Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 154, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2022.113603
Keywords
Pulmonary fibrosis; Autophagy; Astragaloside; Ras; Raf; MEK; ERK signaling pathway; Extracellular matrix
Funding
- National Natural Science Foundation of China [81860646, 31860274]
- Yunnan Provincial Science and Technology Department [2019FI016, 202201AS070084, 202005AC160058, 202101AZ070001-012, 202105AF150031, 202102AE090031]
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Astragaloside (AST) can treat pulmonary fibrosis by modulating the autophagy process and the Ras/Raf/MEK/ERK signaling pathway.
Pulmonary fibrosis is an abnormal wound-healing response to repeated alveolar injury, characterized by continuous inflammation and abnormal collagen deposition. Its treatment is problematic. Astragaloside (AST) is an active component of Astragalus membranaceus with anti-inflammatory and anti-tumor properties. Although the underlying mechanisms are unknown, AST is also used to treat fibrotic diseases. This study aimed to investigate the mechanisms of action of AST in pulmonary fibrosis treatment. We found that AST significantly improved restrictive ventilatory impairment, compliance, total lung capacity, and functional residual capacity. In mice with pulmonary fibrosis, extracellular matrix deposition in the pulmonary parenchyma and intemperate inflammation were reversed. This therapeutic effect can be attributed to autophagy, activating the genes for autophagy flux and autophagic vacuoles. Impaired autophagy increased susceptibility to pulmonary fibrosis by exacerbating collagen deposition in vitro and in vivo. Using a combination of molecular docking and network pharmacology, the Ras/Raf/MEK/ERK signaling pathway was identified as a possible candidate for the phar-macologic target of AST. Functional dephosphorylation of MEK and ERK inhibited the Ras/Raf/MEK/ERK signaling pathway, which converges at the rapamycin switch to initiate autophagy. Inhibitors of Ras and MEK regulated autophagy. These findings suggest that AST might treat pulmonary fibrosis by modulating the Ras/Raf/ MEK/ERK signaling pathway mediated by depression.
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