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二甲双胍是一个一线抗糖尿病药物,然而其详细作用机制仍在研究中。Nrf2信号在保护细胞免受氧化性损伤中起着重要作用,近年来也成为干预糖尿病及其相关并发症的重要药物靶标。本研究在体内外实验中检测了二甲双胍对Nrf2信号的影响,并探究了其可能的机制。首先,二甲双胍激活AMPK和Nrf2信号,并以类似的浓度-和时间-依赖方式在小鼠骨骼肌细胞C2C12中诱导抗氧化基因NQO1和γ-GCSm的表达。其次,过表达AMPK会显著提高基础的和二甲双胍诱导的ARE–萤光素酶报告基因的活性,说明AMPK参与了二甲双胍对Nrf2信号的激活。最后,二甲双胍激活小鼠肝脏和骨骼肌组织中的Nrf2信号,诱导抗氧化基因HO-1和SOD的表达,导致GSH水平的增加。总之,我们的结果说明二甲双胍可以激活Nrf2信号和增强组织的抗氧化能力,并提供了二甲双胍作用的新机制。
Metformin is a first-line antidiabetic drug, but its detailed mechanism of action is still under investigation. Nrf2 signaling plays an important role in protecting cells from oxidative damage and has also become an important drug target in the intervention of diabetes and its related complications in recent years. This study examined the effect of metformin on Nrf2 signaling in vitro and in vivo and explored its possible mechanism. First, metformin activated AMPK and Nrf2 signaling and induced the expression of the antioxidant genes NQO1 and γ-GCSm in mouse skeletal muscle cells C2C12 in a similar concentration- and time-dependent manner. Second, overexpression of AMPK significantly increased basal and metformin-induced ARE-luciferase reporter activity, suggesting that AMPK is involved in the activation of Nrf2 signaling by metformin. Finally, metformin activated Nrf2 signaling in the liver and skeletal muscle of mice, inducing the expression of the antioxidant genes HO-1 and SOD, resulting in an increase in GSH levels. Taken together, our results demonstrate that metformin activates Nrf2 signaling and enhances tissue antioxidant capacity and provides a new mechanism of action of metformin.