Plant sources of antioxidants
Plants are the major source of many antioxidants in nature. According to previous research,32 the reasons for the synthesis and accumulation of these antioxidants in plants are 1. the normal physiologic functions, and protection against pathogenic microbes and animal herbivores, and 2. capacity to build them in response to environmental stress conditions. Some of these antioxidants accumulate as colored pigments in the leaves, fruits, nuts, and roots of many plants. These colored pigments, such as beta-carotene, lutein, lycopene, and zeaxanthin, are all carotenoids either in their primary or secondary forms and abound in leafy vegetables and fruits. For instance, beta-carotene accumulates in carrots, leafy vegetables, spinach, and tomatoes.33 Lutein accumulates in green leafy vegetables, and zeaxanthin accumulates in spinach, while lycopene is abundant in tomatoes, watermelon, guava, pink grapefruit, and blood oranges.25 Likewise, studies have shown that some green tea leaves and herbs31 are better antioxidants than vegetables and fruits.20 Some herbs, such as Cissus quadrangularis L, Erythrina abyssinica Lam. Ex. DC., and Adenium multiflorum Klotzsch used in the management of animal wounds in Zimbabwe have antioxidant activities.34 However, among the herbs tested, C. quadrangularis leaf extract exhibited superior antioxidant activity. Another type of antioxidant that accumulates in plants is vitamins like A, C, and E. Vitamin A is known to be abundant in sweet potatoes, vitamin C (ascorbic acid) in fruits and vegetables as well as in cereals, while vitamin E (α-tocopherol) accumulates in some plant oils, such as wheat germ oil, soybean oil, and corn oil. Essential oils from oregano and clove were found to have potential antioxidants probably due to the high phenolic contents.35 As a result, the accumulation of these antioxidants in plants could be dependent on some intrinsic and extrinsic factors. For instance, cultural practices, genotypes, and environmental conditions influenced the accumulation of lycopene in tomato fruits.36 Some authors30–37 also observed that the reported high activities of antioxidants from plants were based on in vitro studies without corresponding in vivo studies. The implication was that the potency of antioxidants from plants as widely acclaimed may not be 100% correct. According to the authors, during the in vivo studies, the antioxidant activity was influenced by bioavailability, gut absorption, metabolism, and other factors.32
Microbial sources of antioxidants
The microbial community probably contains the largest reservoir of antioxidants in nature. This may be due to the diversity of the bacterial, fungal, and microalgae species. The microbial diversity and their metabolic activities define the diverse biosynthetic pathways that produce the varied bioactive compounds. As such, the term “fermentation” has been used to describe the process of producing various compounds by microorganisms. Thus, the fermentation processes can lead to either an intracellular or extracellular production of bioactive compounds which can be recovered either as an intact whole cell or cell-free extract using organic solvents. In addition, in the bacterial community, both the gram-positive and gram-negative bacteria have the potential to produce antioxidant compounds.43 However, the Streptomyces spp and lactic acid bacteria are probably more prominent in antioxidant production. An extract of a Streptomyces variabilis (EU841661) isolate had scavenging activities against free radicals and hydrogen peroxide at a concentration of 5.0 mg/mL and 0.05 mg/mL, respectively.44 Another previous study indicated that L. plantarum AR501 had the scavenging activity against the α-diphenyl-β-picrylhydrazyl (DPPH) free radical and hydrogen radical in vitro. Moreover, oral administration of L. plantarum AR501 produced functional foods to alleviate oxidative damages in a mouse model of oxidative injury.43 Superoxide dismutases (SODs) are produced in high concentrations by aerobic microorganisms, such as Corynebacterium glutamicum.43 Probiotic bacteria (Streptococcus thermophiles) and many lactic acid bacteria (Lactobacillus spp) are excellent sources of many types of antioxidants either as intact whole cell or cell-free extracts.45 Some species of Streptomyces also produce antioxidants like carotenoids. It was reported that Streptomyces chrestomyceticus produced lycopene, a type of carotenoid, which could be used as a coloring agent in the food industry.43 Furthermore, Xanthophyllomyces dendrorhous could produce high amounts of antioxidants like carotenoids. The concentration and activities of antioxidants produced by microorganisms are dependent on some physicochemical parameters of the fermentation processes,46 as well as the type of organic solvent used for antioxidant extraction.47
There are myriads of fungal species that produce antioxidants, including filamentous fungi, such as Aspergillus spp and Penicillium spp. Aspergillus saitoi and Penicillium roquefortii IFO 5956 contain a bioactive compound (2,3-dihydroxybenzoic acid) with high antioxidant properties.43Aspergillus spp and Penicillium spp can also produce antioxidants, such as citrinin, protocatechuic acid, curvilic acid, atroventin, and gallic acid.43 Antioxidant activity produced by fungal species sometimes depends on the food substrate/fermentation medium. For instance, a methanolic extract of some fermented soybean foods presented antioxidant compounds of a high activity.48 It is further believed that fungal fermentation produce more antioxidants than those produced by bacterial fermentation.43
The microalgal antioxidants are similar to plant antioxidants probably because of the similar characteristics shared by both in terms of the physiology and environmental impact. For instance, both plants and microalgae obtain their food through the process of photosynthesis and receive the same or similar environmental stimulation that triggers oxidative stress. Microalgal species are very diverse and apparently are the richest source of antioxidants in nature. Microalgae accumulate different types of antioxidants, such as polysaccharides, carotenoids, sterols, vitamins (A, C, D, K, and E), flavonoids, amino acids, polyunsaturated fatty acids, minerals, sulfated polysaccharides, sulfolipids, peptides, coenzyme Q, phycocyanin, and scytonemin (a source of blue-green algae).7 Although all the antioxidants produced by microalgae are not commercialized, some of them that are widely produced with a high market value, include lutein, astaxanthin, and β-carotene.49 Under environmentally stressed conditions, every micro-algae species is a potential source of antioxidants although the concentrations and types of antioxidants would depend on the type of stress to which the organism is subjected. Stressed conditions are known to induce enzymatic and non-enzymatic antioxidants in different microalgae species in response to the ROS.50 The different types of abiotic stress for the induction of antioxidants in microalgae species have been reviewed.49 The authors acknowledged that different stressors induced the accumulation of different enzymatic/non-enzymatic antioxidants in diverse species of green microalgae. A recent report51 revealed that Desmodesmus subspicatus LC172266 accumulated carotenoids under nutrient-rich conditions, which would suggest that some microalgae species may spontaneously produce some types of antioxidants. However, the authors were of the view that the accumulated antioxidant may be a primary carotenoid called lutein.
Comparatively, microbial antioxidant productions have more prospects in terms of commercialization than plants or animal resources. This assertion is not just based on the many antioxidants produced by microbes, but on the potential of optimizing productivity through genetic, metabolic, and environmental engineering.52–55
Medicinal uses of antioxidants
Medicinal plants are possible sources of antioxidants and anti-inflammatory compounds that could be used in the management of different diseases. Preclinical and clinical studies of some antioxidants are summarized in Table 1.15,56–72 An imbalance of natural antioxidants causes free radical generation from numerous environmental and biological sources, which would result in a wide range of inflammatory illnesses.73 Additionally, oxidative stress and its accompanying components have now become a major public health concern.74 As such, therapeutic plant extracts and their isolated active ingredients have a wide range of therapeutic effects against a wide range of acute and chronic disorders. Anti-inflammatory studies have shown that extracts and their organic products exercise their bioactivity by inhibiting two main signaling pathways, mitogen-activated protein kinases (MAPKs), and nuclear factor kappa B (NF-ĸB), that are responsible for producing a variety of proinflammatory mediators.74,75 Alkaloids, polyphenols, terpenoids, and flavonoids are well-studied phytonutrients for anti-inflammatory activity.14,76 Plants that contain these phytoconstituents are used as anti-inflammatory agents.
Table 1Classification, preclinical, and clinical studies of some antioxidants
Antioxidant | Class | Mechanism/Pharmacokinetics | Medicinal Uses | Models | Reference |
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Morin | Natural | Morin suppresses the activation of NFekB on kidney models during the existence of free radicals. | Anti-aging | Kidney of rats | 57 |
Ascorbic acid Polyphenols Tocopherols | Natural | They improved the endogenous ROS- elimination system in mammalian tissue and helped in the possible management of skin infections and aging. | Prevent skin aging | Not specified | 58 |
Cyanobacterial phycobiliproteins (PBPs) | Natural | They slow aging and related diseases. | Strong anti-aging agent | Rat | 56 |
Lycopene | | Decreases nitric oxide, ROS, and lipid peroxyl radical. Lycopene has multiple conjugated double bonds that stimulates its anti-oxidant property. It also slows activation of the mTOR/AMPK cascade pathway linked with aging. | Anti-aging | Not specified | 59 |
Methylene Blue (MB) | Synthetic | Effective in stimulating skin fibroblast multiplication and delaying cellular senescence. | Anti-aging | Human | 60 |
Resveratrol | Natural (phenolic) | Inhibits pro-inflammatory cytokines like IL-1 and TNF-a that are periodontitis mediators. It stops liver steatosis through the intonation of insulin conflict and lipid profile on different models. | Anti-inflammatory Anti-cancer Hepatoprotective | Humans Rats and Humans Wistar rats | 61 15 62 |
Quercetin 7-rhamnoside (Q7R) | Natural | Q7R produced hepatoprotection against CCl4 induced hepatotoxicity and cytoprotective, antioxidant effects on H2O2 treated human liver cells. | Hepatoprotective | Humans | 63 |
Trans-4-hydroxystilbene (THS), Resveratrol, RES, Piceatannol, PIC | Natural | Foraged DPPH and OH radicals and stop the accumulation of ROS in neurons. | Neuroprotective | Rats | 64 |
Quercetin + Curcumin | Natural | They control hyperglycemia by promoting the stimulation and release of insulin. | Anti-diabetic | Rats | 65 |
Setanid | | Act by an antitoxic and antiangiogenic mechanism. | Anti-inflammatory HIV infected patients | humans | 66 67 |
Quercetin | Natural | Normalized paracetamol-induced liver and kidney damage by inhibiting oxidative injury | Anti-inflammatory, hepatoprotective | Humans | 68 |
Curcumin | Natural | Reduce malondialdehyde (MDA) concentration and oxidative stress levels significantly. Maintenance of body function and mitochondrial redox balance | Hepatoprotective Nephroprotective Anti-inflammatory Synergistic effects | humans Humans Humans | 69 69 70 70,71 |
Epigallocatechin-3-gallate (EGCG) | Natural (Catechin) | React with superoxide anions and -OH, and is also able to chelate metal ions | Anti-inflammatory | Not specified | 72 |
In oxidative damage and the progression of carcinogenesis, two distinct processes are thought to be involved. The first mechanism is through gene expression regulation. Growth signals and proliferation can be stimulated by epigenetic changes in gene expression.77 Radicals cause genetic changes, such as mutations and chromosomal conformational changes, which might contribute to the onset of carcinogenesis in the second mechanism.78
Antioxidants can also act as anticancer agents74,78,79 because they can scavenge free radicals that can cause DNA conformational changes, DNA/protein cross-links, and DNA damage,16 leading to cell mutation, transformation, and cancer.80 As a consequence, antioxidants can inhibit the growth of oxidative cancer cells by neutralizing free radicals.81
A β-carotene, as an antioxidant, can protect against cancer development.2,82 Its photoprotective activities may guard against UV light-induced cell damage and cancer development, and its immunoenhancement may help to protect against cancer progression.6 Likewise, vitamin C may aid in the prevention of cancer because it has potent antioxidant activity to inhibit the development of nitrosamines, enhance the immunological response, and produce the detoxification of liver enzymes.82,83 Additionally, vitamin E improves immunocompetence by boosting humoral immune responses, bacterial infection resistance, cellular-immunity, tumor necrosis factor generation by inflammatory cells, and inhibiting mutagenesis, DNA repair, and microcell formation.84,85 As a result, vitamin E may be beneficial in preventing cancer and inhibiting carcinogenesis through regulating immune function.
Diabetes is a metabolic disorder marked by relative or absolute insulin secretion deficits leading to chronic hyperglycemia and carbohydrate, lipid, and protein metabolism abnormalities.16 The metabolic disorders cause a variety of complications. Additionally, diabetes mellitus has been linked to increased formation of free radicals and a reduction in antioxidant activities, which also results in the imbalance between the generation of ROS and antioxidants, thus leading to oxidative damage to cell proteins, lipids, and nucleic acids.11,86 Glucose autoxidation is the most important factor in the generation of free radicals among the different variables that cause increased oxidative stress. Other factors also elevate the levels of pro-oxidants, imbalance in cellular oxidation, and a reduction in antioxidant defense. Low concentrations of ascorbate, glutathione, and superoxide dismutase are the most prevalent antioxidant deficits during the pathogenic process of diabetes. Therefore, plants, especially those with high quantities and potent antioxidant chemicals, can treat oxidative stress-related diseases like diabetes mellitus. Many studies have also examined the impact of their antioxidant components on diabetes complications to achieve promising results by demonstrating the benefits of plants with high antioxidant levels in the treatment of diabetes.1,3,11
In addition, antioxidant consumption from fruits and vegetables aids in the management of cardiovascular illnesses. Because oxidative processes can alter cardiovascular disorders, they have the potential to deliver tremendous health and lifespan benefits. Polyunsaturated fatty acids make up a large portion of low-density lipoproteins (LDL) in the blood, and their oxidation plays an important function in atherosclerosis.87 With a high quantity of oxidized lipids in the blood, blood vessel damage occurs, which can result in the formation of foam cells and plaque leading to atherosclerosis. Atherogenic oxidized LDL is thus thought to be essential in the production of atherosclerosis plaque. Moreover, oxidized LDL is cytotoxic and can directly harm endothelial cells.88 Likewise, antioxidants like β-carotene and vitamin E are important in preventing cardiovascular disorders.82
Due to the ever-increasing resistance to synthetic antibiotics, we must shift our focus to natural antioxidant-based antibacterial products, which have a range of scientific diversity and provide an effective therapeutic benefit while preventing microbes from replication and developing resistance. Phenolics are also important antibacterial antioxidants because they inhibit the growth of bacteria and their pathogenic activity.87 Antioxidants act as antibacterial reagents by inhibiting nucleic acid production, the permeability of the outer membrane, and cytoplasm leakage. Antioxidants’ antibacterial effect may be owing to their ability to chelate iron, which is essential for the existence of all bacteria.88 Polyphenols break the cell wall, enhance cytoplasm membrane permeability, as well as release lipopolysaccharides.
However, antioxidant efficacy against microbial infections is becoming more generally accepted.89 They also function in tandem with modern antimicrobial drugs to combat drug-resistant microbes. Hence, antioxidant structure determines its antimicrobial effect. Synthetic antibiotics have a speedy therapeutic impact when used to treat microbial infections, but they also represent a substantial risk of gastrointestinal and renal toxicity, and microbial resistance.88 Nonetheless, natural antioxidants in their purest form have outstanding antibacterial activity against common microbes without evidence to develop resistance to these substances by reinforcing the desire to research natural products to replace synthetic antibiotics.90 Yet, even though antioxidants function slowly to inhibit microbial growth, their effect is consistent, and a thorough assessment in determining the antimicrobial profile of isolated antioxidants could aid in the use of phytochemicals against microbial infections with minimal toxicity as well as the risk of bacterial resistance.91
Liver diseases have also been linked to oxidative stress. Oxidized proteins and a reduction in antioxidant levels contribute to the development of liver diseases.1,92 However, antioxidants, both natural and synthetic, have been utilized to treat liver disease. When antioxidants were given orally or intraperitoneally, animal studies showed a significant beneficial effect on liver disease.5 As a result, a large-scale model would be required to determine their safety and effective dose, optimum treatment absorption, duration, and bioavailability.
Resveratrol guards the liver against cholestasis, alcohol, and toxic damage by boosting the lipid profile and reducing liver fibrosis and cirrhosis.93 In diverse models, this would prevent hepatic steatosis by inducing insulin conflict and altering the lipid profile. In Wistar rats, preclinical research demonstrated that resveratrol had a therapeutic impact on liver disease.1 Yet, greater clinical trials would be needed to give scientific evidence for the management of liver disorders. When there is an imbalance between oxidants and antioxidants in the liver, oxidative stress occurs, thereby impairing liver function.93 Nevertheless, silymarin was discovered to have the greatest hepatoprotective impact94 though additional clinical trials would be important to ascertain the significance of the antioxidants on liver function.
In addition, curcumin’s nephroprotective effect was connected to the bodily function and mitochondrial redox equilibrium.95 In patients and laboratory animals, antioxidant prophylaxis reduced renal adverse effects.96 Green tea extracts (phenolic chemicals) were also found to enhance kidney function and reduce the levels of blood urea nitrogen and serum creatinine.97 Furthermore, antioxidants derived from plants can be combined with nephrotoxic drugs like cisplatin, contrast media, and others. Natural antioxidants defend bioactive molecules by protecting free radicals from cisplatin-enhanced mitochondrial oxidation, but do not affect the drug’s action.78 In patients with low antioxidant levels, administration of vitamin C protects the kidneys by lowering the ROS, and their oxidative damage.6 Additionally, endogenous vitamin C acts as an enzyme cofactor to have a renal protective impact.98
Phenolic diet consumption provides protection against cardiovascular and neurological illnesses, such as Parkinson’s, early onset dementia, and motor neuron disease.15 Antioxidant neuroprotective activities were investigated by suppressing the ROS in in-vitro and in-vivo studies.99 Resveratrol increased the enzyme activity like catalase, SOD, heme oxygenase, and glutathione peroxidase while inhibiting xanthine oxidase.100 In addition, antioxidant supplementation could help people ameliorate stress-related mental and severe anxiety.1
Antioxidant micronutrients like retinol and ascorbic acid may also help prevent eye disorders.101 Natural antioxidants including flavonoids, vitamins, phenolic acids, and carotenoids could help prevent eye defects.102 It has also been found that nanotechnology-based formulations of antioxidant biomolecules could improve bioavailability, solubility, and stability, as well as activity.103 Treatment of eye defects, such as cataracts could be conducted by using nanoparticle-based antioxidant biomolecules that would be effective, biodegradable, and non-toxic.104 Moreover, natural antioxidants have been used as therapeutic reagents to slow the progression of cataracts.1 Vitamins C and E and curcumin, having antioxidant and anti-cataract properties, can be included in the diet to help protect against free radicals.
In addition, free radicals that could cause degenerative changes linked with aging,11,105 DNA, or the buildup of physiological and structural damage are the primary cause of aging.11 Reducing free radicals or slowing their formation with antioxidants would help delay the process of aging. Hence, increased oxidative stress would be prevalent in aged people, and antioxidants could have a major effect on oxidative damage.56 The antioxidant defense could minimize free radical damage, and adequate consumption of antioxidant nutrients could improve the quality of life and help people live longer.11