自噬信号通路与心血管疾病的研究进展

自噬是指自噬溶酶体将自身的细胞器分解并回收利用的一种细胞降解过程,广泛存在于机体组织中。在正常情况下,自噬活动水平在维持细胞的稳态和功能中发挥着重要作用;过量或不足的自噬通量水平都可能导致疾病的发生。在本文中,我们讨论了自噬的概念分类以及自噬信号通路的研究进展,并阐述了自噬对心血管疾病的影响。     

自噬介导肿瘤发展的现状

细胞自噬几乎存在所有的细胞中,是维持细胞内稳态的基本机制,是细胞成分降解和回收运用的根本.在外界刺激下,细胞受损触发自噬性溶酶体形成,降解受损的细胞器和变性蛋白质,为细胞再生、修复提供营养物质和能量,对细胞的破坏起一种防御作用.随着学者对自噬溶酶体的进一步研究,发现有多种自噬性相关基因通过各种信号通路参与调控细胞自噬....     

自噬参与缺血性心脏病的发生发展

细胞自噬广泛存在于真核生物生命过程中,是一种进化上高度保守的细胞内蛋白质再循环机制,它通过细胞内的溶酶体降解自身受损细胞器及异常大分子物质来维持细胞内稳态平衡。研究表明缺血性心脏病发病的不同阶段均可通过多种因素诱导自噬,但其具体作用的类型及机制仍旧存在很大争议。近年来,缺血性心脏病中自噬发生的具体分子学机制已成为国内外学者研究的热点,该文就自噬发生的分子学机制及其在缺血性心脏病的研究进展方面作一综述。     

自噬功能与帕金森病

自噬是广泛存在于真核细胞内的一种溶酶体依赖性降解途径,是细胞进行自我保护的一种重要机制,在维持细胞存活、更新、物质再利用和内环境稳定中起着重要作用。但是,在某些情况下自噬还可导致细胞死亡,被认为是区别于细胞凋亡     

自噬在白血病中的相关研究

自噬现象广泛存在于真核细胞中,且参与细胞的生理和病理过程。真核细胞存在着两大主要的蛋白质降解途径：蛋白酶体和溶酶体途径。自噬作为溶酶体降解途径之一,对于长寿蛋白降解和细胞器的重新利用发挥了重要的作用。细胞通过自噬获得可供生物体合成的氨基酸以及其它的大分子物质;另一方面．自噬也能导致细胞死亡引起Ⅱ型程序性细胞死亡,研究证明自噬的发生受不同基因的调控,如ATG（autophagy）基因、磷酸激酶基因及蛋白激酶等.     

自噬激活与抗肿瘤药物的作用

自噬是一种在正常细胞和病态细胞中普遍存在的生理机制。某些肿瘤细胞中自噬活动低下与肿瘤的发生有一定的关系。抗肿瘤药物可以诱导细胞产生自噬,并参与了自噬的分子调控,同时它也可能导致细胞凋亡。自噬在抗肿瘤药物中作用与给药浓度及细胞的类型等因素有关。抗肿瘤药物引起的细胞自噬对肿瘤细胞产生正负两方面的影响,将自噬途径作为抗肿瘤药物的靶点有着广阔的前景。     

溶酶体与肿瘤相关性的研究进展

溶酶体是细胞内重要的细胞器,被称为细胞内的消化器官,是真核生物细胞蛋白质降解的主要场所,在细胞死亡过程中发挥着重要的作用。细胞自噬和凋亡是细胞死亡的两种主要方式。大量研究表明,它们与肿瘤的发生发展有着密切的联系。溶酶体作为细胞自噬和凋亡的关键参与者,与肿瘤发生发展也存在一定的相关性。本文将对其相关性作一综述。     

自噬与肿瘤

自噬(autophagy)是细胞的溶酶体降解途径,广泛存在于大多数真核细胞中,对维持真核细胞内环境的稳定和新陈代谢起重要作用,但也可诱导真核细胞发生程序性细胞死亡,并称之为2型程序性死亡。自噬涉及一系列复杂的分子机制和信号调控,目前尚未完全研究清楚。近年来的研究发现,自噬与肿瘤等疾病的发生发展密切相关,对肿瘤细胞起到了抑制和保护的双重作用,并可能因此成为肿瘤治疗的潜在靶点。     

细胞自噬在心血管疾病发病过程中的作用

心血管疾病是一类危害心脏和血管功能的疾病,其发病是一个复杂的病理生理过程。细胞自噬（ autophagy）是一种广泛存在于真核细胞、进化上高度保守的细胞降解过程。饥饿、缺血、氧化应激等均可诱导其发生。自噬在细胞的生长、代谢、死亡等过程中起至关重要的作用,也参与了多种疾病的发生。近期发现,自噬与心血管疾病的发生、发展密切相关。正常的细胞自噬对心肌细胞有保护作用,自噬不足或自噬过度则可促发疾病或加重病变,本文对细胞自噬在心血管疾病发病中的作用做一综述。     

自噬与癌症的治疗

自噬是溶酶体降解途径之一,细胞利用自噬维持着胞内大分子和细胞器的循环利用。自噬的功能主要是在营养缺乏状态下维持着细胞代谢的平衡以及在环境压力下清除损伤的细胞器以利于细胞的存活。如今,自噬又显示出其抑制肿瘤的作用。自噬的缺失经常伴随着肿瘤的发生,比如在乳腺癌、卵巢癌和前列腺癌中出现自噬调节基因beclin 1的缺失,而beclin1基因敲除的小鼠更表现出癌变倾向。自噬是怎样抑制肿瘤发生的是当前生命科学界最感兴趣的课题之一,到目前为止,人们已发现细胞自发机制（涉及染色体完整性和稳定性的保护）和非细胞自发机制（涉及坏死和炎症的抑制）参与其中。在治疗过程中,自噬的作用也非常复杂,一方面,由于肿瘤细胞能够依赖自噬功能来缓解由药物和射线诱导的压力而利于自身存活,所以,在化疗和放疗的同时应用自噬的抑制剂被视为当今癌症治疗的一个新手段,另一方面,诱导自噬可以维持细胞内蛋白质和细胞器的更新、抑制DNA的损伤和染色体的突变并且能限制由坏死引起的炎症而实现细胞的适应性,因而,诱导自噬可能在癌症的预防中扮演着重要的角色。     

Mechanisms of silver nanoparticle-induced toxicity and important role of autophagy

Safety concerns have been raised over the extensive applications of silver nanoparticles (AgNPs) because nano dimensions make them highly bioactive, being potentially harmful to the exposed humans. Surface physico-chemistry (shape, surface charge, chemical composition, etc.) that mainly dictates nano-bio interactions is relevant for influencing their biocompatibility and toxicity. Although the hazardousness of AgNPs has been demonstrated in vitro and in vivo, mechanistic understanding of the toxicity particularly at the molecular and organismal levels, in addition to oxidative stress and silver ion dissolution, has remained unclear. A growing body of research has elucidated that autophagy, being activated in response to exposure to various nanomaterials, may serve as a cellular defense mechanism against nanotoxicity. Recently, autophagy activation was shown to correlate with AgNPs exposure; however, the subsequent autophagosome–lysosome fusion was defective. As autophagy plays a crucial role in selective removal of stress-mediated protein aggregates and injured organelles, AgNPs-induced autophagic flux defect may consequently lead to aggravated cytotoxic responses. Furthermore, we suggest that p62 accumulation resulting from defective autophagy may also potentially account for AgNPs cytotoxicity. Intriguingly, AgNPs have been shown to interfere with ubiquitin modifications, either via upregulating levels of enzymes participating in ubiquitination, or through impairing the biological reactivity of ubiquitin (due to formation of AgNPs-ubiquitin corona). Ubiquitination both confers selectivity to autophagy as well as modulates stabilization, activation, and trafficking of proteins involved in autophagic clearance pathways. In this regard, we offer a new perspective that interference of AgNPs with ubiquitination may account for AgNPs-induced defective autophagy and cytotoxic effects.     

Autophagy is involved in nanoalumina-induced cerebrovascular toxicity

The current study focused on blood–brain barrier disruption and neurovascular damage induced by engineered nanomaterials. Exposure to nanoalumina, but not to nanocarbon, induced a dose-dependent mitochondrial potential collapse, increased autophagy of brain endothelial cells, and decreased expression of the tight-junction proteins occludin and claudin-5. Inhibition of autophagy by pretreatment with Wortmannin attenuated the effects of nanoalumina on decreased claudin-5 expression; however, it did not affect the disruption of occludin. These findings were confirmed in mice by administration of nanoalumina into the cerebral circulation. Systemic treatment with nanoalumina elevated autophagy-related genes and autophagic activity in the brain, decreased tight-junction protein expression, and elevated blood–brain barrier permeability. Finally, exposure to nanoalumina, but not to nanocarbon, increased brain infarct volume in mice subjected to a focal ischemic stroke model. Overall, our study reveals that autophagy constitutes an important mechanism involved in nanoalumina-induced neurovascular toxicity in the central nervous system.From the Clinical EditorIn this paper, the effects of nanoalumina on the permeability of the blood-brain barrier is reported, suggesting that autophagy is an important mechanism in nanoalumina-induced neurovascular toxicity.     

Autophagy: An adaptive metabolic response to stress shaping the antitumor immunity

Several environmental-associated stress conditions, including hypoxia, starvation, oxidative stress, fast growth and cell death suppression, modulate both cellular metabolism and autophagy to enable cancer cells to rapidly adapt to environmental stressors, maintain proliferation and evade therapies. It is now widely accepted that autophagy is essential to support cancer cell growth and metabolism and that metabolic reprogramming in cancer can also favor autophagy induction. Therefore, this complex interplay between autophagy and tumor cell metabolism will provide unique opportunities to identify new therapeutic targets. As the regulation of the autophagic activity is related to metabolism, it is important to elucidate the exact molecular mechanism which drives it and the functional consequence of its activation in the context of cancer therapy. In this review, we will summarize the role of autophagy in shaping the cellular response to an abnormal tumor microenvironment and discuss some recent results on the molecular mechanism by which autophagy plays such a role in the context of the anti-tumor immune response. We will also describe how autophagy activation can behave as a double-edged sword, by activating the immune response in some circumstances, and impairing the anti-tumor immunity in others. These findings imply that defining the precise context-specific role for autophagy in cancer is critical to guide autophagy-based therapeutics which are becoming key strategies to overcome tumor resistance to therapies.     

Single-walled carbon nanotubes and graphene oxides induce autophagosome accumulation and lysosome impairment in primarily cultured murine peritoneal macrophages

The wide application of carbon nanomaterials in various fields urges in-depth understanding of the toxic effects and underlying mechanisms of these materials on biological systems. Cell autophagy was recently recognized as an important lysosome-based pathway of cell death, and autophagosome accumulation has been found to be associated with the exposure of various nanoparticles, but the underlying mechanisms are still uncertain due to the fact that autophagosome accumulation can result from autophagy induction and/or autophagy blockade. In this study, we first evaluated the toxicity of acid-functionalized single-walled carbon nanotubes and graphene oxides, and found that both carbon nanomaterials induced adverse effects in murine peritoneal macrophages, and GOs were more potent than AF-SWCNTs. Both carbon nanomaterials induced autophagosome accumulation and the conversion of LC3-I to LC3-II. However, degradation of the autophagic substrate p62 protein was also inhibited by both nanomaterials. Further analyses on lysosomes revealed that both carbon nanomaterials accumulated in macrophage lysosomes, leading to lysosome membrane destabilization, which indicates reduced autophagic degradation. The effects of AF-SWCNTs and GOs on cell autophagy revealed by this study may shed light on the potential toxic mechanism and suggest caution on their utilization.     

Pharmacological modulation of autophagy during cardiac stress

ABSTRACT:: Autophagy is an evolutionarily conserved intracellular mechanism for degradation of long-lived proteins and organelles. Accumulating lines of evidence indicate that autophagy is deeply involved in the development of cardiac disease. Autophagy is upregulated in almost all cardiac pathological states, exerting both protective and detrimental functions. Whether autophagy activation is an adaptive or maladaptive mechanism during cardiac stress seems to depend upon the pathological context in which it is upregulated, the extent of its activation, and the signaling mechanisms promoting its enhancement. Pharmacological modulation of autophagy may therefore represent a potential therapeutic strategy to limit myocardial damage during cardiac stress. Several pharmacological agents that are able to modulate autophagy have been identified, such as mammalian target of rapamycin inhibitors, adenosine monophosphate-dependent kinase modulators, sirtuin activators, myo-inositol-1,4,5-triphosphate and calcium-lowering agents, and lysosome inhibitors. Although few of these modulators of autophagy have been directly tested during cardiac stress, many of them seem to have high potential to be efficient in the treatment of cardiac disease. We will discuss the potential usefulness of different pharmacological activators and inhibitors of autophagy in the treatment of cardiac diseases.     

Autophagy: Molecular mechanisms and their implications for anticancer therapies

Autophagy is a catabolic process whereby cells maintain homeostasis by eliminating unnecessary proteins and damaged organelles. It may be triggered under physiological conditions, such as nutrient starvation, or in response to a variety of stress stimuli, such as exposure to radiations or cytotoxic compounds. Although autophagy is basically a protective mechanism that sustains cell survival under adverse conditions, it has been recently demonstrated that the induction of autophagic process may ultimately lead to cell death. As for the role of autophagy in cancer, it is still very controversial whether it suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. Therefore, the dual role of autophagy in tumor progression and in the response of cancer cells to chemotherapeutic drugs is still open to debate. The first part of this review describes the cellular events occurring during the various phases of the autophagic process. Special attention has been given to the morphological aspects and the regulatory molecules involved in autophagic cell death. Specifically, we have focused on the proteins necessary for autophagosome formation, encoded by the ATG (AuTophaGy-related gene) gene family, and their role in the regulation of the process of autophagy. We also examined the effects of autophagy modulators on cell survival and cell death and discussed the recent efforts aimed at finding novel agents that activate or inhibit autophagy by targeting regulatory molecules of the complex autophagy pathways.     

Inhibiting autophagy enhances sulforaphane-induced apoptosis via targeting NRF2 in esophageal squamous cell carcinoma

Sulforaphane (SFN), a natural anti-tumor compound from cruciferous vegetables, has been reported to induce protective autophagy to cancer cells, which might impair the anti-tumor efficiency of SFN. However, the accurate function and mechanism of SFN inducing autophagy in cancers are still obscure, especially in esophageal squamous cell carcinoma (ESCC), one of malignancies with high incidence in North China. Here, we mainly explored the potential function of autophagy upon SFN treatment in ESCC and molecular mechanism. We demonstrated that SFN could inhibit cell proliferation and induce apoptosis by activating caspase pathway. Moreover, we found activation of NRF2 pathway by SFN was responsible for the induction of autophagy and also a disadvantage element to the anti-tumor effects of SFN on ESCC, indicating that SFN might induce protective autophagy in ESCC. We, therefore, investigated effects of autophagy inhibition on sensitivity of ESCC cells to SFN and found that chloroquine (CQ) could neutralize the activation of SFN on NRF2 and enhance the activation of SFN on caspase pathway, thus improved the anti-tumor efficiency of SFN on ESCC in vitro and in vivo. Our study provides a preclinical rationale for development of SFN and its analogs to the future treatment of ESCC.KEY WORDS: Sulforaphane, Autophagy, Chloroquine, NRF2, Esophageal squamous cell carcinoma     

Death and survival of neuronal and astrocytic cells in ischemic brain injury: a role of autophagy

Autophagy is a highly regulated cellular mechanism that leads to degradation of long-lived proteins and dysfunctional organelles. The process has been implicated in a variety of physiological and pathological conditions relevant to neurological diseases. Recent studies show the existence of autophagy in cerebral ischemia, but no consensus has yet been reached regarding the functions of autophagy in this condition. This article highlights the activation of autophagy during cerebral ischemia and/or reperfusion, especially in neurons and astrocytes, as well as the role of autophagy in neuronal or astrocytic cell death and survival. We propose that physiological levels of autophagy, presumably caused by mild to modest hypoxia or ischemia, appear to be protective. However, high levels of autophagy caused by severe hypoxia or ischemia and/or reperfusion may cause self-digestion and eventual neuronal and astrocytic cell death. We also discuss that oxidative and endoplasmic reticulum (ER) stresses in cerebral hypoxia or ischemia and/or reperfusion are potent stimuli of autophagy in neurons and astrocytes. In addition, we review the evidence suggesting a considerable overlap between autophagy on one hand, and apoptosis, necrosis and necroptosis on the other hand, in determining the outcomes and final morphology of damaged neurons and astrocytes.     

Inhibition of autophagy protects against PAMAM dendrimers-induced hepatotoxicity

Abstract

Toxicity of nanomaterials is one of the biggest challenges in their medicinal applications. Although toxicities of nanomaterials have been widely reported, the exact mechanisms of toxicities are still not well elucidated. Consequently, the exploration of approaches to attenuate toxicities of nanomaterials is limited. In this study, we reported that poly-amidoamine (PAMAM) dendrimers, a widely used nanomaterial in the pharmaceutical industry, caused toxicity of human liver cells by inducing cell growth inhibition, mitochondria damage, and apoptosis. Meanwhile, autophagy was activated in PAMAM dendrimers-induced toxicity and inhibition of autophagy-rescued viability of hepatic cells, indicating that autophagy played a key role in PAMAM dendriemrs-induced hepatotoxicity. To further explore approaches to attenuate PAMAM dendrimers-induced liver injury, effects of autophagic inhibitors on PAMAM dendrimers’ hepatotoxicity were investigated in an in vivo model. Autophagy blockage in PAMAM dendrimers-administered mice led to weight restoration, damage reversion of liver tissue, and protection against changes of serum biochemistry parameters. Moreover, inhibition of Akt/mTOR and activation of Erk1/2 signaling pathways were involved in PAMAM dendrimers-induced autophagy. Collectively, these findings indicated that autophagy was associated with PAMAM dendrimers-induced hepatotoxicity, and supported the possibility that autophagy inhibitors could be used to reduce hepatotoxicity of PAMAM dendrimers.     

8-氮鸟嘌呤通过Akt/mTORC1/ULK1诱导细胞自噬增强其在肝癌细胞中的耐药性

细胞自噬是真核生物中进化保守的对细胞内容物进行降解的生理过程,其利用溶酶体将细胞内物质降解再利用,在应激条件下可以促进癌细胞的存活。8-氮鸟嘌呤(8-azaguanine,8-AG)是一种嘌呤核苷酸生物合成的抑制剂,对多种肿瘤细胞具有抗肿瘤活性。然而,耐药性限制了8-AG作为抗癌药物的应用,其耐药性机制尚不清楚。本研究发现8-AG通过诱导细胞自噬减弱其细胞毒性而产生耐药性。利用HepG2和SMMC-7721肝癌细胞系进行药物处理,结果显示8-AG抑制肿瘤细胞活力,并且通过上调促凋亡蛋白BCL-2样蛋白11(BCL-2-like protein 11,Bim)中的BimS亚型水平来诱导内源性凋亡。此外,Western blot实验检测结果表明8-AG通过抑制Akt(protein kinase B)/mTORC1(mammalian target of rapamycin complex 1)信号通路激活ULK1(Unc-51-like autophagy activating kinase 1)蛋白,从而诱导自噬发生。敲低自噬相关基因7(autophagy-related gene 7,ATG7)显著增加BimS的蛋白水平,促进8-AG引起的细胞死亡;联合使用自噬抑制剂氯喹(chloroquine,CQ)或巴弗洛霉素A1(bafilomycin A1,Baf A1)促进8-AG诱导的肝癌细胞凋亡。以上结果表明,8-AG诱导自噬导致肿瘤细胞产生耐药性,抑制自噬可增加癌细胞对其的敏感性。