RESVERATROL, A POTENTIAL RADIOPROTECTIVE AGENT: A MINI REVIEW

RESVERATROL, A POTENTIAL RADIOPROTECTIVE AGENT: A MINI REVIEW

Dithu Thekkekkara ¹, B Duraiswamy ¹ and Moola Joghee Nanjan ^{* 2}

Department of Pharmacognosy and Phytopharmacy ¹, TIFAC CORE HD ², J.S.S. College of Pharmacy (Off Campus, JSS University, Mysore), Ootacamund, The Nilgiris - 643 001, Tamil Nadu, India.

ABSTRACT: It is well known ionizing radiations produce deleterious effects on humans. In spite of research efforts for the past several years, today we do not have a radio protective agent that meets all the prerequisites like produces no cumulative and irreversible toxicity, offers effective long term protection, possess a shelf life of 2-5 years and can be easily administered. In recent years, attention has been turned to phytochemicals due to their antioxidant properties. This review focuses on the radio protective potential of resveratrol [trans-3, 5, 4’- trihydroxystilbene], a phytoconstituent, mainly found in Vitis vinifera. In particular, it aims to highlight the detailed studies, both in vitro and in vivo, that have been carried out on the radio protective capability of resveratrol. It also focuses on the different possible mechanisms through which resveratrol acts in response to ionizing radiations. Previous studies show both positive and negative aspects of resveratrol on radioprotection. But a thorough analysis including earlier studies and our own preliminary studies clearly support that resveratrol is an attractive and potential candidate and can be developed into radio protective agent.

Resveratrol, Phytochemical, Radioprotection, Antioxidant, DNA damage and apoptosis

INTRODUCTION: After a cell is exposed to ionizing radiations, the exact molecular events happening in the cell and the consequential changes are still not clearly understood. However, receptor tyrosine kinase signalling ¹, NF-kappa B pathway ^{2, 3}, sphingomyelinase pathway ⁴, DNA damage signalling ⁵, redox signalling and apoptosis signalling ⁶ are some of the major signalling cascades which are known to be activated in response to cellular stress including ionizing radiations. These signalling cascades are involved in major cellular events governing cell growth, proliferation and apoptosis. The activation or inhibition of these cascades in response to radiation governs its ultimate effect on the cell.

It is well known that free radicals like superoxide (O.^2-), hydrogen peroxide (H₂O₂), hydroxyl radical (HO.) peroxyl (ROO.) and alkoxyl (RO.), reactive nitrogen species (RNS) and toxic substances generated during radiation, act as secondary messengers and cause damage to genomic integrity of the cell ^{7 - 9}. Several agents have been investigated in the past for their capability to protect against ionizing radiations. Sulfhydryl compounds and antioxidants were the first to be studied with the goal of obtaining the highest dose reduction factor (DRF) achievable for protection against radiation exposure ¹⁰. During 1949, cysteine, a sulphur containing amino acid was reported for its radio protective activity ¹¹. Followed by this, N-acetyl cysteine and cysteamine, thiol protectors, were studied in detail for their radioprotection ¹². Detailed studies of radioprotection have also been carried out on antioxidant nutrients like Vitamin E, selenium, selenium and Vitamin E combinations, Vitamin A, beta carotenoids and Vitamin C ¹³.

In 1995 FDA approved Amifostine, a phosphorylated aminothiol prodrug, as a potent radioprotective agent ¹⁴. When repeatedly administrated in patients undergoing postoperative radiation treatment for head and neck cancer it reduces the incidence of moderate to severe xerostomia ¹⁵. This agent, however, has several side effects and hence is not suitable for prophylactic use during radiation emergencies ¹⁶.

In recent years, several naturally occurring and low toxicity phytochemicals have been investigated for radioprotection. These phytochemicals include flavonoids, methylxanthines and melatonin and plant phenols. They generally show a larger window of protection (Table 1). The flavonoids, orientin and vicenin, obtained from Ocimum sanctum, possess dose-modifying factor (DMF) of 1.3 and 1.37, respectively in 30 days survival assay ⁴⁷. Methyl xanthines such as caffine can protect intestinal cells from radiation injury at 40 mg/kg dose in mice ⁴⁸. Melatonin pre-treatment can reduce chromosomal aberrations and micronuclei in human lymphocytes caused by radiations ⁴⁹.

Plants containing polyphenolic compounds have been shown to exhibit anti-oxidative activities and maintain genomic stability after exposure to ionizing radiations ^{50, 51}. Public preference for complementary and alternative medicine, especially antioxidant to improve their quality of life after chemotherapy or radiotherapy is well known. Several clinical trials are being conducted today to find out the beneficial effect of combinations of dietary antioxidants after chemotherapy or radiation therapy ⁵².

TABLE 1: PHYOCONSITUENTS AND RADIO PROTECTION

In this context, resveratrol (RSV), a polyphenolic phytoalexin found in several plant species, including grape fruits has been studied in detail ⁵³. The present paper reviews the available data and concludes that RSV has a very good potential to act as a radio-protector.

Resveratrol: RSV is mainly present in the skin of grape berries and produced in response to injury as a defense mechanism such as fungal infection, UV exposure or chemical exposure. It is also present in the roots of Veratrum grandiflorum O. Loes and Polygonum cuspidatum ⁵⁴. The percentage of RSV is high in red wine as a result of the fermentation process of the skin of the red grape ⁵⁵. Chemically, RSV is 5-[(E)-2-(4-hydroxyphenyl)ethenyl] benzene-1,3-diol with the molecular formula C₁₄H₁₂O₃ and a molecular weight of 228.247 g/mol ⁵⁶. It exists both as Cis and Trans geometric isomeric forms. The Trans form is biologically more active than Cis form. It is reported to confer protection against cardiovascular dysfunction ⁵⁷, inflammatory process ⁵⁸, Alzheimer’s disease ⁵⁹, diabetics ⁶⁰ and prevents cancer development ^{61, 62}.

FIG. 1: RESVERATROL

RSV is both a free radical scavenger and a potent antioxidant. It also can improve the activity of endogenous antioxidant enzymes. Mitochondrial complex III is the site from where reactive oxygen species (ROS) are generated. RSV can decrease mitochondrial complex III activity by competition with coenzyme Q. It can thus oppose the production of ROS as well as scavenge those ⁶³. The fee radical scavenging activity of RSV has been well studied and it is an effective scavenger of hydroxyl, superoxide, and metal-induced radicals ^{64, 65}. RSV can restore the levels of some of the intracellular antioxidants such as glutathione reductase, glutathione peroxidase, glutathione S-transferase, dismutase and catalase, which are reduced under oxidative stress ^66-68.

Several studies have shown that RSV has a key role in regulating certain signalling pathways, such as inhibit NFkB signalling through suppression of p65 and IkappaB kinase ^69,70, down regulate Akt/GSK and ERK signalling ⁷¹, modulate DNA double strand break repair pathways in an ATM/ATR p53 and Nbs1 dependent manner ⁷² and antiapoptotic activity ⁷³. When damage to DNA occurs, RSV protects the genome through antioxidant activity by inhibition of inflammation, suppression of metabolic carcinogen activation, de novo expression of genes that encode detoxifying proteins. The free radical scavenging capacity of RSV also contributes to the manintance of genomic stability ⁷⁴.

Being a lipophilic, phenolic compound, RSV crosses the plasma membrane and is well absorbed when given orally. But it is rapidly metabolized, via phase II glucocuronide or sulfate conjugations, which gives it a short half-life of ∼8–14 min leading to low bioavailability ^75-77. Administrating RSV with piperine can increase the bioavailability ⁷⁸. Larger doses of RSV (2000 and 4000/3000 mg/kg in mice and 3000 mg/kg in rats) have shown renal toxicity, while a daily dose of 20 mg/kg, 100 mg/kg in rats did not ⁷⁹. Almeida et al., have clearly demonstrated the safety profile of RSV in a multiple dose study in healthy volunteers and shown that RSV is well tolerated in humans on doses up to 5g per day without toxic effects ⁸⁰.

Resveratrol and Radioprotection: A relatively nontoxic compound with the above-mentioned properties, RSV is expected, therefore, to have the potential to act as a radio-protector in normal cells exposed to the damaging effects of ionizing radiation. In this context, several studies have been carried out in the past on the radio-protective capability of RSV.

Carsten et al., have evaluated the radio protective effect of orally administered RSV (100 mg/kg per day), initiated 2 days prior to 3Gy whole body gamma irradiation continued up to 30 days ⁸¹. The study revealed that the frequencies of chromosome aberrations in irradiated mouse (CBS/CaJ) bone marrow cells reduce significantly. It also showed that a daily dose of 100 mg/kg of RSV for 30 days does not produce any chromosomal aberrations in mice. The authors have thus demonstrated for the first time that RSV has radio protective effects, in vivo. In this study the dose of RSV was fixed as 100 mg/kg because it can produce a tissue concentrations between 10-50µm. Dumazet et al., have demonstrated RSV induces of cell cycle arrest at 15-20, 30 and 100µm concentrations in normal leukemic hematopoietic cells ^{82, 83}. The possible mechanism for the radio protective activity of RSV can be explained by its potential to induce cell cycle arrest in s phase and/or at G2/M transition ⁸⁴. It can also provide a longer period for chromosomal repair after irradiation. The direct free radical scavenging activity of RSV or the indirect induction of antioxidants like glutathione and increase in enzymes like superoxide dismutase and catalase are also possible reasons ^{85, 86}.

Denissova et al., have shown that RSV protects mouse embryonic stem cells (mECS) from ionizing radiations by accelerating the recovery from DNA strand breakage and resuming the cell division faster ⁸⁷. They exposed mESC, 48 h pre-treated with RSV (10µM), to 5Gy. RSV treated survival of the stem cells after exposure to ionizing radiations was found to be >2. The influence of RSV on genomic stability was estimated by comparing the frequencies of ionizing radiations induced mutation at a chromosomal reporter locus with RSV treated group with control group. Here the frequencies were not increased, showing that RSV can improve viability in mESC after DNA damage induced by ionizing radiations without compromising the genomic integrity. The radio protective activity of RSV may be due to the more rapid DNA repair, rather than reduced DNA damage or delayed cell cycle progression ^{88, 89}. In other words, RSV can speed up DNA repair by facilitating a critical step in DNA damage sensing pathway by modulating the expression or activity of specific target enzymes like Sirt1. Sirt1 is known to modify DNA and chromatin, alter the conformation of DNA by direct physical interaction and contact by stricture responsive proteins of the DNA damaging signalling pathway. Pre-treatment with RSV 10µm for 48 hr may possibly result in pre-activation of DNA damage response at a low level, which can act positively to up-regulate DNA damage response without inducing cell cycle arrest or apoptosis.

Moreno et al., have studied the radio-protective effect of RSV on mouse connective tissue (NCTC clone 929) and observed protection at 12.5µM, 25µM for 500 and 800Gy, respectively ⁹⁰. The IC₅₀, LD₅₀ values were found to be 50µm and 354Gy, respectively. Their hypothesis is that RSV can be given as an adjuvant to cancer patients during radiotherapy to reduce the radiation hazards. The antioxidant property of RSV was given as the reason for its radio-protective activity. The contradiction that RSV acts as a radio senstitizer for tumour cells but as a radio-protector action for normal cells, however, was not explained.

Simsek et al., have shown that RSV, at a relatively high dose (100 mg/kg), can protect sub-mandibular and parotid glands from the deleterious effects of irradiation ⁹¹. Their studies on histopathological investigations of sub-mandibular gland showed a decrease in the scales of acinar loss, less ductal damage, vacuolization and cellular necrosis in RSV treated group compared to the unirradiated group. When human subjects were exposed to radiotherapy at 2, 5 to 10Gy to the head and neck region, a 50% reduction parotid gland was observed within a few days ^{91, 92}.

Supplementation of RSV was thus shown as an adjuvant therapy for protecting salivary glands. But the major problem, however, is that the efficacy of radiotherapy reduces because RSV also provides antioxidant benefits to the cancer cells along with normal cells ⁹³. RSV thus increases the antioxidant (GSH) levels and reduces lipid per oxidation of the glands exposed to total body irradiation.

Sebastia et al., have evaluated in vitro the radio-protective efficiency, genotoxicity and cytotoxicity of RSV ⁹⁴. Cells were pre-treated with RSV 1h before irradiation (2Gy) to human lymphocytes at concentrations from 0 to 219µm. After 1 h incubation, the chromosomal damage was analyzed. It was found that RSV reduces the radiation induced chromosomal damage. Results showed that RSV has 52% radio-protective effect corresponding to a concentration of 2.19Mµ with minor toxicity. High concentrations of RSV showed negative toxic effects whereas low concentrations show positive toxic effects. RSV can thus induce cytogenetic effect in human peripheral blood cells as acentric chromosomes and gaps. According to the authors the protective activity of RSV against ionizing radiation induced oxidative DNA damage is mainly due to its free radical scavenging activity and its property to maintain intracellular antioxidants. The opposite effects of cytotoxicity that occur at low and high doses can be explained by its hormetic response. The deleterious effect of RSV on the genomic stability may be due to its topo-isomerase poison action.

Zhang Heng et al., have demonstrated that RSV has the potential to protect hematopoietic stem cells from radiation in part via activation of Sirt1 ⁹⁵. In addition, RSV can be used to reduce total body irradiation induced long-term bone marrow injury. This study revealed that RSV can increase the survival of mice exposed to 7.5Gy lethal dose compared to control. Radiation induces the chronic oxidative stress through NADPH oxidase 4(NOX4) derived oxygen species leading to senescence in hemopoietic stem cells. RSV pre treatment helps in the down regulation of NOX 4 expression and up regulation of siritin 1/ Sirt 1 deacetylase activity and Ex 527, superoxide dismutase 2, and glutathione peroxide 1 expression resulting in bone marrow protection.

Yue fu et al., have demonstrated that RSV inhibits ionizing radiation induced inflammation in mesenchymal stem cells (MSC), by activating Sirt1 and limiting NLRP-3 inflamamsome activation ⁹⁶. Pre-treating MSC with RSV 1h before irradiation inhibits the secretion of ILI beta (procytokine) by down regulating the protein and mRNA levels of ILI beta. The authors’ thus demonstrated radiation induced increase in ILI beta through NLRP3 pathway. RSV was shown to inhibit the radiation induced IL-1beta expression in a concentration dependent manner, partially by inhibition of the trans-activation potential of NF-kappa B. The proposed pathway is by suppression of NFkb activity by the functional interaction between Sirt1 and p65 that involve the deacetylation of Lys310 in p65. They have thus provided a theoretical basis for radio protective effect of RSV.

Li jinanguo et al., have demonstrated that RSV inhibits apoptosis induced by radiation in neuronal tissue via the activation of Sirt 1 ⁹⁷. RSV treatment for 21 days following irradiation thus results in an increase in Sirt 1 mRNA. As a result of this the protein activity of Sirt 1also increases resulting in radioprotection.

Though several authors have reported on the radio-protective potential of RSV, Fabre et al., have, however, reported that RSV does not show any radio-protective effect ⁹⁸. We, therefore, carried some studies to check the radio-protective effect of RSV from ionizing radiations. Studies using AA8 (Chinese hamster ovary cell lines) and NIH 3T3 (Standard mouse embryo fibroblast cell line) cell lines using clonogenic survival assay were carried out by us. Initially we checked the toxicity of RSV on these cell lines to fix the nontoxic doses. The nontoxic doses were found to be 2 µM and 5 µM. Cells (300) were seeded in DMEM medium, pre-incubated for 24h with the nontoxic dose (2µM and 5 µM) of RSV and exposed to sub lethal dose of 2Gy using cobalt 60 gamma source and incubated to 1-2 weeks. Colonies obtained were fixed with glutaraldehyde (6.0%v/v), stained with crystal violet (0.5%w/v) and counted using a stereo-microscope ⁹⁹. The results obtained are shown in (Table 2). The data reveal significant radio protection obtained for RSV treated cell lines at 2µM and 5 µM for 2Gy. The survival fraction for treated cell lines is near to 1.

TABLE 2: CLONOGENIC SURVIVAL ASSAY

Notes: Values are mean ± SD. The difference in survival fraction is statistically significant (p<0.01).

CONCLUSION: Humans get exposed to ionizing radiations from several sources. To protect them from the deleterious effects of these ionizing radiations, we need radio-protective agents for prophylactic, therapeutic and mitigator purposes. The antioxidant property of phytochemicals can scavenge free radicals generated in the body and thus involve in radio-protection. RSV is a potent antioxidant and possesses a variety of biological activities that have been studied in detail. It has been shown that RSV can act as a potent radio-protector, both as a prophylactic and therapeutic agent, in radiation exposure situations. In our laboratory, we examined in two cell lines, namely AA8 and   NIH₃T₃, for studying the radio-protective activity of RSV at 2Gy. We found that in both the cell lines, pre-treatment with RSV before exposure to 2Gy gamma irradiation, gives significant radio-protection. Various studies have revealed that only RSV metabolites are present in serum upto 9 h and not RSV. Further studies are, therefore, required to ascertain the protective action of RSV. The problem of its short half-life can be improved by preparing targeted mitochondrial delivery. RSVs bioavailability can be enhanced by combination with piperine. Presently studies in these directions are in progress in our laboratory.

ACKNOWLEDGEMENT: Authors are thankful to DRDO, New Delhi for providing financial assistance.

CONFLICT OF INTEREST: Authors have no conflict of interest.

REFERENCES:

1. Contessa JN, Abell A, Valerie K, Lin PS and Schmidt-Ullrich RK: ErbB receptor tyrosine kinase network inhibition radio sensitizes carcinoma cells. International Journal of Radiation Oncolcolgy Biology Physics 2006; 65: 851-858.
2. Pordanjani SM and Hosseinimehr SJ: The Role of NF-kB Inhibitors in Cell Response to Radiation. Current Medicinal Chemistry 2016; 23: 3951-3963.
3. Hellweg CE: The Nuclear Factor κB pathway: A link to the immune system in the radiation response. Cancer Letters 2015; 368: 275-289.
4. Aureli M, Murdica V, Loberto N, Samarani M, Prinetti A, Bassi R and Sonnino S: Exploring the link between ceramide and ionizing radiation. Glycoconjugate Journal 2014; 31: 449-459.
5. Xu F, Fang Y, Yan L, Xu L, Zhang S, Cao Y, Xu L, Zhang X, Xie J, Jiang G, Ge C, An N, Zhou D, Yuan N and Wang J: Nuclear localization of Beclin 1 promotes radiation-induced DNA damage repair independent of autophagy. Scientific Reports 2017; 7: 45385.
6. Chen N, Zhang R, Konishi T and Wang J: Upregulation of NRF2 through autophagy/ERK 1/2 ameliorates ionizing radiation induced cell death of human osteosarcoma U-2 OS. Mutation Research 2017; 813: 10-17.
7. Szumiel I: Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: the pivotal role of mitochondria. International Journal of Radiation Biology 2015; 91: 1-12.
8. Yakovlev VA: Role of nitric oxide in the radiation-induced bystander effect. Redox Biology 2015; 6: 396-400.
9. Nakano T, Xu X, Salem AM, Shoulkamy MI and Ide H: Radiation-induced DNA-protein cross-links: Mechanisms and biological significance. Free Radical Biology and Medicine 2016; 5849: 31075-31079.
10. Weiss JF and Landauer MR: History and development of radiation-protective agents. International Journal of Radiation Biology 2009; 85: 539-573.
11. Patt HM, Tyree EB, Straube RL and Smith DE: Cysteine Protection against X Irradiation. Science 1949; 110: 213-214.
12. Weiss JF, Srinivasan V, Jacobs AJ and Rankin WA: Effect of sulfur compounds on radiation-induced suppression of delayed-type hypersensitivity to oxazolone in mice. Proceedings of American Association for Cancer Research 1984; 25: 235.
13. Weiss JF and Landauer MR: Protection against ionizing radiation by antioxidant nutrients and phytochemicals. Toxicology 2003; 189: 1-20.
14. Kouvarisa JR, Koulouliasb VE and Vlahosa LJ: Amifostine: The First Selective-Target and Broad-Spectrum Radio-protector. The Oncologist 2007; 12: 738-747.
15. Gu J, Zhu S, Li X, Wu H, Li Y and Hua F: Effect of amifostine in head and neck cancer patients treated with radiotherapy: a systematic review and meta-analysis based on randomized controlled trials. Plos One 2014; 9: e95968.
16. Boccia R: Improved tolerability of amifostine with rapid infusion and optimal patient preparation. Seminars in Oncology 2002; 29: 9-13
17. Fan S, Meng Q, Xu J, Jiao Y, Zhao L, Zhang X, Sarkar FH, Brown ML, Dritschilo A and Rosen EM: DIM (3,3'-diindolylmethane) confers protection against ionizing radiation by a unique mechanism. Proceedings of the national academy of sciences 2013; 110: 18650-18655.
18. Lu L, Dong J, Li D, Zhang J and Fan S: 3, 3'-diindolylmethane mitigates total body irradiation-induced hematopoietic injury in mice. Free Radical Biology and Medicine 2016; 99: 463-471.
19. Cinkilic N, Cetintas SK, Zorlu T, Vatan O, Yilmaz D, Cavas T, Tunc S, Ozkan L and Bilaloglu R: Radioprotection by two phenolic compounds: chlorogenic and quinic acid, on X-ray induced DNA damage in human blood lymphocytes in vitro. Food and Chemical Toxicology 2013; 53: 359-363.
20. Bing SJ1, Ha D, Kim MJ, Park E, Ahn G, Kim DS, Ko RK, Park JW, Lee NH and Jee Y: Geraniin down regulates gamma radiation-induced apoptosis by suppressing DNA damage. Food and Chemical Toxicology 2013; 57: 147-153.
21. Londhe JS, Devasagayam TP, Foo LY and Ghaskadbi SS: Radio protective properties of polyphenols from Phyllanthus amarus Journal of Radiation Research 2009; 50: 303-309.
22. Pillai TG and Uma Devi P: Mushroom beta glucan: potential candidate for post irradiation protection. Mutation Research 2013; 751: 109-115.
23. Gu YH, Takagi Y, Nakamura T, Hasegawa T, Suzuki I, Oshima M, Tawaraya H and Niwano Y: Enhancement of radioprotection and anti-tumor immunity by yeast-derived beta-glucan in mice. Journal of Medicinal Food 2005; 8: 154-158.
24. Ozgen SC, Dokmeci D, Akpolat M, Karadag CH, Gunduz O, Erbaş H, Benian O4, Uzal C5 and Turan FN: The Protective Effect of Curcumin on Ionizing Radiation-induced Cataractogenesis in Rats. Balkan Medical Journal 2012; 29: 358-363.
25. Fukuda K, Uehara Y, Nakata E, Inoue M, Shimazu K, Yoshida T, Kanda H, Nanjo H, Hosoi Y, Yamakoshi H, Iwabuchi Y and Shibata H: A diarylpentanoid curcumin analog exhibits improved radio protective potential in the intestinal mucosa. International Journal of Radiatiation Biology 2016; 92: 388-394.
26. Bansal P, Paul P, Kunwar A, Jayakumar S, Nayak PG, Priyadarsini KI and Unnikrishnan MK: Radioprotection by quercetin-3-O-rutinoside, a flavonoid glycoside – A cellular and mechanistic approach. Journal of Functional Foods 2012; 4: 924-932.
27. Begum N and Prasad N R: Apigenin, a dietary antioxidant, modulates gamma radiation-induced oxidative damages in human peripheral blood lymphocytes. Biomedicine and Preventive Nutrition 2012; 2: 16-24.
28. Yang HM, Ham YM, Yoon WJ, Roh SW, Jeon YJ, Oda T, Kang SM, Kang MC, Kim EA, Kim D and Kim KN: Quercitrin protects against ultraviolet B-induced cell death in vitro and in an in vivo zebra fish model. Journal of Photochemistry and Photobiology 2012; 114: 126-131.
29. Shanthakumar J, Karthikeyan A, Bandugula VR and Prasad NR: Ferulic acid, a dietary phenolic acid, modulates radiation effects in Swiss albino mice. European Journal of Pharmacology 2012; 691: 268-274.
30. Kanimozhi G, Prasad NR, Ramachandran S and Pugalendi KV: Umbelliferone modulates gamma-radiation induced reactive oxygen species generation and subsequent oxidative damage in human blood lymphocytes. European Journal of Pharmacology 2011; 672: 20-29.
31. Chandrasekharan DK, Khanna PK and Nair CK: Cellular radio-protecting potential of glyzyrrhizic acid, silver nanoparticle and their complex. Mutation Research 2011; 723: 51-57.
32. Sandeep D and Nair CK: Radioprotection by α-asarone: prevention of genotoxicity and hematopoietic injury in mammalian organism. Mutation Research 2011; 722: 62-68.
33. Rao BN, Archana PR, Aithal BK and Rao BS: Protective effect of zingerone, a dietary compound against radiation induced genetic damage and apoptosis in human lymphocytes. European Journal of Pharmacology 2011; 657: 59-66.
34. Kang KA, Zhang R, Chae S, Lee SJ, Kim J, Kim J, Jeong J, Lee J, Shin T, Lee NH and Hyun JW: Phloroglucinol (1,3,5-trihydroxybenzene) protects against ionizing radiation-induced cell damage through inhibition of oxidative stress in vitro and in vivo. Chemico Biological Interactions 2010; 185: 215-226.
35. Kalpana KB, Devipriya N, Srinivasan M and Menon VP: Investigation of the radio-protective efficacy of hesperidin against gamma-radiation induced cellular damage in cultured human peripheral blood lymphocytes. Mutation Research 2009; 676: 54-61.
36. Nair CK and Salvi VP: Protection of DNA from gamma-radiation induced strand breaks by Epicatechin. Mutation Research 2008; 650: 48-54.
37. Parihar VK, Dhawan J, Kumar S, Manjula SN, Subramanian G, Unnikrishnan MK and Rao CM: Free radical scavenging and radio-protective activity of dehydrozingerone against whole body gamma irradiation in Swiss albino mice. Chemico- Biological Interactions 2007; 170: 49-58.
38. Maurya DK, Adhikari S, Nair CK and Devasagayam TP: DNA protective properties of vanillin against gamma-radiation under different conditions: possible mechanisms. Mutation Research 2007; 634: 69-80.
39. Li CR, Zhou Z, Zhu D, Sun YN, Dai JM and Wang SQ: Protective effect of paeoniflorin on irradiation-induced cell damage involved in modulation of reactive oxygen species and the mitogen-activated protein kinases. The International Journal of Biochemistry and Cell Biology 2007; 39: 426-438.
40. Jagetia GC and Reddy TK: Modulation of radiation-induced alteration in the antioxidant status of mice by naringin. Life Sciences 2005; 77: 780-794.
41. Parihar VK, Prabhakar KR, Veerapur VP, Kumar MS, Reddy YR, Joshi R, Unnikrishnan MK and Rao CM: Effect of sesamol on radiation-induced cytotoxicity in Swiss albino mice. Mutation Research 2006; 61: 9-16.
42. Rajagopalan R, Ranjan SK and Nair CK: Effect of vinblastine sulfate on gamma-radiation-induced DNA single-strand breaks in murine tissues. Mutation Research 2003; 536: 15-25.
43. Rao S, Jayachander D, Thilakchand KR, Simon P, Rajeev AG, Arora R and Baliga MS: Chapter 103 – Radio protective effects of the Ocimum Flavonoids Orientin and Vicenin: Observations from Preclinical Studies. Polyphenols in Human Health and Disease 2014; 2: 1367-1371.
44. Hsu HY, Yang JJ, Lin SY and Lin CC: Comparisons of geniposidic acid and geniposide on antitumor and radioprotection after sub lethal irradiation. Cancer Letter 1997; 113: 31-37.
45. Hsu HY, Yang JJ and Lin CC: Effects of oleanolic acid and ursolic acid on inhibiting tumor growth and enhancing the recovery of hematopoietic system post irradiation in mice. Cancer Letter 1997; 111: 7-13.
46. Farooqi Z and Kesavan PC: Radioprotection by caffeine pre- and post-treatment in the bone marrow chromosomes of mice given whole-body gamma-irradiation. Mutation Research 1992; 269: 225-230.
47. Uma DP, Ganasoundari A, Vrinda B, Srinivasan KK and Unnikrishnan MK: Radiation protection by the ocimum flavonoids orientin and vicenin: mechanisms of action. Radiation Research 2000; 154: 455-460.
48. Swenberg CE, Landauer MR and Weiss JF: Radio modification by caffeine alone and in combination with phosphorothionates in vivo and cell free studies. Radioprotection 1996; 32:127-131.
49. Gil BF, Moneim AE, Ortiz F, Shen YQ, Mercado VS, Perez MM, Librero AG, Castroviejo DA, Navarro MMM, Verdugo JMG, Sayed RK, Florido J, Luna JD, Lopez LC and Escames G: Melatonin protects rats from radiotherapy-induced small intestine toxicity. PLoS One 2017; 12: e0174474.
50. Parshad R, Sanford KK, Price FM, Steele VE, Tarone RE, Kelloff GJ and Boone CW: Protective action of plant polyphenols on radiation-induced chromatid breaks in cultured human cells. Anticancer Research1998; 18: 3263-3266.
51. Kuntic VS, Stankovic MB, Vujic ZB, Brboric JS and Markovic SMU: Radio-protectors - the evergreen topic. Chemistry and Biodiversity 2013; 10: 1791-1803.
52. Nakayama A, Alladin KP, Igbokwe O and White JD: Systematic Review: Generating Evidence-Based Guidelines on the Concurrent Use of Dietary Antioxidants and Chemotherapy or Radiotherapy. Cancer Investigation 2011; 29: 655–667.
53. Limmongkon A, Janhom P, Amthong A, Kawpanuk M, Nopprang P, Poohadsuan J, Somboon T and Saijeen S: Antioxidant activity, total phenolic, and resveratrol content in five cultivars of peanut sprouts. Asian Pacific Journal of Tropical Biomedicine 2017; 7: 332–338.
54. Baur JA and Sinclair DA: Therapeutic potential of resveratrol: the in vivo Nature Reviews Drug Discovery 2006; 5: 493-506.
55. Saiko P, Szakmary A, Jaeger W and Szekeres T: Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad?. Mutation Research 2008; 658: 68-94.
56. GuisoM, Marra C and Farina A: A new efficient resveratrol synthesis. Tetrahedron Letters 2002; 21: 597–598.
57. Naderali EK: Obesity and cardiovascular dysfunction: A role for resveratrol? Obesity Research and Clinical Practice 2009; 3: 1-52.
58. Gan Y, Tao S, Cao D, Xie H and Zeng Q: Protection of resveratrol on acute kidney injury in septic rats. Human Experimental Toxicology 2016.
59. Karthick C, Periyasamy S, Jayachandran KS and Anusuyadevi M: Intrahippocampal Administration of Ibotenic Acid Induced Cholinergic Dysfunction via NR2A/NR2B Expression: Implications of Resveratrol against Alzheimer Disease Pathophysiology. Frontiers in Molecular Neuroscience 2016; 9: 28.
60. Bhatt JK, Thomas S and Nanjan MJ: Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutrition Research 2012; 32: 537-541.
61. Li X, Wang D, Zhao QC, Shi T and Chen J: Resveratrol Inhibited Non-small Cell Lung Cancer Through Inhibiting STAT-3 Signaling. The American Journal of Medical Sciences 2016; 352: 524-530.
62. Yu W, Fu YC and Wang W: Cellular and molecular effects of resveratrol in health and disease. Journal of Cellular Biochemistry 2012; 113: 752-759.
63. Zini R, Morin C, Bertelli A, Bertelli AAE and Tillement JP: Effects of resveratrol on the rat brain respiratory chain. Drugs under Experimental and Clinical Research 1999; 25: 87-97.
64. Leonard SS, Xia C, Jiang BH, Stinefelt B, Klandorf H, Harris GK and Shi X: Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochemical and Biophysical Research Communications 2003; 309: 1017-1026.
65. Martinez J and Moreno JJ: Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochemical Pharmacology 2000; 59: 865-870.
66. Jagdeo J, Adams L, Lev-Tov H, Sieminska J, Michl J and Brody NJ: Dose-dependent antioxidant function of resveratrol demonstrated via modulation of reactive oxygen species in normal human skin fibroblasts in vitro. Journal of Drugs in Dermatology 2010; 9: 1523-1526.
67. Pintea A, Rugină D, Pop R, Bunea A, Socaciu C and Diehl HA: Antioxidant effect of trans-resveratrol in cultured human retinal pigment epithelial cells. Journal of Ocular Pharmacology and Therapeutics 2011; 27: 315-321.
68. Sheu SJ, Liu NC and Chen JL: Resveratrol protects human retinal pigment epithelial cells from acrolein-induced damage. Journal of Ocular Pharmacology and Therapeutics 2010; 26: 231-236.
69. Ren Z, Wang L, Cui J, Huoc Z, Xue J, Cui H, Mao Q and Yang R: Resveratrol inhibits NF-kB signaling through suppression of p65 and IkappaB kinase activities Die Pharmazie 2013; 68: 689-694.
70. Kumar A and Sharma SS: NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuro-protection in experimental diabetic neuropathy. Biochemical and Biophysical Research Communications 2010; 394: 360-365.
71. Vergara D, Simeone P, Toraldo D, Del Boccio P, Vergaro V, Leporatti S, Pieragostino D, Tinelli A, De Domenico S, Alberti S, Urbani A, Salzet M, Santino A, and Maffia M: Resveratrol down regulates Akt/GSK and ERK signaling pathways in OVCAR-3 ovarian cancer cells. Molecular Biosystems 2012; 8: 1078-1087.
72. Gatz SA, Keimling M, Baumann C, Dork T, Debatin KM, Fulda S and Wiesmuller L: Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR-p53- and -Nbs1-dependent manner. Carcinogenesis 2008; 29: 519-527.
73. Zhang L, Guo X, Xie W, Li Y, Ma M, Yuan T and Luo B: Resveratrol exerts an anti-apoptotic effect on human bronchial epithelial cells undergoing cigarette smoke exposure. Molecular Medicine Reports. 2015; 1: 1752-1758.
74. Gatz SA and Wiesmüller L: Take a break-resveratrol in action on DNA. Carcinogenesis 2008; 29: 321-332.
75. Marier JF, Vachon P, Gritsas A, Zhang J, Moreau JP and Ducharme MP: Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. Journal of Pharmacology and Experimental Therapeutics 2002; 302: 369–373.
76. Asensi M, Medina I, Ortega A, Carretero J, Baño MC, Obrador E and Estrela JM: Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radical Biology and Medicine 2002; 33: 387-398.
77. Walle T, Hsieh F, DeLegge MH, Oatis JE Jr and Walle UK: High absorption but very low bioavailability of oral resveratrol in humans. Drug Metabolism and Disposition 2004; 32: 1377–1382.
78. Johnson JJ, Nihal M, ASiddiqui IA,  Scarlett CO, Bailey HH, Mukhtar H and Ahmad N: Enhancing the bioavailability of resveratrol by combining it with piperine. Molecular Nutrition and Food Research 2011; 55: 1169-1176.
79. Rowell JA, Korytko PJ, Morrissey RL, Booth TD and Levine BS: Resveratrol-associated renal toxicity. Toxicological Sciences 2004; 82: 614–619.
80. Almeida L, Vaz-da-Silva M, Falcao A, Soares E, Costa R, Loureiro AI, Fernandes-Lopes C, Rocha J-F, Nunes T, Wright L and Soares-da-Silva P: Pharmacokinetic and safety profile of transresveratrol in a rising multiple-dose study in healthy volunteers. Molecular Nutrition and Food Research 2009; 53:7-15.
81. Carsten RE, Bachand AM, Bailey SM and Ullrich RL: Resveratrol reduces radiation-induced chromosome aberration frequencies in mouse bone marrow cells. Radiation Research 2008; 169: 633-638.
82. Dumazet HF, Garnier O, Matsuda MM, Vercauteren J, Belloc F, Billiard C, Dupouy M, Thiolat D, Kolb JP, Marit G, Reiffers J and Mossalayi MD: Resveratrol inhibits the growth and induces the apoptosis of both normal and leukemic hematopoietic cells. Carcinogenesis 2002; 23: 1327-1333.
83. Duraj J, Bodo J, Sulikova M, Rauko P and Sedlak J: Diverse resveratrol sensitization to apoptosis induced by anticancer drugs in sensitive and resistant leukemia cells. Neoplasma 2006; 53: 384-392.
84. Li Y, Cao Z and Zhu H: Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress. Pharmacology Research 2006; 53: 6-15.
85. Losa GA: Resveratrol modulates apoptosis and oxidation in human blood mononuclear cells. European Journal of Clinical Investigation 2003; 33: 818-823.
86. Vitrac X, Desmouliere A, Brouillaud B, Krisa S, Deffieux G, Barthe N, Rosenbaum J and Merillon JM: Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sciences 2003; 72: 2219-2233.
87. Denissova NG, Nasello CM, Yeung PL, Tischfield JA and Brenneman MA: Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage. Carcinogenesis 2012; 33: 149-155.
88. Sgambato A, Ardito R, Faraglia B, Boninsegna A, Wolf FI and Cittadini A: Resveratrol, a natural phenolic compound, inhibits cell proliferation and prevents oxidative DNA damage. Mutation Research 2001; 496:171-180.
89. Gatz SA and Wiesmüller L: Take a break-resveratrol in action on DNA. Carcinogenesis 2008; 29: 321-332.
90. Moreno CS, Rogero SO, Ikeda TI, Cruz AS and Rogero JR: Resveratrol and radiation biological effects. International Journal of Nutrology 2012; 5: 28-33.
91. Simsek G, Gurocak S, Karadag N, Karabulut AB, Demirtas E, Karataş E and Pepele E: Protective effects of resveratrol on salivary gland damage induced by total body irradiation in rats. Laryngoscope 2012; 122: 2743-2748.
92. Liem IH, Olmos RA, Balm AJ, Keus RB, van Tinteren H, Takes RP, Muller SH, Bruce AM, Hoefnagel CA and Hilgers FJ: Evidence for early and persistent impairment of salivary gland excretion after irradiation of head and neck tumors. European Journal of Nuclear Medicine and molecular imaging1996; 23: 1485-1490.
93. Nagler RM: The enigmatic mechanism of irradiation-induced damage to the major salivary glands. Oral Disease 2002; 8: 141-146.
94. Sebastia N, Almonacid M, Villaescusa JI, Cervera J, Such E, Silla MA, Soriano JM, and Montoro A: Radio-protective activity and cytogenetic effect of resveratrol in human lymphocytes: an in vitro Food and Chemical Toxicology 2013; 51: 391-395.
95. Zhang H, Zhai Z, Wang Y, Zhang J, Wu H, Wang Y, Li C, Li D, Lu L, Wang X, Chang J, Hou Q, Ju Z, Zhou D and Meng A: Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice. Free Radicial Biology and Medicine 2013; 54: 40-50.
96. FuY ,  Wang Y ,  Du L,  Xu C,  Cao J, Fan T, Liu J, Su X, Fan S, Liu Qand Fan F: Resveratrol Inhibits Ionizing Irradiation-Induced Inflammation in MSCs by Activating SIRT1 and Limiting NLRP-3 Inflammasome Activation. International Journal of Molecular Science 2014; 15: 5928-5939.
97. Li J, Feng L, Xing Y, Wang Y, Du L, Xu C, Cao J, Wang Q, Fan S, Liu Q and Fan F: Radio-protective and antioxidant effect of resveratrol in hippocampus by activating Sirt1.International journal of molecular science 2013; 14: 14105-14118.
98. Fabre KM, Saito K, De Graff W, Sowers AL, Thetford A, Cook JA, Krishna MC, and Mitchell JB: The effects of resveratrol and selected metabolites on the radiation and antioxidant response. Cancer Biology and Therapy 2011; 12: 915-923.
99. Franken NA, Rodermond HM, Stap J, Haveman J and Bree CV: Clonogenic assay of cells in vitro. Nature Protocols 2006; 1: 2315-2319.

How to cite this article:

Thekkekkara D, Duraiswamy B and Nanjan MJ: Resveratrol, a potential radio-protective agent: a mini review. Int J Pharm Sci Res 2017; 8(9): 3640-48.doi: 10.13040/IJPSR.0975-8232.8(9).3640-48.

All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.