State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Department of Oral Radiology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Int J Mol Sci. 2023 Nov 13;24(22):16260. doi: 10.3390/ijms242216260.
Fibrosis commonly arises from salivary gland injuries induced by factors such as inflammation, ductal obstruction, radiation, aging, and autoimmunity, leading to glandular atrophy and functional impairment. However, effective treatments for these injuries remain elusive. Transforming growth factor-beta 1 (TGF-β1) is fundamental in fibrosis, advancing fibroblast differentiation into myofibroblasts and enhancing the extracellular matrix in the salivary gland. The involvement of the SMAD pathway and reactive oxygen species (ROS) in this context has been postulated. Metformin, a type 2 diabetes mellitus (T2DM) medication, has been noted for its potent anti-fibrotic effects. Through human samples, primary salivary gland fibroblasts, and a rat model, this study explored metformin's anti-fibrotic properties. Elevated levels of TGF-β1 ( < 0.01) and alpha-smooth muscle actin (α-SMA) ( < 0.01) were observed in human sialadenitis samples. The analysis showed that metformin attenuates TGF-β1-induced fibrosis by inhibiting SMAD phosphorylation ( < 0.01) through adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-independent pathways and activating the AMPK pathway, consequently suppressing NADPH oxidase 4 (NOX4) ( < 0.01), a main ROS producer. Moreover, in rats, metformin not only reduced glandular fibrosis post-ductal ligation but also protected acinar cells from ligation-induced injuries, thereby normalizing the levels of aquaporin 5 (AQP5) ( < 0.05). Overall, this study underscores the potential of metformin as a promising therapeutic option for salivary gland fibrosis.
纤维化通常由炎症、导管阻塞、辐射、衰老和自身免疫等因素引起的唾液腺损伤引起，导致腺体萎缩和功能障碍。然而，这些损伤的有效治疗方法仍难以捉摸。转化生长因子-β1（TGF-β1）是纤维化的基础，促进成纤维细胞分化为肌成纤维细胞，并增强唾液腺的细胞外基质。SMAD 途径和活性氧（ROS）在这种情况下的参与已被提出。二甲双胍是一种 2 型糖尿病（T2DM）药物，因其强大的抗纤维化作用而受到关注。本研究通过人类样本、原代唾液腺成纤维细胞和大鼠模型探讨了二甲双胍的抗纤维化特性。在人类唾液腺炎样本中观察到 TGF-β1（<0.01）和α-平滑肌肌动蛋白（α-SMA）（<0.01）水平升高。分析表明，二甲双胍通过 AMP 激活蛋白激酶（AMPK）非依赖性途径抑制 SMAD 磷酸化（<0.01），从而抑制 TGF-β1 诱导的纤维化，激活 AMPK 途径，进而抑制 NADPH 氧化酶 4（NOX4）（<0.01），一种主要的 ROS 产生物。此外，在大鼠中，二甲双胍不仅减少了导管结扎后的腺体纤维化，而且还保护了腺泡细胞免受结扎引起的损伤，从而使水通道蛋白 5（AQP5）（<0.05）的水平正常化。总的来说，这项研究强调了二甲双胍作为治疗唾液腺纤维化的一种有前途的治疗选择的潜力。
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