自噬在心肌缺血再灌注中作用的研究进展

自噬是指细胞内的自身物质被溶酶体所降解的过程,为普遍存在的生命现象,是细胞处于饥饿状态时的一种自我保护机制。既往研究表明,在心肌缺血再灌注过程中,自噬被诱导激活,自噬体明显增多。自噬在缺血再灌注中的作用表现出双面性,缺血期主要发挥保护作用,但再灌注时期自噬过度激活则表现出损伤作用,可导致自噬性细胞死亡。自噬具体是如何被激活,怎样发挥其影响作用,至今尚无清楚的答案。本文就自噬在心肌缺血再灌注中作用的研究进展进行综述。     

自噬在肝脏缺血再灌注损伤中的作用及研究进展

肝脏缺血再灌注损伤是肝脏外科常见的一种并发症,是导致术后肝功能障碍的重要原因.肝脏缺血再灌注损伤的发生机制十分复杂,涉及多种因素.自噬是真核细胞内的一种溶酶体依赖的降解途径,具有维持细胞内环境稳定的作用.自噬在肝脏缺血再灌注损伤的发生发展过程中发挥重要的作用,是目前的研究热点之一,但是其具体作用及机制仍有较大争议.本文就自噬在肝脏缺血再灌注损伤中的作用及其机制作一详尽综述.     

哺乳动物雷帕霉素靶蛋白介导的自噬在心血管疾病中作用的研究进展

自噬是生物进化过程中高度保守、依赖溶酶体的胞内降解途径。在心血管系统中,基础水平的自噬是维持心脏结构和功能稳态的一种机制;在应激状态下,自噬适度激活可保护心肌细胞免受应激损伤,而过度激活则会加重心肌损伤,从而参与多种心血管疾病的病理生理过程。生物体内存在多种自噬调控机制,其中哺乳动物雷帕霉素靶蛋白是自噬的关键负调控因子,研究其介导的自噬在心血管疾病中的作用机制,有助于探索临床预防和治疗心血管疾病的新靶点。     

自噬在草酸钙肾结石形成中的作用及相关调控机制研究进展

草酸钙肾结石是常见的泌尿系统疾病，复发率高，防治困难。自噬是机体一种高度保守的细胞代谢机制，可通过溶酶体途径维持细胞稳态。研究表明，草酸钙诱导自噬通过影响细胞氧化损伤参与草酸钙肾结石的发生、发展。自噬在草酸钙肾结石形成过程中表现出保护性或破坏性的双重作用。适度自噬有助于减轻草酸盐诱导的肾小管上皮细胞损伤及晶体沉积，而自噬过度激活则可加重相应的损伤、促进草酸盐沉积。基于自噬相关信号通路、氧化应激、外泌体等途径调控自噬，有望成为防治草酸钙肾结石的新方法。然而目前相关研究多为基础研究，其临床转化仍需要进一步探索。     

自噬与帕金森病研究进展

<正>目前对自噬和神经变性疾病的许多研究,但自噬对神经元细胞死亡是否促进,或起保护作用仍有争议。目前在研究自噬方面虽然已经取得了一定的成绩,但在神经退行性疾病中仍然有很多问题还未解答,本文对自噬和帕金森病(PD)作一综述。1自噬的诱导和形成过程细胞的死亡包括程序性死亡和坏死。其中,程序性细胞死亡可分为凋亡和自噬型细胞死亡。自噬通常依赖于溶酶体降解途径,是细胞保护自己的一种特殊机制,在维持细胞存活、更     

自噬和凋亡在脑缺血中的相互作用

自噬和凋亡是脑缺血时神经元死亡的2种重要方式,二者在缺血半暗带的相互作用可减轻或加重脑缺血损伤.文章对自噬和凋亡在脑缺血中的作用及其相互作用的潜在调节机制进行了综述.     

自噬在脑缺血中的双重作用

自噬是一种细胞内成分降解过程,分为启动、延伸、成熟以及自噬体降解等不同阶段,其作用与细胞损伤程度有关.自噬在饥饿、低氧等情况下适度激活,可促进细胞存活;而在脑缺血时过度激活,可导致细胞裂解和促进细胞死亡.预处理可能通过适当激活自噬而产生缺血耐受作用.自噬受到多种蛋白激酶、凋亡分子以及氧化应激通路的严格调控.     

线粒体功能障碍与脑缺血的研究进展

线粒体功能障碍导致线粒体膜通透性变化、氧化应激、细胞凋亡,激活一系列的病理生理机制导致再灌注期间缺血性神经元损伤加剧。一些特殊的蛋白质通过触发自噬膜上的受体来诱导"线粒体自噬"导致神经变性。总结近年来神经元死亡涉及线粒体功能障碍和线粒体自噬的机制研究进展。     

PAR-2对自噬介导的心肌缺血/再灌注损伤的研究进展

心肌再灌注治疗是急性心肌梗死最重要的治疗方法之一,能够显著改善致死、致残率。但再灌注早期仍难以避免增加心肌损害,引起心肌缺血/再灌注(ischemia/reperfusion,I/R)损伤。心肌缺血阶段激活的自噬对心肌具有保护作用,而再灌注阶段激活的自噬对心肌具有损害作用,其机制可能与缺血阶段AMPK-mTOR信号通路,以及再灌注阶段Bcl-2-Beclin 1信号通路介导的自噬诱导I/R损伤的重要途径有关。蛋白酶激活受体2(protease activated receptor2,PAR-2)在缺血心肌细胞高度表达,是自噬的上游标记物之一,能够显著改善I/R损伤,具有心肌保护作用。在缺血阶段,PAR-2可能通过激活AMPK途径,抑制其下游mTOR表达,从而激活自噬,保护心肌;在再灌注阶段,通过Bcl-2下调激活Beclin 1表达,诱导自噬发生,并且能够上调Bcl-2mRNA表达水平。本文就PAR-2对自噬介导的I/R损伤的研究进展进行综述。     

自噬在肺部疾病中的研究进展

自噬作为一种维持细胞内环境稳定的重要机制,近年来成为一个研究热点。在受到氧化应激、饥饿诱导、炎症刺激等损伤因素作用后,细胞可以通过激活自噬完成对受损蛋白或细胞器的清除,从而维持细胞的稳态。但是自噬的过度激活也会导致细胞功能受损或自噬性死亡。自噬在肺部疾病发病机制所起的调控作用更加复杂,其中一些疾病的发病机制尚不明确,随着自噬与其关系研究的进一步深入,为临床治疗提供了一个新的思路。本文着重讨论自噬在一些常见肺部疾病发病机制中的作用及其临床运用前景。     

Beclin 1与mTOR对心肌缺血/再灌注损伤中自噬的交互调控机制

自噬是一个进化上高度保守的受损或功能障碍的蛋白质聚集体或细胞器降解的过程。在心肌缺血/再灌注(I/R)过程中,可以通过多种因素诱导细胞的自噬活动,而且越来越多的证据表明,自噬在心肌缺血/再灌注损伤(MIRI)中可能起“双刃剑”的作用,适度自噬可促进细胞存活;而不适当的激活自噬可能会加速细胞死亡。Beclin 1介导的自噬/凋亡互反馈信号通路和哺乳动物雷帕霉素靶蛋白(mTOR)介导的自噬与mTOR的互反馈信号通路,是两条经典的自噬激活信号途径,也可能是调控自噬“双刃剑”转向促进细胞存活的重要调控机制。本文将重点综述上述两条信号通路对自噬的交互式调控作用。速发挥作用。因此,Z盘部位实质上成为心肌细胞中的信号转导中心。     

Cardioprotection requires taking out the trash

Autophagy is a critical cellular housekeeping process that is essential for removal of damaged or unwanted organelles and protein aggregates. Under conditions of starvation, it is also a mechanism to break down proteins to generate amino acids for synthesis of new and more urgently needed proteins. In the heart, autophagy is upregulated by starvation, reactive oxygen species, hypoxia, exercise, and ischemic preconditioning, the latter a well-known potent cardioprotective phenomenon. The observation that upregulation of autophagy confers protection against ischemia/reperfusion injury and inhibition of autophagy is associated with a loss of cardioprotection conferred by pharmacological conditioning suggests that the pathway plays a key role in enhancing the heart’s tolerance to ischemia. While many of the antecedent signaling pathways of preconditioning are well-defined, the mechanisms by which preconditioning and autophagy converge to protect the heart are unknown. In this review we discuss mechanisms that potentially underlie the linkage between cardioprotection and autophagy in the heart.     

Recycle or die: the role of autophagy in cardioprotection

Autophagy is a highly conserved cellular process responsible for the degradation of long-lived proteins and organelles. Autophagy occurs at low levels under normal conditions, but is upregulated in response to stress such as nutrient deprivation, hypoxia, mitochondrial dysfunction, and infection. Upregulation of autophagy may be beneficial to the cell by recycling of proteins to generate free amino acids and fatty acids needed to maintain energy production, by removing damaged organelles, and by preventing accumulation of protein aggregates. In contrast, there is evidence that enhanced autophagy can contribute to cell death, possibly through excessive self-digestion. In the heart, autophagy has an essential role for maintaining cellular homeostasis under normal conditions and increased autophagy can be seen in conditions of starvation, ischemia/reperfusion, and heart failure. However, the functional significance of autophagy in heart disease is unclear and controversial. Here, we review the literature and discuss the evidence that autophagy can have both beneficial and detrimental roles in the myocardium depending on the level of autophagy, and discuss potential mechanisms by which autophagy provides protection in cells.     

Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy

Autophagy is an intracellular bulk degradation process for proteins and organelles. In the heart, autophagy is stimulated by myocardial ischemia. However, the causative role of autophagy in the survival of cardiac myocytes and the underlying signaling mechanisms are poorly understood. Glucose deprivation (GD), which mimics myocardial ischemia, induces autophagy in cultured cardiac myocytes. Survival of cardiac myocytes was decreased by 3-methyladenine, an inhibitor of autophagy, suggesting that autophagy is protective against GD in cardiac myocytes. GD-induced autophagy coincided with activation of AMP-activated protein kinase (AMPK) and inactivation of mTOR (mammalian target of rapamycin). Inhibition of AMPK by adenine 9-beta-d-arabinofuranoside or dominant negative AMPK significantly reduced GD-induced autophagy, whereas stimulation of autophagy by rapamycin failed to cause an additive effect on GD-induced autophagy, suggesting that activation of AMPK and inhibition of mTOR mediate GD-induced autophagy. Autophagy was also induced by ischemia and further enhanced by reperfusion in the mouse heart, in vivo. Autophagy resulting from ischemia was accompanied by activation of AMPK and was inhibited by dominant negative AMPK. In contrast, autophagy during reperfusion was accompanied by upregulation of Beclin 1 but not by activation of AMPK. Induction of autophagy and cardiac injury during the reperfusion phase was significantly attenuated in beclin 1(+/-) mice. These results suggest that, in the heart, ischemia stimulates autophagy through an AMPK-dependent mechanism, whereas ischemia/reperfusion stimulates autophagy through a Beclin 1-dependent but AMPK-independent mechanism. Furthermore, autophagy plays distinct roles during ischemia and reperfusion: autophagy may be protective during ischemia, whereas it may be detrimental during reperfusion.     

The role of mitochondrial autophagy in Doxorubicininduced cardiotoxicity

Background Doxorubicin is a widely used drug in all kinds of chemotherapy, but its application is limited by its cardiac toxicity to some extent. Most of scholars have studied doxorubicin induced myocardial injury and cardiomyocytes death, but the specific mechanism remains unclear. Autophagy is a metabolic pathway of degrading longevity protein and organelles by lysosome, especially selective autophagy which called mitochondrial autophagy exists in various cells. The normal range of mitochondrial autophagy helps to maintain the physiological function, otherwise, could lead to the development of disease. Recent studies have suggested that mitochondrial autophagy is involved in the progress of doxorubicin-induced cardiotoxicity. This article reviews the role of mitochondrial autophagy in doxorubicin-induced cardiotoxicity, and how mitochondrial autophagy is involved in the occurrence and development of the progress, in order to provide a theoretical basis of prevention and treatment.     

Mitochondrial quality control: The role of mitophagy in aging

Autophagy is a catabolic process for eliminating macromolecules and damaged organelles by a highly regulated lysosomal pathway. Importantly, autophagy serves as an integral quality control mechanism by recycling cellular constituents for energy consumption and cellular rejuvenation under basal and stress conditions. Nevertheless, there is growing evidence that under certain conditions autophagy can switch from an adaptive survival mechanism to maladaptive process that promotes cell death. Furthermore, defects in autophagy have been linked to mitochondria injury and cell death associated with aging. In this review, we describe the role of autophagy as a physiological mechanism for maintaining homeostasis with its specific involvement in mitochondrial quality control and cardiac aging.     

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.     

How does the heart (not) die? The role of autophagy in cardiomyocyte homeostasis and cell death

Autophagy plays a critical and seemingly dual-purposed role in cardiomyocytes, being implicated as a mechanism of both cellular survival, for example, during ischemia/reperfusion injury and a mechanism of cell death at stages in which progressive myocyte alterations are beyond repair. This review aims to highlight the current literature as it relates to autophagy in cardiomyocytes. It provides background into the mechanisms of cell death, discusses the details that are known about the ubiquitin proteasome system and autophagy, delves into the pathways that are known to initiate and inhibit autophagy, and comments on the role of autophagy in cardiomyocyte homeostasis and cell death.     

Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury

Autophagy is known to be a feature of cardiomyopathies and chronic ischaemia. Here we demonstrate that autophagy is also induced by a single cycle of ischaemia/reperfusion (I/R in neonatal and adult rat cardiac myocytes). Consistent with the critical role for Beclin1 in autophagocytosis, reduction of Beclin1 expression in cardiac myocytes by RNAi reduces I/R-induced autophagy and this is associated with enhanced cell survival. Autophagy is also reduced by urocortin, an endogenous cardiac peptide which we have previously shown to reduce other forms of myocyte cell death induced by I/R. The inhibition of autophagy by urocortin is mediated in part by inhibition of Beclin1 expression, an effect which is mediated by activation of the PI3 kinase/Akt pathway but which does not involve activation of p42/p44 MAPK.