title: Anti-hepatitis B virus effect of matrine-type alkaloid and involvement of p38 mitogen-activated protein kinase and tumor necrosis factor receptor-associated factor 6.
abstract: The matrine-type alkaloid, oxymatrine inhibits hepatitis B virus (HBV) replication but very little is known about these effects in other matrine-type alkaloids, including sophoridine and sophocarpine. Therefore, we compared the in vitro anti-HBV effects of matrine, oxymatrine, sophocarpine, and sophoridine by treating an HBV-transfected cell line (HepG2.2.15) with 0.4-1.6mM of the compounds for 24 or 72h. The levels of the HBV surface antigen (HBsAg) and e antigen (HBeAg) in the culture medium, as well as the intracellular and extracellular HBV DNA levels, were determined. Metabolomic analysis and detection of the mRNA level of p38 mitogen-activated protein kinase (MAPK), tumor necrosis factor receptor-associated factor (TRAF) 6, extracellular signal-regulated kinase (ERK) 1, NOD-like receptor family pyrin domain containing 10 (NLRP10), and caspase-1 were conducted in sophoridine-treated HepG2.2.15 cells. HepG2.2.15 cell exposure to 0.4-1.6mM sophocarpine or sophoridine for 24h reduced the HBsAg level of the medium more effectively than exposure to matrine and oxymatrine did, and reduced the HBeAg levels more effectively than these compounds did at 1.6mM. Sophoridine (0.4-1.6mM) reduced the cell medium HBV DNA levels more than the same concentrations of matrine, oxymatrine, or sophocarpine did. After 72h, 0.4 and 0.8mM sophoridine reduced HBsAg and intracellular HBV DNA levels more potently than matrine, oxymatrine, or sophocarpine did. Furthermore, sophoridine (0.8mM) potently reduced the cell medium HBeAg levels while the metabolomic analyses revealed that HepG2.2.15 cells exposed to 0.8mM sophoridine for 72h exhibited reduced cycloleucine and phytosphingosine levels. In addition, the mRNA expression analyses revealed that HepG2.2.15 cells exposed to 0.8mM sophoridine showed reduced levels of p38 MAPK, TRAF6, ERK1, NLRP10, and caspase-1. Sophoridine produced more potent anti-HBV effects than matrine, oxymatrine, and sophocarpine did. These effects may be related to the sophoridine-mediated reduction of p38 MAPK and TRAF6 levels.
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China; China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China.
authors.forename: Jia-Xin
authors.initials: JX
authors.lastname: Chen
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China. Electronic address: shenhonghui@hotmail.com.
authors.forename: Hong-Hui
authors.initials: HH
authors.lastname: Shen
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Niu
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Guo
authors.affiliation: Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, China.
authors.forename: Xiao-Qiong
authors.initials: XQ
authors.lastname: Liu
authors.affiliation: Chengde Medical University, Chengde, Hebei 067000, China.
authors.forename: Yan-Zhong
authors.initials: YZ
authors.lastname: Han
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China.
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: China Military Institute of Chinese Medicine, 302 Military Hospital, Beijing 100039, China.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhao
authors.affiliation: Research Center of Clinical Medicine, 302 Military Hospital, Beijing 100039, China.
authors.forename: Bing-Ke
authors.initials: BK
authors.lastname: Bai
authors.affiliation: College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China. Electronic address: zouwenjun@vip.163.com.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Zhou
authors.affiliation: Integrative Medical Center, 302 Military Hospital, Beijing 100039, China. Electronic address: pharmacy302@126.com.
authors.forename: Xiao-He
authors.initials: XH
authors.lastname: Xiao
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003470:Culture Media / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D004279:DNA, Viral / Q000032:analysis; D020869:Gene Expression Profiling; D006514:Hepatitis B Surface Antigens / Q000032:analysis; D006513:Hepatitis B e Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D055442:Metabolome; D011807:Quinolizines / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D019014:fas Receptor / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000093842:Matrines
chemical_list: D000470:Alkaloids; D000998:Antiviral Agents; D003470:Culture Media; D004279:DNA, Viral; C491901:FAS protein, human; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D011807:Quinolizines; D019014:fas Receptor; C046246:oxysophocarpine; C037573:oxymatrine; D048051:p38 Mitogen-Activated Protein Kinases; D000093842:Matrines
keywords: Hepatitis B virus; NLRP10; Sophoridine; Tumor necrosis factor receptor-associated factor 6; p38 Mitogen-activated protein kinase