SIRT1功能的研究进展

SIRT1(si1ent mating-type information regulation 2 homologue 1)是Sirtuins去乙酰化酶家族中的一员,是酵母沉默信息调节因子Sir2(silence information regulator)的同源物.它参与了众多基因转录、能量代谢以及细胞衰老过程的调节...     

基质金属蛋白酶8在动脉粥样硬化中的研究进展

基质金属蛋白酶8(matrix metalloproteinase-8,MMP-8)是基质金属蛋白酶家族的重要成员之一。最新研究发现,MMP-8通过降解胶原蛋白及其他活性物质,调节内皮细胞、平滑肌细胞、中性粒细胞及干细胞的功能,促进了动脉粥样硬化斑块的发生发展及不稳定性。MMP-8与冠心病的发生及预后密切相关,其基因多态性与动脉粥样硬化的发生和发展紧密联系。本文就MMP-8与动脉粥样硬化疾病相关的最新研究进展进行综述,讨论MMP-8在动脉粥样硬化中的作用机制,为动脉粥样硬化寻找生物标志物及潜在治疗靶点提供思路。     

细胞凋亡与动脉粥样硬化

细胞调亡是一种生理性或程序性细胞死亡方式，参与机体许多生理病理过程的调节．近未，愈来愈多的研究结果表明，细胞调亡可能在动脉粥样硬化的病理机制中起着重要的作用．本文主要从细胞凋亡在动脉粥样硬化发过程中的作用及其调节两个方面，就最新研究进展加以阐述，以期进一步阐明动脉粥样硬化的发病机制，为探索新的有效的治疗途径提供一些思路．     

活血化瘀中药调控细胞自噬抗动脉粥样硬化的研究进展

自噬是细胞抵御损伤调节凋亡程序化过程,适度自噬能够促进细胞胆固醇流出而影响脂质代谢最终抗动脉粥样硬化。细胞自噬在抗动脉粥样硬化中的机制研究已取得初步进展,一些中药及有效成分被发现可通过调节自噬机制起到抗动脉粥样硬化作用。活血化瘀药物作为中药抗动脉粥样硬化研究中最为深入的一类认为可通过调控自噬达到相关作用。现综述自噬与动脉粥样硬化相关研究及活血化瘀药尤其是芎芍胶囊抗动脉粥样硬化研究进展。     

微小RNA在泡沫细胞形成中的研究进展

泡沫细胞的形成与积累是动脉粥样硬化的标志,研究发现靶向泡沫细胞的形成在动脉粥样硬化的治疗与预防中具有重要作用.对动脉粥样硬化相关微小RNA(miRNA)的研究表明,miRNA可直接靶向胆固醇代谢中相关蛋白的表达,调节泡沫细胞的形成.且近年来对循环miRNA的研究发现,部分循环miRNA有望成为抑制泡沫细胞形成的新靶点....     

相关炎症因子与动脉粥样硬化

近年来,各种细胞炎症因子与动脉粥样硬化的关系引起许多研究者的重视,现将有关进展择要综述。1 Caveolin-1、Caveolae和动脉粥样硬化Caveolae是细胞表面直径50～100 nm的胞膜穴样内陷,于20世纪中期首次发现]。迄今为止,已发现三种Caveolin亚型,分别命名为Caveolin-1、Caveolin-2和Caveolin-3,Caveolin-1和Caveolin-2表达于大部分终末分化细胞,Caveolin-3主要表达于平滑肌细胞和横纹肌细胞。其中,参与动脉粥样硬化的多种细胞均有Caveolae和Caveolin-1的表达,它们在内皮功能失调和动脉粥样硬化过程中起着重要的作用。在跨细胞转运的调节中,Caveolae对于低密度脂蛋白胆固醇(LDL-C)的转运调节与动脉粥样硬化的发生有密切的关系。2 CXCL16与动脉粥样硬化     

细胞衰老与肿瘤发生发展的研究进展

肿瘤是一种典型的年龄相关性疾病，多在老年人发生，1961年Hayflick在对体外培养细胞研究中发现细胞有增殖极限的现象，称之为细胞衰老。目前研究细胞衰老大多集中在对细胞周期机制、自由基及DNA损伤与衰老的关系、衰老的端粒学说、线粒体与衰老、衰老相关基因和长寿基因、细胞信号转导等方面。在对肿瘤和衰老的研究中，人们发现二者的形成过程似乎有一个此消彼长、相互排斥的关系，细胞的衰老可能成为肿瘤形成的天然屏障。大量证据已经显示，细胞除了可以通过凋亡或自杀来抑制肿瘤形成外，还可以通过衰老阻止细胞分裂，进而抑制肿瘤。近期关于癌基因诱导的细胞衰老与肿瘤的关系形成了一个研究的焦点，本文主要对这方面的研究进展进行阐述。     

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,     

长链非编码RNA与动脉粥样硬化

最新研究证明长链非编码RNA(lncRNA)可调节脂质及糖代谢,调控血管壁功能,参与血管内皮细胞和平滑肌细胞的增殖、迁移、老化、凋亡以及血管炎症及免疫应答,从而影响动脉粥样硬化的发生发展。本文就lncRNA与动脉粥样硬化关系研究的进展作一综述。     

基质金属蛋白酶与动脉粥样硬化病变的关系

在正常生理情况下,基质金属蛋白酶-9能够切断任何细胞外基质成分,调节细胞黏着,作用于细胞外成分或其他蛋白成分而启动潜在生物学功能。病理状态下,潜在型基质金属蛋白酶-9可被激活并参与动脉粥样硬化时的血管壁重构、斑块破裂、血栓形成等过程。研究发现,基质金属蛋白酶-3与动脉粥样硬化过程中纤维帽的形成密切相关,同时基质金属蛋白酶-3可激活包括基质金属蛋白酶-3前体在内的其他基质金属蛋白酶,从而加速动脉粥样硬化病变的发展。     

Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence

Atherosclerosis is classed as a disease of aging, such that increasing age is an independent risk factor for the development of atherosclerosis. Atherosclerosis is also associated with premature biological aging, as atherosclerotic plaques show evidence of cellular senescence characterized by reduced cell proliferation, irreversible growth arrest and apoptosis, elevated DNA damage, epigenetic modifications, and telomere shortening and dysfunction. Not only is cellular senescence associated with atherosclerosis, there is growing evidence that cellular senescence promotes atherosclerosis. This review examines the pathology of normal vascular aging, the evidence for cellular senescence in atherosclerosis, the mechanisms underlying cellular senescence including reactive oxygen species, replication exhaustion and DNA damage, the functional consequences of vascular cell senescence, and the possibility that preventing accelerated cellular senescence is a therapeutic target in atherosclerosis.     

Vascular cell senescence: contribution to atherosclerosis

Cardiologists and most physicians believe that aging is an independent risk factor for human atherosclerosis, whereas atherosclerosis is thought to be a characteristic feature of aging in humans by many gerontologists. Because atherosclerosis is among the age-associated changes that almost always escape the influence of natural selection in humans, it might be reasonable to regard atherosclerosis as a feature of aging. Accordingly, when we investigate the pathogenesis of human atherosclerosis, it may be more important to answer the question of how we age than what specifically promotes atherosclerosis. Recently, genetic analyses using various animal models have identified molecules that are crucial for aging. These include components of the DNA-repair system, the tumor suppressor pathway, the telomere maintenance system, the insulin/Akt pathway, and other metabolic pathways. Interestingly, most of the molecules that influence the phenotypic changes of aging also regulate cellular senescence, suggesting a causative link between cellular senescence and aging. For example, DNA-repair defects can cause phenotypic changes that resemble premature aging, and senescent cells that show DNA damage accumulate in the elderly. Excessive calorie intake can cause diabetes and hyperinsulinemia, whereas dysregulation of the insulin pathway has been shown to induce cellular senescence in vitro. Calorie restriction or a reduction of insulin signals extends the lifespan of various species and decreases biomarkers of cellular senescence in vivo. There is emerging evidence that cellular senescence contributes to the pathogenesis of human atherosclerosis. Senescent vascular cells accumulate in human atheroma tissues and exhibit various features of dysfunction. In this review, we examine the hypothesis that cellular senescence might contribute to atherosclerosis, which is a characteristic of aging in humans.     

Molecular genetic studies of cellular senescence

The limited doubling potential of normal cells in culture was first proposed as a model for cellular aging by Hayflick in 1961. This phenomenon of in vitro cellular senescence is now well documented for a number of different normal human cell types. In an attempt to determine whether random events or programmed genetic processes were responsible for cellular aging, we performed a series of cell fusion studies. We determined that hybrids from fusion of normal with immortal human cells had limited proliferative potential, indicating that senescence is a dominant phenotype. We exploited the fact that immortality was recessived to assign a large number of different immortal human cell lines to four complementation groups for indefinite division. More recently, we have determined that the introduction of a single normal human chromosome 4 into HeLa (cervical carcinoma) cells by microcell fusion induced senescence in this immortal line. The results of these whole cell and microcell fusion studies support the hypotheses that propose senescence results from active, genetic mechanisms.     

Antisenescence as a novel therapeutic strategy for vascular aging

Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest state called "cellular senescence." It has been reported that many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. Recently, senescent vascular cells have been demonstrated in human atherosclerotic lesions but not non-atherosclerotic lesions. Moreover, these cells express increased levels of proinflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. More recent evidence suggests that telomere-independent mechanisms are implicated in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby promotes vascular inflammation in vitro and in vivo. Constitutive activation of Akt also induces vascular cell senescence. This novel role of Akt in regulating the cellular lifespan may contribute to various human diseases including atherosclerosis and diabetes mellitus. Although a causal link between vascular aging and vascular cell senescence remains elusive, a large body of data is consistent with cellular senescence contributing to age-associated vascular disorders. This review considers the clinical relevance of vascular cell senescence in vivo and discusses the potential of antisenescence therapy for human atherosclerosis.     

Vascular cell senescence and vascular aging

Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence". A number of genetic animal models carrying targeted disruption of the genes that confer the protection against senescence in vitro have been reported to exhibit the phenotypes of premature aging. Similar mutations have been found in the patients with premature aging syndromes. Many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. We have demonstrated the presence of senescent vascular cells in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of pro-inflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. Another line of evidence suggests that telomere-independent mechanisms are also involved in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby promotes vascular inflammation in vitro and in vivo. It is possible that mitogenic-signaling pathways induce telomere-dependent and telomere-independent senescence, which results in vascular dysfunction. Further understanding of the mechanism underlying cellular senescence will provide insights into the potential of antisenescence therapy for vascular aging.     

Vascular aging: insights from studies on cellular senescence, stem cell aging, and progeroid syndromes

Epidemiological studies have shown that age is the chief risk factor for atherosclerotic cardiovascular diseases, but the molecular mechanisms that underlie the increase in risk conferred by aging remain unclear. Evidence suggests that the cardiovascular repair system is impaired with advancing age, thereby inducing age-associated cardiovascular dysfunction. Such impairment could be attributable to senescence of cardiovascular tissues at the cellular level as a result of telomere shortening, DNA damage, and genomic instability. In fact, the replicative ability of cardiovascular cells, particularly stem cells and/or progenitor cells, has been shown to decline with age. Recently, considerable progress has been made in understanding the pathogenesis of human progeroid syndromes that feature cardiovascular aging. Most of the genes responsible have a role in DNA metabolism, and mutated forms of these genes result in alterations of the response to DNA damage and in decreased cell proliferation, which might be common features of a phenotype of aging. Here we review the cardiovascular research on cellular senescence, stem cell aging, and progeroid syndromes and discuss the potential role of cellular senescence in the mechanisms underlying both normal aging and premature aging syndromes.     

Roles of FGF signaling in stem cell self-renewal, senescence and aging

The aging process decreases tissue function and regenerative capacity, which has been associated with cellular senescence and a decline in adult or somatic stem cell numbers and self-renewal within multiple tissues. The potential therapeutic application of stem cells to reduce the burden of aging and stimulate tissue regeneration after trauma is very promising. Much research is currently ongoing to identify the factors and molecular mediators of stem cell self-renewal to reach these goals. Over the last two decades, fibroblast growth factors (FGFs) and their receptors (FGFRs) have stood up as major players in both embryonic development and tissue repair. Moreover, many studies point to somatic stem cells as major targets of FGF signaling in both tissue homeostasis and repair. FGFs appear to promote self-renewing proliferation and inhibit cellular senescence in nearly all tissues tested to date. Here we review the role of FGFs and FGFRs in stem cell self-renewal, cellular senescence, and aging.     

Premature aging/senescence in cancer cells facing therapy: good or bad?

Normal and cancer cells facing their demise following exposure to radio-chemotherapy can actively participate in choosing their subsequent fate. These programmed cell fate decisions include true cell death (apoptosis-necroptosis) and therapy-induced cellular senescence (TIS), a permanent “proliferative arrest” commonly portrayed as premature cellular aging. Despite a permanent loss of proliferative potential, senescent cells remain viable and are highly bioactive at the microenvironment level, resulting in a prolonged impact on tissue architecture and functions. Cellular senescence is primarily documented as a tumor suppression mechanism that prevents cellular transformation. In the context of normal tissues, cellular senescence also plays important roles in tissue repair, but contributes to age-associated tissue dysfunction when senescent cells accumulate. Theoretically, in multi-step cancer progression models, cancer cells have already bypassed cellular senescence during their immortalization step (see hallmarks of cancer). It is then perhaps surprising to find that cancer cells often retain the ability to undergo TIS, or premature aging. This occurs because cellular senescence results from multiple signalling pathways, some retained in cancer cells, aiming to prevent cell cycle progression in damaged cells. Since senescent cancer cells persist after therapy and secrete an array of cytokines and growth factors that can modulate the tumor microenvironment, these cells may have beneficial and detrimental effects regarding immune modulation and survival of remaining proliferation-competent cancer cells. Similarly, while normal cells undergoing senescence are believed to remain indefinitely growth arrested, whether this is true for senescent cancer cells remains unclear, raising the possibility that these cells may represent a reservoir for cancer recurrence after treatment. This review discusses our current knowledge on cancer cell senescence and highlight questions that must be addressed to fully understand the beneficial and detrimental impacts of cellular senescence during cancer therapy.     

Senescence research from historical theory to future clinical application

Historically, the findings from cellular lifespan studies have greatly affected aging research. The discovery of replicative senescence by Hayflick developed into research on telomeres and telomerase, while stress-induced senescence became known as a telomere-independent event. Senescence-inducing signals comprise several tumor suppressors or cell cycle inhibitors, e.g., p53, cyclin-dependent kinase inhibitor p16 Ink4a and others. Stress-induced senescence serves as a physiological barrier to oncogenesis in vivo, while it activates senescence-associated secretary phenotype, inducing chronic inflammation. Thus, beside telomere length, p16, p53 and inflammatory cytokines have been utilized as biomarkers for cellular senescence. Telomere lengths in human leukocytes correlate well with events of aging-related lifestyle diseases, indicating the importance of cellular senescence in organismal aging. As such, the development of senescence research will have significant future clinical applications, e.g., senolysis. Geriatr Gerontol Int 2021; 21: 125–130 .     

Cellular senescence and tissue aging in vivo

A long-standing controversy concerns the relevance of cellular senescence, defined and observed as a cell culture phenomenon, to tissue aging in vivo. Here the evidence on this topic is reviewed. The main conclusions are as follows. First, telomere shortening, the principal known mediator of cellular senescence, occurs in many human tissues in aging. Second, it is not clear whether this results in cellular senescence or in some other cell fate (e.g., crisis). Third, rodents probably are not appropriate experimental models for these questions, because of important differences in telomere biology between rodent cells and cells from long-lived mammals (e.g., human or bovine cells). Fourth, better and more comprehensive observations on aging human tissues are needed to answer the question of the occurrence of senescent cells in tissues, and new experimental approaches are needed to elucidate the consequences of telomere shortening in tissues in aging.