PMID- 35988735
OWN - NLM
STAT- MEDLINE
DCOM- 20221010
LR  - 20230407
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 204
DP  - 2022 Oct
TI  - Schisandrol B protects against cholestatic liver injury by inhibiting pyroptosis 
      through pregnane X receptor.
PG  - 115222
LID - S0006-2952(22)00316-1 [pii]
LID - 10.1016/j.bcp.2022.115222 [doi]
AB  - Previously, we demonstrated that Schisandrol B (SolB) protected against 
      lithocholic acid (LCA)-induced cholestatic liver injury (CLI) through 
      pregnane X receptor (PXR). Additionally, growing evidence has revealed that 
      pyroptosis is involved in CLI. Whether the hepatoprotective effect of SolB driven 
      by PXR activation is related to pyroptosis in CLI remains unclear. First, the 
      hepatoprotective effect of SolB was confirmed, as evidenced by the decreased 
      mortality, morphological and histopathological changes, and biochemical 
      parameters. The upregulated serum lactic dehydrogenase (LDH) level, increased 
      number of TUNEL-positive cells, and formation of hepatocyte membrane pores 
      induced by LCA were significantly alleviated after SolB pretreatment, indicating 
      that SolB attenuated LCA-induced hepatocyte damage. Further analysis revealed 
      that both NOD-like receptor protein 3 (NLRP3) inflammasome-induced canonical 
      pyroptosis and apoptosis protease activating factor-1 (Apaf-1) 
      pyroptosome-induced noncanonical pyroptosis were significantly inhibited after 
      SolB pretreatment, as illustrated by the decreased expression levels of NLRP3, 
      ASC, caspase-1, and GSDMD and the levels of Apaf-1, caspase-11 p20, caspase-3 
      p20, and GSDME. Furthermore, the activation of the NF-kappaB and FoxO1 signaling 
      pathways was inhibited after SolB pretreatment. In addition, the activation of 
      PXR via SolB was proven by luciferase reporter gene assays and the upregulation 
      of PXR targets. The results illustrated that SolB could significantly inhibit 
      NLRP3 inflammasome-induced canonical pyroptosis through the PXR/NF-kappaB/NLRP3 axis 
      and inhibit Apaf-1 pyroptosome-induced noncanonical pyroptosis through the 
      PXR/FoxO1/Apaf-1 axis. Collectively, this study revealed that SolB protected 
      against CLI by inhibiting pyroptosis through PXR, providing new insights for 
      understanding the molecular mechanism of SolB as a promising anti-cholestatic 
      agent.
CI  - Copyright (c) 2022. Published by Elsevier Inc.
FAU - Liang, Hangfei
AU  - Liang H
AD  - Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of 
      Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
FAU - Yang, Xiao
AU  - Yang X
AD  - NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & 
      Guangdong Provincial Key Laboratory of New Drug Screening, School of 
      Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
FAU - Li, Huilin
AU  - Li H
AD  - Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of 
      Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
FAU - Wang, Xinhui
AU  - Wang X
AD  - School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 
      China.
FAU - Su, Haiguo
AU  - Su H
AD  - Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of 
      Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
FAU - Li, Xuan
AU  - Li X
AD  - Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of 
      Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
FAU - Tian, Jianing
AU  - Tian J
AD  - Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of 
      Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
FAU - Cai, Chenghui
AU  - Cai C
AD  - Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of 
      Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
FAU - Huang, Min
AU  - Huang M
AD  - Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of 
      Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. Electronic 
      address: huangmin@mail.sysu.edu.cn.
FAU - Bi, Huichang
AU  - Bi H
AD  - Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of 
      Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; NMPA Key 
      Laboratory for Research and Evaluation of Drug Metabolism & Guangdong 
      Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical 
      Sciences, Southern Medical University, Guangzhou, China. Electronic address: 
      bihchang@smu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220818
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Cyclooctanes)
RN  - 0 (Dioxoles)
RN  - 0 (Inflammasomes)
RN  - 0 (Lignans)
RN  - 0 (NF-kappa B)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Pregnane X Receptor)
RN  - 58546-54-6 (schizandrol B)
RN  - 5QU0I8393U (Lithocholic Acid)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
EIN - Biochem Pharmacol. 2023 May;211:115526. PMID: 37028254
MH  - Caspase 3/metabolism
MH  - *Cholestasis/chemically induced
MH  - Cyclooctanes
MH  - Dioxoles
MH  - Humans
MH  - Inflammasomes/metabolism
MH  - Lignans
MH  - Lithocholic Acid/metabolism
MH  - Liver/metabolism
MH  - Luciferases/metabolism
MH  - NF-kappa B/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Oxidoreductases/metabolism
MH  - Pregnane X Receptor/metabolism
MH  - *Pyroptosis
OTO - NOTNLM
OT  - Apoptotic protease activating factor-1
OT  - Cholestatic liver injury
OT  - NOD-like receptor protein 3
OT  - Pregnane X receptor
OT  - Pyroptosis
OT  - Schisandrol B
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/08/22 06:00
MHDA- 2022/10/12 06:00
CRDT- 2022/08/21 19:32
PHST- 2022/06/06 00:00 [received]
PHST- 2022/08/12 00:00 [revised]
PHST- 2022/08/12 00:00 [accepted]
PHST- 2022/08/22 06:00 [pubmed]
PHST- 2022/10/12 06:00 [medline]
PHST- 2022/08/21 19:32 [entrez]
AID - S0006-2952(22)00316-1 [pii]
AID - 10.1016/j.bcp.2022.115222 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2022 Oct;204:115222. doi: 10.1016/j.bcp.2022.115222. Epub 2022 
      Aug 18.