Activation of SIRT1 by SRT1720 alleviates dyslipidemia, improves insulin sensitivity and exhibits liver-protective effects in diabetic rats on a high-fat diet: New insights into the SIRT1/Nrf2/NFκB signaling pathway

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-01-06 DOI:10.1016/j.ejps.2025.107002
Elsayed A. Elmorsy , Hossam A. Elsisi , Abdullah S. Alkhamiss , Norah Suliman Alsoqih , Mostafa M. Khodeir , Abdulaziz A. Alsalloom , Ahmad A. Almeman , Sahar R. Elghandour , Eman Hassan Nadwa , Amira Karam khalifa , Bahaa Eldin Ali Khaled , Asmaa Ramadan , Manal M. Kamal , Thamir Saad Alsaeed , Mariam S. Alharbi , Abdel-Moneim Hafez Abdel-Moneim , Abousree T. Ellethy , Sameh Saber
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Abstract

Insulin resistance and diabetes are associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) conditions, which are distinguished by metabolic dysfunction, oxidative stress and inflammation. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, is fundamental in regulating metabolic pathways, reducing inflammation, and improving antioxidant defenses. This is the first study to investigate the effects of SRT1720, a SIRT1 activator, in diabetic rats on a high-fat diet. SRT1720 significantly lowered fasting blood glucose and insulin levels and enhanced glucose tolerance and HOMA-IR and QUICKI scores, indicating increased insulin sensitivity. The treatment also reduced total cholesterol, triglycerides, and LDL levels, showing amelioration of dyslipidemia. Moreover, SRT1720 lowered markers of liver fibrosis, including TGF-β, TIMP-1, Col1a1, and hydroxyproline, and decreased inflammation by reducing NFκB activity and pro-inflammatory cytokines (TNF-α and IL-6). Furthermore, SRT1720 augmented Nrf2 activity and HO-1 levels. Consequently, the SRT1720’s protective role improved liver function and histology and prolonged rats’ survival. These functions were suppressed by the co-administration of the SIRT1 inhibitor EX527, confirming that the beneficial effects of SRT1720 are SIRT1-dependent. Correlation analyses uncovered that increased SIRT1 activity was strongly associated with decreased oxidative stress, inflammation, insulin resistance, and fibrosis markers. To conclude, our results find that SRT1720 represents a promising therapeutic strategy for managing Type 2 diabetes in NAFLD or NASH patients possibly through the modulation of the SIRT1/Nrf2/NFκB signaling pathwa. SRT1720 could potentially halt or reverse the progression of these conditions and associated complications and merits further investigations.

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SRT1720激活SIRT1可缓解高脂饮食下糖尿病大鼠的血脂异常、改善胰岛素敏感性并显示肝脏保护作用:SIRT1/Nrf2/NFκB信号通路的新见解
胰岛素抵抗和糖尿病与非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)有关,这两种疾病的特征是代谢功能障碍、氧化应激和炎症。SIRT1是一种依赖NAD+的去乙酰化酶,在调节代谢途径、减少炎症和提高抗氧化防御能力方面发挥着重要作用。这是第一个研究SRT1720(一种SIRT1激活剂)对高脂肪饮食的糖尿病大鼠的影响的研究。SRT1720显著降低空腹血糖和胰岛素水平,提高葡萄糖耐量和HOMA-IR和QUICKI评分,表明胰岛素敏感性增加。治疗还降低了总胆固醇、甘油三酯和低密度脂蛋白水平,显示了血脂异常的改善。此外,SRT1720降低肝纤维化标志物TGF-β、TIMP-1、Col1a1、羟脯氨酸,并通过降低nf - κ b活性和促炎细胞因子(TNF-α、IL-6)来减轻炎症。此外,SRT1720增强了Nrf2活性和HO-1水平。因此,SRT1720的保护作用改善了肝功能和组织学,延长了大鼠的生存期。这些功能被SIRT1抑制剂EX527抑制,证实SRT1720的有益作用依赖于SIRT1。相关分析发现,SIRT1活性的增加与氧化应激、炎症、胰岛素抵抗和纤维化标志物的降低密切相关。总之,我们的研究结果发现,SRT1720可能通过调节SIRT1/Nrf2/NFκB信号通路,为NAFLD或NASH患者治疗2型糖尿病提供了一种有希望的治疗策略。SRT1720有可能阻止或逆转这些疾病和相关并发症的进展,值得进一步研究。
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9.60
自引率
2.20%
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248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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