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Abstract

Review article base on Free radicals are highly reactive and unstable molecules. Some of the key free radicals include hydroxyl radical, superoxide anion, hydrogen peroxide, singlet oxygen, hypochlorite, nitric oxide, and peroxynitrite. These radicals can damage important biological molecules like DNA, proteins, carbohydrates, and lipids, leading to cell damage. They are also linked to problems like early aging. Both internal and external factors can trigger the production of these reactive species, and oxidative stress plays a major role in many inflammatory diseases. Antioxidants can help neutralize the harmful effects of free radicals. They act by scavenging radicals, donating hydrogen or electrons, breaking down peroxides, quenching singlet oxygen, inhibiting enzymes, working synergistically, and chelating metals. Many natural antioxidants are available, including vitamins (like Vitamin C and E) and enzymes (such as glutathione reductase, glutathione peroxidases, and superoxide dismutase).

Keywords

Free Radical, Scavenger, Antiaging, Antioxidant, Peroxynitrite etc.

Introduction

A free radical is any molecular species that contains an unpaired electron in its atomic orbital. This unpaired electron gives free radicals their typical properties, making many of them unstable and highly reactive. They can either donate or accept electrons from other molecules, functioning as oxidizing or reducing agents.

The most significant oxygen-containing free radicals involved in various disease conditions include hydroxyl radicals, superoxide anion radicals, hydrogen peroxide, singlet oxygen, hypochlorite, nitric oxide radicals, and peroxynitrite radicals. These highly reactive species can damage crucial biological molecules such as DNA, proteins, carbohydrates, and lipids. By attacking these macromolecules, free radicals cause cellular damage and disrupt the body's balance, or homeostasis.

In the body, free radicals can target a wide range of molecules, with lipids, nucleic acids, and proteins being the primary targets.

Generation of reactive oxygen species in the human body:

Free radicals and other reactive oxygen species (ROS) arise from normal basic metabolic processes in the body or from external sources such as exposure to x-rays, ozone, cigarette smoking, air pollutants, and industrial chemicals.

       
            Generation of reactive oxygen species in the human body.jpg
       

Figure 1:  Generation of reactive oxygen species in the human body.

Free radicals are formed as a result, they are continuously in the cells as a consequence of bothEnzymatically and non-enzymatically

       
            Generation of free radical and ROS.jpg
       

Figure 2: Generation of free radical and ROS.

Some internal sources of free radicals: 

  1. Mitochondria
  2. Xanthine oxidase
  3. Peroxisomes
  4. Inflammation
  5. Phagocytosis 
  6. Arachidonic acid pathway 
  7. Exercise
  8. Ischemia/reperfusion injury

Some external sources of free radicals: 

  1. Cigarette
  2. smoke
  3. Environmental pollutants
  4. Radiation
  5. Certain drugs
  6. Pesticides
  7. Industrial solvents
  8. Ozone. 

Ozone can be harmful or beneficial, depending on where it is found. In the troposphere, ozone is called smog. This particular type can be formed by free radicals.However, ozone acts as a shield in the stratosphere. Ozone completely protects the Earth's surface from UV-C radiation. Some UV-.B (which causes more sunburn) and UV- A (which causes more tanning)  still reach  the Earth's environment.

       
            Free Radicals in Biology.jpg
       

Figure 3: Ozone completely protects the Earth's surface from UV-C radiation.

Free Radicals in Biology 

Free radical reactions are expected to cause progressive adverse effects that accumulate throughout the body as we age. 

       
            Free Radicals in Biology.jpg
       

Figure 4: Free Radicals in Biology.

Depending on genetic and environmental factors, they manifest as diseases at a certain age.Cancer and atherosclerosis, the two leading causes of death, are prominent "free radical" diseases. The initiation and development of cancer is associated with chromosomal defects and the activation of oncogenes. 

Antioxidants :

Antioxidants are molecules that are stable enough to donate electrons to vicious free radicals and neutralize them, thereby reducing their ability to cause damage. These antioxidants primarily delay or inhibit cellular damage through their ability to scavenge free radicals. 

       
            Effect of Antioxidants on free radicals.png
       

Figure 5:  Effect of Antioxidants on free radicals.

These small molecule antioxidants can safely interactwith reactive oxygen speciesand haltthe chain reaction before important molecules are damaged. 

The concept of oxidative stress:

The term is used to describe a state of oxidative damage resulting from an unfavorable  critical balance between free radical production and antioxidant defenses. A role for oxidative stress has been postulated in many conditions, includingatherosclerosis, inflammatory diseases, some cancers, and the aging process. Oxidative stress is now thought to be a significant cause of all inflammatory diseases (arthritis, vasculitis, glomerulonephritis, lupus erythematosus, adult respiratory distress syndrome), ischemic diseases (heart disease, stroke, intestinal ischemia), hemochromatosis, AIDS, emphysema, organ transplantation, peptic ulcers, hypertension and preeclampsia, neurological diseases (Alzheimer's disease, Parkinson's disease, muscular dystrophy), alcoholism, and smoking-related diseases. Excessive oxidative stress can lead to oxidation of lipids and proteins, which is associated with changes in their structure and function.

       
            The concept of oxidative stres.jpg
       

       
            The concept of oxidative stres 2.png
       

Figure 6: The concept of oxidative stress.

Free Radical Creating Complications:

  1. Cardiovascular Disease:Oxidation can have enormous benefits for healthand longevity as it can affect cardiovascular health. Polyunsaturated fatty acids occur as a major component  of low-density lipoprotein (LDL) in the blood, and oxidation of these lipid components to LDL plays an important role in atherosclerosis.  HDL: density 1 1.2 g/ml, diameter 5-12 nm.  LDL: density 1 g/ml, diameter 18-25 nm,  Antioxidants such as beta-carotene and vitamin E play an important role in preventing various cardiovascular diseases. 
  2. Carcinogenicity: Reactive oxygen and nitrogen species such as superoxide anion,hydrogen peroxide, hydroxyl radicals, and nitric oxide, and their biological metabolites also play an important role in carcinogenesis. ROS cause DNA damage  by reaction. Free radicals in DNA are involved in chain scission. Base modifications and DNA-protein cross-linking.  Antioxidants can reduce carcinogenesis due to oxidative stress by directly scavenging ROS or by inhibiting cell proliferation by protein phosphorylation. Beta-carotene may prevent cancer through its antioxidant function, as its oxidation products can cause genetic damage.

Vitamin C may help prevent cancer. Possible mechanisms by which  vitamin C may affect carcinogenesis include antioxidant effects, blocking  nitrosamine production, enhancing immune responses, and accelerating liver detoxification enzymes. Vitamin E, an important antioxidant, plays a critical role in immune function by enhancing humoral antibody defense, resistance to bacterial infection, cellular immunity, T cell tumor necrosis factor production, inhibition of mutagenic agent formation, DNA membrane repair, and blocking microglial lineage formation.

       
            ROS cause DNA damage  by reaction.jpg
       

Figure 7: ROS cause DNA damage  by reaction.

  1. Aging: The primary mechanism of aging involves the accumulation of DNA or cellular and functional damage. Reducing free radicals or slowing their production can slow down aging. Free radicals break down collagen in the skin, resulting in unsightly skin blemishes such as wrinkles, dark spots, fine lines, and loose, saggy skin.

Figure 8: The primary mechanism of aging involves the accumulation of DNA or cellular and functional damage.

       
            Effect of antioxidant on human body.png
       

Figure 9: Effect of antioxidant on human body.

  1. Oxidative Damage to Proteins and DNA:

Oxidative damage to protein products can affect enzyme activity, receptors, and membrane transport. Protein oxidation causes aging by affecting signaling mechanisms, enzyme activity, thermal stability, and changes in susceptibility to protein degradation

  1. Signal Transduction Mechanism
  1. Signal transduction is a series of steps by which external stimuli are converted into chemical signals and then into cellular responses.
  2. Cell signaling ultimately leads to the regulation of one or more cellular activities.
  3. Regulation of gene [removed]turning transcription of specific genes on or off) is a common outcome of cell signaling.
  4. Signaling pathways can also lead to important cellular events such as cell division or apoptosis (programmed cell death).

Antioxidant Defense System:

  1. Antioxidants act as radical scavenger, hydrogen donor, electron donor, peroxide decomposer, singlet oxygen quencher, enzyme inhibitor, synergist, and metal-chelating agents.
  2. Both enzymatic and nonenzymatic antioxidants exist in the intracellular and extracellular environment to detoxify ROS

Levels of antioxidant action:

  1. The first line of defense is the preventive antioxidants, which suppress the formation of free radicals.
  1. To suppress such reactions, some antioxidants reduce hydroperoxides and hydrogen peroxide beforehand to alcohols and water, respectively, without generation of free radicals and some proteins sequester metal ions.
  1. The second line of defense: is the antioxidants that scavenge the active radicals to suppress chain initiation and/or break the chain propagation reactions.
  1. Vitamin C, uric acid, bilirubin, albumin, and thiols are hydrophilic, radical-scavenging antioxidants, while vitamin E and ubiquinol are lipophilic radical-scavenging antioxidants.
  2. Vitamin E is accepted as the most potent radical-scavenging lipophilic antioxidant.
  1. The third line of defense: is the repair and de novo (at the beginning) antioxidants.
  1. The proteolytic enzymes, proteinases, proteases, and peptidases, present in the cytosol and in the mitochondria of mammalian cells, recognize, degrade, and remove oxidatively modified proteins and prevent the accumulation of oxidized proteins.
  1. Adaptation: There is another important function called adaptation where the signal for the production and reactions of free radicals induces formation and transport of the appropriate antioxidant to the right site

Enzymatic:

  1. Superoxide dismutase :
  2. Catalase :
  3. Glutathione systems :
  4. glutathione
  5. glutathione reductase   
  6. glutathione peroxidases
  7. glutathione S-transferases

Non-Enzymatic:

  1. Ascorbic acid
  2. Melatonin
  3. Vitamin E
  4. Uric acid

Superoxide dismutase:

  1. Superoxide dismutases (SODs) are a class of closely related enzymes that catalyze the   breakdown of the superoxide anion into oxygen and hydrogen peroxide

Catalase:

  1. Catalase is a common enzyme found in nearly all living organisms, which are exposed to oxygen, where it functions to catalyze the decomposition of hydrogen peroxide to water and oxygen.
  2. Hydrogen peroxide is a harmful by-product of many normal metabolic processes: to prevent damage, it must be quickly converted into other, less dangerous substances. 

Glutathione systems:

  1. These enzymes are at particularly high levels in the liver and also serve indetoxification metabolism

Nutraceutical:

  1. It is defined “as a food or parts of food that provide medical or health benefits, including                  the prevention and treatment of disease.Glucosamine is a natural compound found in cartilage.
  2. Strong antioxidants activities have been found in berries, cherries, citrus, prunes, and olives. Green and black teas have been extensively studied in the recent past for antioxidant properties since they contain up to 30% of the dry weight as phenolic compounds.
  3. Cocoa, potato, yam, tomato, kale, Brussels sprouts, broccoli and others dark green leafy and brightly-colored vegetables as well as legumes and cereals, in addition to spices and fruits such as cherries and citrus, are particularly rich in phenolic compounds.
  4. As is typical for phenolic compounds, they can act as potent antioxidants and metal chelators. They also have long been recognized to possess anti-inflammatory, antiallergic, hepatoprotective, antithrombotic, antiviral, and anticarcinogenic activities.
  5. Cocoa, potato, yam, tomato, kale, Brussels sprouts, broccoli and others dark green leafy and brightly-colored vegetables as well as legumes and cereals, in addition to spices and fruits such as cherries and citrus, are particularly rich in phenolic compounds
  6. Synthetic and natural food antioxidants are used routinely in foods and medicine especially those containing oils and fats to protect the food against oxidation.
  7. Synthetic antioxidants are recently reported to be dangerous to human health. Thus, the search for effective, nontoxic natural compounds with antioxidant activity has been intensified in recent years.

CONCLUSION

As various studies suggest that these free radicles are very harmful for body and they play very vital role in the pathogenesis of various diseases like cancer, cardiovascular diseases, cellular and DNA damage, aging etc. This oxidative damage to the cellsis permanent which cannot be reversed. There are many sources for the generation of these free radicles. The action of these free radicles depends upon their ability to donate electrons to other chemical groups thereby initiating the chain reactions. These chain reactions can be arrest by use of antioxidants and further damage can be prevented. Some naturally occurring antioxidants can prove effective like Vit. C, Vit. E, Catalase, Superoxide dismutase etc. Whereas the synthetic antioxidants can produce harmful side effects on body.  Person should consume the bright colored food which provides a natural antioxidants like vegetables, fruits etc. These substances contain phenolic compounds which are considered as very potent antioxidants.

ACKNOWLEDGMENT

Deepest gratitude is also extended to Professor Ravindra Nikam and the College of Pharmacy in Gondur, Dhule, for kindly providing essential research facilities. Furthermore, I would like to convey my thanks to Dr. A. V. Patil, the Principal of Prof. Ravindra Nikam College of Pharmacy in Gondur and Dhule, for their consistent encouragement and support throughout this make an effort.

Conflict of Interest:

The writer affirms that there are no conflicts of interest to disclose.

Ethical Approval:

Not applicable.

Funding:

Not applicable.

Declarations:

I state that any work of others used in this paper has been appropriately cited and attributed. Any

Assistance received in the research, writing, or editing of this paper has been duly acknowledged.

REFERENCES

  1. Caple F, Williams EA, Spiers A, Tyson J, Burtle B, Daly AK, Mathers JC, Hesketh JE. Inter-individual variation in DNA damage and base excision repair in young, healthy non-smokers: effects of dietary supplementation and genotype. Br J Nutr. 2010;103:1585–1593.
  2. Lasségue B, San Martin A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res. 2012;110:1364–90.
  3. Qin B, Cartier L, Dubois-Dauphin M, Li B, Serrander L, Krause KH. A key role for the microglial NADPH oxidase in APP-dependent killing of neurons. Neurobiol Aging. 2006;27:1577–87.
  4. Aruoma OI. Methodological consideration for characterization for potential antioxidant actions of bioactive components in plants foods. Mutat Res. 2003;532:9–20.
  5. Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol. 2001;54:176–86.
  6. Harman D. Role of free radicals in aging and disease. Ann N Y Acad Sci. 1992;673:126–41.
  7. Mc Cord JM. The evolution of free radicals and oxidative stress. Am J Med. 2000;108:652–9.
  8. Ashok BT, Ali R. The aging paradox: Free radical theory of aging. Exp Gerontol. 1999;34:293–303.
  9. Matill HA. Antioxidants. Annu Rev Biochem. 1947;16:177–92.
  10. Frie B, Stocker R, Ames BN. Antioxidant defences and lipid peroxidation in human blood plasma. Proc Natl Acad Sci. 1988;37:569–71.
  11. Ishibashi, T. Molecular hydrogen: New antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr. Pharm. Des. 2013, 19, 6375–6381.
  12. Bhattacharyya, A.; Chattopadhyay, R.; Mitra, S.; Crowe, S.E. Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol. Rev. 2014, 94, 329–354.
  13. Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free radicals, antioxidants and functional foods: Impact on human health. Pharm. Rev. 2010, 4, 118–126.
  14. Balaban, R.S.; Nemoto, S.; Finkel, T. Mitochondria, oxidants, and aging. Cell 2005, 120, 483–495.
  15. Brigelius-Flohe, R.; Flohe, L. Basic principles and emerging concepts in the redox control of transcription factors. Antioxid. Redox Signal. 2011, 15, 2335–2381.
  16. Flieger, J., Flieger, W., Baj, J., and Maciejewski, R. (2021). Antioxidants: Classification, natural sources, activity/capacity measurements, and usefulness for the synthesis of nanoparticles. Mater. (Basel) 14 (15), 4135.
  17. Van Rammsdonk JM. and HekimiS.Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet 5: e1000361, 2009.

Reference

  1. Caple F, Williams EA, Spiers A, Tyson J, Burtle B, Daly AK, Mathers JC, Hesketh JE. Inter-individual variation in DNA damage and base excision repair in young, healthy non-smokers: effects of dietary supplementation and genotype. Br J Nutr. 2010;103:1585–1593.
  2. Lasségue B, San Martin A, Griendling KK. Biochemistry, physiology, and pathophysiology of NADPH oxidases in the cardiovascular system. Circ Res. 2012;110:1364–90.
  3. Qin B, Cartier L, Dubois-Dauphin M, Li B, Serrander L, Krause KH. A key role for the microglial NADPH oxidase in APP-dependent killing of neurons. Neurobiol Aging. 2006;27:1577–87.
  4. Aruoma OI. Methodological consideration for characterization for potential antioxidant actions of bioactive components in plants foods. Mutat Res. 2003;532:9–20.
  5. Young IS, Woodside JV. Antioxidants in health and disease. J Clin Pathol. 2001;54:176–86.
  6. Harman D. Role of free radicals in aging and disease. Ann N Y Acad Sci. 1992;673:126–41.
  7. Mc Cord JM. The evolution of free radicals and oxidative stress. Am J Med. 2000;108:652–9.
  8. Ashok BT, Ali R. The aging paradox: Free radical theory of aging. Exp Gerontol. 1999;34:293–303.
  9. Matill HA. Antioxidants. Annu Rev Biochem. 1947;16:177–92.
  10. Frie B, Stocker R, Ames BN. Antioxidant defences and lipid peroxidation in human blood plasma. Proc Natl Acad Sci. 1988;37:569–71.
  11. Ishibashi, T. Molecular hydrogen: New antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr. Pharm. Des. 2013, 19, 6375–6381.
  12. Bhattacharyya, A.; Chattopadhyay, R.; Mitra, S.; Crowe, S.E. Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol. Rev. 2014, 94, 329–354.
  13. Lobo, V.; Patil, A.; Phatak, A.; Chandra, N. Free radicals, antioxidants and functional foods: Impact on human health. Pharm. Rev. 2010, 4, 118–126.
  14. Balaban, R.S.; Nemoto, S.; Finkel, T. Mitochondria, oxidants, and aging. Cell 2005, 120, 483–495.
  15. Brigelius-Flohe, R.; Flohe, L. Basic principles and emerging concepts in the redox control of transcription factors. Antioxid. Redox Signal. 2011, 15, 2335–2381.
  16. Flieger, J., Flieger, W., Baj, J., and Maciejewski, R. (2021). Antioxidants: Classification, natural sources, activity/capacity measurements, and usefulness for the synthesis of nanoparticles. Mater. (Basel) 14 (15), 4135.
  17. Van Rammsdonk JM. and HekimiS.Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet 5: e1000361, 2009.

Photo
Lokesh A. Gurav
Corresponding author

OBVS Nikam college of pharmacy, Gondur, Dhule

Photo
Kishan A. Zodage
Co-author

OBVS Nikam college of pharmacy, Gondur, Dhule

Photo
Amit P. Sinhal
Co-author

Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule

Photo
Atish A. Salunkhe
Co-author

Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule

Photo
Jitendra D. More
Co-author

Prof. Ravindra Nikam College of Pharmacy, Gondur, Dhule

Lokesh A. Gurav, Kishan A. Zodage, Amit P. Sinhal, Atish A. Salunkhe, Jitendra D. More, Exploring the Potential of Antioxidants in Reducing Free Radicals: A Comprehensive Review, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 11, 417-424. https://doi.org/10.5281/zenodo.14054935

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