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Oxidative stress
- 2. Overview • Oxidants & Antioxidants in biological systems • Oxidative stress • Molecular targets of oxidative stress • Antioxidant defense mechanisms • Oxidative stress related Diseases
- 3. Free Radicals • Oxidation is a normal and necessary process that takes place in our body. Sometimes referred to as oxidation number, describes the degree of oxidation (loss of electrons) of an atom in a chemical compound. • Free Radicals : are chemical species, that contain one or more unpaired electron in an outer orbit. • Unstable and highly reactive molecules • Autocatalytic reaction
- 4. Formation of Free Radicals • By Reduction-Oxidation reactions during normal metabolic process. • Primary source is our body during energy production • Enzymatic Metabolism of exogenous chemicals and drugs. • During Inflammation. • Prolonged low blood flow states (atherosclerosis, heart attacks & stroke) • Environmental contaminants • Tobacco (Smoking) is a major oxidative stress, that is a source of mutagens. • Absorption of Radiation energy • Diet (fatty and processed foods) • Low levels of antioxidants
- 5. Reactive Oxygen Species • ROS: chemically reactive molecules containing oxygen, highly reactive under normal conditions, ROS are natural biradicals. Responsible for more than 100 human diseases. Aging, cancer, heart attacks, stroke and arthritis also have some beneficial effects. Reactive Oxygen species. Symbol Properties superoxide radical O2 •- weak oxidant hydroperoxyl radical HO2 • stronger oxidant than O2- hydrogen peroxide H2O2 oxidant hydroxyl radical OH• extremely reactive alkoxyl radical RO• less reactive than OH peroxyl radical ROO• weaker oxidant singlet oxygen 1O2 strong oxidant
- 6. Oxidative Stress • It is imbalance between free radicals and antioxidants in the body. • Under normal conditions, cells are able to balance the production of oxidants and antioxidants. Oxidative stress occurs when cells are subjected to excess levels of ROS or as a result of antioxidant depletion. • It is harmful because ROS attack biological molecules such as lipids, proteins, and DNA that involved in the pathogenesis of lifestyle-related diseases. • Oxidative stress has a useful role in physiologic adaptation and in the regulation of intracellular signal transduction. When functioning properly, free radicals can help fight off pathogens to prevent infections.
- 7. Overview of Oxidative stress and ROS
- 8. Oxidative damage of ROS
- 9. Oxidative damage of Lipids • Lipid peroxydation gives rise to lipid hydroperoxides, lipid alkoxyl, and peroxyl radicals. Lipid peroxy radicals react with other lipids, thereby the transfer of electrons and bringing the oxidation of substrates. Peroxisomes, which are organelles responsible for degrading fatty acids and other molecules, produce H2O2 as a by-product, which is then degraded by catalase.. • Cell membranes, are highly susceptible to oxidative attack and, consequently, changes in membrane fluidity, permeability, and cellular metabolic functions result.
- 10. Oxidative damage of Proteins • Oxidative attack on proteins results in site-specific amino acid modifications, fragmentation of the peptide chain, aggregation of cross-linked reaction products, altered electrical charge and increased susceptibility to proteolysis • Sulphur containing amino acids, and thiol groups specifically, are very susceptible sites. • The oxidation of iron-sulphur by superoxide destroys enzymatic function. • Thus it destroys the structure, functions of essential proteins and enzymes and whole cell metabolism is blocked.
- 11. Oxidative damage of DNA • Activated oxygen and agents that generate oxygen free radicals, such as ionizing radiation, induce numerous lesions in DNA that cause deletions, mutations and other lethal genetic effects • Characterizations of this damage to DNA has indicated that both the sugar and the base moieties are susceptible to oxidation, causing base degradation, single strand breakage, and cross-linking to protein. • Oxidative damage to mitochondrial DNA may promote cancer and aging.
- 12. Mitochondrial are the targets of ROS • Oxidative stress is tightly linked to mitochondrial Dysfunction. Mitochondria are both generators and targets of ROS. • In respond to cellular stress, Necrosis, Apoptosis, and autophagy are activated. Mitochondrial turnover is dependent on autophagy. • The mitochondria defends itself against this high rate of damage by a constant turnover, thus presumably removing those damaged mitochondria that produce increased oxidants. Despite this turnover, oxidative lesions appear to accumulate with age in mtDNA at a higher rate than in nuclear DNA. Oxidative damage could also account for the mutations in mtDNA that accumulate with age.
- 14. Antioxidants • An antioxidant is any substance that delays, prevents or removes oxidative damage to a target molecule. • There is no universal best antioxidant! • Their relative importance depends upon: Which, how, where ROS is generated and what target of damage is measured • thus the job of antioxidants is to neutralise or 'mop up' free radicals that can harm our cells.
- 15. Antioxidative Defense Enzymes – catalytically remove ROS (superoxide dismutase, catalase, glutathione peroxidase, peroxidase) Proteins that remove pro-oxidants (metal ions and heme) (transferrin, ferritin, albumin, haptoglobin, ceruloplasmin) Low-molecular weight substances ○ synthesized in vivo (bilirubin, uric acid, NADPH, CoQ) ○ from the diet (vitamins A, C and E, plant phenols) • Antioxidants therefore can decrease mutagenesis, and thus carcinogenesis, in two ways: by decreasing oxidative DNA damage and by decreasing cell division. 2 O2 + +2 2
- 17. Aging and Dietary Restriction • Dietary restriction activates the pituitary- adrenocorticotropic axis, resulting in a decrease in the release of reproductive and mitogenic hormones, as has been shown in various animal studies. This is consistent with suppression of incidence of mammary tumors. • Protein restriction appears to have the same effects as calorie restriction An understanding of mechanisms for this marked effect on aging and cancer is becoming clearer and may in good part be due to reduced oxidative damage, which is supported by the findings of more efficient DNA repair, better coupled mitochondrial respiration, and a delay in the age dependent decline of some antioxidant defenses.
- 18. Antioxidatns and Treatment • antioxidants may be useful in treating patients after a stroke to protect the nerves and brain cells from oxidative damage and lipid peroxidation. • Agents such as superoxide dismutase mimetics, sodium thiopental and propofol can be used to treat reperfusion injury that occurs after traumatic brain injury. • These agents prevent neural cell death. Individuals with neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease also benefit to a certain extent from the use of antioxidants.
Editor's Notes
- As they are highly reactive and unstable, they pull electron from other molecules and cause affected molecules to become free radical and then new free radical pull electron to next molecules , so chain is produce
- Ionizing and ultraviolet radiation. Smoking is a risk factor for heart disease as well as a wide variety of cancers in addition to lung cancer Mt, energy production , As a consequence of normal aerobic respiration, mitochondria consume 02, reducing it by sequential steps to produce H20. Inevitable byproducts of this process, O2•- ,HO2• , H2O2. Chronic infection by viruses, bacteria, or parasites results in a chronic phagocytic activity and consequent chronic inflammation, which is a major risk factor for cancer.
- a biradical – it has two unpaired electrons. Oxidants from normal metabolism. The formation of 02, H202, and -OH occurs by successive additions of electrons to 02. Cytochrome oxidase adds four electrons fairly efficiently during energy generation in mitochondria, but some of these toxic intermediates are inevitable by-products. For oxygen reduction, 4e are required, if these 4e are not accepted all together by oxygen molecule at one step, then ROS are produced.
- A disturbance in the balance between reactive oxygen species (ROS) and antioxidants. Oxidative damage to DNA, protiens and lipids is a major contributor to aging, immune system decline, degenerative of diseases (cardiovascular disease, brain dysfunction, cataracts)
- The biological importance of ROS Physiological positive effects of ROS Kill microorganism, Second messenger (H2O2), Cellular differentiation & proliferation, Regulate signal transduction & transcription( Cytokines and growth factor receptors, non-receptor tyrosine kinases, Protein tyrosine phosphatases, Serine/Threonine kinases).Leukocytes and other phagocytic cells combat bacteria, parasites, and virus-infected cells by destroying them with nitric oxide NO, O2, H202, and OC1, a powerful oxidant mixture. These oxidants protect humans from immediate death from infection but cause oxidative damage to DNA and mutation, thereby contributing to the carcinogenic process.
- The cellular targets of ROS. DNA= chemical changes in bases which leads to .. Proteins= by Oxidation and nitration >> damage and loss of function (enzymes and other proteins) Lipids= (polyunsaturated fatty acids) produce H2O2 by product, under some conditions H2O2 escape degradation resulting its release into other compartment of cells and increase oxidative DNA damage
- Evidence suggests that, under certain conditions, some of the peroxide escapes degradation, resulting in its release into other compartments of the cell and in increased oxidative DNA damage Lipid hydroperoxides are destroyed by glutathione peroxidase.
- some DNA is oxidized. Oxidatively damaged DNA is repaired by enzymes that excise the lesions, Methods have been developed to assay several of these excised damaged bases in the urine of humans, almost all of which appear as the free base from repair by glycosylases. We estimate that the number of oxidative hits to DNA per cell per day is about 10,000 in the human. DNA-repair enzymes efficiently remove most, but not all, of the lesions formed. Oxidative lesions in DNA accumulate with age. The importance of oxidative DNA lesions in cancer and aging is underscored by the existence of specific repair glycosylases that excise these lesions from DNA. In the case of a lesion formed from oxidative damage to guanine residues in DNA, loss of a specific glycosylase activity leads to an appreciable increase in the spontaneous mutation rate, indicating the intrinsic mutagenic potential of this DNA lesion. Many other oxidative DNA lesions are likely to be important as well
- This increase may be due to a lack of mtDNA repair enzymes, a lack of histones protecting mtDNA, and the proximity of mtDNA to oxidants generated during oxidative phosphorylation. Oxidative damage could also account for the mutations in mtDNA that accumulate with age>> Electrons are passed through the complexes and reach their final distination. An oxygen molecule then is reduced to produce water molecule. However, Sometimes the oxygen is incompletely reduced to give superoxide radical O2•-, this can inactive enzymes or initiate lipid peroxidation in its pronated form of Hydroperoxyl.
- Common diseases caused by oxidative stress Damage to biomolecules like Lipids, Proteins, DNA, will eventually lead to diseases like: Atherosclerosis Cancer Diabetes Rheumatoid arthritis Myocardial infarction Cardiovascular diseases Chronic inflammation
- Inhibit oxidation of other molecules. Antioxidants are molecules that can donate an electron to a free radical without making themselves unstable. these substances are industrial chemicals added to products to prevent oxidation, and naturally occurring compounds that are present in foods and tissue.
- bilirubin, carnosine, and ubiquinol. Ubiquinone (CoQ1o), for example, is the critical small molecule for transporting electrons in mitochondria for the generation of energy. Its reduced form, ubiquinol, is an effective antioxidant in membranes. Optimal levels of dietary ubiquinone/ubiquinol could be of importance in many of the degenerative diseases. Oxidants form one important class of agents that stimulate cell division. This may be related to the stimulation of cell division that occurs during the inflammatory process accompanying wound healing.
- *Fruits and vegetables, the main source of antioxidants in the diet, are associated with a lowered risk of degenerative diseases The antioxidant capacity of any food is measured using an ORAC score. ORAC stands for oxygen radical absorbance capacity. The higher an ORAC score the greater the antioxidant capacity of the food. *Herbs and Spices Rich in Antioxidants *Food Rich in Antioxidants
- Block and her colleagues have recently reviewed 172 studies in the epidemiological literature that relate, with great consistency, the lack of adequate consumption of fruits and vegetables to cancer incidence The quarter of the population with low dietary intake of fruits and vegetables has double the cancer rate for most types of cancer (lung, larynx, oral cavity, esophagus, stomach, colon and rectum, bladder, pancreas, cervix, and ovary) when compared with the quarter with high intake.
- Several antioxidants are currently used to treat diseases. For example,