cellular environment that is associated with tissue damage accelerated aging and degenerative diseases. Free radicals and reactive oxygen species (ROS) are species with incomplete electron shells that make them move chemically reactive than those with complete electron shells. They are byproducts of metabolic processes. Some of the reactive species which are of particular interest from the point of view of oxidative stress are

· Super oxide radical (O(2)(-)),
· hydroxyl radical (HO()),
· peroxyl radical (ROO())
· Hydrogen peroxide (H(2)O(2))
· Alkoxyl radical
· singlet oxygen ((1)O(2))
· nitric oxide (()NO)
· peroxynitrite (ONOO(-))
Oxidative stress is induced by a wide range of environmental factors including UV stress, pathogen invasion (hypersensitive reaction), herbicide action, oxygen shortage, cigarette smoke, automobile exhaust fumes, air pollutants.There are numerous types of free radicals that can be formed within the body. The most common ROS include: the superoxide anion (O2-), the hydroxyl radical (OH ·), singlet oxygen (One O2), and hydrogen peroxide (H2O2). Superoxide anions are formed when oxygen (O2) acquires an additional electron, leaving the molecule with only one unpaired electron. Within the mitochondria O2- · is continuously being formed. The rate of formation depends on the amount of oxygen flowing through the mitochondria at any given time. Hydroxyl radicals are short-lived, but are the most damaging radicals within the body. This type of free radical can be formed from O2- and H2O2 via the Harber-Weiss reaction. The interaction of copper or iron and H2O2 also produce OH · as first observed by Fenton. These reactions are significant as the substrates are found within the body and could easily interact.Hydrogen peroxide is produced in vivo by many reactions. Hydrogen peroxide is unique in that it can be converted to the highly damaging hydroxyl radical or be catalyzed and excreted harmlessly as water. Glutathione peroxidase is essential for the conversion of glutathione to oxidized glutathione, during which H2O2 is converted to water.If H2O2 is not converted into water, instead singlet oxygen (one O2) is formed. Singlet oxygen is not a free radical, but can be formed during radical reactions and also cause further reactions. Singlet oxygen violates Hund's rule of electron filling in that it has eight outer electrons existing in pairs leaving one orbital of the same energy level empty. When oxygen is energetically excited one of the electrons can jump to empty orbital creating unpaired electrons. Singlet oxygen can then transfer the energy to a new molecule and act as a catalyst for free radical formation. The molecule can also interact with other molecules leading to the formation of a new free radical.
2.1.2PRODUCTION OF FREE RADICALS IN THE HUMAN BODY:
Free radicals and other reactive oxygen species are derived either from normal essential metabolic processes in the human body or from external sources such as exposure to X-rays, ozone, cigarette smoking, air pollutants and industrial chemicals.
Free radical formation occurs continuously in the cells as a consequence of both enzymatic and non-enzymatic reactions. Enzymatic reactions which serve as sources of free radicals include those involved in the respiratory chain, in phagocytosis, in prostaglandin synthesis and in the cytochrome P450 system. Free radicals also arise in non-enzymatic reactions of oxygen with organic compounds as well as those initiated by ionizing radiations.


Some internally generated sources of free radicals are:
Mitochondria
Phagocytes
Xanthine oxidase
Reactions involving iron and other transition metals
Arachidonate pathways
Peroxisomes
Exercise
Inflammation
Ischaemia/reperfusion.
Some externally generated sources of free radicals are:
Cigarette smoke
Environmental pollutants
Radiation
Ultraviolet light
Certain drugs, pesticides, anesthetics and industrial solvents
Ozone.
If free radicals are not inactivated, their chemical reactivity can damage all cellular macromolecules including proteins, carbohydrates, lipids and nucleic acids. Their destructive effects on proteins may play a role in the causation of cataracts. Free radical damage to DNA is also implicated in the causation of cancer and its effect on LDL cholesterol is very likely responsible for heart disease. In fact, the theory associating free radicals with the aging process has also gained widespread acceptance.

2.1.3 IMPORTANCE OF FREE RADICALS:
Free radicals are naturally produced taken within the body and have beneficial effects that cannot be overlooked. The immune system is the main body system that utilizes free radicals. Foreign invaders or damaged tissue is marked with free radicals by the immune system. This allows for determination of which tissue need to be removed from the body. Because of this there is a need for antioxidant supplementation.



2.1.4OXIDATIVE STRESS IN VARIOUS PHYSIOLOGICAL STAGES: Oxidative stress occurs during various physiological conditions like in infants and during ageing. Infants: Respiratory distress syndrome (RDS) incidence is increased in infants of pre-clamptic mothers with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. RDS and HELLP syndrome have been associated with oxidative stress and inflammatory processes. Oxidative stress is a risk factor for broncho -pulmonary dysplasia in the preterm Newborn. Antioxidant defense is impaired in the preterm newborn. Oxidative stress is also involved in cell growth and development. It is shown that oxygen-derived free radicals, and particularly the super oxide anion, are intermediaries in the formation and activation of osteoclasts. Many antioxidant defense systems depend on micronutrients or are micronutrients themselves. Oxidative stress related to bone indices in newborn infants. Aging:It was proposed that free radicals are the major factor involved in aging process. This gave birth to the free radical theory of aging. This current theory provides the most popular explanation for how aging occurs at the biochemical/molecular level. Ever since1956, this theory has received widespread attention and a large body of evidence has been accumulated in support of its hypotheses which were subsequently refined. The free radical theory of aging postulates that age-associated reductions in physiological functions are caused by an irreversible accumulation of oxidative alterations to macromolecules. This accumulation increases with age and is associated with the life expectancy of organisms. Moreover, this theory suggests the existence of an imbalance between reactive oxygen species (ROS)-producing pathways and (ROS)-scavenging pathways, which is responsible for the generation of oxidative stress syndrome. The free radical theory of aging hypothesizes that oxygen-derived free radicals are responsible for the age-related damage at the cellular and tissue levels. In a normal situation, a balanced-equilibrium exists among oxidants, antioxidants and biomolecules. Excess generation of free radicals may overwhelm natural cellular antioxidant defenses leading to oxidation and further contributing to cellular functional impairment. The identification of free radical reactions as promoters of the aging process implies that interventions aimed at limiting or inhibiting them should be able to reduce the rate of formation of aging changes with a consequent reduction of the aging rate and disease pathogenesis. 2.1.5OXIDATIVE STRESS IN VARIOUS DISEASES:
A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases; however, it remains to be determined whether oxidative stress is a cause, result, or epiphenomenon of the pathological processes.ROS contribute to oxidative stress ,which is linked to numerous degenerative conditions including cardiovascular disease, inflammation,, Alzheimer’s disease Parkinson’s disease, diabetes and Aging etc. Few other conditions associated with oxidative stress are presented in table 1.

1. Conditions associated with oxidative damage:

• Atherosclerosis
• Cancer
• Pulmonary dysfunction
• Cataracts
•Arthritis and inflammatory diseases
• Diabetes
•Shock, trauma and ischemia
• Renal disease and hemodialysis

Mechanisms involved in the role of ROS and oxidative stress in disease development may include alteration of important biomolecules causing oxidative modifications in nucleic acids, modulation of gene expression through activation of redox sensitive transcription factors and modulation of inflammatory responses through signal transduction.
2.1.6EFFECT OF OXIDATIVE STRESS ON BIOLOGICAL MICRO MOLECULES: ROS are highly reactive and their accumulation induces cell damage by modifying molecules, including lipids, proteins and DNA. Oxidative DNA damage in humans could arise also from incorrect nutritional habit and life style. DNA strand breaks with apurinic/apyrimidinic sites, oxidized purines and oxidized pyrimidines.The main cellular components susceptible to damage by free radicals are lipids (per-oxidation of unsaturated fatty acids in membranes), proteins (denaturation), carbohydrates and nucleic acids. Hypoxia also induces oxidative stress which depend on tissue and/or species (i.e. their tolerance to anoxia), on membrane properties, on endogenous antioxidant content and on the ability to induce the response in the antioxidant system. Radicals react with lipids and cause oxidative destruction of unsaturated that is; Polyunsaturated fatty acids, known as lipid per oxidation. Both lipids in biological systems and lipids as food constituents are submitted to this process. Lipid per oxidation in cells leads to direct damage of cell membranes with indirect damages of other cell constituents, caused by reactivity of secondary products of this reaction, aldehydes. This complex reaction is responsible for damages of many tissues and progress of some diseases (atherosclerosis).
2.1.7METAL MEDIATED FREE RADICAL GENERATION:

Metal-mediated formation of free radicals causes various modifications to DNA bases, enhanced lipid per oxidation, and altered calcium and sulfhydryl homeostasis. Lipid peroxides, formed by the attack of radicals on polyunsaturated fatty acid residues of phospholipids, can further react with redox metals finally producing mutagenic and carcinogenic malondialdehyde, 4-hydroxynonenal and other exocyclic DNA adducts (etheno and/or propano adducts). The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. Common mechanisms involving the Fenton reaction, generation of the superoxide radical and the hydroxyl radical appear to be involved for iron, copper, chromium, vanadium and cobalt primarily associated with mitochondria, microsomes and peroxisomes. . Nitric oxide (NO) seems to be involved in arsenite-induced DNA damage and pyrimidine excision inhibition.