International Journal of Current Research and Review
ISSN: 2231-2196 (Print)ISSN: 0975-5241 (Online)
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IJCRR - vol 05 issue 19, October, 2013

Pages: 14-22

Date of Publication: 19-Oct-2013


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ROLE OF FREE RADICALS AND ANTIOXIDANTS IN HUMAN HEALTH AND DISEASE

Author: Neeraj, John Pramod, Sheena Singh, Joydeep Singh

Category: Healthcare

Abstract:Overproduction of free radicals, inconsistent with inactivating capacity of the naturally occurring antioxidants, leads to altered physiology and morbidity. The role of free radicals in normal physiological states like ageing and common health problems like burns, infertility and cancer or systemic diseases of the cardiovascular system e.g. atherosclerosis, hypertension, reperfusion injury as also disease of other systems (CNS, Immunity, endocrine anomalies) have been discussed. This review of available studies explores the role of antioxidants in minimizing the oxidative stress in various disease conditions like diabetes, cataract, inflammatory conditions, AIDS and mutagenic effects of reactive oxygen species.

Keywords: cellular damage, free radicals, antioxidants

Full Text:

INTRODUCTION

Oxygen is essential element for life. Oxidative properties of oxygen play a vital role in diverse biological phenomena. Oxygen has double-edged properties, being essential for life; it can also aggravate the damage within the cell by oxidative events1.

Free radicals and its adverse effects were discovered in the last decade. These dangerous substances are produced during the normal metabolic processes in the body along with toxins and wastes. Free radicals are generated during oxidation of carbohydrates, fats and proteins through both aerobic and anaerobic process. Overproduction of the free radicals can be responsible for tissue injury. Unsaturated lipid molecules of cell membranes are particularly susceptible to free radicals. In addition, other biological molecules including RNA, DNA and protein enzymes are also susceptible to oxidative damage. Free radicals are responsible for causing a wide number of health problems which include cancer, aging, heart diseases and gastric problems etc.  

Anti-oxidants are substances capable of scavenging free radicals and prevent them from causing cell damage. Antioxidants provide protection by neutralizing free radicals, which are toxic byproducts of natural cell metabolism. The human body naturally produces antioxidants but the process is not 100 percent effective in case of overwhelming production of free radicals and that effectiveness also declines with age. Increased intake of antioxidants can prevent diseases and lower the health problems. Foods may possibly enhance antioxidant levels because they contain a lot of antioxidant substances. Fruits and vegetables are rich in key antioxidants such as vitamin A, C, E, beta-carotene and important minerals, including selenium and zinc. Natural products, mainly obtained from dietary sources provide a large number of antioxidants2.

FREE RADICALS

Free radicals, which are independently and freely occurring molecules or fragments of molecules, have long been thought as agents that cause systematic cell damage in various states of health and disease. The rate of production is directly related to the extent of cellular injury. Several types of free radicals have been identified in human beings and other mammals which include superoxide molecules, hydroxyl groups, nitric oxide and hydrogen peroxide. Superoxide, the best known free radical of all the oxygen derived species is an integral part of the process of phagocytosis by leucocytes3. Hydroxyl (OH-­) is the most toxic of the oxygen-based radicals and it wreaks havoc within cells, particularly with macromolecules4. Hydroxyl radical is short lived but most damaging radical in the body. Hydrogen peroxide is not a free radical but falls in the category of reactive oxygen species. It is an oxidising agent and is involved in the production of HOCl by neutrophils. Nitric oxide (NO) is another physiological free radical which is made by vascular endothelium as a relaxing factor, and also by phagocytes and in the brain. It has many important physiological functions but excess can be toxic5. It is known to be involved in various age related diseases like atherosclerosis, hypertension etc. and in many other biological effects such as blood vessel dilatation, signaling, neurotransmission, regulation of hair follicle activity and immune response. Increased NO may contribute to the development of oxidative stress during aging6.

SOURCES OF FREE RADICALS

Free radicals and other reactive oxygen species (ROS) 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 chemicals7,8. The sources include endogenous production from mitochondria9, microsomes10, enzymes or enzymatic reactions11,12 phagocytes13 and metal ions14,15. Exogenous sources of free radicals include cigarette smoke10,16,  alcoholism 17 toxins and drugs18,19 and ionizing radiation10 .

ANTIOXIDANTS

Inactivated free radicals have the potential to cause extensive damage to cellular macromolecules including proteins, lipids, carbohydrates , and nucleic acids8. Fortunately, antioxidants can come to the rescue and minimize the damage. Antioxidants work to protect lipids from peroxidation by free radicals20 and can be defined as a molecule stable enough to donate an electron to a free radical and neutralize it , thus reducing its capacity to damage8 .

A crucial balance between free radical production and antioxidant defense helps in disease prevention7 .Under physiological conditions ROS concentrations are kept low by endogenous oxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase21,22 and also by non enzymatic components such as vitamin C, vitamin E, glutathione (GSH)  and uric acid22. When the production of free radicals is beyond the protective capability of the antioxidant defenses, condition known as oxidative stress (OS) occurs. So oxidative stress has been defined as the loss of balance between free radical or ROS production and antioxidant systems, with negative effects on carbohydrate, lipid and proteins, thus playing a role in cardiovascular diseases, cancer, diabetes and neurodegenerative disorders etc23.  A certain amount of oxidative damage takes place even under normal conditions, however the rate of this damage increases during the ageing process, as the efficiency of antioxidative and repair mechanisms decrease6. One of the important markers of OS is malondialdehyde (MDA) which is an end product of lipid peroxidation24

ROLE IN HEALTH AND DISEASE

The role of free radicals and their inhibition or suppression in various physiological and pathological conditions is mentioned below. Although many abnormal physiological conditions and overt pathology are linked to endogenous or exogenous production of the free radical, their corresponding antioxidants and their mechanism of inhibition of cellular damage by the free radicals have also been a subject of scientific interest till date. We would be limiting our focus on only those conditions in which the specific role of antioxidants and their relationship have been very well documented.

Burns : Free radical mediated cell injury has been supported by postburn increases in systemic and tissue levels of lipid peroxidation products such as conjugated dienes, thiobarbituric acid reaction products, or malondialdehyde (MDA) levels. Antioxidant therapy in burn (glutathione, N-acetyl-L-cysteine, or vitamins A, E, and C alone or in combination) have been shown to reduce burn and burn/sepsis mediated mortality, to protect microvascular circulation, reduce tissue lipid peroxidation, improve cardiac output, and to reduce the volume of required fluid resuscitation25. Antioxidant vitamin therapy in burn trauma provides cardioprotection, at least in part, by inhibiting translocation of the transcription factor NF-kappaB and interrupting cardiac inflammatory cytokine secretion26.  

Ageing: By far, one of the most popular theories of aging is the "Free Radical Theory of Aging." This theory was first proposed by Dr. Denham Harman27, and postulates that aging results from an accumulation of changes caused by reactions in the body initiated by highly reactive molecules known as "free radicals." The changes induced by free radicals are believed to be a major cause of aging, disease development or death.

Cancer: Mutations caused by ROS can result in malignant transformation and the development of cancer28. Since oxidative stress is generally perceived as one of the major causes for the accumulation of mutations in the genome, antioxidants are believed to provide protection against cancer7. Fortunately, certain antioxidant supplements like vitamins C and E can prevent much oxidative damage to DNA and thus reduce the ability of the oxidants to induce cancer8. Supplementing cancer patients with adjuvant therapy of resveratrol (a flavonoid) may have some benefit for a more successful radiotherapy29 . Dietary deficiencies in zinc can contribute to single- and double-strand DNA breaks and oxidative modifications to DNA that increase risk for cancer development30.

Cardiovascular Diseases (CVD): Oxidative damage and the production of free radicals in the endothelium are two of the main factors involved in the pathogenesis of the atherosclerotic process that causes CVD.  Research concerning nutritional regimens has shown that persons who consume large amounts of fruit and vegetables have lower incidences of cardiovascular diseases, stroke, and tumors, although the precise mechanisms for this protective effect are elusive. Possible explanations include (a) increased consumption of dietary fiber, (b) reduced consumption of dietary cholesterol and other lipids, and (c) increased intake of the antioxidant vitamins (A, C, and E)31,32. Risk factors such as hypertension, smoking and diabetes mellitus are all associated with increased oxidative stresses due to excess free radical activity in the vascular wall. This may facilitate the development of vascular disease because of (i) increased oxidation of low-density lipoprotein (LDL) particles which increases their propensity to deposition in the vascular wall, (ii) inactivation of endothelium-derived nitric oxide, and (iii) direct cytotoxicity to endothelial cells. Protective antioxidant molecules include vitamin C and vitamin E of which the latter is the primary antioxidant defense in circulating LDL particles33. Many studies showed that vitamin E intake over an extended period was associated with decreased risk of cardiovascular events34. Tea and wine, rich in flavonoids, seem to have beneficial effects on multiple mechanisms involved in atherosclerosis35.

Reperfusion injury: Reperfusion injury is defined as the damage to cells which occurs following restoration of the blood and oxygen supply to the tissue after a period of ischemia. Antioxidants are able to prevent or reduce the severity of this type of tissue damage36. Bhakuni P et al in their study found that oxidative stress parameters in the post reperfusion patients were restored back to normal or near normal levels by supplementation with vitamin C37.

Hypertension: Increased oxidative stress in hypertensive patients reduces activity of SOD38. Vitamin E supplementation provides protection against oxidative stress by restoring the enzyme activity and preventing further damage caused by lipid peroxidation38. Inclusion of vitamin E in antihypertensive therapy in post reperfusion hypertensive patients results in better management of blood pressure39.  So the consumption of diet rich in vitamin E should be increased in hypertension38.

Atherosclerosis: High levels of ROS (e.g the highly reactive hydroxyl radical) exert antiangiogenic effects and promote arteriosclerosis and endothelial cell death28.

The oxidative modification hypothesis of atherosclerosis centres on the well-known association between low-density lipoprotein (LDL) cholesterol and atherosclerosis and, in particular, on the uptake of oxidised LDL by macrophages within the arterial wall to form foam cells, the earliest stage in atherogenesis38.

Increased plasma levels of MDA and nitrite in patients of myocardial infarction indicate that oxygen free radicals cause endothelial damage, and elevated superoxide dismutase levels in these patients may imply that the body attempts to combat this oxidative stress by raising its level of anti-oxidants40. Antioxidant compounds found in fruit and vegetables, such as vitamin C, carotenoids, and flavonoids, may influence the risk of CVD by preventing the oxidation of cholesterol in arteries42.

Diabetes: oxidative stress plays a major role in the pathogenesis of diabetes mellitus and its underlying complications43. Under conditions of hyperglycemia, excessive amounts of superoxide radicals are produced inside vascular cells and this can interfere with NO production leading to the possible complications44.  It is found that dietary GSH suppresses oxidative stress in vivo in prevention of diabetic complications such as diabetic nephropathy and neuropathy45 .

Cataract: Oxidative stress resulting from extensive oxidation of lens protein and lipid is an initiating factor for the development of maturity onset cataract. H2O2 is the major oxidant involved in cataract formation46.The young lens has substantial reserves of antioxidants to prevent lens damage and proteolytic enzymes, proteases that selectively remove damaged proteins. Compromises of function of the lens with aging are associated and may be causally related to depleted antioxidant reserves, diminished antioxidant enzyme capabilities and decreased proteases47.

Chronic high dose intake of lutein has improved visual acuity in small numbers of subjects with age-related cataract48. Pro-drug antioxidant N-acetylcarnosine, which is acetyl derivative of the natural dipeptide antioxidant l-carnosine found in meat has shown promising results in the prevention of cataract49.

Inflammatory diseases: In inflammation neutrophils and macrophages by virtue of antibacterial killing mechanisms generate superoxide, H2O2, and hypochlorite resulting in activation of proteases and tissue damage. ROS are produced in abnormally high levels in inflammatory bowel diseases. Their destructive effects may contribute to the initiation and/or propagation of the disease50. Antioxidant therapy such as green tea polyphenols and gene therapy with superoxide dismutase has a markedly attenuated disease51. Oxidative stress is an important factor in the pathogenesis of acute pancreatitis52  and of chronic pancreatitis (CP)53.  Antioxidant supplementation is effective in relieving pain and reducing levels of oxidative stress in patients with CP53. Giving antox (specially formulated nutritional supplement) which contains the antioxidants selenium, betacarotene, L-methionine, and vitamins C and E improves the quality of life and reduces pain in patients suffering from chronic pancreatitis54.

Rheumatoid Arthiritis (RA): ROS as well as reactive nitrogen species (RNS) can directly or indirectly damage basic articular constituents and lead to the clinical expression of the inflammatory arthritis.There is an inverse association between serum antioxidant levels and inflammation in RA patients55. There is enhanced production of superoxide ion and peroxynitrite by bloodstream neutrophils and of superoxide ion by monocytes from  RA patients56.

It is known that ROS can function as a second messenger to activate nuclear factor kappa-B, which orchestrates the expression of a spectrum of genes involved in the inflammatory response. Therefore, an understanding of the complex interactions between these pathways might be useful for the development of novel therapeutic strategies for rheumatoid arthritis57. .Role of oxidative stress in RA patients is confirmed now and indicates that antioxidant supplementation play an important role in controlling oxidative stress and decreasing disease activity in these patients58. There is necessity for therapeutic co-administration of antioxidants along with conventional drugs to such patients59.

AIDS: oxidative stress may contribute to several aspects of HIV disease. For this reason, the exogenous supply of antioxidants, as natural compounds (vitamin A, C, E, Se and Zinc) and new-generation antioxidants (cyclodecan-9-yl-xanthogenate (D609), GPI 1046 , Memantine ) that scavenge free radicals might represent an important additional strategy for the treatment of HIV infection in the era after HAART therapy has been applied60.

Diseases of the Central Nervous System: Recent interest has focused on antioxidants such as carotenoids and in particular lycopene, flavonoids and vitamins as potentially useful agents in the management of human neurological disorders like Parkinson's disease, Huntington's disease, Alzheimer's disease (AD) and Schizophrenia61. Overactivity of excitatory amino acid receptors is an important pathogenetic factor that leads to seizure genesis and increased oxidative stress has been implicated in the mechanism of excitotoxicity induced neurodegeration62.

Therefore use of antioxidants could be a potential approach in arresting or inhibiting the seizure genesis caused by excitotoxic agents63.  

The study done by Yogendera K. Gupta et al demonstrates the potential antiepileptic effect of antioxidant curcumin64.

An increasing number of studies demonstrated the efficacy of primary antioxidants, such as polyphenols, or secondary antioxidants, such as acetylcarnitine, to reduce or to block neuronal death occurring in the pathophysiology of AD65.

Several studies have indicated that oxidative stress is a major risk factor for the initiation and progression of sporadic PD and AD. Even a-synuclein and b-amyloid fragments that are associated with the PD and AD, respectively, mediate part of their action via oxidative stress. Therefore, reducing oxidative stress appears to be a rational choice for the prevention and reduction in the rate of progression of these neurological disorders66.

Infertility: Recent research in the field of male infertility is focused on ROS, which is suspected to be one of the major causes of infertility at molecular level67. Seminal ROS levels increase with increase in age68. Increased lipid peroxidation of the plasma membrane of sperms caused by ROS is damaging to the sperms24. There is a negative correlation between sperm concentration, motility and normal morphology and seminal MDA level24. Recently the role of L-carnitine and L-acetyl carnitine in scavenging the free radicals and protecting the cell membrane has gained much importance in treatment of male infertility71.

Also drug intake, smoking, pollution, radiation etc are reported to increase seminal oxidative stress which causes spermatozoa dysfunction leading to male infertility67.  Recent studies have shown raised ROS levels and sperm DNA (nuclear and mitochondrial) damage in idiopathic infertile men67. Vitamin E, a major chain breaking antioxidant in the sperm membrane appears to have dose dependent effect70.  Administration of 100mg of vitamin E thrice daily for six months in a group of asthenozoospermic patients with normal female partner has been found to cause a significant decrease in lipid peroxidation and increase in motility70.

ROS have a statistically significant effect on fertilization rate after IVF, and that the measurement of ROS level in semen specimens before IVF may be useful in predicting IVF outcome71. Assisted reproductive techniques may show significant improvement in in vitro supplementation of antioxidants and metal chelators to achieve a better success72.

CONCLUSION

Although a lot has been documented about role of antioxidants, the field is vast and open for more research in development of inhibitors of molecules or fragments that cause cellular damage and increase morbidity in human beings. The prevention of such damage which is likely to cause enhanced apoptosis, temporary or permanent change and even mutations in the existing DNA is the call of the day. Further sources of free radical production and newer methods of production of antioxidants to supplement the naturally occurring defense mechanisms need to be explored.

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Awards, Research and Publication incentive Schemes by IJCRR

Best Article Award: 

One article from every issue is selected for the ‘Best Article Award’. Authors of selected ‘Best Article’ are rewarded with a certificate. IJCRR Editorial Board members select one ‘Best Article’ from the published issue based on originality, novelty, social usefulness of the work. The corresponding author of selected ‘Best Article Award’ is communicated and information of award is displayed on IJCRR’s website. Drop a mail to editor@ijcrr.com for more details.

Women Researcher Award:

This award is instituted to encourage women researchers to publish her work in IJCRR. Women researcher, who intends to publish her research work in IJCRR as the first author is eligible to apply for this award. Editorial Board members decide on the selection of women researchers based on the originality, novelty, and social contribution of the research work. The corresponding author of the selected manuscript is communicated and information is displayed on IJCRR’s website. Under this award selected women, the author is eligible for publication incentives. Drop a mail to editor@ijcrr.com for more details.

Emerging Researcher Award:

‘Emerging Researcher Award’ is instituted to encourage student researchers to publish their work in IJCRR. Student researchers, who intend to publish their research or review work in IJCRR as the first author are eligible to apply for this award. Editorial Board members decide on the selection of student researchers for the said award based on originality, novelty, and social applicability of the research work. Under this award selected student researcher is eligible for publication incentives. Drop a mail to editor@ijcrr.com for more details.


Best Article Award

A Study by Juna Byun et al. entitled "Study on Difference in Coronavirus-19 Related Anxiety between Face-to-face and Non-face-to-face Classes among University Students in South Korea" is awarded Best Article for Vol 12 issue 16
A Study by Sudha Ramachandra & Vinay Chavan entitled "Enhanced-Hybrid-Age Layered Population Structure (E-Hybrid-ALPS): A Genetic Algorithm with Adaptive Crossover for Molecular Docking Studies of Drug Discovery Process" is awarded Best article for Vol 12 issue 15
A Study by Varsha M. Shindhe et al. entitled "A Study on Effect of Smokeless Tobacco on Pulmonary Function Tests in Class IV Workers of USM-KLE (Universiti Sains Malaysia-Karnataka Lingayat Education Society) International Medical Programme, Belagavi" is awarded Best article of Vol 12 issue 14, July 2020
A study by Amruta Choudhary et al. entitled "Family Planning Knowledge, Attitude and Practice Among Women of Reproductive Age from Rural Area of Central India" is awarded Best Article for special issue "Modern Therapeutics Applications"
A study by Raunak Das entitled "Study of Cardiovascular Dysfunctions in Interstitial Lung Diseas epatients by Correlating the Levels of Serum NT PRO BNP and Microalbuminuria (Biomarkers of Cardiovascular Dysfunction) with Echocardiographic, Bronchoscopic and HighResolution Computed Tomography Findings of These ILD Patients" is awarded Best Article of Vol 12 issue 13 
A Study by Kannamani Ramasamy et al. entitled "COVID-19 Situation at Chennai City – Forecasting for the Better Pandemic Management" is awarded best article for  Vol 12 issue 12
A Study by Muhammet Lutfi SELCUK and Fatma COLAKOGLU entitled "Distinction of Gray and White Matter for Some Histological Staining Methods in New Zealand Rabbit's Brain" is awarded best article for  Vol 12 issue 11
A Study by Anamul Haq et al. entitled "Etiology of Abnormal Uterine Bleeding in Adolescents – Emphasis Upon Polycystic Ovarian Syndrome" is awarded best article for  Vol 12 issue 10
A Study by Arpita M. et al entitled "Estimation of Reference Interval of Serum Progesterone During Three Trimesters of Normal Pregnancy in a Tertiary Care Hospital of Kolkata" is awarded best article for  Vol 12 issue 09
A Study by Ilona Gracie De Souza & Pavan Kumar G. entitled "Effect of Releasing Myofascial Chain in Patients with Patellofemoral Pain Syndrome - A Randomized Clinical Trial" is awarded best article for  Vol 12 issue 08
A Study by Virendra Atam et. al. entitled "Clinical Profile and Short - Term Mortality Predictors in Acute Stroke with Emphasis on Stress Hyperglycemia and THRIVE Score : An Observational Study" is awarded best article for  Vol 12 issue 07
A Study by K. Krupashree et. al. entitled "Protective Effects of Picrorhizakurroa Against Fumonisin B1 Induced Hepatotoxicity in Mice" is awarded best article for issue Vol 10 issue 20
A study by Mithun K.P. et al "Larvicidal Activity of Crude Solanum Nigrum Leaf and Berries Extract Against Dengue Vector-Aedesaegypti" is awarded Best Article for Vol 10 issue 14 of IJCRR
A study by Asha Menon "Women in Child Care and Early Education: Truly Nontraditional Work" is awarded Best Article for Vol 10 issue 13
A study by Deep J. M. "Prevalence of Molar-Incisor Hypomineralization in 7-13 Years Old Children of Biratnagar, Nepal: A Cross Sectional Study" is awarded Best Article for Vol 10 issue 11 of IJCRR
A review by Chitra et al to analyse relation between Obesity and Type 2 diabetes is awarded 'Best Article' for Vol 10 issue 10 by IJCRR. 
A study by Karanpreet et al "Pregnancy Induced Hypertension: A Study on Its Multisystem Involvement" is given Best Paper Award for Vol 10 issue 09
Late to bed everyday? You may die early, get depression
Egg a day tied to lower risk of heart disease
88 Percent Of Delhi Population Has Vitamin D Deficiency: ASSOCHAM Report

List of Awardees

Awardees of COVID-19 Research

Woman Researcher Award

A Study by Neha Garg et al. entitled "Optimization of the Response to nCOVID-19 Pandemic in Pregnant Women – An Urgent Appeal in Indian Scenario" published in Vol 12 issue 09

A Study by Sana Parveen and Shraddha Jain entitled "Pathophysiologic Enigma of COVID-19 Pandemic with Clinical Correlates" published in Vol 12 issue 13

A Study by Rashmi Jain et al. entitled "Current Consensus Review Article on Drugs and Biologics against nCOVID-19 – A Systematic Review" published in Vol 12 issue 09

Emerging Researcher Award

A Study by Madhan Jeyaraman et al. entitled "Vitamin-D: An Immune Shield Against nCOVID-19" published in Vol 12 issue 09

Study by Dheeraj Kumar Chopra et al. entitled "Lipid-Based Solid Dispersions of Azilsartan Medoxomil with Improved Oral Bioavailability: In Vitro and In Vivo Evaluation" published in Vol 12 issue 19


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Disclaimer: International Journal of Current Research and Review (JICRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal.



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International Journal of Current Research and Review (JICRR) provides platform for researchers to publish and discuss their original research and review work. IJCRR can not be held responsible for views, opinions and written statements of researchers published in this journal

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