Activation and inhibition of sirtuins: From bench to bedside.

IF 10.9 1区 医学 Q1 CHEMISTRY, MEDICINAL
Francesco Fiorentino, Emanuele Fabbrizi, Antonello Mai, Dante Rotili
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引用次数: 0

Abstract

The sirtuin family comprises seven NAD+-dependent enzymes which catalyze protein lysine deacylation and mono ADP-ribosylation. Sirtuins act as central regulators of genomic stability and gene expression and control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, and aging. As a result, all sirtuins play critical roles in cellular homeostasis and organism wellness, and their dysregulation has been linked to metabolic, cardiovascular, and neurological diseases. Furthermore, sirtuins have shown dichotomous roles in cancer, acting as context-dependent tumor suppressors or promoters. Given their central role in different cellular processes, sirtuins have attracted increasing research interest aimed at developing both activators and inhibitors. Indeed, sirtuin modulation may have therapeutic effects in many age-related diseases, including diabetes, cardiovascular and neurodegenerative disorders, and cancer. Moreover, isoform selective modulators may increase our knowledge of sirtuin biology and aid to develop better therapies. Through this review, we provide critical insights into sirtuin pharmacology and illustrate their enzymatic activities and biological functions. Furthermore, we outline the most relevant sirtuin modulators in terms of their modes of action, structure-activity relationships, pharmacological effects, and clinical applications.

激活和抑制 sirtuins:从工作台到床边
Sirtuin 家族由七种依赖于 NAD+ 的酶组成,可催化蛋白质赖氨酸脱乙酰化和单 ADP-核糖基化。Sirtuins 是基因组稳定性和基因表达的核心调节因子,控制着能量代谢、细胞周期、分化、凋亡和衰老等关键过程。因此,所有 sirtuins 都在细胞稳态和机体健康中发挥着关键作用,它们的失调与代谢、心血管和神经系统疾病有关。此外,sirtuins 还在癌症中显示出二分法的作用,即充当环境依赖性肿瘤抑制剂或促进剂。鉴于其在不同细胞过程中的核心作用,sirtuin 引起了越来越多的研究兴趣,旨在开发激活剂和抑制剂。事实上,调节 sirtuin 可对许多与年龄有关的疾病(包括糖尿病、心血管和神经退行性疾病以及癌症)产生治疗效果。此外,同工酶选择性调节剂可以增加我们对sirtuin生物学的了解,有助于开发更好的疗法。通过这篇综述,我们提供了有关 sirtuin 药理学的重要见解,并说明了它们的酶活性和生物学功能。此外,我们还从作用方式、结构-活性关系、药理作用和临床应用等方面概述了最相关的sirtuin调节剂。
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来源期刊
CiteScore
29.30
自引率
0.00%
发文量
52
审稿时长
2 months
期刊介绍: Medicinal Research Reviews is dedicated to publishing timely and critical reviews, as well as opinion-based articles, covering a broad spectrum of topics related to medicinal research. These contributions are authored by individuals who have made significant advancements in the field. Encompassing a wide range of subjects, suitable topics include, but are not limited to, the underlying pathophysiology of crucial diseases and disease vectors, therapeutic approaches for diverse medical conditions, properties of molecular targets for therapeutic agents, innovative methodologies facilitating therapy discovery, genomics and proteomics, structure-activity correlations of drug series, development of new imaging and diagnostic tools, drug metabolism, drug delivery, and comprehensive examinations of the chemical, pharmacological, pharmacokinetic, pharmacodynamic, and clinical characteristics of significant drugs.
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