2. Academic Validation
  3. Gancao decoction attenuates hepatic necroptosis via activating caspase 8 in cholestatic liver injury

Gancao decoction attenuates hepatic necroptosis via activating caspase 8 in cholestatic liver injury

  • J Ethnopharmacol. 2024 Feb 11:326:117909. doi: 10.1016/j.jep.2024.117909.
Bin Zou 1,  Shuang Zhang 1,  Fengling Li 1,  Fengyi Weng 1,  Jing Zhao 1,  Jingyi Jin 1,  Dongming Yan 1,  Xiaoqing Xu 1,  Gaofeng Chen 2,  Chenghai Liu 2,  Chengzeng Yao 3,  Yue Li 4,  Furong Qiu 5
Affiliations

Affiliations

  • 1 Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China.
  • 2 Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China.
  • 3 Cardiology Deparment, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: [email protected].
  • 4 Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: [email protected].
  • 5 Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: [email protected].
PMID: 38350503 DOI: 10.1016/j.jep.2024.117909
Abstract

Ethnopharmacological relevance: Gancao Decoction (GCD) is widely used to treat cholestatic liver injury. However, it is unclear whether is related to prevent hepatocellular Necroptosis.

Aim of the study: The purpose of this study is to clarify the therapeutic effects of GCD against hepatocellular Necroptosis induced by cholestasis and its active components.

Materials and methods: We induced cholestasis model in wild type mice by ligating the bile ducts or in Nlrp3-/- mice by intragastrical administering Alpha-naphthylisothiocyanate (ANIT). Serum biochemical indices, liver pathological changes and hepatic bile acids (BAs) were measured to evaluate GCD's hepatoprotective effects. Necroptosis was assessed by expression of hallmarkers in mice liver. Moreover, the potential anti-necroptotic effect of components from GCD were investigated and confirmed in ANIT-induced cholestasis mice and in primary hepatocytes from WT mouse stimulated with Tumor Necrosis Factor alpha (TNF-α) and cycloheximide (CHX).

Results: GCD dose-dependently alleviated hepatic necrosis, reduced serum aminotranferase activity in both BDL and ANIT-induced cholestasis models. More importantly, the expression of hallmarkers of Necroptosis, including MLKL, RIPK1 and RIPK3 phosphorylation (p- MLKL, p-RIPK1, p-RIPK3) were reduced upon GCD treatment. Glycyrrhetinic acid (GA), the main bioactive metabolite of GCD, effectively protected against ANIT-induced cholestasis, with decreased expression of p-MLKL, p-RIPK1 and p-RIPK3. Meanwhile, the expression of Fas-associated death domain protein (FADD), long isoform of cellular FLICE-like inhibitory protein (cFLIPL) and cleaved Caspase 8 were upregulated upon GA treatment. Moreover, GA significantly increased the expression of active Caspase 8, and reduced that of p-MLKL in TNF-α/CHX induced hepatocytes Necroptosis.

Conclusions: GCD substantially inhibits Necroptosis in cholestatic liver injury. GA is the main bioactive component responsible for the anti-necroptotic effects, which correlates with upregulation of c-FLIPL and active Caspase 8.

Keywords

Caspase 8; Cholestasis; Gancao decoction; Glycyrrhetinic acid; Necroptosis.

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