title: Hepatoprotective Effects of Schisandra sphenanthera Extract against Lithocholic Acid-Induced Cholestasis in Male Mice Are Associated with Activation of the Pregnane X Receptor Pathway and Promotion of Liver Regeneration.
abstract: We previously reported that the ethanol extract of Schisandra sphenanthera [Wuzhi (WZ) tablet] significantly protects against acetaminophen-induced hepatoxicity. However, whether WZ exerts a protective effect against cholestasis remains unclear. In this study, the protective effect of WZ on lithocholic acid (LCA)-induced intrahepatic cholestasis in mice was characterized and the involved mechanisms were investigated. WZ pretreatment (350 mg/kg) with LCA significantly reversed liver necrosis and decreased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activity. More importantly, serum total bile acids and total bilirubin were also remarkably reduced. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis showed that hepatic expression of pregnane X receptor (PXR) target genes such as CYP3A11 and UDP-glucuronosyltransferase (UGT) 1A1 were significantly increased by WZ treatment. Luciferase assays performed in LS174T cells illustrated that WZ extract and its six bioactive lignans could all activate human PXR. In addition, WZ treatment significantly promoted liver regeneration via inhibition of p53/p21 to induce cell proliferation-associated proteins such as cyclin D1 and proliferating cell nuclear antigen. In conclusion, WZ has a protective effect against LCA-induced intrahepatic cholestasis, partially owing to activation of the PXR pathway and promotion of liver regeneration.
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Hang
authors.initials: H
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Dongshun
authors.initials: D
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Qin
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Huasen
authors.initials: H
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Xuezhen
authors.initials: X
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Fan
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Yiming
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Yawen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Yixin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.) bihchang@mail.sysu.edu.cn huangmin@mail.sysu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences (H.Z., D.L., H.T., X.Z., X.L., X.F., Y.J., Y.Z., Y.C., Y.W., M.H., H.B.) and First Affiliated Hospital (P.C.), Sun Yat-sen University, Guangzhou, China; and Guangdong Food and Drug Vocational College, Guangzhou, China (X.Q.) bihchang@mail.sysu.edu.cn huangmin@mail.sysu.edu.cn.
authors.forename: Huichang
authors.initials: H
authors.lastname: Bi
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000378:metabolism; D017705:Lignans / Q000494:pharmacology; D008095:Lithocholic Acid / Q000009:adverse effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D011987:Receptors, Steroid / Q000378:metabolism*; D032141:Schisandra / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D000099148:UGT1A1 Enzyme
chemical_list: D000082:Acetaminophen; D051544:Cytochrome P-450 CYP3A; D004365:Drugs, Chinese Herbal; D014453:Glucuronosyltransferase; D017705:Lignans; D008095:Lithocholic Acid; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D020011:Protective Agents; D011987:Receptors, Steroid; D000099148:UGT1A1 Enzyme; C582515:wuzhi