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2与基因转录调控

沉默信息调节因子2(silence information regulator 2,Sir2)家族是一类保守的去乙酰化酶蛋白家族,广泛存在于古细菌到哺乳动物的多种生物中,具有依赖NAD+的去乙酰化酶和ADP-核糖转移酶活性。Sir2在染色质沉默、基因调控、代谢调节和细胞寿命调节等众多生命活动中发挥着重要作用。它主要是通过去乙酰化酶活性以及与其他蛋白相互作用从而调节染色质结构、修饰转录相关因子,实现对基因转录的调节。本文重点对Sir2参与基因转录调控的研究进展作一综述。     

Visfatin与胰岛素抵抗及糖尿病肾病的发病机制

Visfatin是哺乳动物合成烟酰胺腺嘌呤二核苷酸(NAD)的限速酶,同时具有类炎性反应因子样作用,可通过cAMP反应元件结合蛋白/蛋白激酶A途径调控肝脏糖异生及葡萄糖代谢,通过NAD、沉默信息调节因子1参与调节胰岛素敏感性及胰岛β细胞功能.此外,visfatin还可调节肾细胞的胰岛素信号转导及葡萄糖代谢,与炎性因子、肾素-血管紧张素系统相互作用,参与糖尿病肾病的发生、发展,为糖尿病及糖尿病肾病的治疗提供新思路.     

SIRT1与糖尿病相关肿瘤的关系

糖尿病不仅增加肿瘤的患病风险,而且促进肿瘤的复发和转移.沉默信息调节因子1(SIRT1)是机体的能量感受器,具有调节糖、脂代谢,抑制慢性非特异性炎性反应,改善胰岛素抵抗等作用,其表达及活性异常参与了糖尿病及其并发症的发生.同时近期研究发现SIRT1也与肿瘤的发生、发展密切相关.通过去乙酰化调节机制SIRT1可调控大量转录因子及组蛋白的活性,从而参与染色质沉默、细胞凋亡、自噬途径及DNA损伤修复的调控,是联系细胞能量代谢与染色质结构的关键蛋白,因而可能是联系糖尿病及糖尿病相关肿瘤的重要中介.积极干预糖尿病患者中SIRT1信号途径异常,可能具有降低肿瘤风险的作用.     

沉默信息调节因子1在骨关节炎中维持软骨稳态的作用

OA是一种发病机制复杂的多因素疾病, 其病理改变以关节软骨损害为主, 最终发生关节软骨退变、纤维化、断裂、溃疡及整个关节面的损害。然而骨关节炎的发病机制尚不清楚, 难以避免其发展至末期行关节置换, 因此亟需在其早期控制甚至逆转病情的治疗方案而非仅传统的姑息疗法。沉默信息调节因子1(SIRT1)是抗衰老基因Sirtuins家族中目前研究最为广泛的成员, 具有抑制细胞凋亡、延缓衰老、抵抗应激反应、参与新陈代谢等重要作用, 成为近年来热门的药物设计靶标之一。本文综述SIRT1在骨关节炎中维持软骨稳态的研究进展, 以期提升对SIRT1在骨关节炎发病机制中的作用的认识, 更好地指导日后开辟治疗骨关节炎的新途径。     

沉默信息调节因子T1在心血管疾病中的作用

细胞生物学的最新进展表明沉默信息调节因子2(SIR2)相关酶类在心脏应激条件下的病理生理机制中扮演着重要角色。目前大部分物种均存在SIR2同源基因,统称为sirtuins(SIRT)家族,其中研究最广泛的是沉默信息调节因子T1(SIRT1),它是许多心血管疾病发生和发展的关键调节因子。本文综述了SIRT1的基本特征以及其在心血管疾病中的作用及可能机制,为心血管疾病的预防、诊断和治疗提供了新的思路。     

Klotho基因及表达产物与人类衰老相关疾病关系的研究进展

<正>有研究表明,机体的衰老与细胞内的代谢失调密切相关,如端粒的缺失、Klotho基因的表达产物减少、沉默信息调节因子1的失活、过氧化物酶体增殖物激活受体的改变、肾素-血管紧张素系统的激活以及氧化应激等。通常认为糖尿病和代谢综合征加速机体衰老的过程,尤其是在肾脏、心脏和神经系统,而Klotho基因的缺失与多种疾病的发生、发     

SIRT1在肿瘤耐药中的作用研究进展

恶性肿瘤的多药耐药是目前治疗的瓶颈。表观遗传学与肿瘤多药耐药之间的关系引起了越来越多研究者的关注,作为表观遗传学领域的后起新星沉默信息调节因子1(SIRT1)与肿瘤多药耐药的关系成为近年来的研究热点。SIRT1是细胞生理及病理过程如细胞增值、分化、DNA损伤与应激反应、衰老及肿瘤的形成的关键调节器。该文对SIRT1对肿瘤作用及耐药性进行文献回顾,为寻找SIRT1调节剂特别是恶性肿瘤的治疗提供新思路。     

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。     

Sirtuins,aging, and cardiovascular risks

The sirtuins comprise a highly conserved family proteins present in virtually all species from bacteria to mammals. Sirtuins are members of the highly conserved class III histone deacetylases, and seven sirtuin genes (sirtuins 1–7) have been identified and characterized in mammals. Sirtuin activity is linked to metabolic control, apoptosis, cell survival, development, inflammation, and healthy aging. In this review, we summarize and discuss the potential mutual relations between each sirtuin and cardiovascular health and the impact of sirtuins on oxidative stress and so age-related cardiovascular disorders, underlining the possibility that sirtuins will be novel targets to contrast cardiovascular risks induced by aging.     

Diabetische Kardiopathie

Diabetes mellitus is one of the most widespread metabolic diseases in Western industrial countries with increasing prevalence due to a progressively aging population that is also characterized by increasing obesity and a sedentary life style. Cardiovascular conditions are the major prognostic complications of diabetes. Cardiologically, diabetic cardiopathy may become manifest on different structural and functional levels of the heart. Disorders may involve the micro- and macrocirculation (angiopathy), ventricular function (cardiomyopathy) and the intracardial nervous system (autonomous neuropathy).The following survey summarizes the cardiovascular risk with particular attention to the pathogenesis, diagnostics and therapy of diabetes mellitus related coronary disease and diabetic cardiomyopathy.     

Diabetic cardiopathy: pathogenesis, diagnosis and therapy

Diabetes mellitus is one of the most widespread metabolic diseases in Western industrial countries with increasing prevalence due to a progressively aging population that is also characterized by increasing obesity and a sedentary life style. Cardiovascular conditions are the major prognostic complications of diabetes. Cardiologically, diabetic cardiopathy may become manifest on different structural and functional levels of the heart. Disorders may involve the micro- and macrocirculation (angiopathy), ventricular function (cardiomyopathy) and the intracardial nervous system (autonomous neuropathy). The following survey summarizes the cardiovascular risk with particular attention to the pathogenesis, diagnostics and therapy of diabetes mellitus related coronary disease and diabetic cardiomyopathy.     

自噬在糖尿病心肌病的作用机制研究

自噬是真核细胞中普遍存在的一种物质降解途径,通过自噬溶酶体介导,清除自身多余或受损的细胞器,以维持细胞内物质的再循环并调节内环境稳态,对机体生长、发育和衰老均起重要作用。研究发现,自噬影响心血管功能,与心血管疾病的病理生理进程密切相关。本文从自噬的信号转导途径,自噬与糖尿病心肌的关系及其可能的机制的进行探讨,希望从自噬的角度对糖尿病心肌病的发生、发展过程进行阐述,为治疗糖尿病心肌病提供理论依据。     

Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair

The sirtuin gene family comprises an evolutionarily ancient set of NAD+ dependent protein deacetylase and mono-ADP ribosyltransferase enzymes. Found in all domains of life, sirtuins regulate a diverse array of biological processes, including DNA repair, gene silencing, apoptosis and metabolism. Studies in multiple model organisms have indicated that sirtuins may also function to extend lifespan and attenuate age-related pathologies. To date, most of these studies have focused on the deacetylase activity of sirtuins, and relatively little is known about the other biochemical activity of sirtuins, mono-ADP ribosylation. We recently reported that the mammalian sirtuin, SIRT6, mono-ADP ribosylates PARP1 to promote DNA repair in response to oxidative stress. In this research perspective we review the role of SIRT6 in DNA repair and discuss the emerging implications for sirtuin directed mono-ADP ribosylation in aging and age-related diseases.     

Morphological characteristics in diabetic cardiomyopathy associated with autophagy

Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac muscle-specific disease that increases the risk of heart failure and mortality. Its clinical course is characterized initially by diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure from an uncertain mechanism. Light microscopic features such as interstitial fibrosis, inflammation, and cardiomyocyte hypertrophy are observed in diabetic cardiomyopathy, but are common to failing hearts generally and are not specific to diabetic cardiomyopathy. Electron microscopic studies of biopsy samples from diabetic patients with heart failure have revealed that the essential mechanism underlying diabetic cardiomyopathy involves thickening of the capillary basement membrane, accumulation of lipid droplets, and glycogen as well as increased numbers of autophagic vacuoles within cardiomyocytes. Autophagy is a conserved mechanism that contributes to maintaining intracellular homeostasis by degrading long-lived proteins and damaged organelles and is observed more often in cardiomyocytes within failing hearts. Diabetes mellitus (DM) impairs cardiac metabolism and leads to dysregulation of energy substrates that contribute to cardiac autophagy. However, a “snapshot” showing greater numbers of autophagic vacuoles within cardiomyocytes may indicate that autophagy is activated into phagophore formation or is suppressed due to impairment of the lysosomal degradation step. Recent in vivo studies have shed light on the underlying molecular mechanism governing autophagy and its essential meaning in the diabetic heart. Autophagic responses to diabetic cardiomyopathy differ between diabetic types: they are enhanced in type 1 DM, but are suppressed in type 2 DM. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy. Here, we review recent advances in our understanding of the pathophysiology of diabetic cardiomyopathy, paying particular attention to autophagy in the heart, and discuss the therapeutic potential of interventions modulating autophagy in diabetic cardiomyopathy.     

Diabetic cardiomyopathy: concept,heart function,and pathogenesis

The diabetic cardiomyopathy is a disease caused by diabetes and is characterised by the presence of diastolic and/or systolic left ventricular dysfunction. Diabetes may produce metabolic alterations, interstitial fibrosis, myocellular hypertrophy, microvascular disease and autonomic dysfunction. It is thought that all of them may cause cardiomyopathy. Other abnormalities that are usually associated with diabetes such as hypertension, coronary artery disease and nephropathy should be excluded before diagnosing diabetic cardiomyopathy. There is no evidence that diabetic cardiomyopathy alone can produce heart failure. However, subclinical ventricular dysfunction has been described in young asymptomatic diabetic patients without other diseases that could affect the cardiac muscle. In these cases we should consider that diabetes is the only cause of the myocardial disease. More studies are needed to know the natural history of diabetic cardiomyopathy.     

Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer

Abstract:  Histone deacetylases (HDAC) have been under intense scientific investigation for a number of years. However, only recently the unique class III HDAC, sirtuins, have gained increasing investigational momentum. Originally linked to longevity in yeast, sirtuins and more specifically, SIRT1 have been implicated in numerous biological processes having both protective and/or detrimental effects. SIRT1 appears to play a critical role in the process of carcinogenesis, especially in age-related neoplasms. Similarly, alterations in circadian rhythms as well as production of the pineal hormone melatonin have been linked to aging and cancer risk. Melatonin has been found act as a differentiating agent in some cancer cells and to lower their invasive and metastatic status. In addition, melatonin synthesis and release occurs in a circadian rhythm fashion and it has been linked to the core circadian machinery genes ( Clock , Bmal1 , Periods , and Cryptochromes ). Melatonin has also been associated with chronotherapy, the timely administration of chemotherapy agents to optimize trends in biological cycles. Interestingly, a recent set of studies have linked SIRT1 to the circadian rhythm machinery through direct deacetylation activity as well as through the nicotinamide adenine dinucleotide (NAD⁺) salvage pathway. In this review, we provide evidence for a possible connection between sirtuins, melatonin, and the circadian rhythm circuitry and their implications in aging, chronomodulation, and cancer.