Background: Didymin has been reported to have anti-cancer potential. However, the effect of didymin on liver fibrosis remains illdefined. Methods: Hepatic fibrosis was induced by CCl4 in rats. The effects of didymin on liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson's trichrome staining, respectively. Serum transaminases activities and collagen-related indicators levels were determined by commercially available kits. Moreover, the effects of didymin on hepatic stellate cell apoptosis and cell cycle were analyzed by flow cytometry. Mitochondrial membrane potential was detected by using rhodamine-123 dye. The expression of Raf kinase inhibitor protein (RKIP) and the phosphorylation of the ERK/MAPK and PI3K/Akt pathways were assessed by Western blot. Results: Didymin significantly ameliorated chronic liver injury and collagen deposition. It strongly inhibited hepatic stellate cells proliferation, induced apoptosis and caused cell cycle arrest in G2/M phase. Moreover, didymin notably attenuated mitochondrial membrane potential, accompanied by release of cytochrome C. Didymin significantly inhibited the ERK/MAPK and PI3K/Akt pathways. The effects of didymin on the collagen accumulation in rats and on the biological behaviors of hepatic stellate cells were largely abolished by the specific RKIP inhibitor locostatin. Conclusion: Didymin alleviates hepatic fibrosis by inhibiting ERK/MAPK and PI3K/Akt pathways via regulation of RKIP expression.
Background/Aims: Previous studies have shown that trolline possesses various forms of pharmacological activity, including antibacterial and antiviral potency. The present paper addressed the putative hepatoprotective effects of trolline. Methods: Rats received 2 ml/kg CCl4 (mixed 1: 1 in peanut oil) intragastrically twice a week for 8 weeks to induce hepatic fibrosis. The animals were then treated with trolline for additional 4 weeks. Liver pathology and collagen accumulation were observed by hematoxylin-eosin and Masson’s trichrome staining, respectively. Serum transaminase activity and collagen-related indicator level were determined by commercially available kits. NF-κB pathway activation was also examined. Moreover, the effects of trolline on hepatic stellate cell (HSC-T6) apoptosis, mitochondrial membrane potential (MMP), and autophagy were assessed. Results: Trolline significantly alleviated CCl4-induced liver injury and notably reduced the accumulation of collagen in liver tissues. Trolline treatment also markedly decreased inflammatory cytokines levels by inhibiting the NF-κB pathway. Trolline strongly inhibited HSC-T6 activation and notably induced cell apoptosis by modulating the Bax/Bcl-2 ratio, caspase activity, and MMP. Moreover, trolline significantly inhibited HSC-T6 autophagy, as evidenced by the decrease in the formation of autophagic vacuoles and the number of autophagosomes, by regulating the expression levles of LC3, Beclin-1, P62, Atg 5 and 7. Conclusion: Our study demonstrates that trolline ameliorates liver fibrosis, possibly by inhibiting the NF-κB pathway, promoting HSCs apoptosis and suppressing autophagy.
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