SIRT3特性与心、脑血管疾病关系研究进展

正哺乳动物体内的Sirtuins蛋白家族分别参与多种细胞代谢和生理调节,包括基因的稳定性,大部分的氧化应激过程,细胞的增殖、代谢、存活、衰老以及器官的寿命等~([1])。Sirtuins(SIRT1-7)是一类NAD依赖的去乙酰化蛋白和ADP核糖基转移酶,为非组蛋白乙酰化主要调节因子,其酶活性受细胞中NAD+和NADH含量的调节。沉默信息调节因子3(SIRT3)是哺乳动物7个SIRTuins家族成员之一,通过调节新陈代谢以稳定细胞的能量以及调节酶的活性来平衡细胞的氧化还原状态~([2])。蛋白质翻译后修饰过程中乙酰化是一个重要的过程,乙酰化作用于线粒体蛋白的翻译后修饰,     

靶向Sirt3对脑卒中影响的研究进展

脑卒中是当今世界范围内主要致死性疾病之一,其发病机制与线粒体功能障碍密切相关。沉默调节蛋白（SIRT）家族是NAD+依赖性赖氨酸去乙酰化酶和ADP核糖转移酶的进化保守家族,Sirtuin家族的成员——沉默信息调节因子2同源蛋白3(Sirt3),是主要的线粒体去乙酰化酶,其通过调控相关蛋白的乙酰化水平发挥调节线粒体代谢、抗氧化应激、改善线粒体功能等重要作用。发生脑卒中后会使Sirt3的表达量下降,导致其调控线粒体正常生理过程及改善脑缺血再灌注损伤的作用被削弱。     

沉默信息调节因子3在心血管疾病中的作用

心血管疾病是严重威胁人类健康的疾病,其种类繁多,病因复杂,寻找新的有效治疗靶点一直是心血管疾病的研究热点。沉默信息调节因子(SIRT)3是SIRT家族中主要的线粒体去乙酰化酶,SIRT3通过调节线粒体中各种代谢酶的去乙酰化程度影响其活性,涉及心血管系统主要线粒体代谢过程。该文就SIRT3在心血管疾病中的作用作简要阐述。     

SIRT1与代谢及肿瘤的关系

沉默信息调节因子1(SIRT1)是一种依赖烟酰胺腺嘌呤二核苷酸(NAD+)的去乙酰化酶,它在正常的胚胎发育、分化及维持自身平衡中是必不可少的.SIRT1在维持健康及疾病中发挥着很多重要的作用,包括SIRT1在基因组稳定性中的作用[1],在时钟调节下的基因组重构及昼夜节律控制中的作用[2],以及神经元基因和阿尔茨海默病之间关系的调节作用[3].之前也有很多有关健康及疾病中SIRT1的综述[4,5].作为sirtuin家族中一员,SIRT1表现出了对氧化还原代谢物NAD+先天的辅酶需求.这与SIRT1控制关键代谢调节的能力一起,证明了SIRT1在哺乳动物代谢中即是一个感受器,又是一个调节器.SIRT1的大多数功能是通过对基因表达过程中起关键作用的调节蛋白针对性的去乙酰化实现的.SIRT1的作用靶点包括转录因子及代谢调节中的辅酶因子.我们对SIRT1活性与代谢稳态关系的最新研究进展作一综述,并且基于细胞生存中SIRT1的作用,我们研究了相应的治疗方法.     

SIRT3与胰岛素抵抗

沉默信息调节因子(SIRT)3是哺乳动物类NAD+依赖性组蛋白去乙酰化酶家族中的一员.研究表明,SIRT3可以改善胰岛素抵抗、增加胰岛素敏感性.其通过保护胰岛β细胞、促进骨骼肌葡萄糖摄取、调节骨骼肌代谢、减轻氧化应激、抵抗高糖诱导的细胞毒性等途径发挥作用.SIRT3为治疗2型糖尿病、肥胖、线粒体功能障碍等疾病带来了新的研究方向.     

沉默调节蛋白1在非酒精性脂肪性肝病发生发展中的作用

沉默调节蛋白1(SIRT1)为Sirtuin家族的一员,是依赖于烟酰腺嘌呤二核苷酸(NAD+)的去乙酰化酶,其主要作用是参与能量代谢﹑细胞生存、衰老及凋亡。而非酒精性脂肪性肝病(NAFLD)是一种与胰岛素抵抗、氧化应激及脂质过氧化等密切相关的慢性肝脏疾病。从SIRT1与NAFLD者的能量代谢关系﹑SIRT1与氧化应激、脂质过氧化、内质网应激等方面进行了阐述,认为SIRT1与NAFLD的发生发展密切相关。     

组蛋白去乙酰基转移酶SIRT3与心血管疾病关系的研究进展

Sirtuins蛋白是一组具有烟酰胺腺嘌呤二核苷酸(NAD)依赖性的组蛋白去乙酰基转移酶,在调控细胞应激、代谢、生长、衰老和凋亡等方面发挥着重要作用。目前已发现,哺乳动物Sirtuin家族有7个成员,其中SIRT3是Sirtuins家族中唯一被证实在长寿人群中高表达的去乙酰基转移酶。SIRT3广泛参与线粒体内蛋白质的翻译后去乙酰化修饰、氧化磷酸化和ATP的合成。新近研究显示,SIRT3在心血管疾病的防治中可能也发挥着重要作用。本文综述了SIRT3研究的最新进展,并着重探讨了SIRT3与心血管疾病的发展及其治疗的潜在方向。     

表观遗传调节因子SIRT6通过减少小鼠氧化应激来保护肝脏免受酒精诱导的组织损伤

正【据《J Hepatol》2019年6月报道】题:表观遗传调节因子SIRT6通过减少小鼠氧化应激来保护肝脏免受酒精诱导的组织损伤(作者Kim HG等)sirtuin 6(SIRT6)作为一种NAD+依赖性去乙酰化酶及一种关键的表观遗传调节因子,其参与调节代谢、DNA修复和炎症反应。然而,SIRT6在酒精性肝病(ALD)中的作用仍不清楚。该研究旨在探讨SIRT6在ALD发病机制中的作用和机制。来自美国印第安纳大学医学院的Kim等开发并表征了Sirt6敲除(KO)和转基因(Tg)小鼠模型,分别用对     

沉默调节蛋白6在肝脏疾病中的作用及其机制

沉默调节蛋白6(SIRT6)具有去乙酰化酶、单ADP核糖基转移酶以及去脂肪酰化酶等多种功能,在调控多种生理及病理过程中发挥重要作用。概述了SIRT6的结构及生物学功能,详细介绍了SIRT6在病毒性肝炎、非酒精性脂肪性肝病、酒精性脂肪性肝病、肝硬化、肝癌等不同类型的肝脏疾病中的研究进展及相关作用分子机制。了解SIRT6在肝脏疾病中的作用,可能为肝病的治疗提供新思路及治疗靶点。     

白黎芦醇调节SIRT1表达研究的新进展

SIRT1是依赖烟酰胺腺嘌呤二核苷酸(NAD+)的脱乙酰基酶,在低等动物中延长寿命,预防与年龄相关的疾病,包括代谢紊乱。激活SIRT1能增强线粒体的功能、氧化代谢和抵消肥胖。白黎芦醇是非黄酮类多酚类,属于对苯代乙烯组,是一些植物为了应对伤害和真菌攻击自然产生的。因此,白黎芦醇激活SIRT1对与年龄相关的疾病和生理代谢有重要的意义。     

Cross-talk between SIRT1 and p66Shc in vascular diseases

Accumulating evidence indicates that oxidative stress can occur through overproduction of reactive oxygen species (ROS) and/or reduced anti-oxidant potentials under pathophysiological conditions and plays an important role in the development of cardiovascular diseases (CVDs). Adapter protein p66Shc has the property to directly stimulate mitochondrial ROS generation by an oxidoreductase activity. A growing body of evidence implies that p66Shc plays a critical role in the pathophysiology of age-related vascular diseases. Silent mating type information regulator 2 homolog 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase (HDAC), has also been implicated in protection against vascular aging and age-related vascular diseases. Recently, we demonstrated that SIRT1 protects blood vessels from hyperglycemia-induced endothelial dysfunction through a novel mechanism involving the downregulation of p66Shc expression. In this review, we discuss the cross-talk between these two longevity genes as a mechanism of preventing vascular diseases by involving anti-oxidative stress responses and inhibiting endothelial senescence.     

SIRT1与血管性疾病的研究进展

沉默信息调节因子2相关酶1 (SIRT1)是一种高度保守的NAD+依赖的第Ⅲ类组蛋白去乙酰化酶,主要通过翻译后修饰调节DNA损伤修复、氧化应激、炎症、细胞衰老、凋亡与增殖等,从而参与血管性疾病的发生发展.因此,SIRT1可能成为治疗血管性疾病的潜在靶点.本文主要对SIRT1的主要生理作用及其在动脉粥样硬化、高血压、肺动脉高压、糖尿病肾病及糖尿病视网膜病变等常见血管性疾病中的作用作一综述.     

Structure-based development of novel sirtuin inhibitors

Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Mammalia possess seven Sirtuin isoforms, Sirt1-7, which differ in their subcellular localization and in the substrate proteins they deacetylate. The physiological roles of Sirtuins and their potential use as therapeutic targets for metabolic and aging-related diseases have spurred interest in the development of small-molecule Sirtuin modulators. Here, we describe an approach exploiting the structures available for four human Sirtuins for the development of isoform-specific inhibitors. Virtual docking of a compound library into the peptide binding pockets of crystal structures of Sirt2, 3, 5 and 6 yielded compounds potentially discriminating between these isoforms. Further characterization in activity assays revealed several inhibitory compounds with little isoform specificity, but also two compounds with micromolar potency and high specificity for Sirt2. Structure comparison and the predicted, shared binding mode of the Sirt2-specific compounds indicate a pocket extending from the peptide-binding groove as target side enabling isoform specificity. Our family-wide structure-based approach thus identified potent, Sirt2-specific inhibitors as well as lead structures and a target site for the development of compounds specific for other Sirtuin isoform, constituting an important step toward the identification of a complete panel of isoform-specific Sirtuin inhibitors.     

Regulation of cell survival and death by pyridine nucleotides

Pyridine nucleotides (PNs), such as NAD(H) and NADP(H), mediate electron transfer in many catabolic and anabolic processes. In general, NAD(+) and NADP(+) receive electrons to become NADH and NADPH by coupling with catabolic processes. These electrons are utilized for biologically essential reactions such as ATP production, anabolism and cellular oxidation-reduction (redox) regulation. Thus, in addition to ATP, NADH and NADPH could be defined as high-energy intermediates and "molecular units of currency" in energy transfer. We discuss the significance of PNs as energy/electron transporters and signal transducers, in regulating cell death and/or survival processes. In the first part of this review, we describe the role of NADH and NADPH as electron donors for NADPH oxidases (Noxs), glutathione (GSH), and thioredoxin (Trx) systems in cellular redox regulation. Noxs produce superoxide/hydrogen peroxide yielding oxidative environment, whereas GSH and Trx systems protect against oxidative stress. We then describe the role of NAD(+) and NADH as signal transducers through NAD(+)-dependent enzymes such as PARP-1 and Sirt1. PARP-1 is activated by damaged DNA in order to repair the DNA, which attenuates energy production through NAD(+) consumption; Sirt1 is activated by an increased NAD(+)/NADH ratio to facilitate signal transduction for metabolic adaption as well as stress responses. We conclude that PNs serve as an important interface for distinct cellular responses, including stress response, energy metabolism, and cell survival/death.     

High mobility group box-1 release from H_2O_2-injured hepatocytes due to sirt1 functional inhibition

BACKGROUND High mobility group box-1(HMGB1), recognized as a representative of damageassociated molecular patterns, is released during cell injury/death, triggering the inflammatory response and ultimately resulting in tissue damage. Dozens of studies have shown that HMGB1 is involved in certain diseases, but the details on how injured hepatocytes release HMGB1 need to be elicited.AIM To reveal HMGB1 release mechanism in hepatocytes undergoing oxidative stress.METHODS C57 BL6/J male mice were fed a high-fat diet for 12 wk plus a single binge of ethanol to induce severe steatohepatitis. Hepatocytes treated with H_2O_2 were used to establish an in vitro model. Serum alanine aminotransferase, liver H_2O_2 content and catalase activity, lactate dehydrogenase and 8-hydroxy-2-deoxyguanosine content, nicotinamide adenine dinucleotide(NAD+) levels, and Sirtuin 1(Sirt1) activity were detected by spectrophotometry. HMGB1 release was measured by enzyme linked immunosorbent assay. HMGB1 translocation was observed by immunohistochemistry/immunofluorescence or Western blot.Relative m RNA levels were assayed by q PCR and protein expression was detected by Western blot. Acetylated HMGB1 and poly(ADP-ribose)polymerase 1(Parp1) were analyzed by Immunoprecipitation.RESULTS When hepatocytes were damaged, HMGB1 translocated from the nucleus to the cytoplasm because of its hyperacetylation and was passively released outside both in vivo and in vitro. After treatment with Sirt1-si RNA or Sirt1 inhibitor(EX527), the hyperacetylated HMGB1 in hepatocytes increased, and Sirt1 activity inhibited by H2 O2 could be reversed by Parp1 inhibitor(DIQ). Parp1 and Sirt1 are two NAD+-dependent enzymes which play major roles in the decision of a cell to live or die in the context of stress. We showed that NAD+ depletion attributed to Parp1 activation after DNA damage was caused by oxidative stress in hepatocytes and resulted in Sirt1 activity inhibition. On the contrary, Sirt1 suppressed Parp1 by negatively regulating its gene expression and deacetylation.CONCLUSION The functional inhibition between Parp1 and Sirt1 leads to HMGB1 hyperacetylation, which leads to its translocation from the nucleus to the cytoplasm and finally outside the cell.     

Sirt1 regulates aging and resistance to oxidative stress in the heart

Silent information regulator (Sir)2, a class III histone deacetylase, mediates lifespan extension in model organisms and prevents apoptosis in mammalian cells. However, beneficial functions of Sir2 remain to be shown in mammals in vivo at the organ level, such as in the heart. We addressed this issue by using transgenic mice with heart-specific overexpression of Sirt1, a mammalian homolog of Sir2. Sirt1 was significantly upregulated (4- to 8-fold) in response to pressure overload and oxidative stress in nontransgenic adult mouse hearts. Low (2.5-fold) to moderate (7.5-fold) overexpression of Sirt1 in transgenic mouse hearts attenuated age-dependent increases in cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction, and expression of senescence markers. In contrast, a high level (12.5-fold) of Sirt1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating the development of cardiomyopathy. Moderate overexpression of Sirt1 protected the heart from oxidative stress induced by paraquat, with increased expression of antioxidants, such as catalase, through forkhead box O (FoxO)-dependent mechanisms, whereas high levels of Sirt1 increased oxidative stress in the heart at baseline. Thus, mild to moderate expression of Sirt1 retards aging of the heart, whereas a high dose of Sirt1 induces cardiomyopathy. Furthermore, although high levels of Sirt1 increase oxidative stress, moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1.