Abstract
Pulmonary fibrosis (PF) is a devastating lung disease that leads to impaired lung function and ultimately death. Several studies have suggested that melatonin, a hormone involved in regulating sleep–wake cycles, may be effective in improving PF. Ramelteon, an FDA-approved melatonin receptor agonist, has shown promise in exerting an anti-PF effect similar to melatonin. However, further investigations are required for illuminating the extent on its therapeutic benefits and the underlying molecular mechanisms. In this work, a mouse lung fibrosis model was built through intratracheal administration of bleomycin (BLM). Subsequently, the mice were administrated Ramelteon for a duration of 3 weeks to explore its efficacy and mechanism of action. Additionally, we utilized a TGF-β1-induced MRC-5 cell model to further investigate the molecular mechanism underlying ramelteon’s effects. Functionally, Ramelteon partially abrogated TGF-β1-induced pulmonary fibrosis and reduced fibroblast proliferation, extracellular matrix deposition, and differentiation into myofibroblasts. In vivo experiments, ramelteon attenuated BLM-induced pulmonary fibrosis and collagen deposition. Mechanistically, ramelteon exerts its beneficial effect by alleviating translocation and expression of YAP1, a core component of Hippo pathway, from cytoplasm to nucleus; however, overexpression of YAP1 reversed this effect. In conclusion, our findings indicate that ramelteon can improve PF by regulating Hippo pathway and may become a potential candidate as a therapy to PF.
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Acknowledgements
The authors would like to thank the Shenzhen University Health Science Center for instrumental support.
Funding
This study was supported by the National Natural Science Foundation of China (U21A20339, 32171127) and the Outstanding Youth Scientific Fund Project of Heilongjiang Province (JQ2022H001).
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Haihai Liang and Lei Zhang conceived and designed the study. Lei Zhang performed cell experiments, analyzed the data. Ting Cheng was involved in the animal and cell experiments. Wenxian Chen, Changsheng Zhong, and Mengyang Li assisted the animal experiments. Yilin Xie assisted the cell experiments. Qin Deng and Huifang Wang assisted some Immunohistochemistry experiments. Zhenbo Yang and Jin Ju assisted some Western Blotting experiments. The authors declare that all data were generated in-house and that no paper mill was used.
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All animal experiments performed the standards of the Ethics Committee of the College of Pharmacy, Harbin Medical University (Ethical approval number: IRB3035621).
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Zhang, L., Cheng, T., Chen, W. et al. Preventive effects of Ramelteon on bleomycin-induced pulmonary fibrosis in mice. Naunyn-Schmiedeberg's Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02867-x
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DOI: https://doi.org/10.1007/s00210-023-02867-x