A novel antioxidant multitarget iron chelator M30 protects hepatocytes against ethanol-induced injury.
The multitarget iron chelator, M30, is a novel antioxidant and protective agent against oxidative stress in a spectrum of diseases. However, there is no report regarding its role in liver diseases. Since oxidative stress is one of the major pathological events during the progression of alcoholic liver diseases, the protective effects and mechanisms of M30 on ethanol-induced hepatocyte injury were investigated in this study. Rat hepatocyte line BRL-3A was pretreated with M30 prior to ethanol treatment. Cell death, apoptosis, oxidative stress, and inflammation were examined. Specific antagonists and agonists were applied to determine the involvements of hypoxia inducible factor-1 alpha (HIF-1α) and its upstream adenylate cyclase (AC)/cyclic AMP (cAMP)/protein kinase A (PKA)/HIF-1α/NOD-like receptor 3 (NLRP3) inflammasome pathway. We found that M30 significantly attenuated ethanol-induced cellular death, apoptosis, production of reactive oxygen species (ROS), and secretion of inflammatory cytokines and inhibited activation of the AC/cAMP/PKA/HIF-1α/NLRP3 inflammasome pathway. Inhibition and activation of the AC/cAMP/PKA/HIF-1α pathway mimicked and abolished the effects of M30, respectively. In conclusion, inhibition of the AC/cAMP/PKA/HIF-1α/NLRP3 inflammasome pathway by M30 partially contributes to its attenuation of hepatocyte injury caused by ethanol exposure.
National Key Disciplines for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen 518112, China ; Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632, China ; Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong.
Jia
0000-0001-5604-2494
J
Xiao
Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632, China.
Yi
Y
Lv
Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong.
Bin
B
Lin
Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong.
George L
GL
Tipoe
Eve Topf Centers of Excellence, Technion, Rappaport Family Faculty of Medicine and Department of Pharmacology, 31096 Haifa, Israel.
Moussa B H
MB
Youdim
Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632, China.
Feiyue
F
Xing
National Key Disciplines for Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen 518112, China.
Yingxia
Y
Liu
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D000975:Antioxidants; D002352:Carrier Proteins; D002614:Chelating Agents; D006912:Hydroxyquinolines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D000431:Ethanol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases