PMID- 37598766 OWN - NLM STAT- MEDLINE DCOM- 20231122 LR - 20231122 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 319 IP - Pt 1 DP - 2024 Jan 30 TI - Isomaculosidine facilitates NLRP3 inflammasome activation by promoting mitochondrial reactive oxygen species production and causes idiosyncratic liver injury. PG - 117063 LID - S0378-8741(23)00931-5 [pii] LID - 10.1016/j.jep.2023.117063 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dictamnus dasycarpus Turcz. (Dictamni Cortex, DC), a Chinese herbal medicine, is commonly used for treating chronic dermatosis and rheumatism, but can also cause herb-induced liver injury (HILI). Our study has demonstrated that DC can induce idiosyncratic HILI, but the mechanism remains unknown. The NLRP3 inflammasome has become a major target for addressing many diseases. The activation of NLRP3 inflammasome is responsible for many liver-related inflammatory diseases, including idiosyncratic HILI. AIM OF THE STUDY: The objective of our study was to demonstrate the mechanism underlying the idiosyncratic HILI induced by DC and clarify the susceptible component in DC. MATERIALS AND METHODS: Bone marrow-derived macrophages (BMDMs) and THP1 cells were selected to assess the effect of isomaculosidine (IMD) on NLRP3 inflammasome activation in vitro. Western blot, ELISA and Caspase-Glo(R) 1 Inflammasome Assay, flow cytometry and Immunofluorescence were employed to detect the mechanism of IMD on NLRP3 inflammasome activation. To assess the efficacy of IMD in vivo, mice were intravenously administrated with LPS and then IMD were injected intraperitoneally for 6 h. RESULTS: The results of our in vitro studies demonstrate that IMD, the major constituent of DC, specifically promoted ATP- and nigericin-induced activation of NLRP3 inflammasome, but not NLRC4 and AIM2 inflammasomes. Additionally, IMD promoted nigericin-induced ASC oligomerization. Notably, synergistic induction of mtROS played a key role on the activation of NLRP3 inflammasome. IMD increased the mtROS production in the activation of NLRP3 inflammasome induced by nigericin. In addition, the results of our in vivo study showed that the combination of nonhepatotoxic doses of LPS and IMD can increase the levels of ALT, AST, and DBIL, leading to liver injury. CONCLUSIONS: IMD specifically facilitated the activation of NLRP3 inflammasome induced by nigericin and ATP, which is responsible for DC-induced idiosyncratic HILI. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Shi, Wei AU - Shi W AD - School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China; School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China. FAU - Liu, Tingting AU - Liu T AD - Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China; The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, China. FAU - Yang, Huijie AU - Yang H AD - School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China. FAU - Zhao, Jia AU - Zhao J AD - Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China. FAU - Wei, Ziying AU - Wei Z AD - School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China. FAU - Huang, Yujiao AU - Huang Y AD - School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China. FAU - Li, Zhiyong AU - Li Z AD - School of Traditional Chinese Medicine, Capital Medical University, Beijing, China. FAU - Li, Hui AU - Li H AD - School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China. FAU - Liang, Longxin AU - Liang L AD - Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China. FAU - Hou, Xiaorong AU - Hou X AD - Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China. FAU - Chen, Yuanyuan AU - Chen Y AD - Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China. FAU - Gao, Yuan AU - Gao Y AD - School of Traditional Chinese Medicine, Capital Medical University, Beijing, China. Electronic address: anyanggaoyuan@126.com. FAU - Bai, Zhaofang AU - Bai Z AD - Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China. Electronic address: baizf2008@hotmail.com. FAU - Xiao, Xiaohe AU - Xiao X AD - Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China; China Military Institute of Chinese Materia, The Fifth Medical Center of PLA General Hospital, Beijing, China. Electronic address: pharmacy_302@126.com. LA - eng PT - Journal Article DEP - 20230818 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Reactive Oxygen Species) RN - RRU6GY95IS (Nigericin) RN - 0 (Lipopolysaccharides) RN - 8L70Q75FXE (Adenosine Triphosphate) SB - IM MH - Mice MH - Animals MH - *Inflammasomes MH - *NLR Family, Pyrin Domain-Containing 3 Protein MH - Reactive Oxygen Species MH - Nigericin MH - Lipopolysaccharides/pharmacology MH - Liver MH - Adenosine Triphosphate MH - Mice, Inbred C57BL OTO - NOTNLM OT - Dictamni cortex OT - Idiosyncratic HILI OT - Isomaculosidine OT - Mitochondrial reactive oxygen species OT - NLRP3 inflammasome 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- 2023/08/21 00:41 MHDA- 2023/11/22 06:43 CRDT- 2023/08/20 19:24 PHST- 2023/06/19 00:00 [received] PHST- 2023/08/15 00:00 [revised] PHST- 2023/08/17 00:00 [accepted] PHST- 2023/11/22 06:43 [medline] PHST- 2023/08/21 00:41 [pubmed] PHST- 2023/08/20 19:24 [entrez] AID - S0378-8741(23)00931-5 [pii] AID - 10.1016/j.jep.2023.117063 [doi] PST - ppublish SO - J Ethnopharmacol. 2024 Jan 30;319(Pt 1):117063. doi: 10.1016/j.jep.2023.117063. Epub 2023 Aug 18.