Plumbagin protects liver against fulminant hepatic failure and chronic liver fibrosis via inhibiting inflammation and collagen production

// Huafeng Wang 1, 2, 3, * , Huan Zhang 1, 4, * , Yuqing Zhang 5, * , Dan Wang 1, * , Xixi Cheng 1 , Fengrui Yang 1, 2 , Qi Zhang 1 , Zhenyi Xue 1, 2 , Yan Li 1, 2 , Lijuan Zhang 1, 2 , Luhong Yang 3 , Guolin Miao 1, 2 , Daiqing Li 6 , Zhiyu Guan 7 , Yurong Da 1, 2 , Zhi Yao 2 , Fei Gao 8 , Liang Qiao 9 , Li Kong 10 , Rongxin Zhang 1, 2 1 Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, China 2 Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immune Microenvironment and Diseases, Ministry of Education of China, Tianjin Medical University, Tianjin, China 3 School of Life Science, Shanxi Normal University, Linfen, China 4 Clinical Laboratory, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China 5 Department of Hepatobiliary and Pancreatic Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, Tianjin, China 6 Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China 7 Department of Pathogenic Biology, Weifang Medical University, Shandong, China 8 State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China 9 Storr Liver Unit, Westmead Millennium Institute, The Western Clinical School of the University of Sydney, Westmead, NSW, Australia 10 Department of Histology and Embryology, Dalian Medical University, Dalian, China * These authors have contributed equally to this work Correspondence to: Rongxin Zhang, email: rxzhang@tmu.edu.cn , rongxinz@yahoo.com Li Kong, email: kongli@dmu.edu.cn Keywords: plumbagin, fulminant hepatic failure, liver fibrosis, hepatic stellate cell, inflammation Received: August 08, 2016 Accepted: October 04, 2016 Published: October 14, 2016 ABSTRACT Plumbagin is a quinonoid constituent extracted from Plumbago genus, and it exhibits diverse pharmacological effects. This study thoroughly investigated the effects of plumbagin on thioacetamide-induced acute and chronic liver injury. Results shown that plumbagin increased survival rate, reduced liver congestion and inflammation, and decreased macrophages and neutrophils in the fulminant hepatic failure model, and remarkably diminished liver fibrosis and inflammation in the chronic liver injury model. Furthermore, plumbagin significantly suppress the HSCs/myofibroblasts activation by reduced expression of markers α-SMA and COL-1/3, and reduced macrophage in liver. In the in vitro study, plumbagin induced apoptosis and suppressed the proliferation of LX-2 cells (human HSCs). Plumbagin treatment increased AMPK phosphorylation and attenuated NF-κB, STAT3, and Akt/mTOR signals in LX-2 cells, while SMAD2 phosphorylation was not changed. Noticeably, plumbagin promoted AMPK binding to p300 which is a cofactor of SMAD complex, this may further competitively decreases the p300/SMAD complex initiated transcription of COL-1/3 and α-SMA. Additionally, plumbagin hampered inflammation related NF-κB signal in RAW 264.7 cells. In conclusion, these findings indicate that plumbagin may be a powerful drug candidate to protect the liver from acute and chronic damage by inhibiting inflammation and collagen production.