Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver

Abstract

In general, anti-inflammatory treatment is considered for multiple liver diseases despite the etiology. But current drugs for alleviating liver inflammation have defects, making it necessary to develop more potent and safer drugs for liver injury. In this study, we screened a series of (dihydro-)stilbene or (dihydro-)phenanthrene derivatives extracted from Pholidota chinensis for their potential biological activities. Among 31 compounds, the dihydro-stilbene gigantol exerted most potent protective effects on human hepatocytes against lithocholic acid toxicity, and exhibited solid antioxidative and anti-inflammatory effect in vitro. In mice with CCl4-induced acute liver injury, pre-administration of gigantol (10, 20, 40 mg· kg−1· d−1, po, for 7 days) dose-dependently decreased serum transaminase levels and improved pathological changes in liver tissues. The elevated lipid peroxidation and inflammatory responses in the livers were also significantly alleviated by gigantol. The pharmacokinetic studies showed that gigantol was highly concentrated in the mouse livers, which consisted with its efficacy in preventing liver injury. Using a label-free quantitative proteomic analysis we revealed that gigantol mainly regulated the immune system process in liver tissues of CCl4-treated mice, and the complement and coagulation cascades was the predominant pathway; gigantol markedly inhibited the expression of complement component C9, which was a key component for the formation of terminal complement complex (TCC) C5b-9. These results were validated by immunohistochemistry (IHC) or real time-PCR. Confocal microscopy analysis showed that gigantol significantly inhibited the vascular deposition of TCC in the liver. In conclusion, we demonstrate for the first time that oral administration of gigantol potently relieves liver oxidative stress and inflammation, possibly via a novel mechanism of inhibiting the C5b-9 formation in the liver.

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Acknowledgements

This study was supported by the ‘Organ Reconstruction and Manufacturing’ Strategic Priority Research Program of the Chinese Academy of Sciences [grant number XDA16020205], the National Science Foundation of China [grant number 81872927], the International Partnership Program of Chinese Academy of Sciences [grant number 153631KYSB20160004], the Independent Deployment Program of the Institute of Pharmaceutical Innovation of the Chinese Academy of Sciences [grant number CASIMM0120184005], and the China Postdoctoral Science Foundation [grant number 2019M651623].

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YRX, GYP, SY and YY designed the research; YRX and GYP wrote the paper; YRX, QL, ZLP, QQD, BL, SY, and ZHM conducted the experiments; YRX, QL, and ZLP were responsible for the data analysis; SY, QL, LW, and HZ helped revise the paper. All the authors reviewed and agreed on the final version.

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Correspondence to Yang Ye or Guo-yu Pan.

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Xue, Y., Yao, S., Liu, Q. et al. Dihydro-stilbene gigantol relieves CCl4-induced hepatic oxidative stress and inflammation in mice via inhibiting C5b-9 formation in the liver. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-0406-6

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Keywords

  • gigantol
  • Chinese traditional medicine
  • liver injury
  • oxidative stress
  • inflammation
  • label-free proteomic
  • complement and coagulation cascades
  • terminal complement complex