SVKM's Dr Bhanuben Nanavati College of Pharmacy, Vile Parle (W), Mumbai 400056, India.
Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, Mumbai 400056, India.
Pharmacol Res. 2022 Jan;175:106014. doi: 10.1016/j.phrs.2021.106014. Epub 2021 Nov 29.
The prevalence of diabetes is continuously increasing in the recent decades. Persistent hyperglycemia, hyperinsulinemia and the subsequent oxidative stress result in diabetic complications, primarily categorized as microvascular (nephropathy, retinopathy and neuropathy) and macrovascular (cardiomyopathy) complications. The complications are prevalent in both type 1 and type 2 diabetic patients. Polyol pathway, elevated AGE production, PKC activation and hexosamine pathway are indeed the critical pathways involved in the progression of diabetic complications. Silent information regulator 2 or SIR2 or more commonly known as sirtuins are NAD dependent histone deacetylase. SIRT1, a member of the sirtuin family has been extensively studied for its role in lifespan extension and needs to be explored for its beneficial effects in diabetic complications. Moreover, it is also known to regulate the activity of other proteins and transcription factors. One such substrate of SIRT1 is FOXOs transcription factor which has gained much attention as the mediator of various cellular processes such as cell cycle arrest and proliferation, DNA repair and metabolism. It has been reported that SIRT1 regulates the activity of FOXOs, whereas few recent advances also suggest a role FOXOs in governing the activity of SIRT1, which permits for a crosstalk between SIRT1 and FOXOs. Therefore, the focus of the present review is to describe and explore the interaction between SIRT1 and FOXOs, predominantly FOXO1 and FOXO3 and to understand the underlying mechanism of SIRT1-FOXOs in controlling and alleviating diabetic complications. Thus, this crosstalk suggests that SIRT1 and FOXOs may serve as potential therapeutic targets in treating diabetic complications.
在最近几十年中，糖尿病的患病率持续上升。持续的高血糖、高胰岛素血症以及随后的氧化应激导致糖尿病并发症，主要分为微血管（肾病、视网膜病变和神经病变）和大血管（心肌病）并发症。这些并发症在 1 型和 2 型糖尿病患者中都很常见。多元醇途径、AGE 产生的增加、PKC 激活和己糖胺途径确实是糖尿病并发症进展中涉及的关键途径。沉默信息调节因子 2 或 SIR2 或更通常称为 Sirtuins 是 NAD 依赖性组蛋白去乙酰化酶。SIRT1 是 Sirtuins 家族的成员，因其在延长寿命方面的作用而被广泛研究，需要探索其在糖尿病并发症中的有益作用。此外，它还被认为调节其他蛋白质和转录因子的活性。SIRT1 的一种底物是 FOXO 转录因子，作为各种细胞过程（如细胞周期停滞和增殖、DNA 修复和代谢）的调节剂而备受关注。据报道，SIRT1 调节 FOXO 的活性，而最近的一些进展也表明 FOXO 在调节 SIRT1 的活性方面发挥作用，这允许 SIRT1 和 FOXO 之间进行串扰。因此，本综述的重点是描述和探索 SIRT1 和 FOXO 之间的相互作用，主要是 FOXO1 和 FOXO3，并了解 SIRT1-FOXO 在控制和缓解糖尿病并发症中的潜在机制。因此，这种串扰表明 SIRT1 和 FOXO 可能是治疗糖尿病并发症的潜在治疗靶点。
