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 μM)suppressed the phosphorylated activation of NF-κB 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 μM)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.

Jin-cheng Wang;Qi Shi;Qian Zhou;Lu-lu Zhang;Yue-ping Qiu;Da-yong Lou;Li-qin Zhou;Bo Yang;Qiao-jun He;Qin-jie Weng;Jia-jia Wang

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;Hangzhou Institute of Innovative Medicine,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China;Department of Pharmacy,Hangzhou Medical College,Hangzhou 310053,China;Medication Department,Zhuji People's Hospital of Zhejiang Province,Zhuji,Shaoxing 311800,China

中国药理学报（英文版）

[1]Jin-cheng Wang;Qi Shi;Qian Zhou;Lu-lu Zhang;Yue-ping Qiu;Da-yong Lou;Li-qin Zhou;Bo Yang;Qiao-jun He;Qin-jie Weng;Jia-jia Wang-.Sapidolide A alleviates acetaminophen-induced acute liver injury by inhibiting NLRP3 inflammasome activation in macrophages)[J].中国药理学报（英文版）,2022(08):2016-2025

Sapidolide,AILI,Baccaurea,ramiflora

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