自噬在常见心血管疾病中的作用

自噬是细胞利用细胞内溶酶体清除过量或受损的长半衰期蛋白质及细胞器的现象。自噬可通过营养剥夺适应,清除细胞内蛋白质及微细胞器等生理及病理学作用和再利用细胞废物,以维持内环境稳定、参与生长发育和疾病的发生及发展。研究发现,自噬参与了心肌肥厚、心室重构、心肌缺血/再灌注损伤等多种心血管疾病病的理生理过程。本文主要阐述自噬在正常心脏及各种常见心脏疾病中作用的研究进展,并初步探讨可能的治疗新靶点。     

自噬基因Beclin1在宫颈癌中的研究进展

自噬是指从粗面内质网无核糖体附着区脱落的双层膜包裹部分胞质和细胞内需降解的大分子物质（如蛋白质、RNA、过量储存的糖原等）,以及一些细胞内源性底物（包括因生理或病理引起衰老、破损的细胞器）等成分形成自噬体后与溶酶体融合成自噬溶酶体,降解所包裹内容物以实现细胞本身代谢和某些细胞器的更新。但自噬过度上调后可引起细胞死亡,即自噬性细胞死亡。     

细胞自噬对衰老的调节

细胞内损伤物质的积累是所有衰老细胞的普遍特征,能导致生命有机体生存能力降低.细胞自噬能够降解受损蛋白质和衰老或损伤细胞器等细胞结构,是细胞内主要的异化途径,参与衰老以及与衰老相关的各种病理过程.近年来研究发现,衰老进程中,细胞自噬活动下调,而对各种长寿突变体的研究表明自噬活动是寿命延长所必需的,多种自噬相关基因或蛋白直接受长寿途径的调节[1~5],这些发现都支持细胞自噬是各种真核生物衰老非常重要的调节机制.     

细胞自噬在急性肝损伤中的变化及作用

正近年来,细胞自噬已成为热点研究领域,而细胞自噬在肝脏疾病中的作用也越来越受到重视,抑制或促进自噬可能成为一个新的治疗靶点,本文就细胞自噬在急性肝损伤中的变化及作用作一综述。1细胞自噬的概述细胞自噬(autophagy)是存在于真核细胞内的一种溶酶体依赖的降解途径,形成过程包括膜状结构包裹部分胞质和细胞内需降解的长寿蛋白质、受损的细胞器等形成     

自噬在心血管疾病中的作用

自噬是一种维持细胞稳态的重要通路。在特定环境下,细胞中的多余蛋白质和受损细胞器通过自噬这一途径被降解。自噬在多种心血管疾病中的作用正逐渐被阐明,例如缺血/再灌注损伤、动脉粥样硬化、心律失常、高血压和心力衰竭等。本文介绍了影响自噬基本过程的主要分子和调控自噬活性的机制,讨论了自噬与多种心血管疾病之间的关系。     

细胞自噬与乙型肝炎病毒及中医药关系的研究进展

<正>细胞自噬(autophagy)是一种通过降解细胞内长寿的蛋白质和受损的细胞器维持细胞平衡的过程,自噬不足或自噬过度都可以导致细胞病变,甚至死亡,这与中医的阴阳平衡理论似相一致。细胞自噬可能增强了乙型肝炎病毒(HBV)的复制,中医药能否通过调节细胞自噬来治疗HBV感染,目前尚无研究报告,很值得我们     

神经细胞自噬在阿尔茨海默病中的作用机制

细胞自噬的过程,称为细胞的废物管理或内务管理系统,消除了一些回收到细胞质的"废弃"物质和其本身的废组织.自噬途径是负责细胞碎片如损坏的细胞器和细胞内溶酶体降解的大分子的降解过程.根据底物进入溶酶体途径的不同可分为微自噬、巨自噬和分子伴侣介导的自噬[1].自噬形式研究最多的是它可以在各种应激条件下诱导,越来越多的证据表明,自噬除了可以为细胞提供能源外,还可以表现在正常的生理和病理状态过程中,如发育,细胞死亡,衰老,抗原提呈,细菌降解,肿瘤抑制等[2].这种现象不可能在所有的真核细胞得到证实,但至少在哺乳动物细胞中保持基础水平的吞噬蛋白质和细胞器是维持细胞内正常周期的必要程序.基础水平的自噬活动在分裂后的细胞中至关重要的.如神经元,可能是因为他们无法通过细胞自身的功能降解蛋白质和细胞器[3,4].     

自噬与心肌衰老及心血管疾病关系的研究进展

真核细胞降解细胞内物质主要通过2条途径--蛋白酶体降解和自噬(autophagy)降解[1].蛋白酶体主要降解细胞内短寿命蛋白质;细胞内几乎全部的长寿蛋白质、多数大分子物质以及所有的细胞器都通过自噬作用被运输到溶酶体内降解,以实现细胞本身的代谢需要和细胞器的更新.     

细胞自噬在肝纤维化中的作用

细胞自噬是细胞内的一种代谢过程,通过细胞内的膜结构包裹部分胞质和细胞内需降解的细胞器、蛋白质等形成自噬小体,然后与溶酶体融合降解其所包裹内容物,其降解产物氨基酸、游离脂肪酸等可供细胞物质能量循环,细胞自噬在肝脏疾病的发生发展中有重要的作用,最近研究表明,细胞自噬可以通过降解脂滴为肝星状细胞的活化提供能量从而促进肝纤维化的发生。     

自噬在心血管疾病的研究进展

细胞自噬是将细胞内受损、变性或衰老的蛋白质以及细胞器运输到溶酶体内进行消化降解,从而在细胞内成分的合成、降解及再循环利用方面维持平衡。细胞自噬担负着“细胞管家”的职责,维持细胞内环境的完整性。自噬既是一种广泛存在的正常生理过程,又是细胞对不良环境的一种抵御机制,参与多种疾病的病理过程。现将其在缺血/再灌注损伤、急性冠脉综合征、心力衰竭和动脉粥样硬化等方面的研究进展综述如下。     

Crosstalk between autophagy and apoptosis in heart disease

Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In addition, autophagy mediates cell death under specific circumstances. Apoptosis, a form of programmed cell death, has been well characterized, and the molecular events involved in apoptotic death are well understood. Damaged cardiomyocytes that show characteristics of autophagy have been observed during heart failure. However, it remains unclear whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for the failing cardiomyocytes. Although autophagy and apoptosis are markedly different processes, several pathways regulate both autophagic and apoptotic machinery and autophagy can cooperate with apoptosis. This review summarizes the evidence for crosstalk between autophagy and apoptosis.     

Autophagic programmed cell death by selective catalase degradation

Autophagy plays a central role in regulating important cellular functions such as cell survival during starvation and control of infectious pathogens. Recently, it has been shown that autophagy can induce cells to die; however, the mechanism of the autophagic cell death program is unclear. We now show that caspase inhibition leading to cell death by means of autophagy involves reactive oxygen species (ROS) accumulation, membrane lipid oxidation, and loss of plasma membrane integrity. Inhibition of autophagy by chemical compounds or knocking down the expression of key autophagy proteins such as ATG7, ATG8, and receptor interacting protein (RIP) blocks ROS accumulation and cell death. The cause of abnormal ROS accumulation is the selective autophagic degradation of the major enzymatic ROS scavenger, catalase. Caspase inhibition directly induces catalase degradation and ROS accumulation, which can be blocked by autophagy inhibitors. These findings unveil a molecular mechanism for the role of autophagy in cell death and provide insight into the complex relationship between ROS and nonapoptotic programmed cell death.     

Cell death signalling mechanisms in heart failure

Cardiac disease is a global epidemic that is on the rise, despite the recent advances in cardiovascular research. Once the myocardium is injured, it has a limited capacity to activate reparative mechanisms to restore proper cardiac function, leading to the development of systemic heart failure. Autophagy, under certain conditions, may result in cell death, further emphasizing the controversial issues regarding the autophagic process as an adaptive or maladaptive biological response. Although significant progress in understanding the signalling mechanisms of cell death in myocytes has been made, the role of apoptotic cell death and programmed necrosis during heart failure is not completely understood. Insight to how myocytes determine whether to activate apoptotic or programmed necrosis signalling machinery remains under current investigation because it is a major problem for both scientists and clinicians in treating heart failure patients. Herein, the different modes of cell death implicated in heart failure are highlighted, as well as the role of B-cell lymphoma-2 family members and how mitochondria act as central organelles in directing such cell death mechanisms.     

Senescence, apoptosis or autophagy? When a damaged cell must decide its path--a mini-review

Many features of aging result from the incapacity of cells to adapt to stress conditions. When damage accumulates irreversibly, mitotic cells from renewable tissues rely on either of two mechanisms to avoid replication. They can permanently arrest the cell cycle (cellular senescence) or trigger cell death programs. Apoptosis (self-killing) is the best-described form of programmed cell death, but autophagy (self-eating), which is a lysosomal degradation pathway essential for homeostasis, reportedly contributes to cell death as well. Unlike mitotic cells, postmitotic cells like neurons or cardiomyocytes cannot become senescent since they are already terminally differentiated. The fate of these cells entirely depends on their ability to cope with stress. Autophagy then operates as a major homeostatic mechanism to eliminate damaged organelles, long-lived or aberrant proteins and superfluous portions of the cytoplasm. In this mini-review, we briefly summarize the molecular networks that allow damaged cells either to adapt to stress or to engage in programmed-cell-death pathways.     

The role of autophagy in anticancer therapy: promises and uncertainties

Autophagy (literally self-eating) is a catabolic mechanism involved in the recycling and turnover of cytoplasmic constituents. Although often referred to as type II programmed cell death, autophagy is primarily a survival rather than a cell death mechanism in response to different stress stimuli. Autophagy is a process in which part of the cytoplasm or entire organelles are sequestered into double-membrane vesicles, called autophagosomes, which ultimately fuse with lysosomes to degrade their contents. Studies show that autophagy is associated with a number of pathological conditions, including cancer, infectious diseases, myopathies and neurodegenerative disorders. With respect to cancer, it has been suggested that the early stages of tumourigenesis are associated with downregulation of autophagy-related (ATG) genes. Indeed, several ATG genes display tumour suppressor function, including Beclin1, which is frequently hemizygously deleted in breast cancer cells. Conversely, in advanced stages of tumourigenesis or during anticancer therapy, autophagy may promote survival of tumour cells in adverse environmental conditions. Therefore, a thorough understanding of autophagy in different cancer types and stages is a prerequisite to determine an autophagy-activating or autophagy-inhibiting treatment strategy.     

Control of programmed cell death in normal and leukemic cells: new implications for therapy

Programmed cell death (apoptosis) is a normal process by which cells are eliminated during normal embryonic development and in adult life. Disruption of this normal process resulting in illegitimate cell survival can cause developmental abnormalities and facilitate cancer development. Normal cells require certain viability factors and undergo programmed cell death when these factors are withdrawn. The viability factors are required throughout the differentiation process from immature to mature cells. Although many viability factors are also growth factors, viability and growth are separately regulated. Viability factors can have clinical value in decreasing the loss of normal cells including the loss that occurs after irradiation, exposure to other cytotoxic agents or virus infection including AIDS. There is no evidence that occurs after irradiation, exposure to other cytotoxic agents or virus infection including AIDS. There is no evidence that cancer cells are immortal. Programmed cell death can be induced in leukemic cells by removal of viability factors, by cytotoxic therapeutic agents, or by the tumor-suppressor gene wild-type p53. All these forms of induction of programmed cell death in leukemic cells can be suppressed by the same viability factors that suppress programmed cell death in normal cells. A tumor-promoting phorbol ester can also suppress this death program. The induction of programmed cell death can be enhanced by deregulated expression of the gene c-myc and suppressed by the gene bcl-2. Mutant p53 and bcl-2 suppress the enhancing effect on cell death of deregulated c-myc, and thus allow induction of cell proliferation and inhibition of differentiation which are other functions of deregulated c-myc. The suppression of cell death by mutant p53 and bcl-2 increases the probability of developing cancer. The suppression of programmed cell death in cancer cells by viability factors suggests that decreasing the level of these factors may increase the effectiveness of cytotoxic cancer therapy. Treatments that downregulate the expression or activity of mutant p53 and bcl-2 in cancer cells should also be useful for therapy.     

Autophagy in cardiac myocyte homeostasis, aging, and pathology

Autophagy, an intralysosomal degradation of cells' own constituents that includes macro-, micro-, and chaperone-mediated autophagy, plays an important role in the renewal of cardiac myocytes. This cell type is represented by long-lived postmitotic cells with very poor (if any) replacement through differentiation of stem cells. Macroautophagy, the most universal form of autophagy, is responsible for the degradation of various macromolecules and organelles including mitochondria and is activated in response to stress, promoting cell survival. This process is also involved in programmed cell death when injury is irreversible. Even under normal conditions, autophagy is somewhat imperfect, underlying gradual accumulation of defective mitochondria and lipofuscin granules within aging cardiac myocytes. Autophagy is involved in the most important cardiac pathologies including myocardial hypertrophy, cardiomyopathies, and ischemic heart disease, a fact that has led to increasing attention to this process.     

Chemotherapy and autophagy-mediated cell death in pancreatic cancer cells

Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents and plays important physiological roles in human health and disease. It has been proposed that autophagy plays an important role both in tumor progression and in promotion of cancer cell death, although the molecular mechanisms responsible for this dual action of autophagy in cancer have not been elucidated. Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies with 2–3% five-year survival rate. Its poor prognosis has been attributed to the lack of specific symptoms and early detection tools, and its relatively refractory to traditional cytotoxic agents and radiotherapy. Experimental evidence pointed at autophagy as a pancreatic cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors pancreatic cancer cell resistance to treatment. Here, we consider several phenotypical alterations that have been related to increase or decrease the autophagic process in pancreatic tumor cells. We specially review autophagy as a cell death mechanism in response to chemotherapeutic drugs.     

细胞自噬与心血管疾病中炎症反应的相关性

细胞自噬既是保守的细胞防御机制,也是程序性细胞死亡(即调亡)机制,其可维持细胞自身内环境的稳态。心血管疾病多伴有炎症反应并与细胞自噬密切相关。新近研究表明:一方面,自噬可以通过清除堆积蛋白和保持线粒体稳态对抗心血管疾病的炎症反应,此效应可能与抑制炎症小体以及钙蛋白酶依赖的白介素-1α的活性有关;另一方面,自噬在某些情况下也可促进炎症反应,自噬相关蛋白和高尔基体重组-堆叠蛋白参与了自噬的促炎效应。以本文简要综述细胞自噬在心血管疾病炎症反应中的作用,探讨自噬与炎症反应的相关分子机制,为心血管疾病中炎症反应的治疗提供新的思路。     

Leishmania donovani: Immune response and immune evasion with emphasis on PD-1/PDL-1 pathway and role of autophagy

Leishmania donovani is one of the causative agents of visceral leishmaniasis. The immune response against Leishmania depends on CD4+ T helper type 1 cells. The immune system is unable to combat Leishmania because the parasite can exert several immune suppressive mechanisms that facilitate escaping the immune responses. One of these mechanisms is the up-regulation of programmed death-1/programmed death ligand-1 pathway which causes T cells to undergo exhaustion. Autophagy is strongly linked to the immune response, with some research indicating that activating autophagy reduces the immune response to some intracellular pathogens, while others indicate that activating autophagy limits the growth of intracellular pathogens. Leishmania was found to subvert the host defense mechanisms for its own persistence, such as Leishmania-induced autophagy modulation. Leishmania was reported to activate autophagy in different studies, thus getting a dual benefit by evading the immune system and simultaneously utilizing the autophagy byproducts as nutrients. In this review, we introduced different immune evasion/suppressive mechanisms used by Leishmania, and different immunotherapies which were developed accordingly. We focused on the programmed death-1/programmed death ligand-1 pathway as well as autophagy with the potential interplay of both mechanisms.