自噬相关去泛素化酶及其小分子抑制剂的研究进展

自噬是进化上高度保守并受到多途径严密调控的细胞生物学过程,其向溶酶体递送多种细胞质组分以进行细胞内物质的降解以及再循环.这一过程涉及到细胞器的更新、错误折叠蛋白质和蛋白质聚集体以及细胞内病原体的清除.因此,自噬对于细胞稳态的维持至关重要,与许多人类疾病的发生发展密切相关.随着细胞自噬调节机制研究的不断深入,越来越多的去泛素化酶被证明在自噬相关的泛素信号调控系统中发挥了重要的作用.这些去泛素化酶作用于细胞自噬的不同阶段,靶向调节不同的泛素化自噬功能元件或自噬底物.去泛素化酶作为包括神经退行性疾病以及肿瘤在内的细胞自噬相关疾病的治疗靶点受到了广泛的关注,其中各类小分子抑制剂的发现为进一步研究去泛素化酶的自噬调节活性及相关疾病的治疗提供了可能.     

自噬与肺部疾病研究进展

自噬(autophagy)是广泛存在于真核细胞中的基本生命现象,是细胞适应环境变化、防御病原微生物侵袭、维持内环境稳定的重要机制．多种肺部疾病中存在自噬活性的变化,自噬与肺部疾病的发生、发展密切相关．自噬在慢性阻塞性肺病、肺气肿、肺癌、肺结核等许多肺部疾病中发生,且发挥重要作用．现从自噬与多种肺部疾病的关系角度进行综述,有助于了解自噬在肺部疾病中发挥的作用,以便进一步研究自噬的调节,为肺部疾病的治疗提供新思路．     

长链非编码RNA调控自噬的研究进展

长链非编码RNA (lncRNA)是转录本长度超过200个核苷酸的RNA分子,不具备蛋白质编码功能。细胞自噬是真核生物的一种高度保守、用来降解和循环再利用细胞内生物大分子或受损细胞器的过程,有助于维持机体内环境稳态。自噬研究是当下生命科学研究的热点,前期研究发现,lncRNA在细胞自噬调控中发挥着重要作用,深入探索lncRNA调控自噬的分子机制及其与疾病发生的关系对预防和治疗多种人类重大疾病具有重要意义。该文就目前为止报道过的部分lncRNA参与自噬调控的最新进展进行归纳总结,以期为lncRNA调控自噬的相关研究及其在肿瘤等疾病治疗中的作用提供参考。     

自噬与小胶质细胞相关神经炎症

小胶质细胞是中枢神经系统中重要的神经免疫细胞,当中枢神经系统受到刺激后,小胶质细胞通过炎症反应来应对这种刺激,这种炎症反应在神经性疾病中具有重要作用。研究发现,小胶质细胞自噬在炎症的发生与发展中也发挥了重要作用,它能直接或间接地影响炎症反应,同时自身也被其他信号调控。自噬过程有利有弊,适当的自噬过程能促进疾病的恢复,自噬紊乱则使病情恶化,所以明确自噬的调控机制对治疗和预防相关疾病具有重要意义。本文综述了近年来自噬在小胶质细胞相关炎症中研究进展,以及其可能的调控机制,以期为相关研究人员提供一定帮助。     

自噬在疾病中的双重作用

自噬是细胞的一种正常的生理活动,参与细胞内损伤的蛋白质和亚细胞器经溶酶体途径降解的过程。自噬可以抵御外界的不良环境,在多种疾病中起着重要作用。近年来,大量研究表明自噬在细胞新陈代谢和生理功能上有双重作用,在疾病发生的不同时期,自噬起到不同的作用。通常情况自噬可以及时的清除细胞内损伤的蛋白质,作为一种细胞的保护机制,但是自噬的持续活化,导致细胞内大量蛋白质的降解,使细胞无法维持其基本结构,最终将导致细胞坏死或凋亡。自噬、凋亡和坏死的转化,很有可能受到p53、Bcl-2、Beclin-1、ATG5、TG2及p62等信号分子调控。肝脏和心脏是维持人体生命活动的重要器官,自噬在脂肪肝、肝硬化、心肌梗塞及心脏衰竭等疾病中扮演着重要的角色。本文总结了自噬、凋亡及坏死的相互关系,自噬在疾病中的双重作用,并重点介绍自噬在肝脏和心脏疾病中的作用。     

细胞自噬调控的分子机制研究进展

细胞自噬是一种进化上保守的分解代谢过程,涉及细胞内长寿命蛋白和受损伤细胞器的降解,其在细胞内稳态、肿瘤、心力衰竭、衰老相关性疾病、神经退行性疾病以及传染病等多种生命进程中发挥着重要作用。泛素样蛋白系统、m TOR信号通路、micro RNA、caspase等均参与了细胞自噬调控过程。该文综述了细胞自噬过程、功能和分子调控机制的研究进展,以期有助于研究细胞自噬机理,为治疗心脏疾病(如动脉粥样硬化)、癌症(如乳腺癌)等提供理论基础。     

自噬对血管功能的影响及与相关疾病的关联研究进展

自噬(autophagy)是细胞利用溶酶体降解自身受损的细胞器和大分子物质的过程,在稳定细胞内环境中发挥着重要作用．研究发现,自噬影响血管功能,与血管疾病的病理生理进程密切相关．本文从自噬对血管功能的影响,与血管相关疾病(如动脉粥样硬化、腹主动脉瘤、肺动脉高压、糖尿病血管并发症等)的关系及药物对血管壁细胞自噬的调控进行综述,希望从自噬的角度来了解血管的功能和病变及一些疾病的发生发展进程,为治疗血管相关疾病提供新的思路．     

运动：一种双向调控疾病中自噬异常的手段

自噬(autophagy)是一种进化上高度保守的细胞降解过程,它可以完成细胞成分的基本周转,并提供能量和大分子前体以维持生物体的代谢与平衡。近年研究发现,细胞自噬水平的失调与多种疾病的发生和发展密切相关,这一点已在多种疾病动物模型中得到验证。过高或不足的自噬水平都可能导致疾病。运动作为一种与能量代谢及细胞内环境变化密切相关的活动,与细胞自噬过程之间有密切关联。而运动对自噬的调节是一个双向的过程。对于自噬不足或过度引起的疾病,运动可以恢复其正常的自噬功能,并起到改善、延缓疾病进展的作用。当前,对于运动调控疾病背景下异常的自噬水平的理论及机制尚缺乏充分的阐述。深入探索和讨论运动对疾病中异常自噬水平的调节,将有助于我们拓展视野,为更全面地理解运动在预防和改善各种与自噬相关的疾病过程中的潜在机制和作用。因此,本综述分析概括总结了运动改善疾病中过高或不足的自噬水平及运动对疾病的缓解效果,梳理了运动与自噬的双向调控关系,并进一步提炼归纳了运动调控异常自噬水平所涉及的相关信号通路。这为探究运动促进健康的机制及理清运动调控自噬之间的关系提供理论依据与参考。     

自噬发生中的ROS调节机制

活性氧是细胞代谢中产生的有很强反应活性的分子,易将邻近分子氧化,并参与细胞内多种信号转导途径,对相关生理过程进行调控．自噬是真核细胞通过溶酶体机制对自身组分进行降解再利用的过程,在细胞应激及疾病发生等过程中发挥重要作用．本文对活性氧和自噬相关调节进行分类介绍,根据新近研究进展,从活性氧参与的自噬性死亡、自噬性存活以及线粒体自噬3方面探讨了相关信号转导机制,对活性氧作为信号分子参与的自噬调控途径做一总结和介绍．     

自噬的前世今生

自噬是细胞通过溶酶体（或液泡）分解自身组分以达到维持细胞内正常生理活动及稳态的一种细胞代谢过程。自噬作为一种在真核生物中保守存在的细胞通路,与人类的疾病与健康息息相关。2016年,诺贝尔生理学或医学奖颁发给为自噬通路研究做出过卓越贡献的日本生物学家大隅良典（Yoshinori Ohsumi）。本文其一旨在通过介绍自噬及自噬相关基因的发现细节,带领读者了解自噬被发现和阐释的历程;其二旨在通过介绍自噬起始的相关机制及自噬与疾病的联系,引导读者对于自噬生理功能有更深入的理解;最后本文还提出了一些自噬领域目前尚待进一步研究的方向,供读者参考。     

The role of short-chain fatty acids in orchestrating two types of programmed cell death in colon cancer

Autophagy serves a critical function in cellular homeostasis by prolonging survival during nutrient deprivation. Although primarily characterized as a cell survival mechanism, the relationship between autophagy and cell death pathways remains incompletely understood. Autophagy has heretofore not been studied in the context of human pulmonary disease. We have recently observed increased morphological and biochemical markers of autophagy in human lung tissue from patients with chronic obstructive pulmonary disease (COPD). Similar observations of increased autophagy were also made in mouse lung tissue subjected to chronic cigarette smoke exposure, a primary causative agent in COPD, and in pulmonary cells exposed to aqueous cigarette smoke extract. Since knockdown of autophagic regulator proteins inhibited apoptosis in response to cigarette smoke exposure in vitro, we concluded that increased autophagy was associated with increased cell death in this model. We hypothesize that increased autophagy contributes to COPD pathogenesis by promoting epithelial cell death. Further research will examine whether autophagy plays a causative, correlative, or protective role in specific lung pathologies.     

综述: 影响血管内皮细胞自噬的因素及其相关机制探讨

自噬对维持细胞自身的稳定及细胞成分更新、保持正常的生理状态起着至关重要的作用．机体在生理和病理过程中都存在自噬,基础状态下的自噬对细胞具有保护和修复作用,而自噬过度激活会引起细胞的损伤及死亡．近年来,对自噬的研究主要集中于肿瘤细胞,而对正常细胞的自噬研究较少．血管内皮细胞作为人体中最活跃的细胞之一,其功能变化与心血管疾病的发生和发展有密切相关．本文对影响血管内皮细胞自噬的因素及其相关机制进行综述．     

Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: Implication in pathogenesis of COPD

Autophagy is a fundamental cellular process that eliminates long-lived proteins and damaged organelles through lysosomal degradation pathway. Cigarette smoke (CS)-mediated oxidative stress induces cytotoxic responses in lung cells. However, the role of autophagy and its mechanism in CS-mediated cytotoxic responses is not known. We hypothesized that NAD⁺-dependent deacetylase, sirtuin 1 (SIRT1) plays an important role in regulating autophagy in response to CS. CS exposure resulted in induction of autophagy in lung epithelial cells, fibroblasts and macrophages. Pretreatment of cells with SIRT1 activator resveratrol attenuated CS-induced autophagy whereas SIRT1 inhibitor, sirtinol, augmented CS-induced autophagy. Elevated levels of autophagy were induced by CS in the lungs of SIRT1 deficient mice. Inhibition of poly(ADP-ribose)-polymerase-1 (PARP-1) attenuated CS-induced autophagy via SIRT1 activation. These data suggest that the SIRT1-PARP-1 axis plays a critical role in the regulation of CS-induced autophagy and have important implications in understanding the mechanisms of CS-induced cell death and senescence.     

Autophagy inhibition suppresses pulmonary metastasis of HCC in mice via impairing anoikis resistance and colonization of HCC cells

Metastasis is one of the main causes of poor prognosis for hepatocellular carcinoma (HCC), which has been linked to cell-death resistance. Autophagy is an important survival mechanism under conditions of cell stress. We hypothesized that autophagy may play a role in HCC metastasis due to its prosurvival effect. Highly metastatic HCC cell lines with stable autophagy inhibition were established via lentivirus-mediated silencing of BECN1 and ATG5 genes. Mouse models of pulmonary metastasis were then developed using the cells with or without autophagy inhibition. The analysis of lung metastasis by histopathological examination and small animal imaging showed that autophagy inhibition significantly decreased the incidence of pulmonary metastases in vivo. Further invasion, migration, detachment, lung colonization, and epithelial-mesenchymal transition (EMT) assays indicated that autophagy inhibition did not affect cell invasiveness, migration or EMT but attenuated the anoikis-resistance and lung colonization of HCC cells. Investigation of the molecular mechanisms underlying showed that the autophagy-inhibition-mediated anoikis-resistance attenuation was associated with the regulation of apoptotic signaling. As autophagy inhibition was shown to be able to suppress HCC metastasis, an autophagy-based HCC tissue-specific target therapy system (AFP-Cre/LoxP-shRNA) was constructed. In vitro and in vivo analyses showed that the system was able to efficiently inhibit autophagy of HCC cells and tissue in a tissue-specific manner. Further in vivo metastasis assay showed that intratumoral administration of the system could significantly suppress lung metastasis. Together, our findings suggest that autophagy may be involved in HCC metastasis through facilitating anoikis resistance and lung colonization of HCC cells. Autophagy-based HCC tissue-specific target therapy may be a new strategy for the management of HCC metastasis.     

浮游植物细胞自噬作用特点及研究方法

自噬(Autophagy)是真核生物细胞中一类高度保守的、依赖于溶酶体或液泡途径对胞质蛋白和细胞器进行降解的生物学过程。细胞自噬除维持细胞稳态外,在细胞响应各种外界胁迫中也发挥重要作用。近年来,陆续发现浮游植物能够通过细胞自噬应答众多环境胁迫,并在浮游植物细胞中鉴定出了类似于哺乳动物细胞中的核心自噬功能单位。自噬作为一种独特的程序性细胞死亡(PCD)形式,对浮游植物遭受胁迫后的个体存活及种群延续具有至关重要的作用。因此,细胞自噬也将成为浮游植物研究领域的一个新的着力点。主要综述了浮游植物细胞中自噬的保守性、诱导因素、调控机制、自噬与凋亡的交互作用以及浮游植物自噬研究方法等研究进展。     

Na+/H+ Exchangers Induce Autophagy in Neurons and Inhibit Polyglutamine-Induced Aggregate Formation

In polyglutamine diseases, an abnormally elongated polyglutamine results in protein misfolding and accumulation of intracellular aggregates. Autophagy is a major cellular degradative pathway responsible for eliminating unnecessary proteins, including polyglutamine aggregates. Basal autophagy constitutively occurs at low levels in cells for the performance of homeostatic function, but the regulatory mechanism for basal autophagy remains elusive. Here we show that the Na⁺/H⁺ exchanger (NHE) family of ion transporters affect autophagy in a neuron-like cell line (Neuro-2a cells). We showed that expression of NHE1 and NHE5 is correlated to polyglutamine accumulation levels in a cellular model of Huntington''s disease, a fatal neurodegenerative disorder characterized by accumulation of polyglutamine-containing aggregate formation in the brain. Furthermore, we showed that loss of NHE5 results in increased polyglutamine accumulation in an animal model of Huntington''s disease. Our data suggest that cellular pH regulation by NHE1 and NHE5 plays a role in regulating basal autophagy and thereby promotes autophagy-mediated degradation of proteins including polyglutamine aggregates.     

综述: 自噬参与心脏疾病调控的研究进展

细胞自噬(autophagy)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的过程．细胞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防御机制,参与多种疾病的病理过程．正常水平的自噬可以保护细胞免受环境刺激的影响,但自噬过度和自噬不足却可能导致疾病的发生．在心脏中,心肌细胞自噬对维持心肌功能具有重要的作用,自噬的异常可能导致各种心肌疾病如溶酶体储积症(Danon disease)等．各种心血管刺激如心肌缺血(ischemia)、再灌注(reperfusion)损伤、慢性缺氧(chronic hypoxia)等均可诱导心肌细胞自噬增强．而这些情况下心肌细胞自噬的作用还不清楚：它是否是一种潜在的细胞存活机制还是导致细胞死亡或疾病发生的病理性机制,或者是同时具有两种作用,目前还没有定论．心脏疾病是心肌功能出现异常时产生的各种病理状态的总称．在多种心脏疾病中,均伴随有心肌细胞自噬的改变,且影响着疾病的发生发展．在心肌肥厚(hypertrophic cardiomyopathy)中,细胞自噬程度降低而加剧心肌肥厚;在心力衰竭(heart failure,HF)中,细胞自噬增强可导致心肌细胞自噬性死亡;而在心肌梗死(myocardial infarction,MI)中,细胞自噬增强可减小梗死面积．但是细胞自噬在心脏疾病中到底扮演着怎样的角色,取决于细胞自噬发生的水平及病理状态．目前越来越多的人开始关注药物与细胞自噬调节之间的联系,且主要集中于抗肿瘤药物及心血管调节药物的研究．另外,有报道维生素类以及雌激素受体拮抗剂他莫西芬对细胞自噬也具有调节作用．研究心肌细胞自噬与心脏疾病的关系,以及药物对细胞自噬的调节,将有利于从自噬的角度探讨心脏疾病的发生发展过程及机制,开发出治疗心脏疾病的药物．     

Autophagy in idiopathic pulmonary fibrosis

Background

Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis.

Methods

Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β₁ on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model.

Results

Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β₁ inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β₁. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin.

Conclusion

Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β₁ may represent a mechanism for the promotion of fibrogenesis in IPF.