Betulinic acid attenuated bleomycin-induced pulmonary fibrosis by effectively intervening Wnt/β-catenin signaling
Autor: | Xiaohe Li, Wen Ning, Zhenzhen Wang, Yimeng Ren, Yunqian Zhai, Hailong Li, Shaoyan Gao, Qiuyan Jiang, Deng Ruxia, Cheng Yang, Liu Rui, Yang Miao, Shanshan Zhang, Xiaowei Liu, Honggang Zhou |
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Rok vydání: | 2020 |
Předmět: |
Male
Pharmaceutical Science 03 medical and health sciences Idiopathic pulmonary fibrosis Bleomycin 0302 clinical medicine In vivo Fibrosis Drug Discovery Pulmonary fibrosis medicine Animals Phosphorylation Betulinic Acid Myofibroblasts Wnt Signaling Pathway beta Catenin 030304 developmental biology Pharmacology 0303 health sciences Chemistry Wnt signaling pathway LRP6 Fibroblasts medicine.disease Idiopathic Pulmonary Fibrosis Mice Inbred C57BL Wnt Proteins Complementary and alternative medicine Gene Expression Regulation 030220 oncology & carcinogenesis Cancer research Molecular Medicine Pentacyclic Triterpenes Myofibroblast WNT3A Signal Transduction |
Zdroj: | Phytomedicine : international journal of phytotherapy and phytopharmacology. 81 |
ISSN: | 1618-095X |
Popis: | Background Idiopathic pulmonary fibrosis (IPF) is a fatal and progressive fibrotic lung disease lacking a validated and effective therapy. Aberrant activation of the Wnt/β-catenin signaling cascade plays the key role in the pathogenesis of IPF. Betulinic acid is a natural pentacyclic triterpenoid molecule that has excellent antitumor and antiviral activities. Hypothesis We hypothesized that BA has an anti-pulmonary fibrosis effect mediated by the suppression of the Wnt/β-catenin pathway. Study design Pulmonary fibrosis markers were detected in vitro and in vivo to confirm the antifibrotic effect of BA. The Wnt/β-catenin pathway-related proteins were overexpressed to determine the effect of BA on Wnt signaling. Methods and results BA dose-dependently inhibited Wnt3a-induced fibroblast activation in vitro. Moreover, BA decreased Wnt3a- and LiCl-induced transcriptional activity, as assessed by the TOPFlash assay in fibroblasts, and repressed the expression of the Wnt target genes cyclin D1, axin 2, and S100A4. Further investigation indicated that BA restrained the nuclear accumulation of β-catenin, mainly by increasing the phospho-β-catenin ratio (S33/S37/T41 and S45), inhibited the phosphorylation of DVL2 and LRP, and decreased the levels of Wnt3a and LRP6. In agreement with the results of the in vitro assays, the in vivo experiments indicated that BA significantly decreased bleomycin-induced pulmonary fibrosis in mice and suppressed myofibroblast activation by inhibiting Wnt/β-catenin signaling. Conclusion BA may directly interfere with the Wnt/β-catenin pathway to subsequently repress myofibroblast activation and pulmonary fibrosis. |
Databáze: | OpenAIRE |
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