Melatonin Modulates Regulation of NOX2 and NOX4 Following Irradiation in the Lung

Author(s): Masoud Najafi, Alireza Shirazi*, Elahe Motevaseli*, Ghazale Geraily, Peyman Amini, Leila Farhadi Tooli, Dheyauldeen Shabeeb

Journal Name: Current Clinical Pharmacology

Volume 14 , Issue 3 , 2019

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Abstract:

Background: Exposure to ionizing radiation may lead to chronic upregulation of inflammatory mediators and pro-oxidant enzymes, which give rise to continuous production of reactive oxygen species (ROS). NADPH oxidases are among the most important ROS producing enzymes. Their upregulation is associated with DNA damage and genomic instability. In the present study, we sought to determine the expressions of NADPH oxidases; NOX2 and NOX4, in rat’s lung following whole body or pelvis irradiation. In addition, we evaluated the protective effect of melatonin on the expressions of NOX2 and NOX4, as well as oxidative DNA injury.

Methods: 35 male rats were divided into 7 groups, G1: control; G2: melatonin (100 mg/kg) treatment; G3: whole body irradiation (2 Gy); G4: melatonin plus whole body irradiation; G5: local irradiation to pelvis area; G6: melatonin treatment plus 2 Gy gamma rays to pelvis area; G7: scatter group. All the rats were sacrificed after 24 h. afterwards, the expressions of TGFβR1, Smad2, NF- κB, NOX2 and NOX4 were detected using real-time PCR. Also, the level of 8-OHdG was detected by ELISA, and NOX2 and NOX4 protein levels were detected by western blot.

Results: Whole body irradiation led to the upregulation of all genes, while local pelvis irradiation caused upregulation of TGFβR1, NF-κB, NOX2 and NOX4, as well as protein levels of NOX2 and NOX4. Treatment with melatonin reduced the expressions of these genes and also alleviated oxidative injury in both targeted and non-targeted lung tissues. Results also showed no significant reduction for NOX2 and NOX4 in bystander tissues following melatonin treatment.

Conclusion: It is possible that upregulation of NOX2 and NOX4 is involved in radiation-induced targeted and non-targeted lung injury. Melatonin may reduce oxidative stress following upregulation of these enzymes in directly irradiated lung tissues but not for bystander.

Keywords: Melatonin, lung, NOX2, NOX4, radiation, mutation.

[1]
Kim JH, Jenrow KA, Brown SL. Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials. Radiat Oncol J 2014; 32(3): 103-15.
[http://dx.doi.org/10.3857/roj.2014.32.3.103] [PMID: 25324981]
[2]
Abdel-Wahab M, Reis IM, Hamilton K. Second primary cancer after radiotherapy for prostate cancer-a seer analysis of brachytherapy versus external beam radiotherapy. Int J Radiat Oncol Biol Phys 2008; 72(1): 58-68.
[http://dx.doi.org/10.1016/j.ijrobp.2007.12.043] [PMID: 18374503]
[3]
Robbins ME, Zhao W. Chronic oxidative stress and radiation-induced late normal tissue injury: A review. Int J Radiat Biol 2004; 80(4): 251-9.
[http://dx.doi.org/10.1080/09553000410001692726] [PMID: 15204702]
[4]
Zhao W, Robbins ME. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: Therapeutic implications. Curr Med Chem 2009; 16(2): 130-43.
[http://dx.doi.org/10.2174/092986709787002790] [PMID: 19149566]
[5]
Rolland E, Bitker MO, Richard F. Radiation-induced tumours after irradiation for localized prostate cancer: Review and proposals for long-term follow-up. Prog Urol 2007; 17(7): 1302-4.
[http://dx.doi.org/10.1016/S1166-7087(07)78565-2] [PMID: 18271410]
[6]
Prise KM, O’Sullivan JM. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer 2009; 9(5): 351-60.
[http://dx.doi.org/10.1038/nrc2603] [PMID: 19377507]
[7]
Havaki S, Kotsinas A, Chronopoulos E, Kletsas D, Georgakilas A, Gorgoulis VG. The role of oxidative DNA damage in radiation induced bystander effect. Cancer Lett 2015; 356(1): 43-51.
[http://dx.doi.org/10.1016/j.canlet.2014.01.023] [PMID: 24530228]
[8]
Wright EG, Coates PJ. Untargeted effects of ionizing radiation: Implications for radiation pathology. Mutat Res 2006; 597(1-2): 119-32.
[http://dx.doi.org/10.1016/j.mrfmmm.2005.03.035] [PMID: 16438994]
[9]
Chai Y, Calaf GM, Zhou H, et al. Radiation induced COX-2 expression and mutagenesis at non-targeted lung tissues of GPT delta transgenic mice. Br J Cancer 2013; 108(1): 91-8.
[http://dx.doi.org/10.1038/bjc.2012.498] [PMID: 23321513]
[10]
Tomita M, Matsumoto H, Funayama T, et al. Nitric oxide-mediated bystander signal transduction induced by heavy-ion microbeam irradiation. Life Sci Space Res (Amst) 2015; 6: 36-43.
[http://dx.doi.org/10.1016/j.lssr.2015.06.004] [PMID: 26256626]
[11]
Xu W, Wang T, Xu S, et al. Radiation-induced epigenetic bystander effects demonstrated in Arabidopsis thaliana. Radiat Res 2015; 183(5): 511-24.
[http://dx.doi.org/10.1667/RR13909.1] [PMID: 25938771]
[12]
Hu W, Pei H, Sun F, et al. Epithelial-mesenchymal transition in non-targeted lung tissues of Kunming mice exposed to X-rays is suppressed by celecoxib. J Radiat Res (Tokyo) 2018; 59(5): 583-7.
[http://dx.doi.org/10.1093/jrr/rry050] [PMID: 30124886]
[13]
Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 2007; 87(1): 245-313.
[http://dx.doi.org/10.1152/physrev.00044.2005] [PMID: 17237347]
[14]
Chang J, Feng W, Wang Y, et al. Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice. Radiat Res 2015; 183(2): 240-8.
[http://dx.doi.org/10.1667/RR13887.1] [PMID: 25635345]
[15]
Chang J, Feng W, Wang Y, et al. Whole-body proton irradiation causes long-term damage to hematopoietic stem cells in mice. Radiat Res 2015; 183(2): 240-8.
[http://dx.doi.org/10.1667/RR13887.1] [PMID: 25635345]
[16]
Pazhanisamy SK, Li H, Wang Y, Batinic-Haberle I, Zhou D. NADPH oxidase inhibition attenuates total body irradiation-induced haematopoietic genomic instability. Mutagenesis 2011; 26(3): 431-5.
[http://dx.doi.org/10.1093/mutage/ger001] [PMID: 21415439]
[17]
Datta K, Suman S, Kallakury BV, Fornace AJ Jr. Exposure to heavy ion radiation induces persistent oxidative stress in mouse intestine. PLoS One 2012; 7(8) e42224
[http://dx.doi.org/10.1371/journal.pone.0042224] [PMID: 22936983]
[18]
Azzam EI, De Toledo SM, Spitz DR, Little JB. Oxidative metabolism modulates signal transduction and micronucleus formation in bystander cells from alpha-particle-irradiated normal human fibroblast cultures. Cancer Res 2002; 62(19): 5436-42.
[PMID: 12359750]
[19]
Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29(9)e45
[http://dx.doi.org/10.1093/nar/29.9.e45] [PMID: 11328886]
[20]
Frey B, Rückert M, Deloch L, et al. Immunomodulation by ionizing radiation-impact for design of radio-immunotherapies and for treatment of inflammatory diseases. Immunol Rev 2017; 280(1): 231-48.
[http://dx.doi.org/10.1111/imr.12572] [PMID: 29027224]
[21]
Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM. Radiation-induced fibrosis: Mechanisms and implications for therapy. J Cancer Res Clin Oncol 2015; 141(11): 1985-94.
[http://dx.doi.org/10.1007/s00432-015-1974-6] [PMID: 25910988]
[22]
Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis 2009; 30(7): 1073-81.
[http://dx.doi.org/10.1093/carcin/bgp127] [PMID: 19468060]
[23]
Yahyapour R, Motevaseli E, Rezaeyan A, et al. Mechanisms of radiation bystander and non-targeted effects: Implications to radiation carcinogenesis and radiotherapy. Curr Radiopharm 2018; 11(1): 34-45.
[http://dx.doi.org/10.2174/1874471011666171229123130] [PMID: 29284398]
[24]
Lorimore SA, Coates PJ, Scobie GE, Milne G, Wright EG. Inflammatory-type responses after exposure to ionizing radiation in vivo: A mechanism for radiation-induced bystander effects? Oncogene 2001; 20(48): 7085-95.
[http://dx.doi.org/10.1038/sj.onc.1204903] [PMID: 11704832]
[25]
Mortezaee K, Amini P, Shabeeb D, Musa AE, Najafi M. NADPH oxidase as a target for modulation of radiation response; Implications to carcinogenesis and radiotherapy. Curr Mol Pharmacol 2019; 12(1): 50-60.
[http://dx.doi.org/10.2174/1874467211666181010154709] [PMID: 30318012]
[26]
Brown DI, Griendling KK. Nox proteins in signal transduction. Free Radic Biol Med 2009; 47(9): 1239-53.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.07.023] [PMID: 19628035]
[27]
Dludla PV, Nkambule BB, Tiano L, Louw J, Jastroch M, Mazibuko-Mbeje SE. Uncoupling proteins as a therapeutic target to protect the diabetic heart. Pharmacol Res 2018; 137: 11-24.
[http://dx.doi.org/10.1016/j.phrs.2018.09.013] [PMID: 30223086]
[28]
Zhang H, Wang YA, Meng A, et al. Inhibiting TGFβ1 has a protective effect on mouse bone marrow suppression following ionizing radiation exposure in vitro. J Radiat Res (Tokyo) 2013; 54(4): 630-6.
[http://dx.doi.org/10.1093/jrr/rrs142] [PMID: 23370919]
[29]
Chatterjee A, Kosmacek EA, Oberley-Deegan RE. MnTE-2-PyP treatment, or NOX4 inhibition, protects against radiation-induced damage in mouse primary prostate fibroblasts by inhibiting the TGF-Beta 1 signaling pathway. Radiat Res 2017; 187(3): 367-81.
[http://dx.doi.org/10.1667/RR14623.1] [PMID: 28225655]
[30]
Weyemi U, Redon CE, Aziz T, et al. Inactivation of NADPH oxidases NOX4 and NOX5 protects human primary fibroblasts from ionizing radiation-induced DNA damage. Radiat Res 2015; 183(3): 262-70.
[http://dx.doi.org/10.1667/RR13799.1] [PMID: 25706776]
[31]
Park S, Ahn J-Y, Lim M-J, et al. Sustained expression of NADPH oxidase 4 by p38 MAPK-Akt signaling potentiates radiation-induced differentiation of lung fibroblasts. J Mol Med (Berl) 2010; 88(8): 807-16.
[http://dx.doi.org/10.1007/s00109-010-0622-5] [PMID: 20396861]
[32]
Farhood B, Goradel NH, Mortezaee K, Khanlarkhani N, Najafi M, Sahebkar A. Melatonin and cancer: From the promotion of genomic stability to use in cancer treatment. Journal of cellular physiology
[33]
Shirazi A, Mihandoost E, Ghobadi G, Mohseni M, Ghazi-Khansari M. Evaluation of radio-protective effect of melatonin on whole body irradiation induced liver tissue damage. Cell J 2013; 14(4): 292-7.
[PMID: 23577309]
[34]
Shirazi A, Hadadi GH, Ghazi KM, Abou AF, Mahdavi SR, Eshraghian M. Evaluation of melatonin for prevention of radiation myelopathy in irradiated cervical spinal cord 2009.
[35]
Haddadi G, Shirazi A, Sepehrizadeh Z, Mahdavi SR, Haddadi M. Radioprotective effect of melatonin on the cervical spinal cord in irradiated rats. Cell J 2013; 14(4): 246-53.
[PMID: 23577303]
[36]
Aghazadeh S, Azarnia M, Shirazi A, Mahdavi SR, Zangii BM. Melatonin as a protective agent in spinal cord damage after gamma irradiation. Rep Pract Oncol Radiother 2007; 12: 95-9.
[http://dx.doi.org/10.1016/S1507-1367(10)60045-4]
[37]
Roohbakhsh A, Shamsizadeh A, Hayes AW, Reiter RJ, Karimi G. Melatonin as an endogenous regulator of diseases: The role of autophagy. Pharmacol Res 2018; 133: 265-76.
[http://dx.doi.org/10.1016/j.phrs.2018.01.022] [PMID: 29408249]
[38]
Yi C, Zhang Y, Yu Z, et al. Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways. PLoS One 2014; 9(7) e99943
[http://dx.doi.org/10.1371/journal.pone.0099943] [PMID: 25000190]
[39]
Ghobadi A, Shirazi A, Najafi M, Kahkesh MH, Rezapoor S. Melatonin ameliorates radiation-induced oxidative stress at targeted and nontargeted lung tissue. J Med Phys 2017; 42(4): 241-4.
[http://dx.doi.org/10.4103/jmp.JMP_60_17] [PMID: 29296038]
[40]
Li D, Tian Z, Tang W, et al. The protective effects of 5-Methoxytryptamine-α-lipoic acid on ionizing radiation-induced hematopoietic injury. Int J Mol Sci 2016; 17(6): 935.
[http://dx.doi.org/10.3390/ijms17060935] [PMID: 27314327]


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Article Details

VOLUME: 14
ISSUE: 3
Year: 2019
Published on: 31 December, 2019
Page: [224 - 231]
Pages: 8
DOI: 10.2174/1574884714666190502151733

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