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  • MiR has already been implicated in the protective effects of

    2024-05-15

    MiR-21 has already been implicated in the protective effects of Res on lung fibrosis, but the molecular mechanisms are underexplored. Our results showed a clear increase of activation protein 1 (AP-1) activity after TGF-β treatment, which was suppressed by Res in a dose-dependent manner, suggesting that the decrease in miR-21 expression induced by Res is related with AP-1 family proteins. Our results were consistent with a prior study which indicated that Res inhibited the activation of AP-1 [35]. AP-1 is composed of c-Fos and c-Jun, and further experiments found that the expression of p-c-Jun, c-Jun, and c-Fos were markedly increased by TGF-β stimulation and significantly reduced with Res treatment. The miR-21 promoter contains AP-1 binding sites, which acts as a target for the activated AP-1 complex [36]. Res has been shown to decrease the levels of c-Jun and c-Fos at both the protein and mRNA levels in papillary thyroid cancer GSK-3 Inhibitor IX [37], which further supports our results. In addition, the activation of AP-1 is regulated by several MAPKs, including ERK, JNK and p38 [19], which have been proven to be involved in TGF-β–induced phenotypic transformation of human lung fibroblasts into myofibroblasts [38]. We found that activation of AP-1 upon TGF-β stimulation was accompanied by increased levels of p-ERK, p-JNK, and p-p38 in MRC-5 cells, but that TGF-β–induced phosphorylation of ERK, JNK, and p38 was remarkably inhibited by Res treatment. Based on the involvement of MAPKs in tumor growth, apoptosis and inflammation [39], we suspect that the inhibition of MAPK signaling pathways by Res may become a novel direction for the treatment of inflammatory diseases. The results of this study provide strong evidence demonstrating that Res inhibits the activation of MAPK/AP-1 pathways induced by TGF-β. In conclusion, our in vitro and in vivo findings provide the first evidence that Res exerts anti-fibrotic properties in BLM-induced pulmonary fibrosis by regulating fibrosis-related genes of the TGF-β1/Smad pathway via miR-21. Smad7 is identified as a novel target of miR-21 that can inhibit the protective effect of Res on PF. Moreover, the suppression of miR-21 by Res is achieved through c-Jun and c-Fos and blockage of MAPKs/AP-1 signaling pathways. Collectively, we summarize the mechanism of Res in the regulation of pulmonary fibrosis as follows: Res treatment blocks the activation of MAPK/AP-1 pathways and suppresses miR-21 expression, which inhibits Smad7, subsequently leading to an alleviation of pulmonary fibrosis. The present study contributes data for a better understanding of Res-mediated signal transduction and gene regulation involved in pulmonary fibrosis and provides support for the application of resveratrol as a potential therapeutic drug for treating pulmonary fibrosis.
    Conflict of interests
    Acknowledgements This study was supported by Associated Project of Yunnan Province Science and Technology Department and Kunming Medical University Basic Research for Application (Grant No.: 2017FE467(-207)), Yunnan Applied Basic Research Projects (Grant No.: 2016FB131) and National Natural Science Foundation of China (Grant No.: 81760407).
    Introduction Hepatic fibrosis, a wound-healing response, is a necessarily stage from the progression of chronic liver diseases to cirrhosis, even hepatocellular carcinoma (HCC) [1]. Hepatic fibrosis is characterized by the progressive accumulation of extracellular matrix (ECM) [2]. Viral infection (chronic HBV or HCV infection) is one of the most important risk factors which could result in hepatic fibrosis [3]. Hepatocytes themselves possess a significant regenerative capacity. If the liver is damaged continuously and heavily, fibrotic cells would be activated [4]. The activated hepatic stellate cells (HSCs), the most important fibrotic cells, would transform into proliferative and contractile myofibroblast-like cells, and produce a lot of ECMs and related proteins, such as collagen I, α-SMA, and the platelet-derived growth factor (PDGF) receptor. [5–7]. The balance between ECM production and degradation is mediated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which are produced by HSCs. If the balance between them loses, degradation or deposition of ECMs would happen, and hepatic fibrosis would form. Unfortunately, there are not effective pharmaceutical therapies to hepatic fibrosis worldwide [4].