PMID- 35749827 OWN - NLM STAT- MEDLINE DCOM- 20220809 LR - 20220809 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 104 DP - 2022 Sep TI - Kinsenoside alleviates inflammation and fibrosis in experimental NASH mice by suppressing the NF-kappaB/NLRP3 signaling pathway. PG - 154241 LID - S0944-7113(22)00320-8 [pii] LID - 10.1016/j.phymed.2022.154241 [doi] AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) has replaced viral hepatitis as the main driver of the rising morbidity and mortality associated with cirrhosis and liver cancer worldwide, while no FDA-approved therapies are currently known. Kinsenoside (KD), naturally isolated from Anoectochilus roxburghii, possesses multiple biological activities, including lipolysis, anti-inflammation, and hepatoprotection. However, the effects of KD on NASH remain unclear. PURPOSE: This study aimed to explore the roles of KD in NASH and its engaged mechanisms. METHODS: Two typical animal models of NASH, mice fed a methionine-choline-deficient (MCD) diet (representing non-obese NASH) and mice fed a high-fat and -fructose diet (HFFD) (representing obese NASH), were used to investigate the effect of KD on NASH in vivo. Transcriptome sequencing was performed to elucidate the underlying mechanisms of KD. Lipopolysaccharide (LPS)-stimulated THP-1 cells and transforming growth factor beta1 (TGF-beta1)-activated LX-2 cells were applied to further explore the effects and mechanisms of KD in vitro. RESULTS: The intragastric administration of KD remarkably alleviated MCD/HFFD-induced murine NASH almost in a dose-dependent manner. Specifically, KD reduced lipid accumulation, inflammation, and fibrosis in the liver of NASH mice. KD ameliorated alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), and malondialdehyde (MDA) abnormalities. In addition, it decreased the level of serum proinflammatory factors (IL-12p70, IL-6, TNF-alpha, MCP-1, IFN-gamma) and the hepatic expression of typical fibrosis-related molecules (alpha-SMA, Col-I, TIMP-1). Mechanically, KD attenuated the MCD/HFFD-induced NASH through the inhibition of the NF-kappaB/NLRP3 signaling pathway. Consistently, KD reduced inflammation stimulated by LPS in THP-1 cells via suppressing the NF-kappaB/NLRP3 pathway. Furthermore, it prevented the activation of LX-2 cells directly, by inhibiting the proliferation stimulated by TGF-beta1, and indirectly, by inactivating the NLRP3 inflammasome in macrophages. CONCLUSION: For the first time, the practical improvement of NASH by KD was revealed. Our study found that KD exerted its alleviative effects on NASH through the inhibition of the NF-kappaB/NLRP3 signaling pathway. Given its hepatoprotective and nontoxic properties, KD has the potential to be a novel and effective drug to treat NASH. CI - Copyright (c) 2022. Published by Elsevier GmbH. FAU - Deng, Yan-Fang AU - Deng YF AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Xu, Qian-Qian AU - Xu QQ AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Chen, Tian-Qi AU - Chen TQ AD - First College of Clinical Medical Science, China Three Gorges University & Yichang Central People's Hospital, Yichang 443003, China. FAU - Ming, Jia-Xiong AU - Ming JX AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Wang, Ya-Fen AU - Wang YF AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Mao, Li-Na AU - Mao LN AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Zhou, Jia-Jun AU - Zhou JJ AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Sun, Wei-Guang AU - Sun WG AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: weiguang_sun@hust.edu.cn. FAU - Zhou, Qun AU - Zhou Q AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: zqtcm@163.com. FAU - Ren, Hong AU - Ren H AD - Biobank, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: renhong@hust.edu.cn. FAU - Zhang, Yong-Hui AU - Zhang YH AD - Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: zhangyh@mails.tjmu.edu.cn. LA - eng PT - Journal Article DEP - 20220615 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (3-glucopyranosyloxybutanolide) RN - 0 (Lipopolysaccharides) RN - 0 (Monosaccharides) RN - 0 (NF-kappa B) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Transforming Growth Factor beta1) RN - AE28F7PNPL (Methionine) RN - OL659KIY4X (4-Butyrolactone) SB - IM MH - 4-Butyrolactone/analogs & derivatives MH - Animals MH - Fibrosis MH - Inflammation/metabolism MH - Lipopolysaccharides/pharmacology MH - Liver MH - Methionine/metabolism/pharmacology MH - Mice MH - Mice, Inbred C57BL MH - Monosaccharides MH - NF-kappa B/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - *Non-alcoholic Fatty Liver Disease/metabolism MH - Signal Transduction MH - Transforming Growth Factor beta1/metabolism OTO - NOTNLM OT - Fibrosis OT - Inflammation OT - Kinsenoside OT - NASH OT - NLRP3 OT - Steatosis EDAT- 2022/06/25 06:00 MHDA- 2022/08/10 06:00 CRDT- 2022/06/24 18:13 PHST- 2022/01/09 00:00 [received] PHST- 2022/05/27 00:00 [revised] PHST- 2022/06/02 00:00 [accepted] PHST- 2022/06/25 06:00 [pubmed] PHST- 2022/08/10 06:00 [medline] PHST- 2022/06/24 18:13 [entrez] AID - S0944-7113(22)00320-8 [pii] AID - 10.1016/j.phymed.2022.154241 [doi] PST - ppublish SO - Phytomedicine. 2022 Sep;104:154241. doi: 10.1016/j.phymed.2022.154241. Epub 2022 Jun 15.