后处理对缺血-再灌注心肌细胞自噬的影响

正自噬(autophagy)指机体通过合成自噬溶酶体清理体内衰老及受损的蛋白质或细胞器,对分解物质再利用、对维持细胞内稳态起到重要作用,是细胞的一种自我更新途径[1]。机体正常生理状态下,细胞自噬水平较低,对机体产生保护性效应。病理状态下,如心肌缺血-再灌注损伤(myocardial ischemia-reperfusion injury, MIRI)、内质网应激及氧化应激时,自噬被过度激活而产生损伤性效应。     

自噬在糖尿病血管损害发病中的作用及与创面难愈关联性的研究

20世纪60年代Ashford和 Porter用电子显微镜在人的肝细胞中首次观察到自噬现象,1993年有关学者在酵母中发现自噬相关基因及建立酵母突变模型,使得对自噬分子层面的研究取得了突破性进展.目前认为,自噬是真核细胞特有的一种代谢现象,其实质是细胞内的"自我消化",它是自身受损的细胞器和大分子等物质在溶酶体的参与下被降解的生理过程,对于细胞维持稳态、促进生存意义重大.细胞自噬现象在酵母、线虫、果蝇直至高等脊椎动物的细胞中均广泛存在,它的经典过程可以简单的概括为:细胞在接受刺激信号后,胞浆中出现的膜性结构将需要降解的物质包裹形成自噬体(autophagosome),成熟的自噬体被运输至溶酶体形成自噬溶酶体(autolysosome)后被水解酶降解以实现细胞的"自我消化",而其中的氨基酸、核苷酸等重要代谢产物还可被机体循环再利用,以继续提供能量 [1].自噬分为微自噬(microautophagy)、巨自噬(macroautophagy)和分子伴侣介导的自噬(chaperone-mediated autophagy)3种,而我们一般所说的自噬是指巨自噬.自噬的生理作用主要体现在:①它可通过调控细胞器的更新,进而保持细胞内环境的相对稳定;②自噬可参与机体组织的结构重建;③自噬是细胞对外源性刺激的快速适应性反应;④它的降解产物如氨基酸、核苷酸等可提供能量,供机体循环再利用;⑤当细胞遭受氧化应激和病毒感染时, 自噬可作为细胞的防御机制,清除胞质内受损的细胞器及有害的物质进而保护细胞免受损害 [2-3].此外,自噬与自身免疫和衰老 [4]也有密切关系.     

线粒体自噬在肾缺血-再灌注损伤中的作用

线粒体自噬是机体选择性清除受损线粒体的防御性过程,对维持细胞生存有重要意义。一般情况下线粒体自噬阈值较低,当处在能量耗竭、缺血、缺氧等环境中时,线粒体自噬可被激活。肾脏的缺血-再灌注损伤(IRI)是临床中较为常见的病理生理过程,是导致急性肾损伤的主要原因。目前认为IRI与氧化应激、线粒体功能紊乱、自噬和凋亡等密切相关。本文就线粒体自噬的概述、线粒体自噬在肾IRI中的作用以及线粒体自噬的调控进行综述,为临床中防治肾IRI提供新的研究思路。     

自噬及其在前列腺癌治疗中的应用

自噬是一种广泛存在于真核细胞内的重要的生理过程。通过分解细胞质等自身成分以维持在营养能量缺乏状态下的细胞代谢平衡以及在代谢应激下清除损伤的细胞器达到细胞存活的目的。近年来,研究发现细胞自噬在前列腺癌的发生、发展、转归中起着重要作用,并为晚期前列腺癌的治疗提供了新颖的思路。本文就细胞自噬及其在前列腺癌治疗中的进展做一综述。     

细胞自噬与炎症小体相互作用的研究进展

细胞自噬是真核生物细胞内普遍存在的一种自我维持内环境稳定的机制,并在多种生理活动中发挥重要作用,如生存、发育、细胞自我保护等。炎症小体是胱天蛋白酶活化平台,并促进某些促炎因子如IL-1β、IL-18的成熟和分泌,启动机体的固有免疫反应。自噬与炎症小体关系密切,炎症小体能够诱导自噬的发生,自噬对炎症小体也有调控作用。现就细胞自噬和炎症小体的相互作用作一综述。     

细胞自噬在食管癌研究中的进展

细胞自噬(autophagy)是一个在各种外界因素影响下,真核细胞通过溶酶体降解其内部受损的细胞器、错误折叠的蛋白质和侵入其内的病原体并产生可以重新参与生命活动的物质和能量的生物学过程,在维持机体内环境稳定等方面发挥着重要的作用。目前,我国食管癌患者的发病率和病死率均远高于世界平均水平,放化疗联合靶向药物治疗已逐渐应用于食管癌的临床治疗,而这些新兴治疗措施与细胞自噬有着一定的关系。该文就细胞自噬在食管癌发生发展中的作用和调控机制进行综述。     

自噬在糖尿病肾病进展中的作用及机制

糖尿病肾病是导致终末期肾脏疾病的主要病因之一,其发病机制不清。自噬是一种高度保守的细胞学事件,能够降解细胞内异常蛋白和细胞器,维持细胞内环境稳定,在多种急慢性肾脏疾病中发挥着重要的作用。研究发现糖尿病肾病中肾脏自噬功能受损,提示自噬障碍可能参与糖尿病肾病发病。本文将针对肾脏不同类型细胞,对自噬在糖尿病肾病中作用的相关研究进展进行综述。     

自噬在急性胰腺炎中的研究新进展

自噬是细胞清除胞质中受损、缺陷或无用的细胞器、长寿命蛋白质和脂质,并回收其成分以满足生物新陈代谢的营养和能量需要的主要分解代谢过程。急性胰腺炎(AP)是常见临床急症,其发病率也逐年升高。研究显示,自噬在AP的发病过程中起到重要作用,可以导致胰腺腺泡细胞内胰蛋白酶原的激活,腺泡细胞内大液泡积聚,诱发促炎介质的释放,引起胰腺炎症细胞浸润和全身性炎症反应。笔者就自噬的分子机制以及自噬在AP发生、发展中作用机制的研究进展进行综述。     

自噬在肾脏疾病中的研究进展

自噬是细胞利用溶酶体降解细胞内自身受损、变性或衰老的蛋白质、细胞器以及其他大分子物质,为细胞修复提供营养和能量,以维持细胞内稳态和细胞完整性。越来越多的研究表明,自噬与多种肾脏疾病有关,自噬功能紊乱会导致肾脏疾病的发生,如急性肾损伤、慢性肾脏病、糖尿病肾病、狼疮性肾炎、多囊肾病等。本文总结了近年来自噬在肾脏疾病方面的的...     

自噬在人类免疫缺陷病毒和结核分枝杆菌共同感染中的作用

人类免疫缺陷病毒/结核分枝杆菌（HIV/M.tb）共同感染已经成为发展中国家的主要公共卫生威胁。自噬是一种溶酶体分解代谢过程,正常状态下维持细胞内环境的稳态,还涉及细胞内病原体如HIV-1和M.tb的清除,可增强机体的免疫防御能力。本文概述在HIV-1和M.tb单独感染以及共同感染的背景下自噬对机体免疫防御的调控,全面了解病原体与自噬的相互作用,展望未来开发基于自噬原理新的预防性疫苗和治疗干预措施的巨大潜力。     

严重烧伤后骨骼肌消耗的机制与治疗前景思考

过去50年,由于强调了及时有效地防治休克,早期切(削)痂封闭创面,重视尽早以胃肠喂养为主的营养支持、脏器保护与支持、免疫调理与纠正凝血功能紊乱,注重严重吸入性损伤的治疗,合理使用抗生素控制感染等综合措施,予以严重烧伤患者个体化治疗,使得我国烧伤治疗水平居于国际先进行列[1].     

Autophagy: A new player in skeletal maintenance?

Imbalances between bone resorption and formation lie at the root of disorders such as osteoporosis, Paget's disease of bone (PDB), and osteopetrosis. Recently, genetic and functional studies have implicated proteins involved in autophagic protein degradation as important mediators of bone cell function in normal physiology and in pathology. Autophagy is the conserved process whereby aggregated proteins, intracellular pathogens, and damaged organelles are degraded and recycled. This process is important both for normal cellular quality control and in response to environmental or internal stressors, particularly in terminally‐differentiated cells. Autophagic structures can also act as hubs for the spatial organization of recycling and synthetic process in secretory cells. Alterations to autophagy (reduction, hyperactivation, or impairment) are associated with a number of disorders, including neurodegenerative diseases and cancers, and are now being implicated in maintenance of skeletal homoeostasis. Here, we introduce the topic of autophagy, describe the new findings that are starting to emerge from the bone field, and consider the therapeutic potential of modifying this pathway for the treatment of age‐related bone disorders. © 2012 American Society for Bone and Mineral Research.     

2型糖尿病患者骨骼肌萎缩机制及运动干预研究进展

2型糖尿病患者骨骼肌萎缩引起肌力下降和功能丧失，对糖尿病患者身心健康产生严重影响，进一步影响患者日常活动，导致患者生活质量下降。2型糖尿病患者存在胰岛素抵抗、慢性炎症、能量代谢紊乱等因素诱发骨骼肌萎缩，糖尿病周围神经病变也会引起骨骼肌萎缩。线粒体可产生活性氧调节细胞凋亡，也参与糖尿病患者骨骼肌萎缩。因此，本文对国内外因糖尿病诱发骨骼肌萎缩的相关机制及运动干预糖尿病骨骼肌萎缩的研究进展进行综述，旨在为糖尿病骨骼肌萎缩临床和基础医学研究提供理论依据。     

Work-induced changes in skeletal muscle IGF-1 and myostatin gene expression in uremia

Resistance to growth hormone (GH)-induced insulin-like growth factor-1 (IGF-1) gene expression contributes to uremic muscle wasting. Since exercise stimulates muscle IGF-1 expression independent of GH, we tested whether work overload (WO) could increase skeletal muscle IGF-1 expression in uremia and thus bypass the defective GH action. Furthermore, to provide insight into the mechanism of uremic wasting and the response to exercise we examined myostatin expression. Unilateral plantaris muscle WO was initiated in uremic and pairfed (PF) normal rats by ablation of a gastrocnemius tendon and adjoining part of this muscle with the contralateral plantaris as a control. Some rats were GH treated for 7 days. WO led to similar gains in plantaris weight in both groups and corrected the uremic muscle atrophy. GH increased plantaris IGF-1 mRNA >twofold in PF rats but the response in uremia was severely attenuated. WO increased the IGF-1 mRNA levels significantly in both uremic and PF groups, albeit less brisk in uremia; however, after 7 days IGF-1 mRNA levels were elevated similarly, >2-fold, in both groups. In the atrophied uremic plantaris muscle basal myostatin mRNA levels were increased significantly and normalized after an increase in WO suggesting a myostatin role in the wasting process. In the hypertrophied uremic left ventricle the basal myostatin mRNA levels were reduced and likely favor the cardiac hypertrophy. Together the findings provide insight into the mechanisms of skeletal muscle wasting in uremia and the hypertrophic response to exercise, and suggest that alterations in the balance between IGF-1 and myostatin play an important role in these processes.     

Autophagy protects the proximal tubule from degeneration and acute ischemic injury

Autophagy is a bulk protein degradation system that likely plays an important role in normal proximal tubule function and recovery from acute ischemic kidney injury. Using conditional Atg5 gene deletion to eliminate autophagy in the proximal tubule, we determined whether autophagy prevents accumulation of damaged proteins and organelles with aging and ischemic renal injury. Autophagy-deficient cells accumulated deformed mitochondria and cytoplasmic inclusions, leading to cellular hypertrophy and eventual degeneration not observed in wildtype controls. In autophagy-deficient mice, I/R injury increased proximal tubule cell apoptosis with accumulation of p62 and ubiquitin positive cytoplasmic inclusions. Compared with control animals, autophagy-deficient mice exhibited significantly greater elevations in serum urea nitrogen and creatinine. These data suggest that autophagy maintains proximal tubule cell homeostasis and protects against ischemic injury. Enhancing autophagy may provide a novel therapeutic approach to minimize acute kidney injury and slow CKD progression.     

Autophagy in renal diseases

Autophagy is the cell biology process in which cytoplasmic components are degraded in lysosomes to maintain cellular homeostasis and energy production. In the healthy kidney, autophagy plays an important role in the homeostasis and viability of renal cells such as podocytes and tubular epithelial cells and of immune cells. Recently, evidence is mounting that (dys)regulation of autophagy is implicated in the pathogenesis of various renal diseases, and might be an attractive target for new renoprotective therapies. In this review, we provide an overview of the role of autophagy in kidney physiology and kidney diseases.     

Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells

Autophagy is a cellular process of bulk degradation of damaged organelles, protein aggregates and other macromolecules in the cytoplasm. It is thought to be a general response to stress contributing to cell death; alternatively it might act as a cytoprotective mechanism. Here we found that administration of cisplatin induced the formation of autophagic vesicles and autophagosomes in mouse kidneys. In cultured proximal tubular cells, the nephrotoxin caused autophagy in a dose- and time-dependent manner prior to apoptosis. Notably, autophagy occurred within hours of cisplatin administration but this was partially suppressed by the p53 inhibitor pifithrin-alpha, suggesting that p53 is involved in autophagic signaling. This cisplatin-induced autophagy was attenuated in renal cells stably transfected with Bcl-2, suggesting an anti-autophagic role for this well-known anti-apoptotic protein. Blockade of autophagy with pharmacological inhibitors (3-methyladenine or bafilomycin) or shRNA knockdown of the autophagic gene Beclin increased tubular cell apoptosis during cisplatin treatment. Our study has found that autophagy occurs in acute kidney injury and this may be an important protective mechanism for cell survival.     

Autophagy and bone diseases

Autophagy is a ubiquitous cellular process, allowing the removal and recycling of damaged proteins and organelles. At the basal level, this process plays a role in quality control, thus participating in cellular homeostasis. Autophagy can also be induced by various stresses, such as nutrient deprivation or hypoxia, to allow the cell to survive until conditions improve. In recent years, the role of this process has been widely studied in many pathologies such as neurodegenerative diseases or cancers. In bone tissue, various studies have shown that autophagy is involved in the survival, differentiation and activity of osteoblasts, osteocytes and osteoclasts. The evolution of this knowledge has led to the identification of new molecular pathophysiological mechanisms in bone pathologies. This review reports the current state of knowledge on the role of autophagy in 4 bone diseases: osteoporosis, which seems to be associated with a decrease in autophagy, osteopetrosis and Paget's disease where the course of the autophagic process is disturbed, and finally osteosarcoma where autophagy seems to play a protumoral role. A better understanding of the involvement of autophagy in these pathologies should eventually lead to the identification of new potential therapeutic targets.