PMID- 33422760 OWN - NLM STAT- MEDLINE DCOM- 20210625 LR - 20210625 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 92 DP - 2021 Mar TI - Psoralidin, a major component of Psoraleae Fructus, induces inflammasome activation and idiosyncratic liver injury. PG - 107352 LID - S1567-5769(20)33820-0 [pii] LID - 10.1016/j.intimp.2020.107352 [doi] AB - Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially fatal disease that is unpredictable and independent of the dose of the drug. Increasing evidence suggests that the majority of IDILI cases are immune-mediated, and the aberrant activation of inflammasome plays a vital role in progression. Psoraleae Fructus (PF), a tonic Chinese medicine, has been able to cause IDILI, but the precise mechanism of hepatotoxicity remains unclear. In this study, eight bioactive compounds involved in PF-induced inflammasome activation were investigated. The results demonstrated that psoralidin activated the inflammasomes followed by secreting caspase-1 and interleukin 1beta (IL-1beta) in a dose-dependent manner. Interestingly, MCC950, a potent inhibitor of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, could not entirely suppress the psoralidin-induced inflammasome activation. Moreover, psoralidin significantly induced IL-1beta maturation and caspase-1 activation in NLRP3-knockout bone marrow-derived macrophages (BMDMs), suggesting that psoralidin not only activates the NLRP3 inflammasome but also activates other types of inflammasomes. The results also demonstrated that psoralidin activated the inflammasomes by promoting the C-terminal caspase recruitment domain (ASC) oligomerization, and the production of mitochondrial reactive oxygen species (mtROS) is a decisive factor in psoralidin-induced inflammasome activation. Importantly, in vivo data revealed that psoralidin induced hepatic inflammation, increased aminotransferase activity and increased the production of IL-1beta and tumor necrosis factor(TNF-alpha) in a susceptible mouse model of lipopolysaccharide (LPS)-mediated IDILI. In summary, these results confirmed that psoralidin causes IDILI by inducing inflammasome activation. The study suggests that psoralidin is a possible risk factor and is responsible for PF-induced IDILI. CI - Copyright (c) 2020 Elsevier B.V. All rights reserved. FAU - Wang, Yan AU - Wang Y AD - School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China; China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China. FAU - Xu, Guang AU - Xu G AD - China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China. FAU - Wang, Zhilei AU - Wang Z AD - China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. FAU - Li, Ruisheng AU - Li R AD - Research Center for Clinical and Translational Medicine, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100500, China. FAU - Zhan, Xiaoyan AU - Zhan X AD - China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; Integrative Medical Center, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China. FAU - Liu, Hongbin AU - Liu H AD - China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. FAU - Qin, Qin AU - Qin Q AD - China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China. FAU - Li, Weixia AU - Li W AD - Department of Pharmacy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China. FAU - Wang, Xiaoyan AU - Wang X AD - Department of Pharmacy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China. FAU - Zhang, Mingliang AU - Zhang M AD - Department of Pharmacy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China. FAU - Tang, Jinfa AU - Tang J AD - Department of Pharmacy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China. Electronic address: a0519@163.com. FAU - Bai, Zhaofang AU - Bai Z AD - China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; Integrative Medical Center, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: baizf2008@hotmail.com. FAU - Xiao, Xiaohe AU - Xiao X AD - China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; Integrative Medical Center, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: pharmacy302@126.com. LA - eng PT - Journal Article DEP - 20210107 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Benzofurans) RN - 0 (Coumarins) RN - 0 (Inflammasomes) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Phytochemicals) RN - G16ZUQ069L (psoralidin) SB - IM MH - Animals MH - Benzofurans/*toxicity MH - Cells, Cultured MH - Chemical and Drug Induced Liver Injury/etiology/metabolism/*pathology MH - Coumarins/*toxicity MH - Disease Models, Animal MH - Female MH - Inflammasomes/drug effects/*metabolism MH - Lipopolysaccharides/*toxicity MH - Mice MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*metabolism MH - Phytochemicals/toxicity MH - Psoralea/*chemistry OTO - NOTNLM OT - Idiosyncratic drug-induced liver injury OT - Inflammasomes OT - Mitochondrial reactive oxygen species OT - Psoraleae Fructus OT - Psoralidin EDAT- 2021/01/11 06:00 MHDA- 2021/06/29 06:00 CRDT- 2021/01/10 20:34 PHST- 2020/09/05 00:00 [received] PHST- 2020/12/24 00:00 [revised] PHST- 2020/12/26 00:00 [accepted] PHST- 2021/01/11 06:00 [pubmed] PHST- 2021/06/29 06:00 [medline] PHST- 2021/01/10 20:34 [entrez] AID - S1567-5769(20)33820-0 [pii] AID - 10.1016/j.intimp.2020.107352 [doi] PST - ppublish SO - Int Immunopharmacol. 2021 Mar;92:107352. doi: 10.1016/j.intimp.2020.107352. Epub 2021 Jan 7.