自噬和铁死亡的相互联系

自噬是一个保守的细胞内降解系统,在细胞死亡中起着双重作用,可以为细胞在营养缺乏条件下提供一些必要的营养物质促进细胞存活,但是自噬过度发生会导致细胞内一些正常组分被降解从而加速细胞死亡.铁死亡是一种新的细胞死亡调控形式,主要依赖于铁的积累和脂质过氧化.铁死亡在细胞形态、生物化学特征和所涉及的调控因子上都与自噬以及其他类型...     

铁死亡与脑卒中的神经损伤

铁死亡是近年来新发现的一种可调控性细胞死亡形式。与凋亡或坏死等细胞死亡方式不同,铁死亡主要特征是铁依赖的脂质过氧化诱导细胞死亡。铁、脂质和氨基酸代谢是调控铁死亡的主要途径,这个过程能被谷胱甘肽过氧化物酶4 (GPX4)和铁死亡抑制蛋白1 (FSP1)拮抗。铁死亡参与神经系统疾病、癌症等多种疾病的发生和发展过程。近年来研究揭示,铁死亡在脑卒中时能被诱导并加重脑损伤,铁死亡的抑制剂可以减轻脑卒中损伤,铁死亡成为脑卒中干预的潜在靶点。目前研究发现,干预铁死亡能改善脑卒中损伤,并且出血性和缺血性脑卒中铁死亡的发生机制存在异同:相同点是都通过增加细胞内Fe~(2+)与脂质过氧化物的含量诱导铁死亡的发生,不同点是,出血性和缺血性脑卒中时与铁死亡有关的关键通路变化不同,Fe~(2+)与脂质过氧化物含量增多的机制不同。目前,对于在脑卒中时铁死亡的研究更多的是侧重于铁死亡的关键通路,在调控机制方面仍有待进一步探究。在此,本文系统地回顾了目前关于铁死亡在脑卒中方面作用的文献,阐述当前铁死亡的发生机制,总结脑卒中时铁死亡相关的研究发现,为铁死亡在脑卒中治疗方法的应用方面提供新的思路。     

铁死亡在呼吸系统疾病中的研究进展及应用

铁死亡(ferroptosis)是一种新发现的细胞死亡调控方式,依赖于铁和活性氧簇,主要特征是细胞内脂质过氧化物堆积。与其他细胞死亡方式相比,铁死亡在形态、生物化学、遗传学等方面有自身的特点。铁死亡的发生机制与非酶促反应或者酶促反应触发铁催化的脂质过氧化物堆积有关。近年来的研究显示铁死亡与血液系统、心脑血管、肝肾系统等多种疾病相关,然而在呼吸系统疾病中的研究相对较少。本文就铁死亡的定义、机制、诱导剂、病理生理状态下的铁死亡以及铁死亡在呼吸系统疾病中的相关研究展开综述,以期为呼吸系统疾病的临床防治提供新思路、新靶点。     

Ferroptosis的信号通路及调控

Ferroptosis是近年发现的调控细胞死亡的方式,在生化、基因和形态学等方面与其他形式的细胞死亡有显著的差异。Ferroptosis过程受严格而复杂的调控机制控制,其特点是,脂质过氧化物和致死的活性氧(reactive oxygen species,ROS)积累。但Ferroptosis可被铁螯合剂和脂质过氧化反应抑制剂所抑制。Ferroptosis的错误调控与多种生理和病理过程有关,包括肿瘤细胞的死亡、神经退行性疾病、急性肾功能衰竭以及肝和心脏缺血再灌注损伤等。     

铁死亡中的代谢调控网络及其与肺相关疾病的联系

铁死亡(ferroptosis)是新近发现的一种铁依赖性的脂质过氧化驱动的非凋亡形式的调节性细胞死亡方式。目前的研究表明,铁死亡会影响体内许多代谢过程和稳态平衡,并且它与许多肺疾病有关,包括急性肺损伤、慢性阻塞性肺疾病和肺纤维化等。目前,关于铁死亡的研究尚处于起始阶段,现有研究已确认铁死亡受多种基因调控,主要涉及铁稳态和脂质过氧化代谢等方面的基因改变,且机制复杂。本综述基于先前的研究,总结了部分与铁死亡有关的代谢调控网络,并讨论了铁死亡在诸多肺相关疾病病理生理学过程中的作用,期望为此类疾病的研究和治疗提供新的思路和借鉴。     

铁死亡与内质网应激反应

铁死亡是2012年被发现的一种新的受调控的细胞死亡方式,其特征是铁依赖的脂质过氧化物的过度积累(可引起细胞死亡的水平).铁代谢、脂代谢、氨基酸代谢等多种调节机制参与了铁死亡的调控.内质网是蛋白质合成、加工、修饰、转运的重要细胞器.应激状态下,未折叠、错误折叠蛋白在内质网内过度积累,即可诱发内质网应激反应.内质网应激是细胞应对外界压力的保护性机制,但持续的、恶劣的应激也能引起细胞死亡.近年来的研究表明,铁死亡与内质网应激密切相关.在癌细胞中,铁死亡诱导剂能同步激活内质网应激反应,内质网应激通路的启动则抑制铁死亡,导致癌细胞产生抗药性.在某些病理情况下,内质网应激通路的激活却加剧了铁死亡的发生.铁死亡和内质网应激之间究竟存在怎样的密切联系,成为目前认识细胞死亡命运的重要科学问题.本文综述了铁死亡的调控通路以及铁死亡与内质网应激相互联系的最新进展,以期为铁死亡相关疾病的发生机制和治疗提供重要的新参考.     

线粒体在铁死亡中的形态特征和作用

铁死亡是铁依赖性的脂质过氧化作用驱动的一种独特的细胞死亡方式。与细胞凋亡、自噬性程序性细胞死亡和细胞焦亡等细胞死亡方式不同，铁死亡的主要特征是线粒体形态的改变，包括线粒体膜变得致密并伴随体积变小，以及外膜破裂和线粒体嵴的减少或消失。线粒体作为细胞代谢的核心，是铁代谢、脂质代谢和能量代谢中的重要细胞器。但是，线粒体如何参与铁死亡并在其进程中发挥怎样的作用仍存在争议。本文综述了现有对铁死亡发生和防御机制的认识，并且对线粒体在铁死亡进程中的促进和抑制作用进行了描述和分析，包括线粒体三羧酸循环和糖酵解、线粒体活性氧、线粒体脂质代谢对铁死亡的积极驱动过程，以及通过线粒体铁蛋白、线粒体二氢乳酸脱氢酶等分子对线粒体脂质过氧化物解毒并抑制铁死亡的作用机制。最后补充说明了其他涉及铁死亡的线粒体分子调控机制。本文通过综述线粒体在铁死亡进程中的最新研究进展，旨在对深入了解铁死亡中线粒体的功能及其对铁死亡发生发展的作用机制，为细胞生物学基础研究及临床相关疾病的研究提供理论依据和参考。     

铁死亡与缺血性脑卒中

铁死亡是一种铁代谢异常、脂质过氧化物累积构成的可调节性新型细胞死亡方式。缺血性脑卒中是全球第二大常见的脑血管疾病,病死率、致残率、复发率极高,其发生伴随着大量神经元死亡。现有研究证明,缺血性脑卒中发病机制与铁死亡关系密切。缺血性脑卒中损伤中出现的细胞内铁水平升高、脂质过氧化物增多和抗氧化能力下降的现象与铁依赖性非凋亡形式的铁死亡相一致。因此,阐明铁死亡在缺血性脑卒中的发生机制,有利于为其临床治疗提供新靶点。本文将从铁代谢、脂质代谢、氨基酸代谢、活性氧生成的调控等方面论述铁死亡发生的调节机制,着重探讨铁死亡发生在缺血性脑卒中的病理生理机制,期望以铁死亡为切入点,为缺血性脑卒中的临床治疗提供参考。     

天然产物通过诱导铁死亡改善肝纤维化的研究进展

肝纤维化是多种慢性肝病发展为肝硬化和肝癌所必须经历的共同病理过程,在其发生、发展过程中受到多种细胞因子以及信号通路的调控。铁死亡是由铁过载、氧化还原稳态紊乱和脂质过氧化增加引起的一种新的细胞死亡调控模式,与肝纤维化密切相关。诱导肝星状细胞发生铁死亡可能是肝纤维化治疗的潜在靶标。许多天然产物可以诱导肝星状细胞发生铁死亡进而抑制肝纤维化的进展,因此越来越受到关注。然而,关于天然产物通过铁死亡途径调节肝纤维化的综述文章却相对较少。该文简述了天然产物通过铁死亡调控影响肝纤维化的干预机制及应用,重点探讨铁死亡与肝纤维化的关系,以及天然产物靶向铁死亡对肝纤维化的调控作用,旨在为天然产物治疗代谢性疾病和肝脏疾病的发展提供新的理论依据,也为将来的药物制取提供更多的备选策略。     

铁死亡与肾脏疾病相关性的研究进展

铁死亡(ferroptosis)是2012年新发现的一种非凋亡的细胞死亡形式,其实质是依赖铁离子的活性氧(reactive oxygen species,ROS)和脂质氢过氧化物蓄积导致的线粒体形态改变和细胞膜磷脂过氧化损伤。铁死亡与许多肾脏疾病的病理生理进程密切相关。然而铁死亡参与肾脏疾病损伤的分子生物学机制尚缺乏系统和深入的认识。针对铁死亡的调控机制、研究进展及其在肾脏相关疾病中的作用作一综述,以期为肾脏疾病的治疗提供新思路、新靶点。     

Mitochondria regulation in ferroptosis

Ferroptosis is recognized as a new form of regulated cell death which is initiated by severe lipid peroxidation relying on reactive oxygen species (ROS) generation and iron overload. This iron-dependent cell death manifests evident morphological, biochemical and genetic differences from other forms of regulated cell death, such as apoptosis, autophagy, necrosis and pyroptosis. Ferroptosis was primarily characterized by condensed mitochondrial membrane densities and smaller volume than normal mitochondria, as well as the diminished or vanished of mitochondria crista and outer membrane ruptured. Mitochondria take the center role in iron metabolism, as well as substance and energy metabolism as it’s the major organelle in iron utilization, catabolic and anabolic pathways. Interference of key regulators of mitochondrial lipid metabolism (e.g., ASCF2 and CS), iron homeostasis (e.g., ferritin, mitoferrin1/2 and NEET proteins), glutamine metabolism and other signaling pathways make a difference to ferroptotic sensitivity. Targeted induction of ferroptosis was also considered as a potential therapeutic strategy to some oxidative stress diseases, including neurodegenerative disorders, ischemia-reperfusion injury, traumatic spinal cord injury. However, the pertinence between mitochondria and ferroptosis is still in dispute. Here we systematic elucidate the morphological characteristics and metabolic regulation of mitochondria in the regulation of ferroptosis.     

Programmed cell death in spinal cord injury pathogenesis and therapy

Spinal cord injury (SCI) always leads to functional deterioration due to a series of processes including cell death. In recent years, programmed cell death (PCD) is considered to be a critical process after SCI, and various forms of PCD were discovered in recent years, including apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis. Unlike necrosis, PCD is known as an active cell death mediated by a cascade of gene expression events, and it is crucial for elimination unnecessary and damaged cells, as well as a defence mechanism. Therefore, it would be meaningful to characterize the roles of PCD to not only enhance our understanding of the pathophysiological processes, but also improve functional recovery after SCI. This review will summarize and explore the most recent advances on how apoptosis, necroptosis, autophagy, ferroptosis, pyroptosis and paraptosis are involved in SCI. This review can help us to understand the various functions of PCD in the pathological processes of SCI, and contribute to our novel understanding of SCI of unknown aetiology in the near future.     

Surveying the landscape of emerging and understudied cell death mechanisms

Cell death can be a highly regulated process. A large and growing number of mammalian cell death mechanisms have been described over the past few decades. Major pathways with established roles in normal or disease biology include apoptosis, necroptosis, pyroptosis and ferroptosis. However, additional non-apoptotic cell death mechanisms with unique morphological, genetic, and biochemical features have also been described. These mechanisms may play highly specialized physiological roles or only become activated in response to specific lethal stimuli or conditions. Understanding the nature of these emerging and understudied mechanisms may provide new insight into cell death biology and suggest new treatments for diseases such as cancer and neurodegeneration.     

Programmed cell death in atherosclerosis and vascular calcification

The concept of cell death has been expanded beyond apoptosis and necrosis to additional forms, including necroptosis, pyroptosis, autophagy, and ferroptosis. These cell death modalities play a critical role in all aspects of life, which are noteworthy for their diverse roles in diseases. Atherosclerosis (AS) and vascular calcification (VC) are major causes for the high morbidity and mortality of cardiovascular disease. Despite considerable advances in understanding the signaling pathways associated with AS and VC, the exact molecular basis remains obscure. In the article, we review the molecular mechanisms that mediate cell death and its implications for AS and VC. A better understanding of the mechanisms underlying cell death in AS and VC may drive the development of promising therapeutic strategies.Subject terms: Calcification, Cell death     

线粒体在神经元程序性死亡中的作用新进展

神经元的死亡是许多神经系统疾病如阿尔茨海默病、帕金森病、急性青光眼等发生发展过程中的重要事件,传统认为,细胞死亡有凋亡、自噬、坏死三种方式,凋亡和自噬为程序性的细胞死亡,坏死为非程序性的死亡途径。而近年来的研究发现了一种名为程序性坏死(necroptosis)的可调控的坏死,因此,对这些可调控的细胞死亡的研究对治疗这类神经系统疾病有重要的意义。大量研究发现,在能量代谢和自由基代谢中占据着重要地位的线粒体在细胞死亡过程中也发挥重要作用。本文对线粒体在神经元凋亡、自噬和程序性坏死中的生物学作用的最新进展做一综述。     

The role of ferroptosis in melanoma

Melanoma is the deadliest form of skin cancer. Although treatment with targeted therapies and immune checkpoint inhibitors has dramatically improved survival in advanced melanoma, many patients do not benefit from these therapies or relapse after an initial period of response. Thus, future outcomes in these categories of melanoma patients will depend on the identification of novel therapeutic targets and methods to enhance existing targeted therapy and immunotherapy regimens. Ferroptosis is a newly identified form of iron-dependent regulated cell death that is morphologically, biochemically, and genetically distinct from apoptosis, autophagy, pyroptosis, and necroptosis. Dysregulation of ferroptosis has been linked to the development of several forms of cancer. This review examines ferroptosis in the context of melanoma. It presents an overview of ferroptosis biology, summarizes and interprets the current literature, and poses several outstanding questions and areas of future direction.     

Pyroptosis in Kidney Disease

In the last several decades, apoptosis interference has been considered clinically irrelevant in the context of renal injury. Recent discovery of programmed necrotic cell death, including necroptosis, ferroptosis, and pyroptosis refreshed our understanding of the role of cell death in kidney disease. Pyroptosis is characterized by a lytic pro- inflammatory type of cell death resulting from gasdermin-induced membrane permeabilization via activation of inflammatory caspases and inflammasomes. The danger-associated molecular patterns (DAMPs), alarmins and pro-inflammatory cytokines are released from pyroptotic cells in an uncontrolled manner, which provoke inflammation, resulting in secondary organ or tissue injuries. The caspases and inflammasome activation-related proteins and pore-forming effector proteins known as GSDMD and GSDME have been implicated in a variety of acute and chronic microbial and non-microbial kidney diseases. Here, we review the recent advances in pathological mechanisms of pyroptosis in kidney disease and highlight the potential therapeutic strategies in future.     

New insights into the regulation of apoptosis,necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8

Necroptosis and pyroptosis are inflammatory forms of regulated necrotic cell death as opposed to apoptosis that is generally considered immunologically silent. Recent studies revealed unexpected links in the pathways regulating and executing cell death in response to activation of signaling cascades inducing apoptosis, necroptosis, and pyroptosis. Emerging evidence suggests that receptor interacting protein kinase 1 and caspase-8 control the cross-talk between apoptosis, necroptosis, and pyroptosis and determine the type of cell death induced in response to activation of cell death signaling.     

Autophagy,anoikis, ferroptosis,necroptosis, and endoplasmic reticulum stress: Potential applications in melanoma therapy

Melanoma as the most major skin malignancy has attracted much attention, so far. Although a successful therapeutic strategy requires an accurate understanding of the precise mechanisms for the initiation and progression of the melanoma. Several types of cell death mechanisms have recently been identified along with conventional cell death mechanisms such as apoptosis and necrosis. Among those mechanisms, necroptosis, anoikis, ferroptosis, and autophagy may be considered to have remarkable modulatory impacts on melanoma. In the present review, we explain the mechanisms of cell death signaling pathways related to autophagy, ferroptosis, anoikis, necroptosis, and reticulum endoplasmic stress in cells and describe how those mechanisms transduce signals in melanoma cells. Meanwhile, we describe how we can modulate those mechanisms to eliminate melanoma.     

Autophagy in cell survival and death

Macroautophagy hereafter referred to as autophagy is a major lysosomal catabolic pathway for macromolecules and organelles conserved in eukaryotic cells. The discovery of the molecular basis of autophagy has uncovered its importance during development, life extension and in pathologies such as cancer, certain forms of myopathies and neurodegenerative diseases. Autophagy is a cell survival mechanism during starvation that is controlled by amino acids. Starvation-induced autophagy is an anti-apoptotic mechanism. However autophagy is also an alternative to apoptosis through autophagic cell death. In many situations apoptosis and autophagy can both contribute to cell dismantlement.