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Acta pharmacologica Sinica
Aug, 2022;43 (8): 2016-2025.

Sapidolide A alleviates acetaminophen-induced acute liver injury by inhibiting NLRP3 inflammasome activation in macrophages.

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
Author Information
  1. Jin-Cheng 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.
  2. Qi Shi: 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.
  3. Qian Zhou: Department of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, China.
  4. Lu-Lu Zhang: 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.
  5. Yue-Ping Qiu: 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.
  6. Da-Yong Lou: Medication Department, Zhuji People's Hospital of Zhejiang Province, Zhuji, Shaoxing, 311800, China.
  7. Li-Qin Zhou: Medication Department, Zhuji People's Hospital of Zhejiang Province, Zhuji, Shaoxing, 311800, China.
  8. Bo Yang: 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.
  9. Qiao-Jun He: 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.
  10. Qin-Jie Weng: 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.
  11. 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. wangjiajia3301@zju.edu.cn.
PMID: 35022542 DOI: 10.1038/s41401-021-00842-x

Abstract

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.

Keywords

NLRP3 inflammasome Sapidolide A acetaminophen acute liver injury bone marrow-derived primary macrophages (BMDM) pyroptosis

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MeSH Term

Acetaminophen
Adenosine Triphosphate
Animals
Humans
Inflammasomes
Lipopolysaccharides
Liver
Macrophages
Mice
Mice, Inbred C57BL
NLR Family, Pyrin Domain-Containing 3 Protein
NLR Proteins

Chemicals

Inflammasomes
Lipopolysaccharides
NLR Family, Pyrin Domain-Containing 3 Protein
NLR Proteins
Nlrp3 protein, mouse
Acetaminophen
Adenosine Triphosphate
Journal Article
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Word Cloud

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