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Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Review Article

Mechanisms for Radioprotection by Melatonin; Can it be Used as a Radiation Countermeasure?

Author(s): Peyman Amini, Hanifeh Mirtavoos-Mahyari, Elahe Motevaseli, Dheyauldeen Shabeeb, Ahmed Eleojo Musa, Mohsen Cheki, Bagher Farhood, Rasoul Yahyapour, Alireza Shirazi, Nouraddin Abdi Goushbolagh and Masoud Najafi*

Volume 12, Issue 1, 2019

Page: [2 - 11] Pages: 10

DOI: 10.2174/1874467211666180802164449

Price: $65


Background: Melatonin is a natural body product that has shown potent antioxidant property against various toxic agents. For more than two decades, the abilities of melatonin as a potent radioprotector against toxic effects of ionizing radiation (IR) have been proved. However, in the recent years, several studies have been conducted to illustrate how melatonin protects normal cells against IR. Studies proposed that melatonin is able to directly neutralize free radicals produced by IR, leading to the production of some low toxic products.

Discussion: Moreover, melatonin affects several signaling pathways, such as inflammatory responses, antioxidant defense, DNA repair response enzymes, pro-oxidant enzymes etc. Animal studies have confirmed that melatonin is able to alleviate radiation-induced cell death via inhibiting pro-apoptosis and upregulation of anti-apoptosis genes. These properties are very interesting for clinical radiotherapy applications, as well as mitigation of radiation injury in a possible radiation disaster. An interesting property of melatonin is mitochondrial ROS targeting that has been proposed as a strategy for mitigating effects in radiosensitive organs, such as bone marrow, gastrointestinal system and lungs. However, there is a need to prove the mitigatory effects of melatonin in experimental studies.

Conclusion: In this review, we aim to clarify the molecular mechanisms of radioprotective effects of melatonin, as well as possible applications as a radiation countermeasure in accidental exposure or nuclear/radiological disasters.

Keywords: Melatonin, radiation, radiotherapy, radiation mitigation, inflammatory responses, redox system, oxidative stress, DNA repair, mitochondria.

Graphical Abstract
Reboul, F.L. Radiotherapy and chemotherapy in locally advanced non-small cell lung cancer: Preclinical and early clinical data. Hematol. Oncol. Clin. North Am., 2004, 18(1), 41-53.
Denis-Bacelar, A.M.; Chittenden, S.J.; McCready, V.R.; Divoli, A.; Dearnaley, D.P.; O’Sullivan, J.M.; Johnson, B.; Flux, G.D. Bone lesion absorbed dose profiles in patients with metastatic prostate cancer treated with molecular radiotherapy. Br. J. Radiol., 2018, 20170795.
Oyen, W.J.; de Bono, J.S. Targeted α-Based Treatment of Metastatic Castration-Resistant Prostate Cancer: Revolutionizing Systemic Radiotherapy? J. Nucl. Med., 2016, 57(12), 1838-1839.
Oyen, W. Radiopharmaceuticals in the elderly cancer patient: Practical considerations, with a focus on prostate cancer therapy. Eur. J. Cancer, 2017, 77, 127-139.
Rose, T.; Garcia, E.; Bachand, F.; Kim, D.; Petrik, D.; Halperin, R.; Crook, J. QOL comparison of acute side effects from a high dose rate vs. low dose rate prostate brachytherapy boost combined with external beam radiotherapy. Brachytherapy, 2015, 14, S36.
Savard, J.; Ivers, H.; Savard, M.H.; Morin, C.M. Cancer treatments and their side effects are associated with aggravation of insomnia: results of a longitudinal study. Cancer, 2015, 121(10), 1703-1711.
De Francesco, I.; Thomas, K.; Tait, D. Pelvic intensity-modulated radiotherapy: Can we better quantify the late side-effects? Clin. Oncol. , 2015, 27(7), 428.
Harrabi, S.B.; Adeberg, S.; Welzel, T.; Rieken, S.; Habermehl, D.; Debus, J.; Combs, S.E. Long term results after fractionated stereotactic radiotherapy (FSRT) in patients with craniopharyngioma: Maximal tumor control with minimal side effects. Radiat. Oncol., 2014, 9(1), 203.
West, C.; Azria, D.; Chang-Claude, J.; Davidson, S.; Lambin, P.; Rosenstein, B.; De Ruysscher, D.; Talbot, C.; Thierens, H.; Valdagni, R. The REQUITE project: Validating predictive models and biomarkers of radiotherapy toxicity to reduce side-effects and improve quality of life in cancer survivors. Clin. Oncol. , 2014, 26(12), 739-742.
Chung, S.I. Smart, D.K.; Chung, E.J.; Citrin, D.E. In: Increasing the Therapeutic Ratio of Radiotherapy; Springer, 2017; pp. 79-102.
Johnke, R.M.; Sattler, J.A.; Allison, R.R. Radioprotective agents for radiation therapy: Future trends. Fut Oncol., 2014, 10(15), 2345-2357.
Prasanna, P.G.; Narayanan, D.; Hallett, K.; Bernhard, E.J.; Ahmed, M.M.; Evans, G.; Vikram, B.; Weingarten, M.; Coleman, C.N. Radioprotectors and radiomitigators for improving radiation therapy: The Small Business Innovation Research (SBIR) gateway for accelerating clinical translation. Radiat. Res., 2015, 184(3), 235-248.
Rosen, E.M.; Day, R.; Singh, V.K. New approaches to radiation protection. Front. Oncol., 2015, 4, 381.
Alok, A.; Chaudhury, N. Tetracycline hydrochloride: A potential clinical drug for radioprotection. Chemico-Biological Interactions., 2016, 245, 90-99.
Nimesh, H.; Tiwari, V.; Yang, C.; Gundala, S.R.; Chuttani, K.; Hazari, P.P.; Mishra, A.K.; Sharma, A.; Lal, J.; Katyal, A. Preclinical evaluation of DMA, a bisbenzimidazole, as radioprotector: Toxicity, pharmacokinetics, and biodistribution studies in Balb/c mice. Mol. Pharmacol., 2015, 88(4), 768-778.
Smith, B.R.; Eastman, C.M.; Njardarson, J.T.; Beyond, C. H, O, and N! Analysis of the Elemental Composition of US FDA Approved Drug Architectures: Miniperspective. J. Med. Chem., 2014, 57(23), 9764-9773.
Gu, J.; Zhu, S.; Li, X.; Wu, H.; Li, Y.; 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(5), e95968.
Singh, V.K.; Fatanmi, O.O.; Wise, S.Y.; Newman, V.L.; Romaine, P.L.; Seed, T.M. The potentiation of the radioprotective efficacy of two medical countermeasures, gamma-tocotrienol and amifostine, by a combination prophylactic modality. Radiat. Protect. Dos, 2016, 172(1-3), 302-310.
Koukourakis, M.I.; Giatromanolaki, A.; Zois, C.E.; Kalamida, D.; Pouliliou, S.; Karagounis, I.V.; Yeh, T-L.; Abboud, M.I.; Claridge, T.D.; Schofield, C.J. Normal tissue radioprotection by amifostine via Warburg-type effects. Sci. Rep., 2016, 6, 30986.
Kamran, M.Z.; Ranjan, A.; Kaur, N.; Sur, S.; Tandon, V. Radioprotective agents: Strategies and translational advances. Med. Res. Rev., 2016, 36(3), 461-493.
Tan, D-X.; Manchester, L.C.; Esteban-Zubero, E.; Zhou, Z.; Reiter, R.J. Melatonin as a potent and inducible endogenous antioxidant: Synthesis and metabolism. Molecules, 2015, 20(10), 18886-18906.
Vriend, J.; Reiter, R.J. Melatonin feedback on clock genes: A theory involving the proteasome. J. Pineal Res., 2015, 58(1), 1-11.
Tordjman, S.; Chokron, S.; Delorme, R.; Charrier, A.; Bellissant, E.; Jaafari, N.; Fougerou, C. Melatonin: Pharmacology, functions and therapeutic benefits. Curr. Neuropharmacol., 2017, 15(3), 434-443.
Vinther, A.; Claesson, M. The influence of melatonin on the immune system and cancer. Article in Danish]. Ugeskr. Laeger, 2015, 177, V10140568.
Lacoste, B.; Angeloni, D.; Dominguez‐Lopez, S.; Calderoni, S.; Mauro, A.; Fraschini, F.; Descarries, L.; Gobbi, G. Anatomical and cellular localization of melatonin MT1 and MT2 receptors in the adult rat brain. J. Pineal Res., 2015, 58(4), 397-417.
Ren, W.; Liu, G.; Chen, S.; Yin, J.; Wang, J.; Tan, B.; Wu, G.; Bazer, F.W.; Peng, Y.; Li, T. Melatonin signaling in T cells: Functions and applications. J. Pineal Res., 2017, 62(3)
Hardeland, R. Melatonin-More than just a pineal hormone. Biomed. J. Sci. Tech. Res, 2017, 1, 1-4.
Liu, R.; Fu, A.; Hoffman, A.E.; Zheng, T.; Zhu, Y. Melatonin enhances DNA repair capacity possibly by affecting genes involved in DNA damage responsive pathways. BMC Cell Biol., 2013, 14, 1.
Sliwinski, T.; Rozej, W.; Morawiec-Bajda, A.; Morawiec, Z.; Reiter, R.; Blasiak, J. Protective action of melatonin against oxidative DNA damage: chemical inactivation versus base-excision repair. Mutat. Res., 2007, 634(1-2), 220-227.
Majidinia, M.; Sadeghpour, A.; Mehrzadi, S.; Reiter, R.J.; Khatami, N.; Yousefi, B. Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways. J. Pineal Res., 2017, 63(1)
Ferreira, S.G.; Peliciari-Garcia, R.A.; Takahashi-Hyodo, S.A.; Rodrigues, A.C.; Amaral, F.G.; Berra, C.M.; Bordin, S.; Curi, R.; Cipolla-Neto, J. Effects of melatonin on DNA damage induced by cyclophosphamide in rats. Braz. J. Med. Biol. Res., 2013, 46(3), 278-286.
Santoro, R.; Marani, M.; Blandino, G.; Muti, P.; Strano, S. Melatonin triggers p53Ser phosphorylation and prevents DNA damage accumulation. Oncogene, 2011, 31, 2931-2942.
Chuffa, L.G.; Fioruci-Fontanelli, B.A.; Mendes, L.O.; Ferreira Seiva, F.R.; Martinez, M.; Favaro, W.J.; Domeniconi, R.F.; Pinheiro, P.F.; Delazari Dos Santos, L.; Martinez, F.E. Melatonin attenuates the TLR4-mediated inflammatory response through MyD88- and TRIF-dependent signaling pathways in an in vivo model of ovarian cancer. BMC Cancer, 2015, 15, 34.
Nduhirabandi, F.; Lamont, K.; Albertyn, Z.; Opie, L.H.; Lecour, S. Role of toll-like receptor 4 in melatonin-induced cardioprotection. J. Pineal Res., 2016, 60(1), 39-47.
Hu, Y.; Wang, Z.; Pan, S.; Zhang, H.; Fang, M.; Jiang, H.; Zhang, H.; Gao, Z.; Xu, K.; Li, Z.; Xiao, J.; Lin, Z. Melatonin protects against blood-brain barrier damage by inhibiting the TLR4/ NF-kappaB signaling pathway after LPS treatment in neonatal rats. Oncotarget, 2017, 8(19), 31638-31654.
Esposito, E.; Cuzzocrea, S. Antiinflammatory Activity of Melatonin in Central Nervous System. Curr. Neuropharmacol., 2010, 8(3), 228-242.
Favero, G.; Franceschetti, L.; Bonomini, F.; Rodella, L.F.; Rezzani, R. Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation. Int. J. Endocrinol., 2017, 2017, 1835195.
Reiter, R.J.; Calvo, J.R.; Karbownik, M.; Qi, W.; Tan, D.X. Melatonin and its relation to the immune system and inflammation. Ann. N. Y. Acad. Sci., 2000, 917, 376-386.
Reiter, R.J.; Tan, D.X.; Manchester, L.C.; Qi, W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem. Biophys., 2001, 34(2), 237-256.
Reiter, R.J.; Acuna-Castroviejo, D.; Tan, D.X.; Burkhardt, S. Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann. N. Y. Acad. Sci., 2001, 939, 200-215.
Reiter, R.J.; Tan, D.X.; Gitto, E.; Sainz, R.M.; Mayo, J.C.; Leon, J.; Manchester, L.C. Vijayalaxmi; Kilic, E.; Kilic, U. Pharmacological utility of melatonin in reducing oxidative cellular and molecular damage. Pol. J. Pharmacol., 2004, 56(2), 159-170.
Yahyapour, R.; Amini, P.; Rezapour, S.; Cheki, M.; Rezaeyan, A.; Farhood, B.; Shabeeb, D.; Musa, A.E.; Fallah, H.; Najafi, M. Radiation-induced inflammation and autoimmune diseases. Mil. Med. Res., 2018, 5(1), 9.
Vijayalaxmi; Reiter, R.J.; Tan, D.X.; Herman, T.S.; Thomas, C.R. Jr. Melatonin as a radioprotective agent: a review. Int. J. Radiat. Oncol. Biol. Phys., 2004, 59(3), 639-653.
Zetner, D.; Andersen, L.P.; Rosenberg, J. Melatonin as Protection Against Radiation Injury: A Systematic Review. Drug Res. (Stuttg.), 2016, 66(6), 281-296.
Das, B.; Bennett, P.V.; Cutter, N.C.; Sutherland, J.C.; Sutherland, B.M. Melatonin protects human cells from clustered DNA damages, killing and acquisition of soft agar growth induced by X-rays or 970 MeV/n Fe ions. Int. J. Radiat. Biol., 2011, 87(6), 545-555.
Vijayalaxmi; Reiter, R.J.; Meltz, M.L. Melatonin protects human blood lymphocytes from radiation-induced chromosome damage. Mutat. Res., 1995, 346(1), 23-31.
Vijayalaxmi; Reiter, R.J.; Herman, T.S.; Meltz, M.L. Melatonin and radioprotection from genetic damage: In vivo/in vitro studies with human volunteers. Mutat. Res., 1996, 371(3-4), 221-228.
Vijayalaxmi; Reiter, R.J.; Herman, T.S.; Meltz, M.L. Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes. Mutat. Res., 1998, 397(2), 203-208.
Manda, K.; Ueno, M.; Anzai, K. AFMK, a melatonin metabolite, attenuates X-ray-induced oxidative damage to DNA, proteins and lipids in mice. J. Pineal Res., 2007, 42(4), 386-393.
Sener, G.; Jahovic, N.; Tosun, O.; Atasoy, B.M.; Yegen, B.C. Melatonin ameliorates ionizing radiation-induced oxidative organ damage in rats. Life Sci., 2003, 74(5), 563-572.
Koc, M.; Buyukokuroglu, M.E.; Taysi, S. The effect of melatonin on peripheral blood cells during total body irradiation in rats. Biol. Pharm. Bull., 2002, 25(5), 656-657.
Vijayalaxmi; Meltz, M.L.; Reiter, R.J.; Herman, T.S. Melatonin and protection from genetic damage in blood and bone marrow: Whole-body irradiation studies in mice. J. Pineal Res., 1999, 27(4), 221-225.
Assayed, M.E.; Abd El-Aty, A.M. Protection of rat chromosomes by melatonin against gamma radiation-induced damage. Mutat. Res., 2009, 677(1-2), 14-20.
Badr, F.M.; El Habit, O.H.; Harraz, M.M. Radioprotective effect of melatonin assessed by measuring chromosomal damage in mitotic and meiotic cells. Mutat. Res., 1999, 444(2), 367-372.
Manda, K.; Ueno, M.; Anzai, K. Space radiation‐induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: Ameliorative potential of the melatonin metabolite, AFMK. J. Pineal Res., 2008, 45(4), 430-438.
Alonso-Gonzalez, C.; Gonzalez, A.; Martinez-Campa, C.; Gomez-Arozamena, J.; Cos, S. Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair. J. Pineal Res., 2015, 58(2), 189-197.
Alonso-Gonzalez, C.; Gonzalez, A.; Martinez-Campa, C.; Menendez-Menendez, J.; Gomez-Arozamena, J.; Garcia-Vidal, A.; Cos, S. Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis. Cancer Lett., 2016, 370(1), 145-152.
Griffin, F.; Marignol, L. Therapeutic potential of melatonin for breast cancer radiation therapy patients. Int. J. Radiat. Biol., 2018, 94(5), 472-477.
Manchester, L.C.; Coto‐Montes, A.; Boga, J.A.; Andersen, L.P.H.; Zhou, Z.; Galano, A.; Vriend, J.; Tan, D.X.; Reiter, R.J. Melatonin: An ancient molecule that makes oxygen metabolically tolerable. J. Pineal Res., 2015, 59(4), 403-419.
Zhang, H.M.; Zhang, Y. Melatonin: A well‐documented antioxidant with conditional pro‐oxidant actions. J. Pineal Res., 2014, 57(2), 131-146.
Ogawa, Y.; Sekine-Suzuki, E.; Nakanishi, I.; Matsumoto, K-i. LET dependent hydroxyl radical generation in water by heavy-ion beam irradiation. Free Radic. Biol. Med., 2017, 112, 63.
Lafargue, A.; Degorre, C.; Corre, I.; Alves-Guerra, M-C.; Gaugler, M-H.; Vallette, F.; Pecqueur, C.; Paris, F. Ionizing radiation induces long-term senescence in endothelial cells through mitochondrial respiratory complex II dysfunction and superoxide generation. Free Radic. Biol. Med., 2017, 108, 750-759.
Marklund, S.L.; Westman, N.G.; Lundgren, E.; Roos, G. Copper-and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues. Cancer Res., 1982, 42(5), 1955-1961.
Simon, H-U.; Haj-Yehia, A.; Levi-Schaffer, F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis, 2000, 5(5), 415-418.
Leach, J.K.; Van Tuyle, G.; Lin, P-S.; Schmidt-Ullrich, R.; Mikkelsen, R.B. Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res., 2001, 61(10), 3894-3901.
Spitz, D.R.; Azzam, E.I.; Li, J.J.; Gius, D. Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastasis Rev., 2004, 23(3-4), 311-322.
Jaiswal, M.; LaRusso, N.F.; Nishioka, N.; Nakabeppu, Y.; Gores, G.J. Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res., 2001, 61(17), 6388-6393.
Chien, Y-H.; Bau, D-T.; Jan, K-Y. Nitric oxide inhibits DNA-adduct excision in nucleotide excision repair. Free Radic. Biol. Med., 2004, 36(8), 1011-1017.
Reiter, R.J.; Mayo, J.C.; Tan, D.X.; Sainz, R.M.; Alatorre‐Jimenez, M.; Qin, L. Melatonin as an antioxidant: under promises but over delivers. J. Pineal Res., 2016, 61(3), 253-278.
Karbownik, M.; Reiter, R.J. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc. Soc. Exp. Biol. Med., 2000, 225(1), 9-22.
Marta, B.; Szafrańska, K.; Posmyk, M.M. Exogenous melatonin improves antioxidant defense in cucumber seeds (Cucumis sativus L.) germinated under chilling stress. Front. Plant Sci., 2016, 7, 575.
Gurer-Orhan, H.; Suzen, S. Melatonin, its metabolites and its synthetic analogs as multi-faceted compounds: Antioxidant, prooxidant and inhibitor of bioactivation reactions. Curr. Med. Chem., 2015, 22(4), 490-499.
Koc, M.; Taysi, S.; Emin Buyukokuroglu, M.; Bakan, N. The Effect of Melatonin against Oxidative Damage during Total-Body Irradiation in Rats. Radiat. Res., 2003, 160(2), 251-255.
Erol, F.S.; Topsakal, C.; Ozveren, M.F.; Kaplan, M.; Ilhan, N.; Ozercan, I.H.; Yildiz, O.G. Protective effects of melatonin and vitamin E in brain damage due to gamma radiation. Neurosurg. Rev., 2004, 27(1), 65-69.
Bhatia, A.L.; Manda, K. Study on pre-treatment of melatonin against radiation-induced oxidative stress in mice. Envi. Toxicol. Pharmacol., 2004, 18(1), 13-20.
Karslioglu, I.; Ertekin, M.V.; Taysi, S.; Kocer, I.; Sezen, O.; Gepdiremen, A.; Koc, M.; Bakan, N. Radioprotective effects of melatonin on radiation-induced cataract. J. Radiat. Res., 2005, 46(2), 277-282.
Kailash, M.; Megumi, U.; Kazunori, A. Space radiation‐induced inhibition of neurogenesis in the hippocampal dentate gyrus and memory impairment in mice: ameliorative potential of the melatonin metabolite, AFMK. J. Pineal Res., 2008, 45(4), 430-438.
Ündeğer, Ü.; Giray, B.; Zorlu, A.F.; Öge, K.; Baçaran, N. Protective effects of melatonin on the ionizing radiation induced DNA damage in the rat brain. Exp. Toxicol. Pathol., 2004, 55(5), 379-384.
Şener, G.; Atasoy, B.M.; Ersoy, Y.; Arbak, S.; Şengöz, M.; Yeğen, B.Ç. Melatonin protects against ionizing radiation‐induced oxidative damage in corpus cavernosum and urinary bladder in rats. J. Pineal Res., 2004, 37(4), 241-246.
Yildirim, O.; Comoğlu, S.; Yardimci, S.; Akmansu, M.; Bozkurt, G.; Sürücü, S. Preserving effects of melatonin on the levels of glutathione and malondialdehyde in rats exposed to irradiation. Gen. Physiol. Biophys., 2008, 27(1), 32-37.
Sharma, S.; Haldar, C. Melatonin prevents X-ray irradiation induced oxidative damagein peripheral blood and spleen of the seasonally breeding rodent, Funambulus pennanti during reproductively active phase. Int. J. Radiat. Biol., 2006, 82(6), 411-419.
Sharma, S.; Haldar, C.; Chaube, S.K. Effect of exogenous melatonin on X-ray induced cellular toxicity in lymphatic tissue of Indian tropical male squirrel, Funambulus pennanti. Int. J. Radiat. Biol., 2008, 84(5), 363-374.
Najafi, M.; Shirazi, A.; Motevaseli, E.; Geraily, G.; Norouzi, F.; Heidari, M.; Rezapoor, S. The melatonin immunomodulatory actions in radiotherapy. Biophys. Rev., 2017, 9(2), 139-148.
Miller, E.; Morel, A.; Saso, L.; Saluk, J. Melatonin redox activity. Its potential clinical applications in neurodegenerative disorders. Curr. Top. Med. Chem., 2015, 15(2), 163-169.
Guo, Y.; Sun, J.; Li, T.; Zhang, Q.; Bu, S.; Wang, Q.; Lai, D. Melatonin ameliorates restraint stress-induced oxidative stress and apoptosis in testicular cells via NF-κB/iNOS and Nrf2/ HO-1 signaling pathway. Sci. Rep., 2017, 7, 9599.
Jung, K.H.; Hong, S.W.; Zheng, H.M.; Lee, H.S.; Lee, H.; Lee, D.H.; Lee, S.Y.; Hong, S.S. Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaB in rats. J. Pineal Res., 2010, 48(3), 239-250.
Janjetovic, Z.; Jarrett, S.G.; Lee, E.F.; Duprey, C.; Reiter, R.J.; Slominski, A.T. Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways. Sci. Rep., 2017, 7(1), 1274.
Tripathi, D.N.; Jena, G.B. Effect of melatonin on the expression of Nrf2 and NF-kappaB during cyclophosphamide-induced urinary bladder injury in rat. J. Pineal Res., 2010, 48(4), 324-331.
Negi, G.; Kumar, A.; Sharma, S.S. Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: Effects on NF-kappaB and Nrf2 cascades. J. Pineal Res., 2011, 50(2), 124-131.
Yahyapour, R.; Motevaseli, E.; Rezaeyan, A.; Abdollahi, H.; Farhood, B.; Cheki, M.; Rezapoor, S.; Shabeeb, D.; Musa, A.E.; Najafi, M.; Villa, V. Reduction-oxidation (redox) system in radiation-induced normal tissue injury: Molecular mechanisms and implications in radiation therapeutics. Clin. Transl. Oncol., 2018, 20(8), 975-988.
Szumiel, I. Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: The pivotal role of mitochondria. Int. J. Radiat. Biol., 2015, 91(1), 1-12.
Cheki, M.; Yahyapour, R.; Farhood, B.; Rezaeyan, A.; Shabeeb, D.; Amini, P.; Rezapoor, S.; Najafi, M. COX-2 in Radiotherapy; A potential target for radioprotection and radiosensitization. Curr. Mol. Pharmacol., 2018, 11(3), 173-183.
Yahyapour, R.; Amini, P.; Rezapoor, S.; Rezaeyan, A.; Farhood, B.; Cheki, M.; Fallah, H.; Najafi, M. Targeting of inflammation for radiation protection and mitigation. Curr. Mol. Pharmacol., 2018, 11(3), 203-210.
Najafi, M.; Motevaseli, E.; Shirazi, A.; Geraily, G.; Rezaeyan, A.; Norouzi, F.; Rezapoor, S.; Abdollahi, H. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: Clinical implications. Int. J. Radiat. Biol., 2018, 94(4), 335-356.
Wang, Y.; Liu, L.; Pazhanisamy, S.K.; Li, H.; Meng, A.; Zhou, D. Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells. Free Radic. Biol. Med., 2010, 48(2), 348-356.
Pazhanisamy, S.K.; Li, H.; Wang, Y.; Batinic-Haberle, I.; Zhou, D. NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability. Mutagenesis, 2011, 26(3), 431-435.
Mao, X.W.; Nishiyama, N.C.; Campbell-Beachler, M.; Gifford, P.; Haynes, K.E.; Gridley, D.S.; Pecaut, M.J. Role of NADPH oxidase as a mediator of oxidative damage in low-dose irradiated and hindlimb-unloaded mice. Radiat. Res., 2017, 188(4), 392-399.
Sakai, Y.; Yamamori, T.; Yoshikawa, Y.; Bo, T.; Suzuki, M.; Yamamoto, K.; Ago, T.; Inanami, O. NADPH oxidase 4 mediates ROS production in radiation-induced senescent cells and promotes migration of inflammatory cells. Free Radic. Res., 2018, 52(1), 92-102.
Weyemi, U.; Redon, C.E.; Aziz, T.; Choudhuri, R.; Maeda, D.; Parekh, P.R.; Bonner, M.Y.; Arbiser, J.L.; Bonner, W.M. Inactivation of NADPH oxidases NOX4 and NOX5 protects human primary fibroblasts from ionizing radiation-induced DNA damage. Radiat. Res., 2015, 183(3), 262-270.
Collins-Underwood, J.R.; Zhao, W.; Sharpe, J.G.; Robbins, M.E. NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells. Free Radical . Biol. Med., 2008, 45(6), 929-938.
Cagin, Y.F.; Parlakpinar, H.; Polat, A.; Vardi, N.; Atayan, Y.; Erdogan, M.A.; Ekici, K.; Yildiz, A.; Sarihan, M.E.; Aladag, H. The protective effects of apocynin on ionizing radiation-induced intestinal damage in rats. Drug Dev. Ind. Pharm., 2016, 42(2), 317-324.
Wang, Y.; Liu, Q.; Zhao, W.; Zhou, X.; Miao, G.; Sun, C.; Zhang, H. NADPH Oxidase Activation Contributes to Heavy Ion Irradiation-Induced Cell Death. Dose Response, 2017, 15(1), 1559325817699697.
Khayyal, M.T.; El-Ghazaly, M.A.; El-Hazek, R.M.; Nada, A.S. The effects of celecoxib, a COX-2 selective inhibitor, on acute inflammation induced in irradiated rats. Inflammopharmacology, 2009, 17(5), 255-266.
Pinheiro, R.M.; Calixto, J.B. Effect of the selective COX-2 inhibitors, celecoxib and rofecoxib in rat acute models of inflammation. Inflamm. Res., 2002, 51(12), 603-610.
Malaviya, R.; Gow, A.J.; Francis, M.; Abramova, E.V.; Laskin, J.D.; Laskin, D.L. Radiation-Induced Lung Injury and Inflammation in Mice: Role of Inducible Nitric Oxide Synthase and Surfactant Protein D. Toxicol. Sci., 2015, 144(1), 27-38.
Hosseinimehr, S.J.; Fathi, M.; Ghasemi, A.; Shiadeh, S.N.R.; Pourfallah, T.A. Celecoxib mitigates genotoxicity induced by ionizing radiation in human blood lymphocytes. Research in Pharmaceutical Sciences., 2017, 12(1), 82-87.
Fardid, R.; Najafi, M.; Salajegheh, A.; Kazemi, E.; Rezaeyan, A. Radiation-induced non-targeted effect in vivo: Evaluation of cyclooygenase-2 and endothelin-1 gene expression in rat heart tissues. J. Cancer Res. Ther., 2017, 13(1), 51-55.
R., Ramis M.; Esteban, S.; Miralles, A.; Tan, D.-X.; J Reiter, R. Protective effects of melatonin and mitochondria-targeted antioxidants against oxidative stress: A review. Curr. Med. Chem., 2015, 22(22), 2690-2711.
Zhou, J.; Zhang, S.; Zhao, X.; Wei, T. Melatonin impairs NADPH oxidase assembly and decreases superoxide anion production in microglia exposed to amyloid-beta1-42. J. Pineal Res., 2008, 45(2), 157-165.
Tain, Y.L.; Chen, C.C.; Lee, C.T.; Kao, Y.H.; Sheen, J.M.; Yu, H.R.; Huang, L.T. Melatonin regulates L-arginine transport and NADPH oxidase in young rats with bile duct ligation: Role of protein kinase C. Pediatr. Res., 2013, 73(4 Pt 1), 395-401.
Li, D.; Tian, Z.; Tang, W.; Zhang, J.; Lu, L.; Sun, Z.; Zhou, Z.; Fan, F. The Protective Effects of 5-Methoxytryptamine-α-lipoic Acid on Ionizing Radiation-Induced Hematopoietic Injury. Int. J. Mol. Sci., 2016, 17(6), 935.
Fardid, R.; Salajegheh, A.; Mosleh-Shirazi, M.A.; Sharifzadeh, S.; Okhovat, M.A.; Najafi, M.; Rezaeyan, A.; Abaszadeh, A. Melatonin ameliorates the production of cox-2, inos, and the formation of 8-ohdg in non-targeted lung tissue after pelvic irradiation. Cell J., 2017, 19(2), 324-331.
Ghobadi, A.; Shirazi, A.; Najafi, M.; Kahkesh, M.H.; Rezapoor, S. Melatonin ameliorates radiation-induced oxidative stress at targeted and nontargeted lung tissue. J. Med. Phys., 2017, 42(4), 241.
Shirazi, A.; Hadadi, G.H.; Ghazi, K.M.; Abou, A.F.; Mahdavi, S.R.; Eshraghian, M. Evaluation of melatonin for prevention of radiation myelopathy in irradiated cervical spinal cord. 2009, 11(1), 43-48.
Haddadi, G.; Shirazi, A.; Sepehrizadeh, Z.; Mahdavi, S.R.; Haddadi, M. Radioprotective effect of melatonin on the cervical spinal cord in irradiated rats. Cell J. (Yakhteh), 2013, 14(4), 246.
Aghazadeh, S.; Azarnia, M.; Shirazi, A.; Mahdavi, S.R.; Zangii, B.M. Melatonin as a protective agent in spinal cord damage after gamma irradiation. Report . Pract. Oncol. Radioth., 2007, 12(2), 95-99.
Ortiz, F.; Acuna-Castroviejo, D.; Doerrier, C.; Dayoub, J.C.; Lopez, L.C.; Venegas, C.; Garcia, J.A.; Lopez, A.; Volt, H.; Luna-Sanchez, M.; Escames, G. Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J. Pineal Res., 2015, 58(1), 34-49.
Leach, J.K.; Van Tuyle, G.; Lin, P.S.; Schmidt-Ullrich, R.; Mikkelsen, R.B. Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res., 2001, 61(10), 3894-3901.
Strom, E.; Sathe, S.; Komarov, P.G.; Chernova, O.B.; Pavlovska, I.; Shyshynova, I.; Bosykh, D.A.; Burdelya, L.G.; Macklis, R.M.; Skaliter, R.; Komarova, E.A.; Gudkov, A.V. Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation. Nat. Chem. Biol., 2006, 2(9), 474-479.
Fischer, T.W.; Zmijewski, M.A.; Wortsman, J.; Slominski, A. Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes. J. Pineal Res., 2008, 44(4), 397-407.
Mohseni, M.; Mihandoost, E.; Shirazi, A.; Sepehrizadeh, Z.; Bazzaz, J.T.; Ghazi-khansari, M. Melatonin may play a role in modulation of bax and bcl-2 expression levels to protect rat peripheral blood lymphocytes from gamma irradiation-induced apoptosis. Mutat. Res., 2012, 738-739, 19-27.
Kawanishi, S.; Ohnishi, S.; Ma, N.; Hiraku, Y.; Oikawa, S.; Murata, M. Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells. Genes Environ., 2016, 38(1), 26.
Basudhar, D.; Somasundaram, V.; de Oliveira, G.A.; Kesarwala, A.; Heinecke, J.L.; Cheng, R.Y.; Glynn, S.A.; Ambs, S.; Wink, D.A.; Ridnour, L.A. Nitric oxide synthase-2-derived nitric oxide drives multiple pathways of breast cancer progression. Antioxid. Redox Signal., 2017, 26(18), 1044-1058.
Vaccaro, M.; Irrera, N.; Cutroneo, G.; Rizzo, G.; Vaccaro, F.; Anastasi, G.P.; Borgia, F.; Cannavò, S.P.; Altavilla, D.; Squadrito, F. Differential expression of nitric oxide synthase isoforms nNOS and iNOS in patients with non-segmental generalized vitiligo. Int. J. Mol. Sci., 2017, 18(12), 2533.
Zhou, J.; Cheng, G.; Pang, H.; Liu, Q.; Liu, Y. The effect of 131I-induced hypothyroidism on the levels of nitric oxide (NO), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), total nitric oxide synthase (NOS) activity, and expression of NOS isoforms in rats. Bosn. J. Basic Med. Sci., 2018, 18(4)
Nagane, M.; Yasui, H.; Sakai, Y.; Yamamori, T.; Niwa, K.; Hattori, Y.; Kondo, T.; Inanami, O. Activation of eNOS in endothelial cells exposed to ionizing radiation involves components of the DNA damage response pathway. Biochem. Biophys. Res. Commun., 2015, 456(1), 541-546.
Zhang, S.; Li, J.; Li, Y.; Liu, Y.; Guo, H.; Xu, X. Nitric oxide synthase activity correlates with OGG1 in ozone-induced lung injury animal models. Front. Physiol., 2017, 8, 249.
Jaiswal, M.; LaRusso, N.F.; Nishioka, N.; Nakabeppu, Y.; Gores, G.J. Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res., 2001, 61(17), 6388-6393.
Chevillard, S.; Radicella, J.P.; Levalois, C.; Lebeau, J.; Poupon, M.F.; Oudard, S.; Dutrillaux, B.; Boiteux, S. Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours. Oncogene, 1998, 16(23), 3083-3086.
Mahjabeen, I.; Ali, K.; Zhou, X.; Kayani, M.A. Deregulation of base excision repair gene expression and enhanced proliferation in head and neck squamous cell carcinoma. Tumour Biol., 2014, 35(6), 5971-5983.
Mahjabeen, I.; Chen, Z.; Zhou, X.; Kayani, M.A. Decreased mRNA expression levels of base excision repair (BER) pathway genes is associated with enhanced Ki-67 expression in HNSCC. Med. Oncol., 2012, 29(5), 3620-3625.
Kumar, A.; Pant, M.C.; Singh, H.S.; Khandelwal, S. Reduced expression of DNA repair genes (XRCC1, XPD, and OGG1) in squamous cell carcinoma of head and neck in North India. Tumour Biol., 2012, 33(1), 111-119.
Galano, A.; Tan, D-X.; Reiter, R.J. Melatonin: A Versatile Protector against Oxidative DNA Damage. Molecules, 2018, 23(3), 530.
Majidinia, M.; Sadeghpour, A.; Mehrzadi, S.; Reiter, R.J.; Khatami, N.; Yousefi, B. Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways. J. Pineal Res., 2017.
Rezapoor, S.; Shirazi, A.; Abbasi, S.; Bazzaz, J.T.; Izadi, P.; Rezaeejam, H.; Valizadeh, M.; Soleimani-Mohammadi, F.; Najafi, M. Modulation of radiation-induced base excision repair pathway gene expression by melatonin. J. Med. Phys., 2017, 42(4), 245-250.
Karbownik, M.; Reiter, R.J.; Qi, W.; Garcia, J.J.; Tan, D.X.; Manchester, L.C. Vijayalaxmi. Protective effects of melatonin against oxidation of guanine bases in DNA and decreased microsomal membrane fluidity in rat liver induced by whole body ionizing radiation. Mol. Cell. Biochem., 2000, 211(1-2), 137-144.
Valizadeh, M.; Shirazi, A.; Izadi, P.; Tavakkoly Bazzaz, J.; Rezaeejam, H. Expression levels of two DNA repair-related genes under 8 Gy ionizing radiation and 100 Mg/Kg melatonin delivery in rat peripheral blood. J. Biomed. Phys. Eng., 2017, 7(1), 27-36.
Farhood, B.; Goradel, N.H.; Mortezaee, K.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Shabeeb, D.; Musa, A.E.; Fallah, H.; Najafi, M. Intercellular communications-redox interactions in radiation toxicity; Potential targets for radiation mitigation. J. Cell Commun. Signal., 2018.
Yahyapour, R.; Motevaseli, E.; Rezaeyan, A.; Abdollahi, H.; Farhood, B.; Cheki, M.; Najafi, M.; Villa, V. Mechanisms of radiation bystander and non-targeted effects: Implications to radiation carcinogenesis and radiotherapy. Curr. Radiopharm., 2018, 11(1), 34-45.
Najafi, M.; Shirazi, A.; Motevaseli, E.; Rezaeyan, A.H.; Salajegheh, A.; Rezapoor, S. Melatonin as an anti-inflammatory agent in radiotherapy. Inflammopharmacology, 2017, 25(4), 403-413.
Xu, Y.; Chen, Y.; Liu, H.; Lei, X.; Guo, J.; Cao, K.; Liu, C.; Li, B.; Cai, J.; Ju, J. Heat-killed Salmonella typhimurium (HKST) protects mice against radiation in TLR4-dependent manner. Oncotarget, 2017, 8(40), 67082.
Ho, M.-F.; Ingle, J.N.; Bongartz, T.; Kalari, K.R.; Goss, P.E.; Shepherd, L.E.; Mushiroda, T.; Kubo, M.; Wang, L.; Weinshilboum, R.M. TCL1A SNPs and estrogen-mediated toll-like receptor- MYD88-dependent NF-

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