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二甲双胍通过AMPK信号通路减轻声带纤维化。

Metformin Attenuates Vocal Fold Fibrosis via AMPK Signaling.

作者信息

Cai Jie, Fang Lucheng, Zhou Peng, Wu Jianghao, Song Yuliang, Tuohuti Aikebaier, Sun Yuechen, Chen Xiong

机构信息

Department of Otorhinolaryngology, Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China.

出版信息

Inflammation. 2024 Oct 24. doi: 10.1007/s10753-024-02165-5.

Abstract

Vocal fold fibrosis is a challenging condition with no clear consensus on effective treatment methods. Given the demonstrated efficacy of metformin in treating various fibrotic diseases, we hypothesized that metformin could reduce vocal fold fibrosis via the AMPK signaling pathway. In our study, we induced vocal fold injury in rabbits and administered metformin intraperitoneally at a dose of 250 mg/kg two weeks post-injury. Four weeks after the injury, vocal folds were excised and analyzed for fibrosis using Masson's trichrome staining, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), and Western blotting. In vitro, vocal fold fibroblasts treated with metformin (10 μM) ± TGF-β1 (10 ng/mL) were utilized to assess metformin's antifibrotic effects, with Compound C (10 μM) employed to inhibit AMPK signaling. Our results demonstrate that metformin significantly improved the structural integrity of the vocal fold lamina, reduced collagen deposition, and decreased the expression levels of COL1A1 and α-SMA. Furthermore, metformin activated the AMPK signaling pathway in vocal fold fibroblasts, resulting in decreased expression of COL1A1, α-SMA, TGF-β, Smad2, and Smad3. These findings suggest that metformin attenuates vocal fold fibrosis by modulating the AMPK signaling pathway, providing a foundation for developing new therapeutic options for vocal fold fibrosis.

摘要

声带纤维化是一种具有挑战性的病症,对于有效的治疗方法尚无明确的共识。鉴于二甲双胍在治疗各种纤维化疾病方面已证实的疗效,我们推测二甲双胍可通过AMPK信号通路减轻声带纤维化。在我们的研究中,我们在兔身上诱导声带损伤,并在损伤后两周以250mg/kg的剂量腹腔注射二甲双胍。损伤四周后,切除声带并使用Masson三色染色、免疫组织化学、定量实时聚合酶链反应(qPCR)和蛋白质免疫印迹法分析纤维化情况。在体外,使用经二甲双胍(10μM)±转化生长因子-β1(TGF-β1,10ng/mL)处理的声带成纤维细胞来评估二甲双胍的抗纤维化作用,使用化合物C(10μM)抑制AMPK信号。我们的结果表明,二甲双胍显著改善了声带黏膜层的结构完整性,减少了胶原蛋白沉积,并降低了COL1A1和α-平滑肌肌动蛋白(α-SMA)的表达水平。此外,二甲双胍激活了声带成纤维细胞中的AMPK信号通路,导致COL1A1、α-SMA、TGF-β、Smad2和Smad3的表达降低。这些发现表明,二甲双胍通过调节AMPK信号通路减轻声带纤维化,为开发声带纤维化的新治疗选择奠定了基础。

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