An Understanding of Antioxidants and Oral Lesions

PRODUCTION OF UNSTABLE RADICALS

Both enzymatic and non-enzymatic mechanisms result in cells’ continual production of unstable radicals. These can be produced by biochemical procedures such as the respiratory chain, destroying tissue, creating prostaglandin and the cytochrome P-450 system.^[10]

Free radicals can originate from numerous internal sources, example:^[11]

• Mitochondria

• Inflammation

• Phagocytosis

• Physical activity

• Ischemia/reperfusion injury

• External sources are:

• Smoking

• Contaminants from atmosphere

• Irradiation

• Solvents used in manufacturing

• Ozone

These radicals are produced in the following ways.

1. The electron transport mechanism in mitochondria consumes around 90% of the cell’s oxygen during normal aerobic metabolism.

2. One of the processes utilized to eradicate bacteria and viruses and denature foreign proteins, or antigens, is oxidative burst produced by phagocytes, or white blood cells.

3. Xenobiotic metabolism, commonly known as detoxification of dangerous chemicals.

Therefore, factors like intense physical activity, which quickens the metabolism of cells, prolonged inflammation, sickness, having a “leaky gut” condition, getting subjected to medications, and toxic substances like smoking, emissions, and insecticides may all increase the body’s oxidant load.^[12]

THE BIOLOGY OF NO-CHARGE RADICAL

As we age, reactive oxygen species cause sluggish, unfavorable alterations to spread throughout the body. All people regularly go through these “normal” aging changes. Significant disorders include cardiovascular and carcinoma, two leading causes of death. Internal radical processes, which are comparable to those caused by ionizing radiation, may be the cause of tumor formation. A higher level of lipid peroxidation may cause a highly substantial association between dietary fat and oil intake and death rates from leukaemia.^[13] Research on atherosclerosis suggests that the disorder may be caused by dietary lipid free radical interactions in serum and arterial wall that result in peroxides and other compounds.^[14]

PERSPECTIVE ON OXIDATIVE DAMAGE

The word describes oxidative damage when radical production and antioxidant defense activity are out of balance.^[15] Numerous chemical species are damaged by oxidative damage, which develops when the creation of harmful radicals and antioxidant defenses are out of balance.^[16] Immediate oxidative stress may occur in cells that have been damaged. Unbound radicals have been linked to the development and progression of dementia, Parkinson’s disease, age-associated eye disease, and brain diseases.^[17]

OXIDATIVE STRESS IN THE ORAL CAVITY

The issues could be internal, like ongoing inflammation, or external, such as cigarettes and pollution of the air with included chemicals. Superoxide, hydrogen peroxide, and hydroxyl radicals are examples of reactive species that are typical consequences of metabolic activity. The immune system also creates these reactive oxygen species when tissue is inflamed or injured, such as in persistent periodontal issues.^[18] Antioxidants are receiving a lot of attention on a global scale. The discussion of ANTIOXIDANTS is expanded to include systemic & premalignant oral mucosal lesions & diseases, as well as oral cancer.^[19]

Numerous disorders, including atherosclerosis, certain cancers, and advancing age, have been linked to oxidative damage. This damage is now believed to significantly impact all inflammatory diseases, including osteoarthritis, vascular inflammation, kidney disease, lupus erythematosus, adult pulmonary syndrome, lung disease, and elevated blood pressure.^[20]

ANTIOXIDANTS

It is a sufficiently stable component to provide an electron to a runaway liberated radical, neutralizing it and lowering the radical’s potential for harm.^[21] Because of their small molecular weight, these antioxidants may safely react with damaging free radicals to halt the chain reaction before damaging crucial components. Several antioxidants like glutathione, ubiquinol, and uric acid—are created by the body as part of normal metabolic processes^[22] beta-carotene, citrus fruits, and retinol are the principal vitamins, even though the body has a variety of complex enzyme systems that absorb harmful radicals.^[23]

MECHANISM OF ACTION

Antioxidants provide a sophisticated ecosystem where harmful radicals are scavengers. Following incredibly plausible mechanisms are used by antioxidants to protect cells from free radicals.^[24]

1. Chain breaking mechanism

   • ✔

     One way to break the oxidation chain is by scavenging free radicals. E.g. albumin, bilirubin, ubiquinol, and vitamins A, C, and E.

2. Preventive mechanism

   • ✔

     An antioxidant breaks down the free radical or chelates the transition metal. Citric acid, transferrin, ceruloplasmin, haptoglobin, and lactoferrin are a few examples.

3. Synergistic mechanism

   • ✔

     The potency of two antioxidants is increased when combined. E.g. By mixing tocopherol, which may break chains, and citric acid, which can chelate metals.

TYPES OF ANTIOXIDANTS

Antioxidants play several defense-related roles, such as prevention, reactive scavenging, maintenance, new synthesis, the final line of protection, or adaptability. Preventative antioxidants that halt free radicals’ production are the initial line of defence. One of the main contributors to the production of radicals in vivo, must be the metal-induced disintegration of peroxides. Some antioxidants inhibit these reactions by converting hydroperoxides and hydrogen peroxides into ethanol and water without producing harmful radicals, while certain proteins attach metallic ions to stop these reactions.

Antioxidants that scavenge the active radicals to halt or impede chain-start reactions, are the subsequent stage of protection. Free radicals are neutralized by various endogenous antioxidants, some of which are hydrophilic and others lipophilic. Vitamin C, uric acid, bilirubin, albumin, and thiols are hydrophilic ROS, whereas vitamin E and ubiquinol are lipophilic radicals. Tocopherol is one of the best lipophilic antioxidants for scavenging free radicals.

Maintenance and new-generation antioxidants are the last line of protection. Proteinases, proteases, and peptidases are proteolytic enzymes that recognise, degrade, and eliminate molecules undergoing oxidative modification. They are found in the cytosol and mitochondria of mammalian cells.

Genetic material activities are integral to the system’s defense against oxidative damage. Nucleases and glycosylases are just two of the many enzymes that can repair DNA damage.^[25]

CLASSIFICATION

A robust immune system and a balanced diet are necessary for the body to maintain its antioxidant state. They are divided into groups based on how easily the body absorbs them. Endogenous antioxidants are a class of compounds that have the power to scavenge harmful radicals. Exogenous antioxidants include a subclass of antioxidants that must be ingested by the body to protect cells against oxidants and support a healthy metabolism.^[24]

External antioxidants: Carotenoids (beta-carotene, lycopene, lutein, zeaxanthin) Flavonoids (Quercetin, chrysin, catechin, cyanidin, genistein) Phenolic acids (Garlic acid, ellagic acid, ferulic acid, p-coumaric acid) Vitamins (A, B, C, E, K) Minerals (Selenium, iron, magnesium, copper, zinc).

Internal antioxidants: Thiols (Uric acid, Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and Nicotinamide adenine dinucleotide hydrogen (NADH), Bilirubin) Metal binding proteins (Albumin, Ceruloplasmin, Transferrin, Ferritin, Myoglobin) Hormones (Melatonin) Others (Glutathione, N-acetyl cysteine, Alpha lipoic acid) [Figure 1].

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Figure 1:

Classification - BHA: Butylated hydroxyanisole, BHT: Butylated hydroxytoluene, TBHQ: Tert-butylated hydroquinone, NPs: Nanoparticles

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ANTIOXIDANTS AND CANCER PREVENTION

Interactions of harmful radicals with genetic material results in Deoxyribonucleic acid (DNA) protein cross-links, strand breaks, and base modifications. ROS damages DNA. Radicals are a significant factor in DNA chain reaction, along with double bond pyrimidine bases and the elimination of hydrogen from sugar moiety.^[9] The capabilities of antioxidant B-carotene may protect against cancer due to the potential for genetic harm brought on by oxidative products. Therefore, the benefits of B-carotene photoprotective properties may protect against Ultraviolet (UV) light-induced cancer. B-carotene may also have an anticarcinogenic effect by altering how the liver processes carcinogens.^[26] Vitamin C may help prevent cancer.^[27] Some proposed methods by which vitamin C may affect carcinogenesis include antioxidant actions, decreasing the production of nitrosamines, and increasing the immune response.^[28] The most important etiology of mouth cancer is tobacco use. Long-term tobacco smoking harms the body’s oxidative defenses. Alcoholics also generate an excessive amount of free radicals. Single nucleotide polymorphism in Cytochrome P450 2E1 (CYP2E1) brought on by prolonged ethanol usage can increase ROS generation.^[29] Combining alcohol and tobacco usage increases the likelihood that dysplastic disorders may progress to oral cancer.^[30] Antioxidant micronutrients block transforming growth factor (TGF) alpha that stops angiogenesis in cancer.^[31] Antioxidants are thought to be one of the chemopreventive medications. Retinoids, beta-carotene, curcumin, lycopene, zinc, selenium, vitamin C (ascorbic acid), vitamin E (tocopherol), and vitamin A (carotene) are known to be protective against mouth cancer. Retinoids and curcumin have been found to have different anti-mutagenic and anti-proliferative effects.^[31]

Treatment: Vitamin A (1 mg/Kg/day), Beta carotene (25,000-100,000 IU/day), Selenium (40-75 microgram/day), Vitamin E (400-800 mg/day), Vitamin C (140-500 mg/day), Curcumin (300 mg/day), Lycopene (12 mg/day).

NUTRITION WITH FUNCTIONALITY AS A VISION

Functional eating is evolving from its historical focus on maintaining health to include the exciting potential of nutrition to promote health and ward off chronic disorders. Foods that offer consumers additional physiological benefits and essential nourishment are called “Nutritional foods.”^[32]

PRO-OXIDANT EFFECTS OF ANTIOXIDANTS

Antioxidants are well-known to act as pro-oxidants in foods and in vitro when given in high doses and under specific circumstances (i.e., by encouraging the production of oxygen free radicals). Ascorbate can occasionally worsen DNA damage in people, according to current studies. The recently discovered “redox signaling” of antioxidants is strongly related to their paradoxical activity (pro-oxidant impact). Whether antioxidants from food sources, particularly those in high concentrations, have pro-oxidant effects on people is still debated among scientists.^[33]

OXIDANTS IN ORAL LESIONS OF THE MOUTH

Numerous investigations are undertaken to ascertain the importance of oxidants in the therapy for mouth issues, including testing facilities, experimental animals, statistical surveys, and therapeutic trials. The following are some antioxidants’ potential therapeutic applications for oral mucosal ulcers.^[34]

1. Preventing the growth of abnormalities in people at high risk who have visually normal-looking mucosa and absence of either oral Potentially Malignant Disorders (PMDs) or cancerous abnormalities.

2. Management of problems that could be malignant

3. To prevent recurrence of previously treated abnormalities.

Oral lichen planus (OLP) and lichenoid reactions: keratinocyte antigen presentation changes due to numerous cytokines produced by T cell lymphocytes. This inflammatory process kills the basal epithelium’s cells.^[35] Malondialdehyde (MDA) and 4-hydroxy-2-nonenal, two indicators of oxidative stress, are present in greater concentrations in 35 OLP patients. They are byproducts of lipid peroxidation. Antioxidants may be administered to OLP patients to minimize the condition’s propensity to change. The most potent biological antioxidant is lycopene, a well-known carotenoid with a peculiar ability to bind to chemical species that react to oxygen. In a placebo-controlled study, giving OLP patients supplements containing 4–8 mg/day of lycopene for three months had beneficial results; the burning feeling was reduced by 84%, and oxidative stress was reduced by 67% compared to the control group.^[36] Curcuminoids, found in turmeric, have anti-inflammatory and antioxidant properties. Greater doses of curcumin (up to 6,000 mg/day), according to trials to date, dramatically improved symptom control in a large percentage of OLP patients.^[37]

Treatment: Lycopene (6–60 mg/day), Curcumin (6000 mg/day), Selenium (40–80 microgram/day).

Oral Leukoplakia (OL): The most common ailment, it has a complicated etiology and may be cancerous. Lycopene can be used to treat leukoplakia successfully. Lycopene promotes the production of the gene-generating connexion-43, a gap junction protein, independently of its provitamin-A or antioxidant actions.^[38] Isotretinoin is an effective treatment for oral leukoplakia. Topical 13-retinoic acid (0.1 percent isotretinoin gel) therapy resulted in a complete clinical response, and none of the patients reported any harmful effects. Taking 3–9 lakh International Unit (IU) of vitamin A daily helped to cure leukoplakia partially or totally.^[39]

Treatment: Beta-carotene (20–90 mg/day) and systemic dose (300,000 IU), Retinoids vitamin A/Retinol (0.5–1 mg/day), Lycopene (8 mg/day), Vitamin E (8–10 mg/day), Curcumin (4000–8000 mg/day).

Oral submucous fibrosis: Areca nuts are among the most addictive foods on the planet because they contain alkaloid arecoline, polyphenols, and trace metals like copper. The first study to demonstrate that areca nut aqueous extracts can generate superoxide anion and hydrogen peroxide at pH levels higher than 9.5 was conducted by Nair et al.^[40] Lycopene has been seen to significantly reduce clinical signs and symptoms at a dosage of 16 mg per day when used in conjunction with other therapy methods including intralesional injection.^[41] Other synthetic antioxidants have been found to possess potent antioxidant, DNA-protective, and antimutagenic effects, such as curcuminoids.^[42]

Treatment: Lycopene (16 mg/day), Curcumin (500-800 mg/day), Alpha lipoic acid (50 mg/day), Alpha tocopheryl acetate (10 IU).

Aphthous stomatitis: is a disorder that results in the development of oral mucosa of painful circular ulcers with clearly defined reddened edges and a yellowish central area. Full healing occurred in 35% of patients between 2 and 4 days, 90% 7 days, and all patients treated with quercetin in >7 days when quercetin was given topically to treat minor mouth ulcers.^[43] Other herbal topical therapies, like curcumin, contain anti-ulcerogenic properties.^[44]

Treatment: Quercetin (500–1000 mg/day), Curcumin (150 mg/day).

CONCLUSION

Our bodies produce reactive substances such as nitrogen and oxygen due to various internal systems’ responses to different physicochemical circumstances or diseases. For optimum functioning of the body, antioxidants and free radicals must coexist in balance. Oxidative damage results when the body’s defenses against radicals that are free are overpowered. As a result, reactive oxygen species damage lipids, proteins, and DNA and cause various human disorders. Therefore, using external oxidants can help manage this oxidative damage. Recently, it has been suggested that synthetic antioxidants like butylated hydroxytoluene and butylated hydroxyanisole are harmful to the well-being of humans. As a result, efforts to find potent, safe, natural substances with antioxidative action have increased in recent years.