PMID- 35022542 OWN - NLM STAT- MEDLINE DCOM- 20220803 LR - 20230802 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 43 IP - 8 DP - 2022 Aug TI - Sapidolide A alleviates acetaminophen-induced acute liver injury by inhibiting NLRP3 inflammasome activation in macrophages. PG - 2016-2025 LID - 10.1038/s41401-021-00842-x [doi] AB - Macrophages play a critical role in the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure or even death. Sapidolide A (SA) is a sesquiterpene lactone extracted from Baccaurea ramiflora Lour., a folk medicine used in China to treat inflammatory diseases. In this study, we investigated whether SA exerted protective effects on macrophages, thus alleviated the secondary hepatocyte damage in an AILI. We showed that SA (5-20 muM) suppressed the phosphorylated activation of NF-kappaB in a dose-dependent manner, thereby inhibiting the expression and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in LPS/ATP-treated mouse bone marrow-derived primary macrophages (BMDMs). In human hepatic cell line L02 co-cultured with BMDMs, SA (10 muM) protected macrophages from the pyroptosis induced by APAP-damaged L02 cells. Moreover, SA treatment reduced the secondary liver cell damage aggravated by the conditioned medium (CM) taken from LPS/ATP-treated macrophages. The in vivo assessments conducted on mice pretreated with SA (25, 50 mg/kg, ip) then with a single dose of APAP (400 mg/kg, ip) showed that SA significantly alleviated inflammatory responses of AILI by inhibiting the expression and activation of the NLRP3 inflammasome. In general, the results reported herein revealed that SA exerts anti-inflammatory effects by regulating NLRP3 inflammasome activation in macrophages, which suggests that SA has great a potential for use in the treatment of AILI patients. CI - (c) 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society. FAU - Wang, Jin-Cheng AU - Wang JC AD - Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Shi, Qi AU - Shi Q AD - Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. AD - Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Zhou, Qian AU - Zhou Q AD - Department of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, China. FAU - Zhang, Lu-Lu AU - Zhang LL AD - Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Qiu, Yue-Ping AU - Qiu YP AD - Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Lou, Da-Yong AU - Lou DY AD - Medication Department, Zhuji People's Hospital of Zhejiang Province, Zhuji, Shaoxing, 311800, China. FAU - Zhou, Li-Qin AU - Zhou LQ AD - Medication Department, Zhuji People's Hospital of Zhejiang Province, Zhuji, Shaoxing, 311800, China. FAU - Yang, Bo AU - Yang B AD - Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. AD - Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - He, Qiao-Jun AU - He QJ AD - Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. AD - Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Weng, Qin-Jie AU - Weng QJ AD - Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. AD - Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Wang, Jia-Jia AU - Wang JJ AD - Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. wangjiajia3301@zju.edu.cn. LA - eng PT - Journal Article DEP - 20220112 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Inflammasomes) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLR Proteins) RN - 0 (Nlrp3 protein, mouse) RN - 362O9ITL9D (Acetaminophen) RN - 8L70Q75FXE (Adenosine Triphosphate) SB - IM MH - Acetaminophen MH - Adenosine Triphosphate/metabolism MH - Animals MH - Humans MH - *Inflammasomes/metabolism MH - Lipopolysaccharides/pharmacology MH - Liver/metabolism MH - Macrophages/metabolism MH - Mice MH - Mice, Inbred C57BL MH - *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - NLR Proteins/metabolism PMC - PMC9343373 OTO - NOTNLM OT - NLRP3 inflammasome OT - Sapidolide A OT - acetaminophen OT - acute liver injury OT - bone marrow-derived primary macrophages (BMDM) OT - pyroptosis COIS- The authors declare no competing interests. EDAT- 2022/01/14 06:00 MHDA- 2022/08/04 06:00 PMCR- 2023/08/01 CRDT- 2022/01/13 06:05 PHST- 2021/08/10 00:00 [received] PHST- 2021/12/10 00:00 [accepted] PHST- 2022/01/14 06:00 [pubmed] PHST- 2022/08/04 06:00 [medline] PHST- 2022/01/13 06:05 [entrez] PHST- 2023/08/01 00:00 [pmc-release] AID - 10.1038/s41401-021-00842-x [pii] AID - 842 [pii] AID - 10.1038/s41401-021-00842-x [doi] PST - ppublish SO - Acta Pharmacol Sin. 2022 Aug;43(8):2016-2025. doi: 10.1038/s41401-021-00842-x. Epub 2022 Jan 12.