PMID- 35749855 OWN - NLM STAT- MEDLINE DCOM- 20220815 LR - 20220824 IS - 1090-2120 (Electronic) IS - 0045-2068 (Linking) VI - 127 DP - 2022 Oct TI - Dehydromevalonolactone ameliorates liver fibrosis and inflammation by repressing activation of NLRP3 inflammasome. PG - 105971 LID - S0045-2068(22)00376-5 [pii] LID - 10.1016/j.bioorg.2022.105971 [doi] AB - Liver fibrosis is an important process in chronic liver disease and is strongly related to poor prognosis. Dehydromevalonolactone (C8) is a natural product isolated from a fungus of Fusarium sp. CPCC 401218, and its pharmacological activity has never been reported before. In this study, the potential of C8 as an anti-hepatic fibrosis agent was investigated. In human hepatic stellate cell (HSC) line LX-2, C8 suppressed the increased expression of COL1A1 and alpha-SMA induced by TGFbeta1, which indicated that C8 could repress the activation of HSCs. In bile duct ligated rats, C8 administration (100 mg/kg, i.p.) markedly attenuated liver injury, fibrosis, and inflammation, and suppressed the expression of the macrophage surface marker F4/80. In terms of mechanism, C8 treatment blocked the activation of the NLRP3 inflammasome, which was stimulated by LPS and nigericin in bone marrow-derived macrophages (BMDMs) and companied by the release of active IL-1beta. In addition, the activation of LX-2 cells induced by IL-1beta released from BMDMs was also inhibited after C8 administration, which indicated that C8 repressed HSCs activation by inhibiting the activation of NLRP3 inflammasome in macrophages. Furthermore, C8 exhibited the effects of anti-fibrosis and inhibiting the expression of NLRP3 inflammasome in non-alcoholic steatohepatitis (NASH) mice. Finally, C8 can be commendably absorbed in vivo and was safe for mice at the concentration of 1000 mg/kg (p.o.). In summary, our study reveals that C8 ameliorates HSCs activation and liver fibrosis in cholestasis rats and NASH mice by inhibiting NLRP3 inflammasome in macrophages, and C8 might be a safe and effective candidate for the treatment of liver fibrosis. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Niu, Wei-Xiao AU - Niu WX AD - Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. FAU - Bao, Yun-Yang AU - Bao YY AD - Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. FAU - Zhang, Na AU - Zhang N AD - Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. FAU - Lu, Zhen-Ning AU - Lu ZN AD - Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. FAU - Ge, Mao-Xu AU - Ge MX AD - Department of Pharmacy, Qilu Hospital of Shandong University, Jinan 250012, China. FAU - Li, Yi-Ming AU - Li YM AD - Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. FAU - Li, Yi AU - Li Y AD - Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. FAU - Chen, Ming-Hua AU - Chen MH AD - Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: chenminghua@imb.pumc.edu.cn. FAU - He, Hong-Wei AU - He HW AD - Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: hehwei@imb.pumc.edu.cn. LA - eng PT - Journal Article DEP - 20220616 PL - United States TA - Bioorg Chem JT - Bioorganic chemistry JID - 1303703 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Nlrp3 protein, rat) RN - 661X270Z3L (mevalonolactone) RN - S5UOB36OCZ (Mevalonic Acid) SB - IM MH - Animals MH - Fibrosis MH - Humans MH - *Inflammasomes/metabolism MH - Inflammation/metabolism MH - Liver/metabolism MH - Liver Cirrhosis/chemically induced/drug therapy/metabolism MH - Mevalonic Acid/*analogs & derivatives/analysis/pharmacology/therapeutic use MH - Mice MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - *Non-alcoholic Fatty Liver Disease/drug therapy MH - Rats OTO - NOTNLM OT - Bile duct ligation OT - Hepatic stellate cells OT - IL-1beta OT - Liver fibrosis OT - NASH OT - NLRP3 inflammasome EDAT- 2022/06/25 06:00 MHDA- 2022/08/16 06:00 CRDT- 2022/06/24 18:15 PHST- 2022/03/04 00:00 [received] PHST- 2022/06/07 00:00 [revised] PHST- 2022/06/13 00:00 [accepted] PHST- 2022/06/25 06:00 [pubmed] PHST- 2022/08/16 06:00 [medline] PHST- 2022/06/24 18:15 [entrez] AID - S0045-2068(22)00376-5 [pii] AID - 10.1016/j.bioorg.2022.105971 [doi] PST - ppublish SO - Bioorg Chem. 2022 Oct;127:105971. doi: 10.1016/j.bioorg.2022.105971. Epub 2022 Jun 16.