PMID- 36566009 OWN - NLM STAT- MEDLINE DCOM- 20230117 LR - 20230117 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 940 DP - 2023 Feb 5 TI - 20(S)-Protopanaxatriol ameliorates MAFLD by inhibiting NLRP3 inflammasome. PG - 175468 LID - S0014-2999(22)00729-4 [pii] LID - 10.1016/j.ejphar.2022.175468 [doi] AB - Metabolic associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases and may develop into non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even hepatocellular carcinoma, which has threatened human health. Although NLRP3 inflammasome is widely recognized in the pathogenesis of MAFLD, there are currently no drugs targeting NLRP3 inflammasome approved by regulatory agencies. Panax ginseng and its main saponin components have been used to regulate inflammatory and metabolic disorders. Notably, 20(S)-protopanaxatriol (PPT) is an active metabolite of protopanaxatriol saponins with prominent anti-inflammatory activity. However, the mechanism by which PPT ameliorates MAFLD has not been fully elucidated. Therefore, this study explored the efficacy and mechanism of PPT in treating MAFLD based on the inhibition of NLRP3 inflammasome activation. First, we screened potential NLRP3 inflammasome blockers from protopanaxadiol saponins in mouse primary bone marrow-derived macrophages (BMDMs) stimulated by LPS and different inflammasome inducers. Second, LPS-primed mouse BMDMs, mouse primary hepatocytes, mouse primary Kupffer cells and human peripheral blood mononuclear cells (PBMCs) stimulated by cholesterol and ATP were used to evaluate the effect of PPT in inhibiting NLRP3 inflammasome. Finally, MCD-induced mouse MAFLD were established to verify the therapeutic effect of PPT by inhibiting NLRP3 inflammasome. Our results showed that PPT of ginseng saponins significantly inhibited NLRP3 inflammasome activation in multiple primary cells, suppressed systemic inflammation, restored liver function, and attenuated liver inflammation as well as fibrosis in MCD--induced mouse MAFLD. Collectively, protopanaxatriol saponins metabolite PPT, may serve as a potent therapeutic agent for MAFLD by inhibiting NLRP3 inflammasome activation. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Lu, Bingjie AU - Lu B AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: bingjie_luna@126.com. FAU - Wang, Dan AU - Wang D AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: 18317366750@qq.com. FAU - Xie, Dong AU - Xie D AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: xdieong@163.com. FAU - Wu, Chao AU - Wu C AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: wuchaotcm@163.com. FAU - Sun, Mingyu AU - Sun M AD - Shuguang Hospital, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: mysun248@hotmail.com. LA - eng PT - Journal Article DEP - 20221222 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 34080-08-5 (protopanaxatriol) RN - 0 (Lipopolysaccharides) RN - 0 (Saponins) RN - 0 (Nlrp3 protein, mouse) SB - IM MH - Humans MH - Animals MH - Mice MH - Inflammasomes/metabolism MH - *Non-alcoholic Fatty Liver Disease/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Lipopolysaccharides MH - Leukocytes, Mononuclear/metabolism MH - Inflammation/pathology MH - Fibrosis MH - *Saponins/pharmacology/therapeutic use MH - Mice, Inbred C57BL OTO - NOTNLM OT - 20(S)-Protopanaxatriol OT - Metabolic associated fatty liver disease 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- 2022/12/25 06:00 MHDA- 2023/01/18 06:00 CRDT- 2022/12/24 19:17 PHST- 2022/11/13 00:00 [received] PHST- 2022/12/03 00:00 [revised] PHST- 2022/12/13 00:00 [accepted] PHST- 2022/12/25 06:00 [pubmed] PHST- 2023/01/18 06:00 [medline] PHST- 2022/12/24 19:17 [entrez] AID - S0014-2999(22)00729-4 [pii] AID - 10.1016/j.ejphar.2022.175468 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Feb 5;940:175468. doi: 10.1016/j.ejphar.2022.175468. Epub 2022 Dec 22.