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  2. Rosmarinic acid alleviates toosendanin-induced liver injury through restoration of autophagic flux and lysosomal function by activating JAK2/STAT3/CTSC pathway

Rosmarinic acid alleviates toosendanin-induced liver injury through restoration of autophagic flux and lysosomal function by activating JAK2/STAT3/CTSC pathway

  • J Ethnopharmacol. 2024 Aug 10:330:118196. doi: 10.1016/j.jep.2024.118196.
Li Luo 1 Jinxian Lin 1 Sixin Chen 1 Jiajie Ni 1 Hongjie Peng 1 Feihai Shen 2 Zhiying Huang 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, China. Electronic address: tobyshum12@163.com.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: hzhiying@mail.sysu.edu.cn.
Abstract

Ethnopharmacological relevance: Rosmarinic acid (RA), a natural polyphenol abundant in numerous herbal remedies, has been attracting growing interest owing to its exceptional ability to protect the liver. Toosendanin (TSN), a prominent bioactive compound derived from Melia toosendan Siebold & Zucc., boasts diverse pharmacological properties. Nevertheless, TSN possesses remarkable hepatotoxicity. Intriguingly, the potential of RA to counteract TSN-induced liver damage and its probable mechanisms remain unexplored.

Aim of the study: This study is aimed at exploring whether RA can alleviate TSN-induced liver injury and the potential mechanisms involved Autophagy.

Materials and methods: CCK-8 and LDH leakage rate assay were used to evaluate cytotoxicity. Balb/c mice were intraperitoneally administered TSN (20 mg/kg) for 24 h after pretreatment with RA (0, 40, 80 mg/kg) by gavage for 5 days. The autophagic proteins p62 and LC3B expressions were detected using western blot and immunohistochemistry. RFP-GFP-LC3B and transmission electron microscopy were applied to observe the accumulation levels of autophagosomes and autolysosomes. LysoTracker Red and DQ-BSA staining were used to evaluate the lysosomal acidity and degradation ability respectively. Western blot, immunohistochemistry and immunofluorescence staining were employed to measure the expressions of JAK2/STAT3/CTSC pathway proteins. Dual-luciferase reporter gene was used to measure the transcriptional activity of CTSC and RT-PCR was used to detect its mRNA level. H&E staining and serum biochemical assay were employed to determine the degree of damage to the liver.

Results: TSN-induced damage to hepatocytes and livers was significantly alleviated by RA. RA markedly diminished the autophagic flux blockade and lysosomal dysfunction caused by TSN. Mechanically, RA alleviated TSN-induced down-regulation of CTSC by activating JAK2/STAT3 signaling pathway.

Conclusion: RA could protect against TSN-induced liver injury by activating the JAK2/STAT3/CTSC pathway-mediated Autophagy and lysosomal function.

Keywords

Autophagy; Hepatotoxicity; JAK2/STAT3/CTSC pathway; Rosmarinic acid; Toosendanin.

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