title: Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling.
abstract: Overdose of acetaminophen (APAP) can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. The traditional Chinese herb Bupleurum falcatum has been widely used for the treatment of several liver diseases in eastern Asian countries, and saikosaponin d (SSd) is one of its major pharmacologically-active components. However, the efficacy of Bupleurum falcatum or SSd on APAP toxicity remains unclear. C57/BL6 mice were administered SSd intraperitoneally once daily for 5days, followed by APAP challenge. Biochemical and pathological analysis revealed that mice treated with SSd were protected against APAP-induced hepatotoxicity. SSd markedly suppressed phosphorylation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and reversed the APAP-induced increases in the target genes of NF-κB, such as pro-inflammatory cytokine Il6 and Ccl2, and those of STAT3, such as Socs3, Fga, Fgb and Fgg. SSd also enhanced the expression of the anti-inflammatory cytokine Il10 mRNA. Collectively, these results demonstrate that SSd protects mice from APAP-induced hepatotoxicity mainly through down-regulating NF-κB- and STAT3-mediated inflammatory signaling. This study unveils one of the possible mechanisms of hepatoprotection caused by Bupleurum falcatum and/or SSd.
authors.affiliation: Medical School of Ningbo University, Ningbo 315211, China; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: liuaiming@nbu.edu.cn.
authors.forename: Aiming
authors.initials: A
authors.lastname: Liu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Hunan Normal University, Changsha 410081, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Guo
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Zhongze
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Ningbo College of Health Sciences, Ningbo 315100, China.
authors.forename: Julin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D058633:Antipyretics / Q000037:antagonists & inhibitors / Q000633:toxicity; D029972:Bupleurum; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D010946:Plants, Medicinal; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D058633:Antipyretics; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D047493:PPAR alpha; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D012503:Saponins; C494087:Stat3 protein, mouse; D000082:Acetaminophen; D009828:Oleanolic Acid; C025759:saikosaponin D
keywords: Acetaminophen; Hepatotoxicity; NF-κB; STAT3; Saikosaponin d