Journal
DRUG DESIGN DEVELOPMENT AND THERAPY
Volume 12, Issue -, Pages 3595-3605Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S179876
Keywords
asiatic acid; liver fibrosis; Nrf2-ARE; NF-kappa B/I kappa B alpha; JAK1/STAT3
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Funding
- National Natural Science Foundation of China [81773797, 81803815]
- Shanghai Jiao Tong University School of Medicine [JDYX2017QN008]
- Shanghai municipal medical and discipline construction projects [2017ZZ02015]
- Fundamental Research Funds for the Central Universities [1515219051]
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Purpose: Currently, there are no effective therapies for liver fibrosis; hence, the development of anti-liver fibrosis agents is urgently needed. Here, we attempted to investigate the therapeutic effect and mechanism of asiatic acid (AA) on liver fibrosis, mainly focusing on the impact of AA on nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor-kappa B (NF-kappa B)/I kappa B alpha, and JAK1/signal transducer and activator of transcription 3 (STAT3) signaling pathways. Methods: Rats were induced liver fibrosis by carbon tetrachloride (CCl4) for 6 weeks and concomitantly treated with AA (5 and 15 mg/kg) or vehicle by daily gavage. After AA treatment, the morphology of liver tissue was analyzed by H&E and Masson's trichrome staining, and serum biochemical indicators were also assayed. Thereafter, the protein levels of Nrf2, HO-1, NQO-1, GCLC, NF-kappa B, I kappa B alpha, JAK1, p-JAK1, STAT3, and p-STAT3 were determined by Western blotting. Results: Our results showed that AA treatment dramatically ameliorated CCl4-induced oxidative stress, inflammation, and fibrosis in rats. The expression of nuclear Nrf2 was increased after AA treatment, whereas cytoplasm Nrf2 levels were decreased. The protein expression of Nrf2 target proteins including HO-1, NQO-1, and GCLC was significantly increased by AA treatment. Furthermore, AA treatment decreased the levels of nuclear NF-kappa B to inhibit NF-kappa B/I kappa B alpha signaling pathway. In addition, we also found that AA treatment regulated JAK1/STAT3 signaling by decreasing the phosphorylation levels of JAK1 and STAT3. Conclusion: These results demonstrate that AA ameliorates CCl4-induced liver fibrosis in rats by regulating Nrf2/ARE, NF-kappa B/I kappa B alpha, and JAK1/STAT3 signaling pathways, which suggests that AA might be a new antifibrosis agent that improves liver fibrosis.
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