Inhibition of iron overload-induced apoptosis and necrosis of bone marrow mesenchymal stem cells by melatonin
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Fan Yang2,*, Yuan Li2,*, Gege Yan2, Tianyi Liu2, Chao Feng2, Rui Gong2, Ye Yuan3, Fengzhi Ding2, Lai Zhang2, Elina Idiiatullina4, Valentin Pavlov4, Zhenbo Han2, Wenya Ma2, Qi Huang2, Ying Yu2, Zhengyi Bao2, Xiuxiu Wang2, Bingjie Hua2, Zhimin Du3, Benzhi Cai2,3, Lei Yang1
1Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
2Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin 150081, China
3Department of Clinical Pharmacy, The Affiliated Second Hospital of Harbin Medical University, Harbin 150086, China
4Central Laboratory of Scientific Research, Bashkir State Medical University, Ufa 450008, Russia
*These authors contributed equally to this work
Lei Yang, email: firstname.lastname@example.org
Benzhi Cai, email: email@example.com
Keywords: bone marrow mesenchymal stem cells, melatonin, iron overload, apoptosis, necrosis
Received: January 30, 2017 Accepted: March 02, 2017 Published: March 18, 2017
Iron overload induces severe damage to several vital organs such as the liver, heart and bone, and thus contributes to the dysfunction of these organs. The aim of this study is to investigate whether iron overload causes the apoptosis and necrosis of bone marrow mesenchymal stem cells (BMSCs) and melatonin may prevent its toxicity. Perls’ Prussion blue staining showed that exposure to increased concentrations of ferric ammonium citrate (FAC) induced a gradual increase of intracellular iron level in BMSCs. Trypan blue staining demonstrated that FAC decreased the viability of BMSCs in a concentration-dependent manner. Notably, melatonin protected BMSCs against apoptosis and necrosis induced by FAC and it was vertified by Live/Dead, TUNEL and PI/Hoechst stainings. Furthermore, melatonin pretreatment suppressed FAC-induced reactive oxygen species accumulation. Western blot showed that exposure to FAC resulted in the decrease of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bax and Cleaved Caspase-3, and necrosis-related proteins RIP1 and RIP3, which were significantly inhibited by melatonin treatment. At last, melatonin receptor blocker luzindole failed to block the protection of BMSCs apoptosis and necrosis by melatonin. Taken together, melatonin protected BMSCs from iron overload induced apoptosis and necrosis by regulating Bcl-2, Bax, Cleaved Caspase-3, RIP1 and RIP3 pathways.
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