Melatonin protects against burn-induced hepatic oxidative injury by inducing HO-1 via the Nrf2 pathway
G. Bekyarova, M. Tzaneva, M. Hristovahttps://doi.org/10.17221/8530-VETMEDCitation:Bekyarova G., Tzaneva M., Hristova M. (2015): Melatonin protects against burn-induced hepatic oxidative injury by inducing HO-1 via the Nrf2 pathway. Veterinarni Medicina, 60: 621-628.
Melatonin exerts beneficial effects on early liver injury by modulating hepatic oxidative stress. In order to understand the protective effect of melatonin against burn-induced hepatic injury we investigated the expression of 4-hydroxynonenal (4-HNE), a main product of lipid peroxidation and mediator of oxidative injury, the inducible heme-oxygenase-1 (HO-1), an antioxidant enzyme, and the anti-oxidative stress regulator erythroid 2-related factor 2 (Nrf2) in a burn rat model. Expression and localisation of HO-1, 4-HNE and Nrf2 in liver were investigated using light immunochemistry. Thermal skin injury caused a significant elevation in hepatic 4-HNE and degenerative liver changes. Concurrently, there was increased expression of HO-1, a rate-limiting enzyme for haem degradation and an oxidative stress marker in sinusoidal endothelial cells (SECs) and hepatocytes without changes in Nrf2 expression in the liver. Melatonin (20 mg/kg b.w.) augmented the increase in HO-1 expression, upregulated Nrf2 expression and also led to decreased 4-HNE levels and reduced levels of histopathological changes in rat liver. In conclusion, our results suggest that melatonin ameliorates burn-induced liver injury through the inhibition of oxidative stress, upregulation of the antioxidant enzyme HO-1 and activation of the antioxidant Nrf2 pathway. Stimulation of cellular protective mechanisms by activating the antioxidant stress response through Nrf2 is a new mechanism for protection against liver damage in burns.Keywords:melatonin; Nrf2; HO-1; 4-HNE; oxidative stress; liverReferences:
Aleksunes Lauren M., Manautou José E. (2007): Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease. Toxicologic Pathology, 35, 459-473 https://doi.org/10.1080/01926230701311344Ashino Takashi, Sugiuchi Jinko, Uehara Junna, Naito-Yamamoto Yumiko, Kenmotsu Sachiyo, Iwakura Yoichiro, Shioda Seiji, Numazawa Satoshi, Yoshida Takemi (2011): Auranofin protects against cocaine-induced hepatic injury through induction of heme oxygenase-1. The Journal of Toxicological Sciences, 36, 635-643 https://doi.org/10.2131/jts.36.635Bekyarova G., Tancheva S., Hristova M. (2009): Protective effect of melatonin against oxidative hepatic injury after experimental thermal trauma. Methods and Findings in Experimental and Clinical Pharmacology, 31, 11- https://doi.org/10.1358/mf.2009.31.1.1346609Bekyarova G, Apostolova M, Kotzev I (2012): Melatonin protection against burn-induce hepatic injury by down-regulation of nuclear factor kappa B activation. International Journal of Immunopathology and Pharmacology 25, 591–596.Bekyarova Ganka, Tzaneva Maria, Hristova Minka (2013): Melatonin modulates the expression of Bcl-2 family proteins in liver after thermal injury in rats. Advances in Bioscience and Biotechnology, 04, 41-47 https://doi.org/10.4236/abb.2013.411A2006Brouard S. (): Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis. Journal of Experimental Medicine, 192, 1015-1026 https://doi.org/10.1084/jem.192.7.1015Chan K., Han X.-D., Kan Y. W. (2001): An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophen. Proceedings of the National Academy of Sciences, 98, 4611-4616 https://doi.org/10.1073/pnas.081082098Chen ZH, Niki E (2006): 4-hydroxynonenal (4-HNE) has been widely accepted as an inducer of oxidative stress. Is this the whole truth about it or can 4-HNE also exert protective effects? International Union of Biochemistry and Molecular Biology Life 58, 372–373.Crespo Irene, Miguel Beatriz S., Laliena Almudena, Álvarez Marcelino, Culebras Jesús M., González-Gallego Javier, Tuñón María J. (2010): Melatonin prevents the decreased activity of antioxidant enzymes and activates nuclear erythroid 2-related factor 2 signaling in an animal model of fulminant hepatic failure of viral origin. Journal of Pineal Research, , no-no https://doi.org/10.1111/j.1600-079X.2010.00787.xDulak J, Jozkowicz A (2003): Carbon monoxide – a “new” gaseous modulator of gene expression. Acta Biochimica Polonica 50, 31–47.Farombi E. Olatunde, Shrotriya Sangeeta, Na Hye-Kyung, Kim Sung-Hoon, Surh Young-Joon (2008): Curcumin attenuates dimethylnitrosamine-induced liver injury in rats through Nrf2-mediated induction of heme oxygenase-1. Food and Chemical Toxicology, 46, 1279-1287 https://doi.org/10.1016/j.fct.2007.09.095Fischer Tobias W., Kleszczyński Konrad, Hardkop Lena H., Kruse Nathalie, Zillikens Detlef (2013): Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2'-deoxyguanosine) in ex vivo human skin. Journal of Pineal Research, 54, 303-312 https://doi.org/10.1111/jpi.12018Galano Annia, Tan Dun Xian, Reiter Russel J. (2013): On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. Journal of Pineal Research, 54, 245-257 https://doi.org/10.1111/jpi.12010Jaiswal Anil K (2004): Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radical Biology and Medicine, 36, 1199-1207 https://doi.org/10.1016/j.freeradbiomed.2004.02.074Jeschke MG, Low JF, Spies M, Vita R, Hawkins HK, Herndon DN, Barrow RE (2001): Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats. American Journal of Physiology, Gastrointestinal Liver Physiology 280, G1314–1320Jung Kyung Hee, Hong Sang-Won, Zheng Hong-Mei, Lee Don-Haeng, Hong Soon-Sun (2009): Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model. Journal of Pineal Research, 47, 173-183 https://doi.org/10.1111/j.1600-079X.2009.00698.xHorton Jureta W. (2003): Free radicals and lipid peroxidation mediated injury in burn trauma: the role of antioxidant therapy. Toxicology, 189, 75-88 https://doi.org/10.1016/S0300-483X(03)00154-9Klein Dagmar, Schubert Thomas, Horch Raymund E., Jauch Karl-Walter, Jeschke Marc G. (2004): Insulin Treatment Improves Hepatic Morphology and Function Through Modulation of Hepatic Signals After Severe Trauma. Annals of Surgery, 240, 340-349 https://doi.org/10.1097/01.sla.0000133353.57674.cdLee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA (2005): Nrf2, a multi-organ protector? Journal of the Federation of American Societies for Experimental Biology 19, 1061–1076.Lee I-Ta, Luo Shue-Fen, Lee Chiang-Wen, Wang Shyi-Wu, Lin Chih-Chung, Chang Chia-Chi, Chen Yuh-Lien, Chau Lee-Young, Yang Chuen-Mao (2009): Overexpression of HO-1 Protects against TNF-α-Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress. The American Journal of Pathology, 175, 519-532 https://doi.org/10.2353/ajpath.2009.090016Mauriz JL, Collado PS, Veneroso C, Reiter RJ, Gonzalez-Gallego J (2013): A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. Journal of Pineal Research 54, 1–14.Miller Darren M., Singh Indrapal N., Wang Juan A., Hall Edward D. (2013): Administration of the Nrf2–ARE activators sulforaphane and carnosic acid attenuates 4-hydroxy-2-nonenal-induced mitochondrial dysfunction ex vivo. Free Radical Biology and Medicine, 57, 1-9 https://doi.org/10.1016/j.freeradbiomed.2012.12.011Niki Etsuo (2009): Lipid peroxidation: Physiological levels and dual biological effects. Free Radical Biology and Medicine, 47, 469-484 https://doi.org/10.1016/j.freeradbiomed.2009.05.032Ohta Yoshiji, Kongo Mutsumi, Sasaki Emi, Nishida Keiji, Ishiguro Isao (2000): Therapeutic effect of melatonin on carbon tetrachloride-induced acute liver injury in rats. Journal of Pineal Research, 28, 119-126 https://doi.org/10.1034/j.1600-079X.2001.280208.xOsburn William O., Wakabayashi Nobunao, Misra Vikas, Nilles Tricia, Biswal Shyam, Trush Michael A., Kensler Thomas W. (2006): Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion. Archives of Biochemistry and Biophysics, 454, 7-15 https://doi.org/10.1016/j.abb.2006.08.005Otterbein LE, Choi AM (2000): K Heme oxygenase: colors of defense against cellular stress. American Journal of Physiology: Lung Cellular and Molecular 279, L1029–L1037.Öz Eser, İlhan Mustafa N. (2006): Effects of melatonin in reducing the toxic effects of doxorubicin. Molecular and Cellular Biochemistry, 286, 11-15 https://doi.org/10.1007/s11010-005-9003-8Parihar Arti, Parihar Mordhwaj S., Milner Stephen, Bhat Satyanarayan (2008): Oxidative stress and anti-oxidative mobilization in burn injury. Burns, 34, 6-17 https://doi.org/10.1016/j.burns.2007.04.009Park Sang-Won, Choi Sun-Mi, Lee Sun-Mee (2007): Effect of melatonin on altered expression of vasoregulatory genes during hepatic ischemia/reperfusion. Archives of Pharmacal Research, 30, 1619-1624 https://doi.org/10.1007/BF02977332Piantadosi Claude A., Carraway Martha S., Suliman Hagir B. (2006): Carbon monoxide, oxidative stress, and mitochondrial permeability pore transition. Free Radical Biology and Medicine, 40, 1332-1339 https://doi.org/10.1016/j.freeradbiomed.2005.11.020Reiter Russel J., Paredes Sergio D., Manchester Lucien C., Tan Dan-Xian (2009): Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Critical Reviews in Biochemistry and Molecular Biology, 44, 175-200 https://doi.org/10.1080/10409230903044914Rodriguez Carmen, Mayo Juan C., Sainz Rosa M., Antolin Isaac, Herrera Federico, Martin Vanesa, Reiter Russel J. (2004): Regulation of antioxidant enzymes: a significant role for melatonin. Journal of Pineal Research, 36, 1-9 https://doi.org/10.1046/j.1600-079X.2003.00092.xRyter Stefan W., Choi Augustine M. K. (2013): Carbon monoxide: present and future indications for a medical gas. The Korean Journal of Internal Medicine, 28, 123- https://doi.org/10.3904/kjim.2013.28.2.123Ryter SW, Otterbein LE, Morse D, Choi AM (2002): Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. Molecular and Cellular Biochemistry 234–235, 249–263. https://doi.org/10.1023/A:1015957026924Vinha Paula Pileggi, Martinez Edson Zangiacomi, Vannucchi Helio, Marchini Julio Sergio, Farina Jayme Adriano, Jordao Alceu Afonso, Cunha Selma Freire (2013): Effect of Acute Thermal Injury in Status of Serum Vitamins, Inflammatory Markers, and Oxidative Stress Markers. Journal of Burn Care & Research, 34, e87-e91 https://doi.org/10.1097/BCR.0b013e31826fc506Yang Fwu-Lin, Subeq Yi-Maun, Lee Chung-Jen, Lee Ru-Ping, Peng Tai-Chu, Hsu Bang-Gee (2011): Melatonin Ameliorates Hemorrhagic Shock-Induced Organ Damage in Rats. Journal of Surgical Research, 167, e315-e321 https://doi.org/10.1016/j.jss.2009.07.026Zhang Hong-Mei, Zhang Yiqiang (2014): Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. Journal of Pineal Research, 57, 131-146 https://doi.org/10.1111/jpi.12162