Protective rules of natural antioxidants against gamma‐induced damage—A review

Abstract Phytochemicals accessible in food have demonstrated efficiency against impairment by gamma radiation. The review presented here is an attempt to show the pharmacological outline of the activity of the natural antioxidants and its primary action of molecular mechanism against the damage induced by gamma rays. This research focused on the results of the in vitro dosage of natural antioxidants relationship, and on the correlation of this information with the statistical variables. Moreover, it deliberated the natural compounds which could decrease the unwelcome impacts of gamma radiation and safeguard biological systems from radiation‐stimulated genotoxicity. The outcomes indicated that natural compounds can be utilized as an adjunct to orthodox radiotherapy and cultivate it as an effectual drug for the clinical administration of ailments.

or genotoxicity induced by radiation. Herbal as well as natural plant extracts, neutraceuticals, and phytoceuticals have been demonstrated to protect the tissues and cells against the ionizing radiation without unpleasant effects (Harikrishnan et al., 2020). Several research and review articles regarding pharmacological studies have emphasized determining the capacity of natural antioxidants to alleviate micronuclei formation in human (Abdel-Magied & Elkady, 2019; . Peripheral blood lymphocytes exposed to gamma-ray decrease free radical damage produced by ionizing radiation (Smith et al., 2017) and offer protection against gamma-ray-induced cellular damage (Ahmadi et al., 2020). However, there is no systematic review to-date covering antioxidants' impacts against provoked impairment by gamma radiation. Therefore, this study intends to cover the protective function of the natural antioxidants with emphasis on underlying mechanisms of action which is available in published works regarding the relationship between the dose of natural antioxidant and their effect on oxidative stress by gamma radiation.

| OXIDATIVE S TRE SS AND D IS E A S E S INDUCED BY G AMMA R AD IATI ON
Cell apoptosis, mucosal injury, intracellular nucleic acid damage, mitochondrial dysfunction, as well as necrosis, and ulcers are few of the impacts of exposure to Gamma emission ( Figure 1). IR exhibits direct as well as indirect interaction with cellular constituents. Direct impacts encompass the direct interface between the DNA and IR. In case of indirect impacts, free radicals like reactive nitrogen species (RNS) and reactive oxygen species (ROS) that are formed from the radiolysis of water molecules intermingle with adjacent DNA molecules to trigger impairments causing disparity of the antioxidant and pro-oxidant activities, thereby weakening the antioxidant capability of radiation tissues (Yi et al., 2020). Another process through which IR stimulates toxicities is through systemic impacts, also called "nontargeted" impacts. It is a procedure wherein tissues or cells that do not directly intermingle with IR are stimulated with intricate radiation impacts comprising radio adaptive response, bystander impacts, and genomic instability . Nonetheless, late impacts such as organ dysfunction, necrosis, death, and cancer might surface months to years after exposure (Peña et al., 2000). Histological observations have demonstrated that accrual of inflammatory cells plays a vital role in the inception of chronic oxidative damage, fibrosis, and inflammation, thus leading to disparities in the normal attributes of the heart as well as a rise in the chances of a heart attack (Taunk et al., 2015). Research has demonstrated that the constant manufacture of free radicals by means of immune system-redox interactions has a key role in the late impacts of radiation exposure in heart tissues, which comprise fibrosis and inflammation (Farhood et al., 2019). Unduly manufactured peroxides, if not removed by endogenous antioxidants, could trigger mitochondrial dysfunction and oxidative stress (Baulch, 2019). Oxidative stress results in disorders that include chronic intestinal damage. Radiation can also increase the oxidative stress in the intestinal epithelial cells (Roy et al., 2016).
Raised levels of free oxygen radicals in the mitochondria trigger protein DNA and lipid impairments (El Bakary et al., 2020).

| ROLE OF ANTI OXIDANT AG AIN S T G AMMA R ADIATION
Antioxidants are found naturally in several vegetables and fruits (Shaban et al., 2017). Since we are exposed to gamma ray frequently in daily life, it is of utmost importance to develop active and safe radio protectors (Zhu et al., 2019). Phytochemicals observed in plants and foods lacking toxicity have drawn significant attention (Cheng et al., 2019), as against synthetic compounds (Deng et al., 2019). Conversely, as certain antioxidants demonstrate prooxidant activity under specific circumstances, it is more significant to consume natural products comprising different health-functional foodstuffs or antioxidants which are confirmed to be nontoxic, instead of consuming a huge quantity of single antioxidants (Das et al., 2012). Natural antioxidants aid in improving pathological conditions and averting different ailments by assuaging disease advancement ( Figure 2). Thus, these kind of plant extracts can be utilized as an aide to traditional radiotherapy (Das et al., 2012). Contact with ionizing radiation provokes the manufacture of reactive oxygen classes, such as hydroxyl radicals, superoxide, singlet oxygen, and hydrogen peroxide. Such free radicals react with vital cellular constituents, like RNA, DNA, membranes, and proteins, causing cell dysfunction and loss of life (Deng et al., 2019). Three endogenous enzymes, which include catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), are accountable for the reactive oxygen species deactivation and are the principal antioxidant system in cells (Sorenson, 2012), and also have the ability to prevent cellular oxidative injury occurring due to presence of free radicals in the body (Choi et al., 2015).

| B I OLOG I C AL AC TIVITIE S OF NATUR AL ANTI OXIDANTS AG AIN S T D IVER S E CHRONI C D IS E A S E S
In the present research, we review several natural materials that have been examined for defense against oxidative stress induced by gamma radiation. The choice of natural materials is due to their low harmfulness, cost-effectiveness, and availability. All previous studies are summarized in Table 1 in one glance.

| Effects of epigallocatechin gallate against gamma radiation
Epigallocatechin gallate (EGCG) is the polyphenol present in green tea and has been proved to be an antioxidant (Tiwari et al., 2017). Table 1 provides a summary of the antioxidant effect of EGCG in vitro test models and its ability to reduce the harmful effects caused by gamma radiation by altering histopathological and biochemical biomarkers of oxidative stress. Previous study showed that administering Epigallocatechin gallate in doses of 6.25, 12.5, and 25 mg/ kg of body weight 30 days after exposure to radiation with 6 Gy to male Kunming mice improved the transforming capability of the lymphocytes present in the spleen because of the improvement of the impact of immune regulation in vivo, decreased ROS levels, and increased antioxidant enzymes activities including glutathione peroxidase, glutathione, catalase, and superoxide dismutase suppressing peroxidation of lipids, malondialdehyde in the spleen, and liver of irradiated mice (Yi et al., 2020). Another review by (Tiwari et al., 2017) found administering EGCG (0.1833EGCG (0. , 0.2749 well as 0.5499) mg/kg of body weight to male Kunming mice following whole-body gamma irradiation with 2.5 Gy reduced the DNA damage induced by radiation in bone-marrow nucleated tissues, prevented HDAC activity, survival compared with the case of whole body lethally irradiated mice, increased acetylation state of histones that triggers the chromatin to achieve a more open confirmation, facilitated DNA repair, and improved recovery rate from hematopoietic depression, particularly in the restoration of lymphocyte percentage.
In another report by (Richi et al., 2012), it was discovered that administering GCG with doses of 10, 25, 50, and 100 µm in order, to Male Swiss albino mice prior to irradiating with doses of (3, 5, 7 Gy) shielded the plasmid DNA, decreased the formation of breaks in DNA strands, decreased the breaks induced in plasmid DNA strands, reduced cell deaths, reduced TBARS level, shielded membrane splenocytes, increased viability of cells, increased SOD and GST enzymes activity, reduced the LDH level, and preserved GSH level. F I G U R E 1 Diverse diseases in different phases of oxidative stress by gamma radiation

| Effects of gallic acid against gamma radiation
Gallic acid chemically called 3,4,5-trihydroxybenzoic acid (Hari Kumar & Kuttan, 2004) is an antioxidant that exists in several fruits and vegetables, and it has various bioactivities such as lipid peroxidation prevention and radical scavenging (Alfei et al., 2020). Various fruits and foodstuffs, including bananas, strawberries, and grapes, comprise different quantities of GA (Kaliora et al., 2013). Table 1 provides a summary of the antioxidant impact of gallic acid in vitro experimental models and capability to reduce the harmful effects caused by gamma radiation by altering histopathological and biochemical biomarkers of oxidative stress. Review of the literature showed that adding gallic acid with (50, 100 μM) to human blood sample after exposing it to radiation of 2 Gy prevented strand breaks in DNA and partially inhibited the suggesting DNA protection (Gandhi & Nair, 2005). In another report by (Gandhi & Nair, 2005), it was found that administrating Swiss albino mice with 80 mg/kg of gallic acid before exposing them to a dose of 4 Gy for 30 min decreased the lipid peroxidation and cellular DNA damage.

| Effects of lycopene against gamma radiation
Lycopene is an organic pigment produced by microorganisms and plants. It is a carotenoid, which is an acyclic β-carotene-isomer, and does not have vitamin A activity (Kelloff et al., 1999). It is a greatly unsaturated, straight chain hydrocarbon having conjugated and 2 nonconjugated double bonds (Müller et al., 2011). It is present in several vegetables and fruits such as papaya, pink grapefruit, pink guava, and water melon (Müller et al., 2011). Nonetheless, processed tomato products and tomatoes are a major lycopene source in diet (Stahl et al., 2006). Recent attraction of lycopene has concentrated on its antioxidant characteristics (Stahl et al., 2006), and it has found that adding lycopene to chemotherapy and radiotherapy in patients leads to a positive outcome (Tsen et al., 2006). A number of studies have confirmed that lycopene possesses antioxidant properties against cell membrane damage induced by exposure to gamma radiation (Wood et al., 2008), and it is also antitumor (Huang et al., 2008).
Exposure of animals to ionizing radiations causes development of a dose-dependent, complex series of changes, which include reduction in villus height, number of villi, reduction in crypt cells amount, as well as damage of goblet and epithelial cells (Akpolat et al., 2009). Table 1 provides a summary of the lycopene antioxidant effects in vitro experimental models and capability to reduce the harmful effects caused by gamma radiation by altering histopathological and biochemical biomarkers of oxidative stress.
The review of literature has demonstrated that administering lycopene orally in dose of (5 mg/kg BW) to male albino rats, through gavages, for 7 consecutive days, prior to exposure of gamma radiation to whole body with 6 Gy reduced the activity of XO and the TBARS level with noteworthy simultaneous increase in the CAT and SOD enzyme activity, and reduced the GSH content, compared to their corresponding amounts in irradiated rats. Furthermore, a substantial increase was recorded in the monoamines level related to   (2018) Abbreviations: Gy, gray; min, minute; bw, body weight.

TA B L E 1 (Continued)
a significant decrease in the MAO activity. As a result, lycopene would safeguard cellular membrane from lipid peroxidation induced by radiation, thus maintaining the structure of small intestine and inhibiting monoamines release (Saada et al., 2010). Fathy Waer & Shalaby (2012) report demonstrated lycopene effects with dosage of 5 mg/kg daily on adult and healthy male albino rats exposed to radiation of (1/2) Gy. It showed that Lycopene induces great improvement in the cellular organoids structure against cellular damaged induced by the gamma radiation. The cytoplasm sustained its granulation and gained its usual pattern with revival of ribosomes. The nucleotic mitochondria also gets normal. Other remarkable finding in this research was that droplets of lipid still found in Lycopene-treated mammals in considerable averages in comparison to γ-irradiated rats. This is probably because of the antioxidant effect of Lycopene in reducing lipid peroxidation and enhancing antioxidant status that prevents cell damage.
Another review by Srinivasan et al. (2009) demonstrated lycopene effect at a dose of (5 g/ml) on samples of human blood that were sterilely collected in heparinized sterilized glass tubes from median cubital vein of healthy nonsmokers of 22-25 years, with (4 Gy).
Preprocessing of lycopene with gamma-irradiated lymphocytes caused reduction in lipid peroxidation, increased CAT, GPx, and SOD activities in lymphocytes. Lycopene modulates phase II enzymes such as glutathione reductase (GR), glutathione S-transferase (GST) and glutathione peroxidase (GPx), and levels of GSH preventing radiation damage to lymphocytes by inhibiting lipid peroxidation and formation of breaks in DNA strands induced by free radicals.
Another review by Cavusoglu and Yalcin (Cavusoglu & Yalcin, 2009) demonstrated lycopene effect for doses (0.018, 0.015, and 0.020 μM) on human lymphocytes. Samples of peripheral blood were gathered from ten healthy individuals, and they were selected randomly from a bunch of nonsmokers. Among these individuals were 5 males and 5 females, and the individuals' average age was (20-25) years. These samples were treated with 10 Gy irradiation for a duration of 30 min. The lymphocytes were treated with lycopene doses which caused a substantial decrease in chromosomal aberrations frequency. Addition of Lycopene caused beneficial outcomes against genotoxic injury induced by gamma radiation in lymphocytes. Moreover, it was suggested that lycopene can avert carcinogenesis by safeguarding vital molecules like DNA. It was also showed that addition of lycopene increases myocardial infarction, which is regarded as a sensitive indicator of antioxidant activity of lycopene.

| Effects of betalains against gamma radiation
Betalains are regarded as pigments that are water-soluble and can be categorized as betacyanins (Gandhi & Nair, 2005). A rich source pertaining to betalain pigments is red beet. As a natural additive, betalain pigment can be employed for cosmetics and food (Janiszewska, 2014). These pigments are categorized as antioxidants, that is, compounds that can prevent or delay the processes of oxidation, subsequently preventing diseases like cancer as well as cardiovascular diseases (Ravichandran et al., 2013). Betalains contain hydroxyl groups, which enable increase in scavenging activity of free radicals (Gandía-Herrero et al., 2009). When rats were fed with betalain-rich red beet juice, it minimized the action of the hepatotoxic compounds N-nitrosodiethylamine, 7,12-dimethylbenz (a) anthracene and carbon tetrachloride, because of the enhanced antioxidant status as well as increased expression pertaining to quinine reductase (Szaefer et al., 2014). Table 1

| Effects of walnut oligopeptides against gamma radiation
Walnut as a crop is grown worldwide and contains different functional components possessing excellent antioxidant activity , which also offer protection against cardiovascular diseases (Sánchez-González et al., 2017). In addition, walnuts have been found to prevent liver fat accumulation (Choi et al., 2016).
The walnut extract also demonstrated to confer protection with regards to the cholinergic system and antioxidant system by keeping a check on superoxide dismutase contents, malondialdehyde levels, decreased glutathione contents, acetylcholinesterase activity, and acetylcholine levels (Kim et al., 2020). In a rat model, walnuts have also demonstrated to confer protection via anti-inflammatory action against ethanol-induced gastric mucosal injury .

| Effects of boswellic acids against gamma radiation
Boswellic acid can be defined as a phytochemical (Deng et al., 2019), which includes a series of pentacyclic triterpene molecules. It can be isolated from the gum resin of Boswellia carteri and Boswellia serrata produced by the trees called as Indian olibanum (Roy et al., 2016). Boswellic acids are potent, novel, specific anti-inflammatory agents, which can be attributed to the nonredox inhibition pertaining to 5-lipoxygenase enzyme (Iram et al., 2017).

| Effects of arabinoxylan rice bran (MGN-3/ Biobran) on gamma radiation
MGN-3/Biobran can be defined as a natural product extracted from rice bran hemicelluloses (Badr El-Din et al., 2020), a polysaccharide that includes beta-1,4-xylosyl hemicellulose. The key chemical structure pertaining to MGN-3 includes an arabinoxylan possessing a xylose in its main chain and in its side chain with an arabinose polymer (Ooi et al., 2018). Table 1   antithrombotic, and anti-inflammatory activities (Dos et al., 2015). It helps avoid lipid peroxidation as well as provides protection against oxidative damage of the cellular membrane , offers antiviral properties, improves immune functions, antithrombotic , and decreases damage done to human leukemia cells (Nita & Grzybowski, 2016). CAT, SOD, and GPx, nonenzymatic antioxidants with regards to GSH activities in tissues samples, alleviate the loss of crypt and villi within the small intestine and minimize radiation-induced death in mice .

| Effects of kaempferol against gamma radiation
A low molecular weight flavonoid is Kaempferol (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4-H-1-benzopyran-4-one), which includes a phenolic ring and hydroxyl group that are prone to donating an electron or a hydrogen atom in order to free radicals, and thus extending the conjugate aromatic system pertaining to delocalization of an unpaired electron (Dai & Mumper, 2010 (Gouveia et al., 2016). Kaempferol is said to possess antiinflammatory, antioxidant, and immunomodulatory characteristics (Martino et al., 2014), like inhibiting human monoamine oxidases-A pertaining to the peripheral tissues and brain as well as inhibiting cell growth of pancreatic cancer (Lee & Kim, 2016) and (Gidaro et al., 2016). Table 1 provides a summary of the antioxidants effect pertaining to Kaempferol for in vitro test models and the capability to reduce the harmful impacts of gamma radiation by changing histopathological and biochemical biomarkers pertaining to oxidative stress.
Previous study demonstrated that oral gavage administration of kaempferol to male mice at a dose levels of 5 and 15 mg/kg body weight for 30 days before irradiation with gamma (7 and 8.5 Gy) radiation can significantly mitigate the loss of weight post radiation, as well as attenuate radiation-induced injury with regards to spleen, jejunal, and thymus. Pretreatment with kaempferol may also considerably inhibit radiation-induced cell apoptosis in mice models (Wang et al., 2018). As per a separate report by (Wang et al., 2018),

| Effects of melittin against gamma radiation
Bee venom chiefly includes melittin component, which can be defined as a peptide of 26 amino acids (Hwang, Kim and Bae, 2015). It is also regarded as a key active ingredient found in honeybee venom . Melittin includes many pharmacological, biological and toxicological activities, including antifungal and antibacterial activities, as well as possible antitumor activity. With regards to cancer treatment, radiotherapy is regarded as a key modality (Son et al., 2007). Melittin possesses antitumor properties and is also regarded as a natural therapeutics for cancer chemotherapy (Jeong et al., 2014). Melittin has potential anticancer impacts against breast, ovarian (Jo et al., 2012), leukemia, hepatocellular carcinoma (Hoshina & Marin-Morales, 2014), and melanoma, prostate (Liu et al., 2013). Table 1 provides a summary or the antioxidants effect pertaining to melittin for in vitro test models as well as the capability to reduce the harmful impact caused due to gamma radiation by changing histopathological and biochemical biomarkers pertaining to oxidative stress. According to previous study, it is observed that the adminis-

| Effects of polysaccharide of hohenbuehelia serotina against gamma radiation
Hohenbuehelia serotina refers to a kind of mushroom that grows in the North Hemisphere. In traditional China, this mushroom is consumed as a medicinal fungus (Xie et al., 2016). A key component of the Hohenbuehelia serotina is polysaccharide, which is proven to have significant antitumor and antioxidant benefits (Li et al., 2014).
Polysaccharides are long chain molecules, composed of ketoses or aldoses, and bonded with glycosidic links (Kanagasabapathy et al., 2014). As concluded in various research works, the bioactivities of polysaccharides were strongly driven by their structural characteristics. The polysaccharides with the main chain of (1→3)β-glucan could be regarded as immunomodulator, while the polysaccharides with the backbone of (1→3)α-glucan generally behaved as tumor inhibitor (Singdevsachan et al., 2016). The structural characteristics of the polysaccharides predominantly included the monosaccharide composition, molecular weight, types of glycoside bond, extent of polymerization, and degree of branching, as well as the three-dimensional advanced conformation, and all these traits determined the biological activities of the polysaccharides (Jing et al., 2015). Polysaccharide of Hohenbuehelia serotina had substantial biological activities, like immunomodulatory (Wong et al., 2011), antioxidant (Wu et al., 2013), antitumor (Li et al., 2012), and lowering blood (Zhang et al., 2013).

| Effects of melatonin against gamma radiation
Melatonin (N-acetyl-5-methoxytryptamine) is generally present in cereals, walnuts, tomatoes, legumes, ginger, olive, and pineapple (Meng et al., 2017). Melatonin has the ability to minimize the DNA damage responses and apoptosis with its antioxidant and antiinflammatory effects, which eventually results in reduction of cell death and consequent inflammation (Shabeeb et al., 2018). Table 1 presents the antioxidant effect of Melatonin in in vitro test models and its capability to reduce the damaging impacts of gamma radiation by changing the histopathological and biochemical biomarkers of oxidative stress. According to the literature study, the administration of melatonin through oral gavage of male Wistar rats in a dose of 100 mg/kg in 24 hr and 30 min before exposing them to 10 Gy gamma rays and continued for 3 days after irradiation protects ileum against radiation toxicity, protects vessels and goblet cells, prevents infiltration of macrophages and lymphocytes or mucositis, stimulates antioxidant defense in cells, protects against radiation-induced apoptosis, reduces inhibitory effect on radiation-induced apoptosis, preserves villi length, and inhibits inflammation in the intestine .
In another report , it was observed that administration of 50, 100 mg/kg of melatonin to abdominal regions of male Wistar rats for 30 min before exposing them to 8 Gy gamma rays from gamma radiation resulted in reduction of levels of malondialdehyde (MDA), protection of the tissues against radiotherapy-induced intestinal damage, prevention of enteritis, and improvement of catalase and superoxide dismutase activities of the tissues. In a different report by (Assayed & Abd El-Aty, 2009), it was observed that administration of 2.5 mg/kg of melatonin to male albino rats intraperitoneally daily for 5 consecutive days before exposing them to 4 Gy from gamma radiation led to protection of the chromosomes and bone-marrow cells of those rats, and activation of certain cellular enzymatic antioxidant defense mechanisms, which involve glutathione peroxidase, catalase, and superoxide dismutase, and amelioration of the radiation-induced enhancement of 4-hydroxyalkenal plus malondialdehyde and protein carbonyls, along with protection of the genome against DNA damage.

| Effects of ferulic acid against gamma radiation
Ferulic acid (FA) can be defined as a phytochemical that is found in fruits and vegetables like sweet corn, tomatoes, rice bran, wheat, and broccoli (Srinivasan, Sudheer, et al., 2006). It includes a strong antioxidant that enables nitric oxide scavenging activity as well as hydroxyl radical scavenging activity. It has become a popular choice due to its properties such as cost-effectiveness (Ou & Kwok, 2004). Table 1 provides a summary of the antioxidant effect pertaining to ferulic acid in vitro test models as well as the ability to minimize the harmful effects of gamma radiation by adjusting the histopathological and biochemical biomarkers pertaining to oxidative stress.
A previous study showed that administration of ferulic acid at a dose of 50 mg/kg body weight orally once daily, prior to exposing a single dose of 10 Gy whole-body irradiation in swiss albino mice, was found to considerably prevent the radiation-mediated damage pertaining to plasmid DNA, activate nonhomologous end-joining DNA (repair process) as well as significantly increase the antioxidant enzymes via scavenging reactive oxygen species (ROS) (Das et al., 2017).
As per a report by (Das et al., 2014), administration of 50 mg/ kg body weight of ferulic acid to Swiss albino mice for 5 days before exposure to a single dose of 10 Gy was found to increase the activity pertaining to superoxide dismutase, glutathione and catalase levels, decrease the lipid peroxidation, mitigate the radiation induced via inflammatory response, prohibit the rise in cycloxygenase-2 (Cox-2) protein, induce lipid peroxidation in liver, and increase the level of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a) in serum.
In a different report by (Maurya & Devasagayam, 2013), intraperitoneal administration of 50 mg/kg body weight of ferulic acid to Male Swiss mice before and immediately post whole-body Ɣirradiation of mice with 4 Gy was found to decrease the level of DNA strand breaks in murine peripheral blood leukocytes and improve the survival of mice, which could be due to the minimization of DNA damage and micronuclei formation. In a report by (Shanthakumar et al., 2012), intraperitoneal administration of 50 mg/kg body weight of ferulic acid to Male Swiss mice post whole-body Ɣ-irradiation of mice with 8 Gy, for five consecutive days was found to increase the levels of catalase, super oxide dismutase and glutathione peroxidase activities, decrease the depletion level of glutathione concentration in liver, spleen and intestine, and decrease the number of inflammatory, dead and mitotic cells and preserved villus height.

| Effects of salvianolic acid B against gamma radiation
Salvia miltiorrhiza is the source from which salvianolic acid is extracted (Rahmani et al., 2020). Traditional Chinese medicine uses Salvia miltiorrhiza and is among the extensively used herbs (Shen et al., 2017). Salvianolic acid is an effective antioxidant that captures free radicals of oxygen (Qian et al., 2014). Contemporary pharmacological research indicates that Salvia protects vascular endothelial cells, has anti-arrhythmic properties, enhances blood flow to the coronary artery, removes free radicals, enhances microcirculation, slows atherosclerosis, protects against pulmonary fibrosis and lipid peroxidation, and protects liver cells (Paik et al., 2011).

| Effects of crocin against gamma radiation
Crocin is a water-soluble pigment carotenoid that is extracted from the stigma of the Crocus sativus L.  (Tamaddonfard et al., 2013) and antidepressant characteristics (Rahaiee et al., 2015). Crocin is found to have cancer-opposing activity against specific tumor cells (Bakshi et al., 2017). It reduces the damage caused by DNA breakage caused by hydroxyl radicals produced due to radiation (Kudryasheva & Rozhko, 2015). There is documentation indicating the protective effects of crocin against radiation poisoning of the kidneys, heart, liver, and skeletal muscles (Samarghandian et al., 2016). Table 1 lists the antioxidant effect of Crocin specific to in vitro tests. It decreases the adverse effects of gamma radiation by changing the histopathological and biochemical markers of oxidative stress. The literature indicates that oral Crocin administration in male Swiss albino mice at 50 mg per kg body weight in the 2 days following 2 Gy wholebody radiation exposure leads to enhanced free radical removal.
Moreover, micro-nucleated polychromatic erythrocytes and genotoxicity decrease; there is lesser damage to testicular tissue. Crocin provides protection DNA strand breakage caused by hydroxyl free radicals (Koul & Abraham, 2018).

| CON CLUS ION
Gamma radiation exposure is risky; it should be reduced to decrease the risks. The present study focused on the use of natural antioxidants that are considered to have therapeutic effects against radiation. The emphasis is on substances that are cost-effective and readily available. Individuals working around radiation sources or in the radiotherapy field should be provided natural antioxidants.
Empirical data indicate that the reviewed substances offer protection against gamma radiation. The use of gamma radiation and chemotherapeutic drugs like Doxorubiein for treating cancer causes significant damage to the liver. Orally administered natural antioxidants can prevent or reduce the harm caused by such drugs or radiation therapy. These observations indicate the efficacy of supplementing natural antioxidants for protection against the effects of gamma radiation. The need for other medicines can be reduced, and quality of life can be enhanced. The study showed that the natural substances did not lead to toxicity; hence, potential clinical trial safety concerns are addressed. Nevertheless, the effectiveness of such substances remains to be assessed during clinical trials. We propose that these substances be assessed in future clinical trials to establish their efficacy and practicality in clinical settings. Moreover, clinical trials are expected to yield more information concerning experimental outcomes on human cells. Furthermore, the mechanisms through which radiation protection is achieved need to be clarified.
The study results might lead to a noteworthy increase in the therapeutic index and the effectiveness of radiotherapy. We assessed the correlation between natural antioxidants and their effects on oxidative stress caused by gamma rays. The data are correlated with statistical factors. It is shown that natural substances may be used to augment radiotherapy. Further studies are necessary to investigate the therapeutic effects of the natural antioxidants on gammainduced damage as a nutraceutical supplement.

ACK N OWLED G M ENT
The authors received no specific funding for this work.

CO N FLI C T O F I NTE R E S T
The authors declare that they do not have any conflict of interest.

E TH I C A L A PPROVA L
The study did not involve any human or animal testing.

DATA AVA I L A B I L I T Y S TAT E M E N T
All authors consent that raw data presented in this review are available after publication.