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INTERNATIONAL RESEARCH JOURNAL OF PHARMACY www.irjponline.com ISSN 2230 – 8407

Review Article

OXIDATIVE STRESS INDUCED ULCER PROTECTED BY NATURAL ANTIOXIDANTS: A REVIEW

Gupta Priya*, Nain Parminder, Sidana Jaspreet

M.M College of Pharmacy, Maharishi Markandeshwar University, Mullana, Ambala, Haryana, India

Article Received on: 10/03/12 Revised on: 22/04/12 Approved for publication: 09/05/12 *E-mail: priya_gupta1919@yahoo.com ABSTRACT Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates, which ultimately leads to oxidative deterioration of protein, lipid and DNA. In humans, oxidative stress is involved in pathology of many diseases, such as atherosclerosis, Parkinson’s disease, heart failure, myocardial infarction, and chronic fatigue syndrome. Reactive oxygen species (ROS) can be beneficial, as they are used by the immune system as a way to attack and kill pathogens. To counteract oxidative stress, the body produces an armory of antioxidants to defend itself. It's the job of antioxidants to neutralize free radicals that can harm the cells. Body's internal production of antioxidants is not enough to neutralize all the free radicals. It’s a well-known fact that ROS are involved in the aetio-pathogenesis of the inflammatory and ulcerative lesions of the gastrointestinal tract. The present review focuses on the studies where oxidative damage due to stress has been linked causally to loss of cell integrity mainly in peptic ulcer cured by natural antioxidants. Keywords: Oxidative Stress, Peptic Ulcer, Natural Antioxidants INTRODUCTION Oxygen is vital for aerobic life processes. However, about 5% or more of the inhaled oxygen is converted to reactive oxygen species (ROS) such as superoxide anion (O2

-), hydrogen peroxide(H2O2) and hydroxyl ion(OH ) by univalent reduction of oxygen.1 ROS (reactive oxygen species) are a necessary evil of aerobic life, being generated continuously during the process of respiration, but always threatened with the insult of ROS, which however are efficiently taken care of by the highly powerful antioxidant systems of the cell without any untoward effect. When the balance between ROS production and antioxidant defenses is lost, ‘oxidative stress’ results.2 The potential to cause oxidative deterioration of protein, lipid and DNA. ROS generation is elevated by a range of different stress conditions.3 Chemical stressors such as organic and inorganic pollutants as well as certain natural stressors such as radiation can have different modes of action, but one effect common to many of these are association with oxidative damage in cells.4,5 Reactive oxygen species (ROS) can attack vital cell components like polyunsaturated fatty acids, proteins, and nucleic acids. To a lesser extent, carbohydrates are also the targets of ROS. These reactions can alter intrinsic membrane properties like fluidity, ion transport, loss of enzyme activity, protein cross-linking, inhibition of protein synthesis, DNA damage: ultimately resulting in cell death.6 Scheme (Figure No-1) depicting major routes of ROS action in cells. Lipid Peroxidation: Lipid peroxidation is a natural metabolic process under normal aerobic conditions and it is one of the most investigated consequences of ROS action on membrane structure and function. Lipid peroxy radicals react with other lipids, proteins, and nucleic acids; propagating thereby the transfer of electrons and bringing about the oxidation of substrates. Cell membranes, which are structurally made up of large amounts of polyunsaturated fatty acids (PUFA), are highly susceptible to oxidative attack and, consequently, changes in membrane fluidity,

permeability, and cellular metabolic functions result. The initiation phase of lipid peroxidation includes activation of O2 which is rate limiting. Hydroxyl radicals and singlet oxygen can react with the methylene groups of PUFA forming conjugated dienes, lipid peroxy radicals and hydroperoxides:7

PUFA–H + X· → PUFA· + X–H PUFA· + O2 → PUFA–OO·

The peroxyl radical formed is highly reactive and is able to propagate the chain reaction:

PUFA–OO· + PUFA–H → PUFA–OOH + PUFA The formation of conjugated dienes occurs when free radicals attack the hydrogens of methylene groups separating double bonds and leading to a rearrangement of the bonds.8 Mechanism could be seen in Figure No-2. At the cellular level, when proteins are exposed to reactive oxygen species, modifications of amino acid side chains occur 9 and, consequently, alter the protein structure is either through direct chemical interaction or indirectly, involving end products of lipid peroxidation. A number of amino acids can be modified; for example, cysteine can be oxidized to cystine, and both proline and arginine are converted to glutamylsemialdehyde. Such modifications can affect the function of proteins. In some cases, the damaged amino acids are repaired in situ, whereas in other cases, the entire protein is removed and degraded.10,11 Oxidative Damage To DNA: ROS can cause oxidative damages to DNA of both nuclear and mitochondrial. The nature of damages include mainly base modification, deoxyribose oxidation, strand breakage, and DNA protein cross-links. Among the various ROS, hydroxyl radical generates various products from the DNA bases which mainly includes C-8 hydroxylation of guanine to form 8-oxo-7,8 dehydro-2¢ deoxyguanosine and 2,6-diamino-4-hydroxy-5- form amimodipyrimidine, 8-OH-adenine, 2-OH-adenine, thymine glycol, cytosine glycol etc.12 For example, mutation arising from selective modification of guanosine:cytosine sites specially indicates oxidative attack on DNA by ROS. The action of 8-oxodeoxy- guanosine as a promutagen, as

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well as in altering the binding of methylase to the oligomer so as to inhibit methylation of adjacent cytosine has been reported in cases of cancer development.13,14 ROS also damage DNA by various mutagenic alterations as well eg- ROS activate mutations in human C-Ha-ras-1 protooncogene, and to induce mutation in the p53 tumour-suppressor gene.15

Oxidative stress has been identified and proven to be the root cause of more than 70 chronic degenerative diseases such as stroke, diabetes, alzheimer’s dementia, parkinson’s disease, macular degeneration and other serious ailments which through a series of events deregulates the cellular functions leading to various pathological conditions including cardiovascular dysfunction, neurodegenerative diseases, gastroduodenal pathogenesis, metabolic dysfunction of almost all the vital organs, cancer, and premature aging (Figure No-3). Whereas ROS-mediated damage to cellular constituents is very widely described in the literature, the present review focuses on the specific minority of the studies where oxidative damage to has been linked causally to loss of cell integrity and/or viability mainly in peptic ulcer. Gastric ulcer is an illness that affects a considerable number of people worldwide. It is the most common gastrointestinal disorder. Peptic ulcer is an excoriated area of the gastric or duodenal mucosa caused by action of the gastric juice. It is a chronic and recurrent disease, and is the most predominant of the gastrointestinal diseases.16 It is caused by a lack of equilibrium between the gastric aggressive factors and the mucosal defensive factors.17 Various aggressive and defensive factors such as acid–pepsin secretion, parietal cell, mucosal barrier, mucus secretion, blood flow, cellular regeneration and endogenous protective agents such as prostaglandins and epidermic growth factors.18 Some other factors, such as inadequate dietary habits, excessive ingestion of non-steroidal anti-inflammatory agents, stress, hereditary predisposition and infection by Helicobacter pylori, may be responsible for the development of peptic ulcer.19 OXIDATIVE STRESS IN GASTRIC MUCOSA: Gastric mucus is an important protective factor for the gastric mucosa and consists of a viscous, elastic, adherent and transparent gel formed by 95% water and 5% glycoproteins that covers the entire gastrointestinal mucosa. Moreover, mucus is capable of acting as an antioxidant, and thus can reduce mucosal damage mediated by oxygen free radicals. The protective properties of the mucus barrier depend not only on the gel structure but also on the amount or thickness of the layer covering the mucosal surface.20 A decrease in gastric mucus renders the mucosa susceptible to injuries induced by acid, aspirin or cold restraint stress.21 If some oxygen radicals are generated in surface epithelium containing mucus, intracellular mucus could scavenge them. Even when cells containing mucus are damaged by extracellular oxygen radicals, intracellular mucus may be released into the gastric tissue and prevent additional damage by scavenging them.22 ROS can be derived from numerous sources in vivo. These include autooxidation, photochemical, enzymatic reactions, and may involve both endogenous compounds and various xenobiotics. The number of different enzymes shown to be capable of generating ROS is extensive i.e cytochrome p450, oxidases, peroxidases, lipoxygenases and dehydrogenases. The involvement of xenobiotics can be particularly important in determining the extent of ROS generated by these

enzymes.23 In addition, NADPH oxidase is well known to generate ROS as part of its antibacterial function on phagocytic cells. Perhaps the most important in vivo source of ROS is the mitochondrion. There is no doubt this organelle can generate ROS, particularly hydrogen peroxide and the superoxide anion.24 Research over the past 30 years has demonstrated that there are a number of reactive species present in biological systems that have the potential to induce damage. These include hydrogen peroxide, organic hydroperoxides and hypohalous acids, the peroxyl radical and nitric oxide, peroxynitrite , superoxide anion, singlet oxygen and the alkoxyl radical etc. Various factors contributing to mucus rupture are as follows: Ø The lipids content apparently determines the degree of

resistance of mucin to peptic degradation and contribute significantly to mucus viscosity, hydrophobicity and impedance to hydrogen ion diffusion.25 Lipid peroxidation leads to loss of membrane fluidity, ion transport and membrane integrity of the surface epithelial cell and helps to generate gastric lesions.26

Ø Haemorrhagic shock often is followed by rapid development of gastric mucosal lesions because gastric blood flow is considerably reduced during haemorrhagic shock. In the fundic mucosa the reduction of blood flow is more extensive than in the antral mucosa.27,28

Ø During the shock, it has been seen ATP concentrations are drastically reduced in many organs resulting in raised hypoxanthine concentrations in plasma.29-31

Ø Some of aldehydes, are very reactive and can damage molecules such as proteins.32 Unlike reactive free radicals, aldehydes are rather long lived and can therefore diffuse from the site of their origin and attack targets which are distant from the initial free-radical event, acting as “second toxic messengers” of the complex chain reactions initiated. Among many different aldehydes which can form during lipid peroxidation, the most intensively studied are malonaldehyde (MDA) and 4-hydroxyalkenals, in particular 4-hydroxynonenal (HNE).33

Ø Superoxide radicals (O₂-) play an important role in the formation of gastric lesions produced by ischaemia. Hydroxyl radical (OH )̄ appears to be the major oxygen radical contributing to ischaemic damage of gastric musoca.34 Involvement of oxygen derived free radicals are well established in the pathogenesis of ischaemic injury of gastrointestinal mucosa and also in other models of mucosal damage induced by non-steroidal anti-inflammatory drugs,35 ethanol,36 feeding rectriction stress,37 and H.pylori.38-33

Ø In H.pylori - infected gastric mucosa and duodenal gastric metaplasia, active inflamation with infiltration of neutrophils in the acute stage of the infection and of macrophages/monocytes, lymphocytes and plasma cells in the chronic stage, is observed in the lamina propria of the stomach. These neutrophils and macrophage/monocytes produce a large quantity of oxygen derived free radicals that could cause cells damage and lead ultimately to mucosal injury.39,40

Ø Under stress conditions, nitric oxide (produced by iNOS) reacts with O₂- (produced by neutrophils) to form peroxynitrites. These NO-derived reactive compounds contribute to the nitrosative and oxidative stress burden of

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vulnerable tissue such as the mucosa of the stomach and duodenum.41

Ø Cold-restraint stress induced myeloperoxidase activity (MPO) significantly, by activation of neutrophils that is associated with gastric ulcer formation. Activated neutrophils produce many enzymes and free radicals that damage the gastric mucosa.42

Ø Stress causes the elevation of corticosteroids, which leads to vasoconstriction due to increase in catecholamine.43 The elevation of these hormones can also disrupt gastric motility through the increase in stomach concentrations.44 Vasoconstriction and gastric hypermotility can impair gastric microcirculation and lead to the formation of gastric lesions.45

ANTIOXIDANTS: These are substances or nutrients in our foods which can prevent or slow the oxidative damage to our body. When our body cells use oxygen, they naturally produce free radicals (by-products) which can cause damage. Antioxidants act as "free radical scavengers" that prevent and repair damage done by these free radicals. Types of antioxidants are summarized as follows: Primary Defense: Endogenous Defense / Antioxidant Enzymes: Superoxide dismutase (SOD), catalase, and glutathione peroxidases constitute a mutually supportive team of defense against ROS. Superoxide Dismutase: a metalloprotein found in both prokaryotic and eukaryotic cells.46 The iron-containing (Fe-SOD) and manganese-containing (Mn-SOD) enzymes are characteristic of prokaryotes. In eukaryotic cells, the predominant forms are copper-containing enzyme and zinc-containing enzyme, located in the cytosol. The second type is manganese containing SOD found in the mitochondrial matrix. Superoxide dismutase (SOD) catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. Thus catalyzes the destruction of O₂ free radical. SOD 2O₂- + 2H⁺ H₂O₂ + O₂ Glutathione Peroxidases: Glutathione peroxidase47 catalyses the reaction of hydroperoxides with reduced glutathione (GSH) to form glutathione disulphide (GSSG) and the reduction product of the hydroperoxide.48 GSH, which consists of three amino acids, is an essential component of this system and serves as a cofactor for an enzyme called glutathione transferase. GPX H₂O₂ + GSH H₂O + GSSG GR GSSG + NAD(P)H GSH + NAD(P)⁺ Catalases: Catalase is a heme-containing enzyme that catalyses the dismutation of hydrogen peroxide into water and oxygen. The enzyme is found in all aerobic eukaryotes and is important in the removal of hydrogen peroxide generated in peroxisomes (microbodies) by oxidases involved in ß-oxidation of fatty acids, glyoxylate cycle (photorespiration) and purine catabolism.49 2H₂O₂ 2H₂O + O₂ Secondary Defense : In addition to the primary defense against ROS by antioxidant enzymes, secondary defense against ROS is also offered by small molecules which react

with radicals to produce another radical compound, the ‘scavengers’. When these scavengers produce a lesser harmful radical species, they are called ‘antioxidants.50 Exogenous Defense / Non- Enzymatic: · Natural antioxidant: natural antioxidants such as vitamin

A (retinoids), vitamin C (ascorbic acid), vitamin E (tocopherols), selenium and carotenoids have been implicated in the prevention of cancer and oxidative stress related diseases.51

· Plant phenolic and polyphenolic compounds- Plant phenolics antioxidants include flavonoid compounds, cinnamic acid derivatives, coumarins, tocopherols and polyfunctional acids.

· Food source of antioxidant: antioxidants are found in varying amount in foods such as vegetables, fruits, grain cereals, eggs, meat, legumes and nuts.52

· Synthetic antioxidants include : Butylated hydroxyl anisole (BHA), Butylated hydroxyl toluene ( BHT), propyl gallate (PG) and tertiary Butyl hydroquinone (TBHQ).53

NATURAL ANTIOXIDANTS AND MARKET PREPARATIONS: Antioxidants are powerful nutrients found in certain plant-based foods. Just as the name suggests, they fight off oxidation caused by damaging free radicals in our body. No matter how healthy our diet and lifestyle may be , antioxidants are the key to alleviating your continual exposure to free radicals. Flavonoids and other phenolic compounds of plant origin are reported as scavengers of free radicals.54 Hence, nowadays search for natural antioxidant source is gaining much importance. Some market preparations rich in natural antioxidants are mentioned here: Table no.1. CONCLUSION Inspite of certain discrepancies related to the ‘antioxidant hypothesis’, the message that antioxidants are good for health has a considerable momentum. The nutrition and other scientific societies tend to recognize today the importance of herbal antioxidants as agents promoting health. Oxidative stress has been implicated in the pathology of many diseases and condition including diabetes, cardiovascular diseases, inflammatory conditions, cancer and aging. An increasing number of investigations have been carried out to find antioxidative drugs, which not only prolong the shelf life of food products but also participate as radical scavengers in living organisms .As with other synthetic food additives, commercial antioxidants have been criticized, mainly due to possible toxic effects. Therefore, there is an increasing interest in the antioxidative activity of natural compounds. REFERENCES 1. Harman D. Free radical involvement in aging: pathophysiology and therapeutic implications. Drugs Aging 1993;3:60-80 2. Thomas CE, Kalyanaraman B. Oxygen Radicals and the Disease Process. 2nd ed. Hardwood Academic Publishers, Netherlands. 1997 3. Roberts RA, Laskin DL, Smith CV, Robertson FM, Allen EMG, Doorn JA, Slikkerk W. Nitrative and oxidative stress in toxicology and disease. Toxicol. Sci. 2009;112:4–16. 4. Avery SV. Metal toxicity in yeasts and the role of oxidative stress. Adv. Appl. Microbiol. 2001;49:111–142. 5. Limon-Pacheco J, Gonsebatt ME. The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress. Mutat. Res. 2009;674:137–147 6. Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in disease: An overview. Methods Enzymol. 1990;186:1-85. 7. Smirnoff N. Antioxidant systems and plant response to the environment. In: Smirnoff N, ed. Environment and plant metabolism: flexibility and acclimation. Oxford: BIOS Scientific Publishers.1995; 217–243.

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37. Yelken B, Dorman T, Erkasap S et al. Clonidine pretreatment inhibits stress-induced gastric ulcer in rats. Anesth Analg 1999;89: 159-62. 38. Santra A, Chowdhury A, Chaudhuri S, et al. Oxidative stress in gastric mucosa in helicobacter pylori infection. Indian J Gastroenterol 2000; 19: 21-3 39. Mooney C, Keenan J, Munster D, et al. Neutrophil activation by Helicobacter pylori. Gut 1991; 32: 853-7. 40. Davies GR, Simmonds NJ, Stevens TRJ et al. Helicobacter pylori stimulates antral mucosal reactive oxygen metabolite production in vivo. Gut 1994; 35: 179-85. 41. Kobata A, Kotani T, Komatsu Y, et al. Dual action of nitric oxide in the pathogenesis of ischemia/reperfusion-induced mucosal injury in mouse stomach. Digestion 2007;75:188–97. 42. Nishida K, Ohta Y, Kobayashi T, Ishiguro I. Involvement of the xanthine-xanthine oxidase system and neutrophils in the development of acute gastric mucosal lesions in rats with water immersion restraint stress. Digestion 1997; 58: 340-351 43. Ainsah o, nabishah BM, Osman CB, Khalid BAK. Short and long term effects of glycyrrhizic acid in repetitive stress. J Clin Exp Pharmacol Physiol 1999; 26: 444-8. 44. Ephgrave K, Brasel K, Culln J, Broadhurst K . gastric mucosal protection from enteral nutrients: role of motility. J Am Coll Surg 1998; 186: 434-40. 45. Matteri RL, Watson JG, Moberg GP. Stress or acute ACTH treatment suppresses LHRH- induced LH release in the rat. J Repord Fertil 1984;72:385-93. 46. Fridovich I. Assaying for superoxide dismutase activity. Annu. Rev. Pharmacol. Toxicol., 1983; 23: 29– 2 22. 47. Meister A, Anderson, ME. Glutathione. Annu. Rev. Biochem. 1983; 52: 711–760. 48. Chance B, Sies H, Boveris A. Superoxide production by the mitochondrial chain. Physiol. Rev. 1979; 59: 527–605 49. Deisseroth A, Dounce AL. Presence of high molecular weight form of catalase in enzyme purified from mouse liver. Physiol. Rev. 1970; 50: 319– 375. 50. Halliwell B. Reactive oxygen species in living systems: source, biochemistry and role in human diseases. Am. J. Med. 1991; 91: 14S–22S. 51. Blake DR, Allen RE, Lunec J. Free radicals in biological systems- a review oriented to inflammatory processes. Br. Med. Bull. 1987; 43: 371–385 52. Donald Hensrud M.D. Endocrinology, mayo clinic Rochester, Minn. “Food sources the best choice for antioxidants”. Mayo clinic, 2009 53. Kahl R, Kappus H. “ Toxicology of synthetic antioxidants BHA and BHT in comparison with the natural antioxidant vitamin E” . Z Lebensm Unters Forsch. 1993; 196(4): 329-38. 54. Formica JV and Regelson W. Review of the biology of quercetin and related bioflavonoids. Food Chem. Toxicol. 1995;33: 1061-1080. 55. Claudia A, Graciela E, Ferraro, Rosana F. Total Polyphenol Content and Antioxidant Capacity of Commercially Available Tea (Camellia sinensis) in Argentina, J. Agric. Food Chem. 2008; 56: 9225–9229. 56. Howard LR, Clark JR, Brownmiller C.“Antioxidant capacity and phenolic content in blueberries as affected by genotype and growing season,” Journal of the Science of Food and Agriculture 2003; 83:1238-1247. 57. Middha Anil, Dr. Purohit Suresh . Determination Of Free Radical Scavenging Activity In Herbal Supplement: Chyawanprash, International Journal of Drug Development & Research Jan-March 2011 ; Vol. 3 : Issue 1 , ISSN 0975-9344 58. Vidhi M, Shubhi M ,Vandna K .Antioxidant and antimicrobial activities of aqueous extract of Withania somnifera against methicillin-resistant S.aureus, J. Microbiol. Biotech. Res., 2011, 1 (1): 40-45. 59. Bhattacharya A, Chatterjee A, Ghosal S, Bhattacharya SK Antioxidant activity of active tannoid principles of Emblica officinalis (amla). Indian J Exp Biol 1999; Jul 37(7):676-80 60. Bhattacharya SK, Bhattacharya A, Kumar A, Ghosal S..Antioxidant activity of Bacopa monniera in rat frontal cortex, striatum and hippocampus. Phytother Res 2000b ;14:174-179. 61. Sonia M, Mohamed D, in vitro antioxidant activities of aloe vera leaf skin extracts, . Journal de la Societe chimique de tunisie 2008; 10: 101-109. 62. Vani T, Rajani M, Sarkar S, Shishoo CJ. Antioxidant properties of the ayurvedic formulation Triphala and its constituents. Inter. J. Pharmacognosy 1997;35: 313- 317. 63. MB Mielnik E, Olsen G, Vogt D, Adeline G, Skrede .Grape seed extract as antioxidant in cooked, cold stored turkey meat LWT 2006; 39:191–198. 64. Sameera o, Bafeel , mohamed m. Ibrahim. Antioxidants and accumulation of α-tocopherol induce chilling tolerance in Medicago sativa. International Journal Of Agriculture And Biology ISSN Print: 1560–8530; ISSN Online: 1814–9596

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Table-1 Market Preparations Contains Natural Antioxidants

MARKET PREPARATIONS NATURAL ANTIOXIDANT

MANUFACTURERS

Green tea Green tea extract55 Organic India, Hanumatey , G.R Internationals, India.

Blueberry drink Blueberries56 Harbin yeekong herb inc., china

Chyawanprash57 many natural herbs Organic India, Dabur, India.

Ashwagandha capsules Ashwagandha58 Organic India, Divya pharmacy , India.

Amalaki capsules Amla fruits59 Himalaya, Organic India, Dabur

Brahmi forte capsules Brahmi herb60 Organic India, Plant med laboratories Pvt Ltd, India

Aloe vera juice, Aloe vera61 Capac mediflora, Pinnacle Wellness Concepts Pvt Ltd, India

Triphala powder, Triphala capsules

Triphla62 Quality india herbal products, Pinnacle wellness concepts pvt ltd, India

Grape seed powder Grape seed extract63 Kuber implex ltd, IBIS chemie international., India

Alfalfa tonic Alfalfa plant64 S.B.L private limited, Newdelhi

Blackberry juices Blackberry65 A.M.V Botanics, jaipur

Betatene Natural carotenoids66 Wil cure remedies pvt ltd, Indore, India

Olive oil Polyphenols67 Sai export India, pro-active foods, India

Apple juice Apples68 Yesraj Enterprises, Mumbai

Grape juices Grapes63 Kool foods, Hyderabad

Prime health – amla juice Amla fruits59 Prime Herbonixhealth products pvt ltd. Pune, Sathyaa Associates, krishnagiri

Guava puree and pulp juices Guava69 Manuj Enterprises , Pune

Pineapple juices Pineapple70 Rohini’s food products, Chennai Jamun karela juice Blackberry,karela65,71 Austro labs, Newdelhi

Mint lemonade Mint72 Sab foods, Chennai

Figure 1: Major Routes Of ROS Action In Cells6

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Figure 2: Mechanism Of Lipid Peroxidation8

Figure 3: Diseases Caused By Oxidative Stress16