Natural Radioprotectors on Current and Future Perspectives: A Mini-Review.

Radiation therapy is used as the primary treatment for cancer. Eighty percent of cancer patients require radiation therapy during treatment or for medical purposes. During treatment, radiation causes various biological defects in the cells. The prevalence of cytotoxicity limits the dose used for effective treatment. This method is designed to strike a balance between removing cancer cells and protecting normal tissues. Unfortunately, effective radiation is unavailable once acute toxicity occurs during clinical radiation therapy. Therefore, a lot of research interest is needed in the discovery of radioprotective drugs to accelerate treatment to reduce this toxicity (i.e., normal tissue toxicity to cancer cell death). Radiation protectors may be chemicals or drugs that minimize the damage caused due to radiation therapy in living organisms. The determination of effective and nontoxic radiation protection is an essential goal for radiation oncologists and basic radiobiologists. However, despite the advantages, many radioprotectors were found to have disadvantages which include cost, less duration, toxicity, and effect on the central nervous system. Therefore in recent years, the focus has been diverted to finding out optimal natural products to act as radioprotectors. Natural radiation protectors are plant compounds that protect normal (noncancerous) cells from damage from radiation therapy. Natural herbal products are nontoxic with proven therapeutic benefits and have long been used to treat various diseases. In conclusion, we find that there are various radiation protectors with different purposes and mechanisms of action. Copyright:

INTRODUCTION

Radiation therapy is one of the most effective treatments for cancer patients. Approximately 60% of all cancer patients get ionizing radiation (IR) as part of their treatment procedure.[1] IR is a powerful tool to kill cancer cells, but it is also toxic to normal cells and causes cell damage and various side effects. IR directly or indirectly affects biological molecules. The direct effect of IR is affected by direct contact with different parts of DNA, and indirect effects using reactive oxygen species (ROS) originating from surrounding DNA molecules.[2] Since biological systems contain 75%–90% water, the indirect effect is due to the reaction of water to radiolysis products (OH: hydroxyl radicals, solvent electrons, and hydrogen atoms) with DNA. Hydroxyl groups are highly reactive, have a strong oxidizing effect, and can react differently with all cellular components. DNA, lipids, and proteins are the main targets for hydroxyl radical attack. In response to IR-induced DNA damage, ROS formation, and cell death, the release of damage-related molecules and cytokines or chemokines activates the immune system and causes inflammation. This immune activation results in an acute inflammatory phase characterized by an enhanced anti-inflammatory response. The signaling of inflammation and repair after IR leads to a chronic phase of IR injury, in parallel with mitotic cell death and subsequent release of cytokines and growth factors.[3] It has been observed that multiple diseases are found to be associated with IR response, including diseases caused by acute stage lesions (inflammation of various organs) or chronic stage lesions (blood vessel damage, fibrosis, secondary malignancy, atrophy, and infertility).

Attention has to be provided during IR to protect the healthy cells during the procedure. To this end, technical improvements in the IR delivery procedure, the accuracy of treatment, and pharmacological agents used for the treatment regime are the subject of recent research. The National Cancer Institute's IR Research Program proposed pharmacological classification of the following drugs with IR-protective properties based on the timing of administration: (a) protection, (b) palliative, and (c) therapeutic.[4]

Ideal radioprotective compounds should shield the healthy cells of the body from the harmful effects of the IR but should not prevent the effectiveness of the IR on the tumor cells. Radioprotectors are used as a strategy to avoid exposure to chemicals according to the proposed classification schedule. It is used to prevent acute or chronic effects before radiation therapy or infrared radiation. IR therapy is used during and after treatment to reduce side effects or chronic effects and is administered after the onset of symptoms.[5] Many compounds have been studied as radiation protectors, modifiers, and therapeutics and are currently in the US Food and Drug Administration (FDA) or FDA-Examined New Drug (IND) for approval.[6]

STUDY METHODOLOGY

The current article is a mini-review of the existing literature on radioprotectors. A search of the PubMed and Google Scholar was undertaken using the search terms “Radio protectors” “review” in various permutations and combinations. We also searched for referenced papers to identify further studies. A total of 360 review papers on radio protectors out of which 317 papers extending back to the year 2005 using MeSH terms. Out of these 66 papers, were included. Careful literature searches were conducted by going through Google Scholar on the basis of radioprotection 40. papers selected based on protecting humans and animals from the effects of IR. The work outlined here suggests that there are many potential radiation protectors with different purposes and mechanisms. [Figure 1]

Figure 1

Possible mechanism of natural radioprotectors against ionizing radiation-induced damage

RADIOPROTECTORS

Radioprotective agents may be chemicals or drugs that reduce the harm caused when IR therapy is administered to living organisms. Determination of an effective and nontoxic radiation protector is an essential goal for radiation oncologists and basic radiobiologists. The most radioprotective substances to date are amino thiols and their derivatives include aminoethyl isothiouronium bromide hydrobromide (AET), sistemin, and amipocene (WR-2721). Some of these compounds have been used successfully to prevent radiotherapy complications in cancer patients and are believed to protect against radiation risks in clinical use and incidental radiation exposure scenarios.[5] Despite current clinical use, amifostin has not been approved for use in clinical nuclear/radiation conditions. Side effects of amifostin include cost, limited use, and narrow duration, toxicity, effect on the central nervous system.[7] Sulfasalazine (SAZ) is another compound that was reported to protect mice at 120 mg/kg without toxicity. At this dose, SAZ protected the plasmid DNA (pGEM-7Zf) from dissolution from the Fenton reaction, suggesting free radical scavenging as one of the possible mechanisms of radioactivity, but some levels of toxicity have also been observed. The practical applicability of most synthetic compounds was still limited due to their high toxicity. Ideal protective agents provide a high degree of protection against normal tissues, little or no protection against tumor cells, and most importantly, they must be nontoxic.[8]

Because more effective and less toxic radioprotective substances could not be obtained from synthetic compounds, researchers had to focus on assessing the radioprotective potential of natural products.[9] Therefore, worldwide research is underway on radioprotective drugs that do not cause cumulative or irreversible toxicity, provide effective long-term protection, remain stable for many years with long shelf life, and have all the essentials of an ideal radioprotective drug.[10]

NATURAL RADIOPROTECTORS

Natural radiation protectors are plant compounds that protect normal (noncancerous) cells from damage from radiation therapy. Natural herbal products are nontoxic with proven therapeutic benefits and have been used to treat various diseases. Of the 1144 new drugs developed in the last 25 years, about 60% come from natural resources. To date, approximately 74 plant products have been tested for their radioprotective potential in a variety of in vitro and in vivo studies. Among them a few plants extract with their mode of action as a radio protector are mentioned in Table 1. The use of herbs and diet modulators, along with improved radiation to sensitize tumor cells with radiation, protected normal cells from radiation.[8105]

Table 1

List of various plants extract with their mode of action as a radioprotector

Plant name and source for the study	Experimental model	Major active constituents	Radiation source	Mode of action(s)	References
A. marmelos Fruit extract	Mice (in vivo studies)	Skimmianine, luvangetin, psoralen, marmin, marmelide, aurapten, marmelosin, lupeol, aegelin, marmrsinin, eugenol, and coumarin	Gamma-radiation	Protection against both gastrointestinal and hematopoietic toxicities	[50]
A. senticosus Harms Plant extract	Mice (in vivo studies)	Triterpenoid saponins, lignans, coumarins, and flavones	Irradiation by 60 Co	Protective effect on endogenous recovery of CFU-S	[51]
A. calamus Plant extract	Mice (in vivo studies)	α-and β-asarones	γ-irradiation	Protective effect of cellular DNA from radiation-induced damage and enhanced DNA repair	[52]
A. vasica Leaf extract	Mice (in vivo studies)	Alkaloids containing pyrroquinazoline ring derivatives like vasicine, vasicol, vasicinone	60 Co source	Protective effect by decreasing the level of acid phosphatase and increase in level of alkaline phosphatase	[53]
A. Cepa Bulb onion extract	In vitro and rats for in vivo studies	Glycosides i.e., quercetin and kaempferol	Cobalt-60	Therapeutic gain due to the radiation sensitivity of normal tissues adjacent to the tumour which are exposed to radiation, by strengthening the antioxidant system	[54]
A. vera Leaf extract	Mice (in vivo studies)	Vitamins, enzymes, minerals, sugars, lignin, saponins, salicylic acids, anthraquinones	Gamma irradiation	Damage-resistant properties against radiation-induced biochemical alterations in swiss albino mice	[55]
A. scholaris Bark extract	Mice (in vivo studies)	Iridoids, alkaloids, coumarins, flavonoids, leucoanthocyanins, phenolic, steroids, tannins, saponins and volatile oils	Whole-body gamma irradiation	Protects against radiation-induced hematological and biochemical alterations	[56]
A. racemosus Root extract	Mice (in vivo studies)	Saponins: shatavarin I-IV, the glycosides of sarsasapogenin	Whole-body electron beam radiation	Free radical scavenging, anti-inflammation, facilitation of repair activity, regeneration of hematopoietic cells and affecting to molecular levels	[49]
A. paniculatus Leaf extract	Mice (in vivo studies)	Flavonoids hesperidin and rutin One phenolic acid (E)-ferulic acid (3), two amino acids, two sterols comprising spinasterol and spinasterol 3-O-β-D-glucopyranoside	Gamma radiation	Protection against biochemical alterations of endogenous antioxidant enzymes	[57]
A. conyzoides Plant extract	Mice (in vivo studies)	Terpenoid, sterol, flavonoid, chromene, pyrrolizidine alkaloid, coumarin, pyrrolon, and lignan	Gamma-radiation	Protection against gastrointestinal and bone marrow related death and scavenging of ROS	[58]
B. sensitivum Aerial parts of the plant extract	Mice (in vivo studies)	Two biflavones: cupressuflavone and amentoflavone; three flavonoids: luteolin 7-methyl ether, isoorientin and 3’-methoxyluteolin 7-O-glucoside; two acids: 4-Caffeoylquinic acid and 5-Caffeoylquinic acid	X-irradiation	Protection against radiation-induced hematological, biochemical alterations and immunomodulation as well as sequential induction of IL-1beta, GM-CSF and IFN-γ	[59]
B. diffusa Plant extract	Mice (in vivo studies)	b-sitosterol, a-2-sitosterol, palmitic acid, ester of b-sitosterol, tetracosanoic, hexacosonoic, stearic, arachidic acid, urosilic acid, hentriacontane, b-Ecdysone, triacontanol	Whole-body irradiation	Protection against radiation induced biochemical alterations and DNA damage	[60]
C. digyna Dried root extract	Mice (in vivo studies)	Friedelin, hexacosanoic acid, β-sitosterol and stigmasterol	Gamma-radiation	Protection against radiation-induced lipid peroxidation, protein carbonylation and DNA damage	[61]
C. asiatica Plant extract	In vitro and mice for in vivo studies	Triterpenoid, flavonoid, phenolic acid, sterols, acetylenes	Gamma-radiation	Protection against radiation-induced decline in antioxidant enzyme levels Protection to DNA and membranes against radiation exposure	[62]
Coronopus didymus Plant extract	Mice (in vivo studies)	7-methoxy luteolin, 4’,5,8- trihydroxy-6-methoxyflavone-7- O-rhamnoside and apigenin -7-O-arabinoside. the other three namely apigenin 7-O-rhamno-glucoside, Acacetin-7-Orhamnoside and chrysoeriol -6-O-rhamnoside from butanol fraction	Gamma-radiation	Protection by reversal of the levels of endogenous antioxidant enzymes and lipid peroxidation indicates reduced oxidative stress	[63]
C. lanatus Rind extract	In vitro studies	Flavonoids and β-sitosterol	X-ray irradiation	Radiation recovery in cells more specifically, cytotoxicity and genotoxicity studies	[64]
C. papaya Leaf extract	Mice (in vivo studies)	Alkaloids, carpaine, and pseudocarpine	Electron beam radiation	Radiation-induced hematological and biochemical alterations	[65]
C. longa Root extract	In vitro and in vivo studies	Cucurminoids, cucurmine	Chemo- photothermal synergetic therapy	Multifunctional delivery system for curcumin bioavailability enhancement, chemo-photothermal synergetic therapy of cancer, and radioprotection of healthy tissue	[24252627]
E. officinalis extract	Mice (in vivo studies)	Tannins, alkaloids, quercetin, emblicanin A and B, and ellagotannin	60 Co gamma radiation	Protection against radiation-induced increase in goblet cells/villus section and dead cells/crypt section in jejunum and enhancing antioxidant status	[66]
F. racemose Stem and bark	Invitro studies	Glycosides (leucocyanidin-3-O-β-D-glucopyrancoside, leukopelargonidin-3-O-β-D-glucopyranoside, Leucopelargonidin-3-O-β-D-glucopyranoside, and leucopelargonidin-3-O-α-L-rhamnopyranoside); sterols (β-sitosterol, stigmasterol, α-amyrin acetate, lupeol, and lupeol acetate); and tannins (ellagic acid)	Gamma-radiation	The cytokinesis-block proliferative index indicated that ficus does not alter radiation induced cell cycle delay	[67]
G. lucidum Lingzhi mushroom extarct	Balb/c mice In vivo and in vitro studies	Ganoderic acid, polysaccharides (beta - D - glucan polysaccharides) together with other active compounds such as sterol (ergosterol), fungal lysozyme, alkaloids, proteins, riboflavin, ascorbic acid, and lipids	Gamma-radiation and X-ray	Improve long-term renovation processes, and attenuate chronic cardiac fibrosis and necrosis from X-rays Protection of DNA in blood leukocytes, bone marrow cells, brain cells, and intestine cells and enhancing antioxidant status	[68]
G. asiatica Fruit	In vitro studies	Anthocyanin-type cyanidin 3-glucoside, Vitamins C and A, minerals, carotenes, and dietary fiber	Whole-body irradiation	Significant protection of DNA and RNA in testis was also noticed Protection against radiation-induced biochemical alterations	[69]
G. biloba and A. archangelica Root extract	Rat (in vivo studies)	G. biloba: Ginkgolides, bilobalides, and flavonoids A. archangelica: α-pinene, δ-3-carene, limonene, β-phellandrene, α-phellandrene, and p-cymene	99mTc-sestamibi.	Free radical scavenging, antioxidant properties and protection against oxidative organ damage	[70]
G. glabra Root extract	Rat (in vivo studies)	Saponins are glycyrrhizin, liquiritic acid, and glycyrretol. In flavonoids, the active constituents include liquirtin, liquiritigenin, and neoliquiritin	Gamma-radiation	Protect microsomal membranes, as evident from reduction in lipid peroxidation, and could also protect plasmid DNA from radiation-induced strand breaks	[71]
H. indicus Root extract	In vitro studies	Tannins, saponins, flavonoids, alkaloids, terpenoids, coumarins, and phenols	Gamma-radiation	Protect microsomal membranes as evident from reduction in lipid peroxidation values. DNA from radiation-induced strand breaks	[72]
H. rhamnoides Sea buckthorn extract	In vitro studies	Hexatriacontane, lupeol, its octacosanoate, α-amyrin, β-amyrin, its acetate and sitosterol	Whole-body lethal irradiation	The ability of RH-3 to interact with DNA could be playing a significant role in preventing radiation-induced DNA damage	[73]
I. indigotica Root extract	Mice (in vivo studies)	Isolariciresinol , lariciresinol, lariciresinol-9-O-beta- D-glucopyranoside, lariciresinol-4’- O-beta -D-glucopyranosid, lariciresinol-4,4’- bis-O-beta-D-glucopyranoside, 3-formylindole, 1-methoxy-3-indolecarbaldehyde, 1-methoxy-3-indoleacetonitrile, deoxyvasicinone,epigoitrin, adenosine	Whole-body irradiation	Recovery of hematopoietic system, reduction of inflammatory cytokines and intestinal toxicity	[74]
M. arvensis/M. piperita Leaf extract	Mice (in vivo studies)	Alkaloids, flavonoids, phenols, tannins, saponins, diterpenes, and monoterpenes	Gamma-radiation	Free radical scavenging, antioxidant, metal chelating, anti-inflammatory, antimutagenic, and enhancement of the DNA repair processes	[75]
M. oleifera Leaf extract	Rat (in vivo studies)	Flavonoids of the genus are rutin , quercetin, rhamnetin, kaempferol, apigenin, and myricetin Isothiocyanate, glucosinolates marumoside A (and marumoside B, Terpenes	EMR	Protecting rat testis against EMR-induced impairments, anti-oxidants, and oxidative stress marker	[76]
Morin Morin extract	Mice (in vivo studies)	Natural bioflavonoid	Gamma radiation	Anticlastogenic activity	[77]
N. nucifera LSPCs	Mice (in vivo studies)	Sesquiterpenes, flavonoids, triterpenes, and alkaloids	Gamma-radiation	Protection against radiation-induced hematological and biochemical alterations endogenous antioxidant enzymes in liver and bone marrow chromosomal damage	[78]
O. sanctum Leaves extract	In vitro and mice for in vivo studies	Alkaloids, tannin, saponin, steroid, terpenoid, flavonoid, cardiac glyceride, orientin, vicenin, eugenol, and arsenic acid	Gamma-radiation	Prevent radiation-induced clastogenesis Radiation-induced Gastrointestinal damage Prenatal irradiation-induced genomic instability and tumorigenesis	[79]
O. europaea L. Leaves extract	Mice (in vivo studies)	Rutin, oleuropein, hydroxytyrosol, verbascoside, luteolin	X-irradiation	Anticlastogenic activity and antioxidant capacity	[80]
P. guajava L. Leaf extract	Rat (in vivo studies)	Phenolic compounds, isoflavonoids, gallic acid, catechin, epicatechin, rutin, naringenin, kaempferol	X-irradiation	Improved antioxidant enzyme activities, hematological parameters and reduced the intestinal damage by recovering the architecture of the small intestine	[81]
P. angolensis Warb Seed extract	In vitro studies	Lignans and flavonoids	X-ray	Radioprotective and lower antimutagenic capacities	[82]
P. Maritima Bark extract	Hairless mice (in vivo studies)	Phenolic acids, polyphenols, and in particular flavonoids mixture	Ultraviolet radiation	Provide strong evidence about the preventive anticancer activity of this extract on nonmelanoma skin cancer	[83]
P. betel Leaf extract	Rat (in vivo studies)	Eugenol, caryophyllene, terpinolene, terpinene, cadinene and 3-carene	Gamma-ray	Antioxidant activity Prevented radiation-induced DNA strand breaks, lymphoproliferative activity	[84]
P. zeylanica Plant extract	Rat (in vivo studies)	Naphthoquinone, coumarin, and anthraquinone derivatives	Gamma	The protection to lipids, proteins, and enzymes of rat liver mitochondrial preparation against radiation-induced damage	[85]
P. avium Fruit extract	Mice (in vivo studies)	Anthocyanin content and phenolic compound	Gamma	Radiation-induced metabolic disorders may be due to synergistic action of various antioxidants, minerals, Vitamins	[86]
P. granatum Whole fruit and rind extract	Mice (in vivo studies)	Flavonoids, ellagitannin, punicalagin, ellagic acid, Vitamins, and minerals	60 Co gamma radiation	Renders protection against biochemical changes in mouse testes	[87]
P. koraiensis Synergism with Auricularia auricula-judae (Bull.) J Synergism extract	Mice (in vivo studies)	P. koraiensis: Limonene, alpha-pinene, beta-pinene, 3-carene, beta-myrcene, isolongifolene, (-)-bornyl acetate, caryophyllene, and camphene Auricularia auricula-judae: Polysaccharide, cellulose, chitin, pectin, uronic acids, amino acid and mineral element contents	60Coγ-ray radiation	Protection from radiation by clastogenic effect and reduced chromosome distortion rate	[88]
P. microphylla	Mice (in vivo studies)	Quercetin-3-O-rutinoside; 3-O-caffeoylquinic acid, luteolin-7-o-glucoside; apigenin-7-o-rutinoside; apigenin-7-o-β-d-glucopyranoside; quercetin	Gamma radiation	Protected the hematopoietic system as assessed by endogenous spleen colony assay, contributing to the overall radioprotective ability	[89]
P. hexandrum		Epipodophyllotoxin, podophyllotoxone, aryltetrahydronaphthalene lignans, and flavonoids	Gamma radiation	Protection from radiation by modulation of expression of the proteins associated with apoptosis	[90]
P. ginseng Root	Mice (in vivo studies)	Ginseng saponins, ginsenosides	Gamma radiation	Protection against radiation-induced hematological and biochemical alterations in Swiss albino mice Role in increasing levels of several cytokines and immunomodulating capabilities	[9192]
P. amarus Plant extract	Rat (in vivo studies)	Amariin, 1-galloyl-2,3-DHHDP-glucose, repandusinic acid, geraniin, corilagin, phyllanthusiin D, and flavonoids namely rutin, and quercetin 3-O-glucoside	Electron pulse radiolysis	Radioprotective ability to scavenge different radicals more or less efficiently, relieving the oxidative stress	[93]
P. Americana Leaf extract	Rat (in vivo studies)	Tannins, phenylpropanoids, terpenoids, phenolics, flavonoids, alkaloids, saponins glycosides	X-ray	Antioxidant activity, antigenotoxic effect, and antagonizing the radiation effects	[94]
R. imbricata Plant extract	Mice (in vivo studies)	Flavonoids, proanthocyanidins, tyrosol, cinnamyl alcohol, glycosides, organic acids, essential oils, su ars, fats, alcohols, and protein	Whole-body lethal radiation	Colony-forming units per spleen in irradiated mice	[95]
R. officinalis Leaf extract	Mice (in vivo studies)	Camphor, 1,8-cineole, α-pinene, borneol, camphene, β-pinene and limonene	Gamma	Hematological parameters and endogenous antioxidant enzymes	[96]
S. cumin Leaf extract	In vitro studies Human lymphocytes	Anthocyanins, glucoside, ellagic acid, isoquercetin, kaemferol and myrecetin	Gamma	Protects against the radiation-induced DNA damage	[97]
S. platensis Blue-green edible microalgae extract	Rat (in vivo studies)	Phycocyanin and carotenoids	Electromagnetic phone’s radiations	Reduced the level of DNA damage and oxidative stress	[98]
T. chebula Fruit extract	In vitro studies Human lymphocytes	Gallic acid, ellagic acid, tannic acid, ethyl gallate, chebulic acid, chebulagic acid, corilagin, mannitol, ascorbic acid	Gamma-radiation	Decrease in radiation-induced damage to DNA	[99]
T. cordifolia Stem extract	Mice (in vivo studies)	Cordifolioside-A	Gamma-radiation	In vitro cytoprotective activity	[100]
T. parthenium Leaf extract	Mice (in vivo studies)	Sesquiterpene lactone Udesmanolides, and guaianolides Parthenolide is a germacranolide	Electron beam radiation	Potent anti-inflammatory, antioxidant activity and protect against radiation-induced oxidative damage	[10101102]
V. cinerea Plant extract	Balb/c mice (in vivo studies)	Gallic acid, rutin, quercetin, caffeic acid and ferulic acid	Whole-body irradiation	Enhancing antioxidant status and stimulated the production of other cytokines such as GM-CSF and IFN-γ	[103]
V. vinifera Grape seeds extract	Mouse (in vivo studies)	Procyanidins	X-ray	Scavenging capacity by antioxidant and anticlastogenic activity	[104]
X. aethiopica Fruit extract	Rat (in vivo studies)	Cardiac glycosides Flavonoids, phenol, terpenoids, phlobatannin, tannin, saponin, steroids	Gamma radiation	Ameliorated the radiation-induced decreases in antioxidant status	[105]

A. marmelos: Aegle marmelos, A. senticosus: Acanthopax senticosus, A. calamus: Acorus calamus, A. vasica: Adhatoda vasica, A. Cepa: Allium Cepa, A. vera: Aloe vera, A. scholaris: Alstonia scholaris, A. racemosus: Asparagus racemosus, A. paniculatus: Amaranthus paniculatus, A. conyzoides: Ageratum conyzoides, B. sensitivum: Biophytum sensitivum, B. diffusa: Boerhaavia diffusa, C. digyna: Caesalpinia digyna, C. asiatica: Centella asiatica, C. didymus: Coronopus didymus, C. papaya: Carica papaya, C. longa: Curcuma longa, E. officinalis: Emblica officinalis, F. racemose: Ficus racemose, G. lucidum: Ganoderma lucidum, G. asiatica: Grewia asiatica, G. biloba: Ginkgo biloba, A. archangelica: Angelica archangelica, G. glabra: Glycyrrhiza glabra, H. indicus: Hemidesmus indicus, H. rhamnoides: Hippophae rhamnoides, I. indigotica: Isatis indigotica, M. arvensis: Mentha arvensis, M. piperita: Mentha piperita, M. oleifera: Moringa oleifera, N. nucifera: Nelumbo nucifera, O. sanctum: Ocimum sanctum, O. europaea: Olea europaea, P. guajava: Psidium guajava, P. angolensis: Pycnanthus angolensis, P. Maritima: Pinus Maritima, P. betel: Piper betel, P. zeylanica: Plumbago zeylanica, P. avium: Prunus avium, P. granatum: Punica granatum, P. koraiensis: Pinus koraiensis, P. microphylla: Pilea microphylla,

P. hexandrum: Podophyllum hexandrum, P. ginseng: Panax ginseng, P. amarus: Phyllanthus amarus, P. Americana: Persea Americana, R. imbricate: Rhodiola imbricate, R. officinalis: Rosmarinus officinalis, S. cumin: Syzygium cumin, S. platensis: Spirulina platensis, T. chebula: Terminalia chebula, T. cordifolia: Tinospora cordifolia, T. parthenium: Tanacetum parthenium, V. cinerea: Vernonia cinerea, V. vinifera: Vitis vinifera, X. aethiopica: Xylopia aethiopica, CFU-S: Spleen colony-forming units, EMR: Electromagnetic radiation, LSPCs: Lotus seedpod extract, DHHDP: Dehydrohexahydroxydiphenyl, GM-CSF: Granulocyte monocyte-colony stimulating factor, IFN-γ: Interferon-gamma, IL β: Interleukin 1 beta, RNA: Ribonucleic acid, ROS: Reactive oxygen species

NEED FOR THE NATURAL RADIOPROTECTORS

Radiation protectors are drugs or chemicals designed to reduce radiation damage in the human body, damaging IR such as gamma rays, X-rays, cosmic rays, and radiation from radionuclides such as uranium, strontium-90, thorium, cesium-137, radium, and radon. Therefore, radiation oncologists and biologists must research and develop pharmaceutically dynamic, efficient, nontoxic, effective, and easy-to-use radiation protectors to protect humans from this dangerous and destructive IR. An effective radiation protector must have the following characteristics: (i) In most tissues and organs, it provides comprehensive protection against the harmful effects of radiation with minimal side effects, (ii) It should have a long shelf life and be stable, and can easily be administered orally or intramuscularly, (iii) It should be accessible, economically feasible, and compatible with a wide variety of drugs during clinical treatment, (iv) Should be used in recommended doses during a wide range of available, economically viable, and clinical therapies that should be capable enough to reach the target organ and cross the blood-brain barrier, (v) In the event of an emergency, its effect should last for a long time.[9]

Therefore, it can be said that the ideal radiation protector should be nontoxic, and, conversely, able to provide a high degree of protection to normal cells with minimal protection against tumor cells. Failure to develop efficient, effective, low-cost, low-toxic, or nontoxic radioprotectors has led researchers around the world to focus on natural products with radioactive protection potential. Natural herbal products have long been used to treat a wide variety of human diseases, and according to recent databases, about 400,000 medicines from natural sources have been reported.[11]

The detailed descriptions of a few pure form of natural radioprotectors are as follows.

Apigenin

Apigenin (40, 5,7-trihydroxyflavone) is among the most abundant flavonoids and is found in large amounts in the leaves and stems of many fruits and vegetables, including black pepper, Chinese cabbage, broccoli, French peas, garlic, celery, tomato, guava, and onion. It is also found in drinks such as tea and wine produced from plant sources. Apigenin significantly reduces the frequency of IR-induced micronuclei. Furthermore, pre-IR treatment of Apigenin significantly reduces DNA damage in irradiated human peripheral blood lymphocytes, suggesting that Apigenin protects lymphocytes from IR-induced cytogenetic changes.[12]

Bergenin

Bergenin is isolated from the Caesalpinia digyn root extract. These compounds activate various signaling pathways such as ERK1/2, MAP kinase, and SAPK/JNK pathway and induce the production of tumor necrosis factor alpha, nitric oxide, and interleukin (IL-12) in infected macrophages. Bergenin is a hydrolyzable tannin derivative with anti-liver toxicity, anti-ulcer, anti-HIV, anti-arrhythmia, anti-malarial, anti-inflammatory, neuroprotective, and immunomodulatory effects.[13] Bergenin efficiently guards the cells against DNA damage, and its hydroxyl radical scavenging activity is considered important to protect against this DNA damage.[14]

Caffeine

Methylxanthine derivatives caffeine has also shown protective activity against IR damage.[15] Caffeine reduces infrared-induced skin damage associated with radiation therapy and provided radiation therapy for infrared-induced injuries.[16] It has been shown to have radioprotective properties on the mouse BM chromosome before and after systemic IR administration.[17]

Caffeine has both anti-inflammatory and antioxidant properties,[18] which may enhance its protective effect against IR-induced damage. In particular, caffeine purifies hydroxyl radicals[15] and competes with oxygen for IR electronic electrons. Furthermore, caffeine restores the normal cell cycle after IR-induced arrest in the G2 phase of the mouse embryo, and this effect depends on protein synthesis. Finally, caffeine has been shown to reduce UV-induced proteins in melanoma cells.[19]

CHLOROGENIC ACID AND QUINIC ACID

Chlorogenic acid (5-O-caffeinoquinic acid) is an ester form of caffeic acid and quinic acid and belongs to the group of hydroxycinic acid.[20] Chlorogenic acid is an essential polyphenol extracted from a plant that is abundant in coffee beans and fruits.[21] Quinic acid (1,3,4,5-tetrahydroxyclohexanecarboxylic acid) is a polyphenol that occurs naturally in cocoa beans, wine, coffee, and fruits and can be chemically synthesized from chlorogenic acid. Coffee beans are the major source of chlorogenic and quinic acid.[20] In one study, alkaline comet tests showed that quinic and chlorogenic acids protect against IR-induced DNA damage, indicating significant radiation-protective effects of these compounds.[22] Coniferyl aldehyde and confederal alcohol were isolated from the shells of Eucommia ulmoides oliver and have been shown to induce heat shock transcription factor 1 (HSF1) and protect against IR damage. Simultaneous exposure of cells normal to CA and IR or the chemotherapy drug paclitaxel suggests a protective effect of CA that depends on HSF1 Ser326 phosphorylation. Furthermore, CA in mice inhibited IR-induced BM cell depletion and IR-related increase in terminal deoxynucleotide transferase, which is a DuP NP and labeling (TUNEL) positive BM cell. Studies using the A549 orthotopic lung tumor model have shown that CA does not affect IR-induced lung tumor nodule proliferation while normal lung tissue is protected from radiation. Taken together, these studies suggest that CA can be used to induce HSF1 and protect normal cells from damage caused by IR and/or chemotherapeutic agents.[23]

DELPHINIDIN

Delphinidin; an anthocyanidin agent, has potent anti-inflammatory and antioxidant effects in other diverse biological activities.[28] It is found abundantly in pigmented vegetables such as carrots, tomatoes, and red onions, as well as fruits such as cranberries and Concord grapes. Among the anthocyanins, delphinidin has the strongest antioxidant activity due to its many hydroxyl radicals.[29] Delfinidine also protects normal tissue from high linear energy-transfer radiation, such as protons.[30] Considering all these it has been reported that delphinidin is an efficient radioprotector.

EPIGALLOCATECHIN-3-GALLATE

Epigallocatechin-3-gallate (EGCG) is a major component of polyphenols in green tea and is widely known as a potent free radical scavenger. Studies have shown that EGCG is effective in treating many disorders.[31] In particular, EGCG has been shown to have anti-aging, anti-angiogenic, anti-arthritis, anti-viral, anti-inflammatory, and neuroprotective effects. EGCG has also been reported to increase levels of several antioxidant enzymes, including glutamate-cysteine ligase, superoxide dismutase (SOD), and heme oxygenase-1 (HO1),[19] both in vivo and in vitro. In addition, EGCG can reduce the radiation sensitivity of cellular systems and improve DNA repair activity after catastrophic IR injury. The protective effect of EGCG against ultraviolet rays, which inhibit skin photoaging, has been widely reported. In addition, a mouse study reported that EGCG showed a radioprotective effect against IR-induced lesions measured along with the spleen.[32]

HESPERIDIN

Hesperidin (hesperetin-7-rhamnoglucoside) is a flavone glycoside from the flavonoid family. Hesperidin is the predominant flavonoid in lemons and sweet oranges and has radiation-protective properties due to its anti-inflammatory and antioxidant properties. In particular, it can prevent oxidative stress damage due to IR exposure to lung tissue. In addition, hysteripidin has been shown to protect lymphocytes from genetic damage that occurs in vitro by the radioactive tracer 99 mTc-MIBI.[33] Furthermore, hesperidin inhibited the IR response in mice[34] and showed antioxidant and anti-apoptotic activity in mouse testes damaged by IR.[35]

LYCOPENE

Lycopene is a widespread dietary carotenoid found in red fruits and vegetables such as pink grapes, tomatoes, apricots, pink guava, papayas, and watermelons,[36] and has exhibited significant protective effects against damage induced by radiation. The antioxidant properties of lycopene have been extensively evaluated in vitro and in vivo and are influenced by its ability to collect ROS.[37] Previous reports have also suggested that lycopene can reduce IR damage by removing intact oxygen and releasing free radicals. Lycopene sham significantly reduced micronuclei, eccentric abnormalities, and occurrence in irradiated human lymphocytes and rat hepatocytes. Lipid peroxidation by IR was reduced by lycopene pretreatment and increased the activity of antioxidant enzymes, including SOD, antacid, and glutathione peroxidase.[38]

N-ACETYL TRYPTOPHAN GLUCOPYRANOSIDE

The bacterial secondary metabolite, N-acetyl-tryptophan glycoside (NATG), was purified from the radiolabeled bacterium Bacillus subtilis. NATG pretends to have radiation protection by increasing the cytoprotective cytokines interferon-c, IL-17A, and IL-12 to prevent IR-induced apoptosis.[39] Inhibition of NATG has also been shown to protect J774A.1 macrophages from IR-induced DNA damage[40] along with increased antioxidant activity against IR-induced damage in murine macrophages.[41]

SESAMOL

Sesamol (3,4-methylenedioxyphenol), a component of sesame and sesame oil, is a natural phenolic antioxidant. Seasamol has strong ROS absorption and antioxidant properties and can protect against IR-induced DNA damage in human lymphocytes.[42] Furthermore, cisamol significantly reduces IR-induced DNA damage in the mouse hematopoietic system,[43] and reduces the genotoxicity of bone marrow cells.[44] Further, it protects the gastrointestinal and hematopoietic systems against IR-induced injury in mice.[45] The radioprotective effect of sesamol is affected by ROS purification and enhancing DNA repair activity.[46]

LUTEIN

Lutein, a carotenoid that is devoid of any provitamin A activity, contains β-and ε-ionones. It is one of several carotenoids that are found naturally in plants such as egg yolk, green leafy vegetables (spinach, cabbage), animal fat, and corn. Lutein is found in both the macula and lens of the human eye and performs a dual function in both tissues by acting as a powerful antioxidant, and filtering high-energy blue light thus protect the eye from oxidative stress. Preradiation treatment with lutein has been reported to reduce radiation risk while reducing total antioxidant capacity, hematologic parameters, antioxidant enzyme levels, and maintaining MDA and GSH.[47] In addition, the presence of β-and ε-hydroxyl motif can increase antioxidant levels and overall antioxidant capacity, protecting and enhancing membrane stabilization and thrombolytic potential,[48] antioxidant enzyme activity, thereby increasing its radiation-protective properties.[47]

CONCLUSION AND FUTURE DIRECTIONS

Protecting humans and animals from the effects of IR radiation is an important issue in radiobiology and medicine. The work outlined here suggests that there are many potential radiation protectors with different purposes and mechanisms. Radioprotective agents inhibit or destroy free radicals, activate enzymes involved in DNA breakdown repair, stimulate the hematopoietic and immune systems, or interact with proteins in signaling and apoptosis pathways, resulting in IR-Induced trauma and/or IR-related syndromes. These radiation preservatives include both synthetic compounds and natural products. However, naturally occurring compounds have significant advantages for use in radiation protection. The main advantage of using naturally found compounds is that they have increased safety compared to synthetic compounds. In addition, natural products are effective in treating symptoms similar to radiation syndrome.[47] Studies investigating these compounds as a novel approach to radiation protection have shown the efficacy of herbal compounds. Cellular and animal model research suggests that radioprotective agents can reduce DNA damage through various mechanisms; however, most of the available information in the literature suggest that Free radical scavenging role and free radical induction role of natural radio protectors.[48] Further research is warranted to determine the radioprotector has an efficient therapeutic regime. In addition, the direction for future strategies relevant to the development of radio protectors is also addressed as a pivotal step for successful identification of radio protectors by drug discovery process. This emphasizes the need for not new on the strategies for the development of novel radio protectors for drug development.[47]

Financial support and sponsorship

We'd like to thank our RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates, for their encouragement and support.

Conflicts of interest

There are no conflicts of interest.