修回日期: 2015-11-30
接受日期: 2015-12-08
在线出版日期: 2016-01-18
手术切除是原发性肝癌的最佳治疗方法, 手术治疗往往面临肝脏储备功能衰退、残肝缺血再灌注损伤等弊端, 这些因素明显增加了肝癌手术治疗或肝移植的难度和风险. 自噬是肝脏缺血再灌注后细胞程序性死亡方式之一, 其在缺血再灌注伤损中的作用是近年来研究的热点. 在模拟肝脏缺血再灌注损伤的实验研究时, 常检测到自噬相关蛋白Beclin 1的变化, 并以此代表自噬活动变化. 目前已发现多种预处理方法可降低肝脏缺血再灌注损伤模型中Beclin 1蛋白的含量并且减轻肝损伤. 现就Beclin 1在肝脏缺血再灌注损伤模型中的研究进展作一综述.
核心提示: Beclin 1是自噬重要的正调节因子, 在代表细胞自噬的活动变化中发挥重要作用, 且鉴于其与细胞凋亡千丝万缕的关系, 可能会在肝脏缺血再灌注损伤(ischemia-reperfusion injury)领域和其他学科应用中展现出更为广阔的研究前景.
引文著录: 徐玉彬, 张培建, 刘谦, 毛旭南, 王超臣. 自噬相关蛋白Beclin 1在肝脏缺血再灌注损伤模型中的作用. 世界华人消化杂志 2016; 24(2): 209-214
Revised: November 30, 2015
Accepted: December 8, 2015
Published online: January 18, 2016
Surgical resection is the optimal treatment for primary liver cancer, but surgery is often faced with recession of the liver function reserve, ischemia-reperfusion injury of the residual liver and other disadvantages. Autophagy is a form of programmed cell death after hepatic ischemia-reperfusion, and its role in ischemia-reperfusion injury is a hotspot of research in recent years. In the experimental research of simulated liver ischemia-reperfusion injury, the variation of autophagy related protein Beclin 1 is often detected, which suggests the change of autophagy activity. Many pretreatment methods have been found to be able to reduce the level of Beclin 1 and relieve the hepatic damage in the model of hepatic ischemia-reperfusion injury. Here we discuss the research progress in understanding the role of Beclin 1 in hepatic ischemia-reperfusion injury.
- Citation: Xu YB, Zhang PJ, Liu Q, Mao XN, Wang CC. Role of autophagy related protein Beclin 1 in model of hepatic ischemia-reperfusion injury. Shijie Huaren Xiaohua Zazhi 2016; 24(2): 209-214
- URL: https://www.wjgnet.com/1009-3079/full/v24/i2/209.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i2.209
既往的研究认为肝细胞的坏死和凋亡是肝脏缺血再灌注损伤(ischemia-reperfusion injury, IRI)的主要原因, 但随后的研究表明细胞坏死和凋亡这两种死亡方式不能很好的解释IRI实验研究中的全部现象[1-3]. 后来有人提出, 在肝脏的IRI中还存在细胞自噬的活动变化, 自此, 细胞自噬作为一种新的细胞程序性死亡方式进入了科研人员的视野[4].
细胞自噬是指细胞内受损、衰老细胞器或变性的蛋白质被运输到溶酶体, 通过溶酶体对其消化降解, 以双层膜结构包裹部分胞质和细胞器的自噬体为标志的细胞自我消化的过程[5-9]. 根据底物进入溶酶体途径的不同, 可将自噬分为3种类型: 巨自噬、微自噬、分子伴侣介导的自噬, 其中对巨自噬的研究较多, 且通常所说的"细胞自噬"即主要指巨自噬[10,11]. 在正常生理状态下, 自噬对维持细胞的稳态具有十分的重要; 在某些病理状态下, 如缺血再灌注损伤、营养物质的消耗等应激状态下可诱发加重细胞自噬, 从而加强损伤蛋白的清除及能源物质的回收, 以使细胞适应这些应激状态, 但过度的自噬会导致正常蛋白及细胞器的过度降解, 损伤细胞[12-14].
作为一种程序性死亡方式, 细胞自噬在组织器官IRI中的作用是近年来研究的热点. 现有的研究表明细胞自噬在组织器官IRI期间发挥着"双刃剑"的作用, 其可通过调节不同的信号通路从而发挥截然不同的作用, 即细胞自噬在缺血早期呈保护作用, 而在再灌注期间的过度增强将呈损伤作用[15,16]. 这种"双刃剑"的作用分别在心肌、肝脏、肾脏、脑等组织器官的IRI实验研究中得到了验证[14,17-24].
调控自噬的信号通过分为哺乳动物雷帕霉素靶蛋白(mammalian traget of rapamycin, mTOR)依赖型和非mTOR依赖型途径. mTOR是细胞内氨基酸和ATP等营养物质的感受器, 细胞营养丰富时mTOR被激活而导致细胞自噬的抑制, 而当细胞处于饥饿状态时mTOR被抑制而诱发自噬[25,26]. mTOR依赖型主要是由Ⅰ型磷酸肌醇三磷酸激酶(phosphatidylinositol 3 kinase, PI3K)来完成, Ⅰ型PI3K通过激活mTOR而抑制自噬的发生. 研究[27]发现mTOR抑制剂雷帕霉素预处理的大鼠在肝缺血早期转氨酶、炎性因子的表达水平均低于IR对照组, 且肝组织标本在光镜下的结果显示预处理组的损伤程度明显轻于IR对照组, 这表明自噬在大鼠肝脏缺血早期具有保护作用且可能是通过mTOR被抑制而导致自噬增强实现的. 非mTOR依赖型与自噬相关基因Beclin 1的表达、3型PI3K活性氧化物等密切相关, 故又称为Beclin 1依赖型自噬途径, 3-甲基腺嘌呤(3-methyladenin, 3-MA)可抑制此途径, 因此常用作自噬抑制剂[28]. 研究表明3-MA预处理的大鼠在肝缺血后再灌注期转氨酶、炎性因子的表达水平均低于IR对照组, 且肝组织标本在电镜下的结果显示预处理组的自噬体的数量明显少于IR对照组, 同时Beclin 1蛋白的水平较IR对照组明显下降, 这表明自噬活动在大鼠肝脏缺血后再灌注期的增强具有损伤作用且可能与自噬相关基因Beclin 1表达水平的升高有关[29].
Beclin 1是哺乳动物中发现的最早的一个自噬相关基因, 已有研究[30,31]证实Beclin 1是自噬重要的正调节因子. Beclin 1最早是Liang等[32]在研究抗凋亡蛋白B淋巴细胞瘤-2(B cell lymphoma-2, Bcl-2)如何保护中枢神经系统抵御Sindbis病毒感染时发现的基因. 通过对Beclin 1序列和结构研究发现, 他除了含有中央卷曲螺旋区、进化保守区外, 还有与Bcl-2家族蛋白类似的BH3区域, 故被称为Bcl-2家族中新型的BH3-only蛋白[33]. 抗凋亡蛋白Bcl-2的结合凹槽可与Beclin 1的BH3结构域结合, 从而抑制Beclin 1依赖型自噬途径[34].
实验性肝脏IRI是一种常见的病理生理过程, 在肝肿瘤行肝叶切除时阻断人肝血流、肝移植等均涉及IRI. 目前, 肝脏IRI后的细胞自噬实验研究较为引人关注. 尽管实验模型各不相同, 但许多研究都会通过对模型中Beclin 1蛋白的检测来反映细胞自噬水平的变化. 在众多的研究模型中, 部分模型的应用较为广泛和成熟, 如Mendes-Braz等[35]描述了大鼠部分肝脏IRI模型的建立: 分离肝十二指肠韧带后, 游离第一肝门, 用灭菌的无损伤血管夹夹闭肝中、肝左叶血管的共干, 造成肝中、肝左叶缺血, 实现约70%的肝组织缺血, 松开并去除血管夹从而恢复血流即为再灌注. 还有几种方法可制作常温下的肝缺血模型, 如pringle法、splecnocaval分流等, 目前已较少用[36,37]. 另外, 国内也有学者曾提出保留半肝动脉血供的入肝血流阻断法, 并通过比较发现该方法手术操作简单, 效果较好[38]. 在肝移植模型研究方面, Kamada等[39]在1983年报道二袖套法大鼠原位肝移植手术模型以来, 该模型在肝胆外科研究领域应用广泛, 是经典的大鼠原位肝移植模型之一. 由于该模型操作复杂, 学习时间较长, 目前大多用改良的方法建立模型.
各种实验模型基础上, 检测肝组织Beclin 1蛋白的水平发现, Beclin 1蛋白常常较假手术组明显升高, 这种变化变化反映了肝细胞自噬活动的增强[40,41]. 如Yun等[42]在进行大鼠肝脏IR实验时发现, 肝组织标本在电镜下的结果显示实验组肝细胞内的自噬体的数量明显多于假手术组, 同时Beclin 1蛋白的水平较假手术组明显升高, RT-PCR的方法检查Beclin 1的mRNA水平的结果显示Beclin 1 mRNA的水平较假手术组也明显升高. 另外, Shimada等[43]通过动物实验研究也得出了相似的结果.
细胞自噬是缺血性损伤、缺血再灌注损伤的病理变化形式, Beclin 1蛋白参与了肝脏缺血再灌注损伤中细胞自噬的调控, 这提示可以通过干预相关蛋白表达而达到防治缺血再灌注损伤的目的. 目前已发现多种预处理的方式可以下调Beclin 1的表达, 同时减轻IRI后的细胞自噬活动. 如Cheng等[44]通过予大鼠术前腹腔注射H2S预处理后发现: (1)在电镜下观察肝细胞发现, 与IR实验组相比, 药物组中出现自噬体的肝细胞明显减少, 这提示H2S预处理降低了大鼠肝脏IRI后细胞自噬的水平; (2)用Western blot及RT-PCR检测结果显示, 与IR实验组相比, 药物组中Beclin 1的蛋白及mRNA的表达水平明显下降; (3)Beclin 1蛋白在肝组织的免疫组织化学染色结果显示: 与IR实验组相比, 药物组中Beclin 1在肝组织中的表达明显减少. 近年来, Shen等[45]、Rickenbacher等[46]、Kim等[47]、Li等[48]等分别用丙酮酸乙酯、禁食、卡马西平、虾青素的方法进行预处理后发现, 与IR实验组相比, 肝细胞自噬水平明显下降, 且预处理组肝组织中Beclin 1蛋白的表达明显下降.
在组织器官的IRI中, 细胞凋亡和自噬都是应激状态下的程序性死亡, 两者之间是否存在某种关系是近年来研究的热点. 前面提到Beclin 1有与Bcl-2家族蛋白类似的BH3区域, 且抗凋亡蛋白Bcl-2的结合凹槽可与Beclin 1的BH3结构域结合, 这可能便是Beclin 1与细胞凋亡存在某些关系的基础之一. 生理条件下, 抗凋亡蛋白Bcl-2与自噬相关蛋白Beclin 1结合, 抑制Beclin 1的自噬活性, 而缺血再灌注时, Bcl-2表达下降, 释放了与之结合的Beclin 1, 进而增强了自噬活性[49]. 另外, 有研究[50]表明细胞凋亡启动过程中激活的Caspase蛋白可以剪切Beclin 1, 剪切后形成的C端Beclin 1可以结合线粒体, 并促进线粒体细胞色素C释放, 进而导致细胞凋亡. 由此可见, 细胞凋亡与自噬在Beclin 1蛋白的作用下表现为既有拮抗也有协同的关系, 这在IRI研究领域中可能具有重要作用.
自噬相关蛋白Beclin 1作为细胞自噬重要的正调节因子, 是目前细胞自噬实验研究中广泛应用的指标之一, 且鉴于其与细胞凋亡千丝万缕的关系, 可能会在肝脏IRI领域和其他学科的临床应用中展现出更为广阔的研究前景.
手术切除是原发性肝癌的最佳治疗方法, 手术治疗往往面临残肝缺血再灌注损伤的弊端. 自噬参与了肝脏缺血再灌注损伤的过程, 且在其中的作用是研究的热点.
张振海, 副主任医师, 山东省立医院肝胆外科; 赵春华, 副主任医师, 湖北省宜昌市夷陵医院感染性疾病科
自噬在肝脏缺血再灌注损伤中发挥的作用是研究的热点. 自噬和凋亡在肝脏缺血再灌注损伤中可能存在着更多的潜在关联. 如何进一步减轻肝脏缺血再灌注损伤依然是亟待研究的问题.
Shen等在研究小鼠肝脏缺血再灌注实验时发现, 用丙酮酸乙酯预处理过的小鼠, 再灌注后的损伤明显减轻, 且可能是通过抑制自噬和凋亡的内在通路实现的.
总结了Beclin 1 作为自噬重要的正调节因子在肝脏缺血再灌注实验中的作用, 并指出了在Beclin 1蛋白的作用下, 细胞凋亡与自噬表现为既有拮抗也有协同的关系.
在肝脏缺血再灌注模型的实验中, Beclin 1蛋白含量的变化可代表自噬活动的变化, 并且将在自噬信号通路与凋亡信号通路关系的研究中继续发挥作用.
3-甲基腺嘌呤(3-MA): 通过抑制Ⅲ型Ⅰ型磷酸肌醇三磷酸激酶而抑制自噬, 作为一种自噬抑制剂被广泛应用, 另外, 3- MA能够增强抗肿瘤药物的化疗作用.
本文总结了Beclin 1在肝脏缺血再灌注损伤模型中的作用, 具有一定科学性、可读性, 基本上反映了该领域的最新成果.
编辑:于明茜 电编:闫晋利
1. | Gujral JS, Bucci TJ, Farhood A, Jaeschke H. Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis? Hepatology. 2001;33:397-405. [PubMed] [DOI] |
2. | Jaeschke H. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol. 2003;284:G15-G26. [PubMed] [DOI] |
3. | Jaeschke H, Woolbright BL. Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplant Rev (Orlando). 2012;26:103-114. [PubMed] [DOI] |
4. | Cursio R, Colosetti P, Saint-Paul MC, Pagnotta S, Gounon P, Iannelli A, Auberger P, Gugenheim J. Induction of different types of cell death after normothermic liver ischemia-reperfusion. Transplant Proc. 2010;42:3977-3980. [PubMed] [DOI] |
5. | Sun K, Xie X, Liu Y, Han Z, Zhao X, Cai N, Zhang S, Song J, Wei L. Autophagy lessens ischemic liver injury by reducing oxidative damage. Cell Biosci. 2013;3:26. [PubMed] [DOI] |
6. | Maiuri MC, Grassia G, Platt AM, Carnuccio R, Ialenti A, Maffia P. Macrophage autophagy in atherosclerosis. Mediators Inflamm. 2013;2013:584715. [PubMed] [DOI] |
7. | Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ. 2005;12 Suppl 2:1542-1552. [PubMed] [DOI] |
8. | Deretic V. Autophagy in innate and adaptive immunity. Trends Immunol. 2005;26:523-528. [PubMed] [DOI] |
9. | Crotzer VL, Blum JS. Autophagy and intracellular surveillance: Modulating MHC class II antigen presentation with stress. Proc Natl Acad Sci USA. 2005;102:7779-7780. [PubMed] [DOI] |
10. | Wang P, Guan YF, Du H, Zhai QW, Su DF, Miao CY. Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy. 2012;8:77-87. [PubMed] [DOI] |
11. | Doria A, Gatto M, Punzi L. Autophagy in human health and disease. N Engl J Med. 2013;368:1845. [PubMed] [DOI] |
12. | Wang J, Yang H, Hu X, Fu W, Xie J, Zhou X, Xu W, Jiang H. Dobutamine-mediated heme oxygenase-1 induction via PI3K and p38 MAPK inhibits high mobility group box 1 protein release and attenuates rat myocardial ischemia/reperfusion injury in vivo. J Surg Res. 2013;183:509-516. [PubMed] [DOI] |
13. | Kaushal GP. Autophagy protects proximal tubular cells from injury and apoptosis. Kidney Int. 2012;82:1250-1253. [PubMed] [DOI] |
14. | Zhang X, Yan H, Yuan Y, Gao J, Shen Z, Cheng Y, Shen Y, Wang RR, Wang X, Hu WW. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy. 2013;9:1321-1333. [PubMed] [DOI] |
15. | Thapalia BA, Zhou Z, Lin X. Autophagy, a process within reperfusion injury: an update. Int J Clin Exp Pathol. 2014;7:8322-8341. [PubMed] |
16. | Dong Y, Undyala VV, Gottlieb RA, Mentzer RM, Przyklenk K. Autophagy: definition, molecular machinery, and potential role in myocardial ischemia-reperfusion injury. J Cardiovasc Pharmacol Ther. 2010;15:220-230. [PubMed] [DOI] |
17. | Ma S, Wang Y, Chen Y, Cao F. The role of the autophagy in myocardial ischemia/reperfusion injury. Biochim Biophys Acta. 2015;1852:271-276. [PubMed] |
18. | Han Z, Cao J, Song D, Tian L, Chen K, Wang Y, Gao L, Yin Z, Fan Y, Wang C. Autophagy is involved in the cardioprotection effect of remote limb ischemic postconditioning on myocardial ischemia/reperfusion injury in normal mice, but not diabetic mice. PLoS One. 2014;9:e86838. [PubMed] [DOI] |
19. | Cursio R, Colosetti P, Gugenheim J. Autophagy and liver ischemia-reperfusion injury. Biomed Res Int. 2015;2015:417590. [PubMed] [DOI] |
20. | Decuypere JP, Ceulemans LJ, Agostinis P, Monbaliu D, Naesens M, Pirenne J, Jochmans I. Autophagy and the Kidney: Implications for Ischemia-Reperfusion Injury and Therapy. Am J Kidney Dis. 2015;66:699-709. [PubMed] [DOI] |
21. | Liu S, Hartleben B, Kretz O, Wiech T, Igarashi P, Mizushima N, Walz G, Huber TB. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy. 2012;8:826-837. [PubMed] [DOI] |
22. | Guan X, Qian Y, Shen Y, Zhang L, Du Y, Dai H, Qian J, Yan Y. Autophagy protects renal tubular cells against ischemia reperfusion injury in a time-dependent manner. Cell Physiol Biochem. 2015;36:285-298. [PubMed] [DOI] |
23. | Rami A, Langhagen A, Steiger S. Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis. 2008;29:132-141. [PubMed] [DOI] |
24. | Guo Z, Cao G, Yang H, Zhou H, Li L, Cao Z, Yu B, Kou J. A combination of four active compounds alleviates cerebral ischemia-reperfusion injury in correlation with inhibition of autophagy and modulation of AMPK/mTOR and JNK pathways. J Neurosci Res. 2014;92:1295-1306. [PubMed] [DOI] |
25. | Czaja MJ, Ding WX, Donohue TM, Friedman SL, Kim JS, Komatsu M, Lemasters JJ, Lemoine A, Lin JD, Ou JH. Functions of autophagy in normal and diseased liver. Autophagy. 2013;9:1131-1158. [PubMed] [DOI] |
26. | Fimia GM, Piacentini M. Regulation of autophagy in mammals and its interplay with apoptosis. Cell Mol Life Sci. 2010;67:1581-1588. [PubMed] [DOI] |
27. | Wang D, Ma Y, Li Z, Kang K, Sun X, Pan S, Wang J, Pan H, Liu L, Liang D. The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice. Autophagy. 2012;8:954-962. [PubMed] [DOI] |
28. | Zhang J, Morris MW, Dorsett-Martin WA, Drake LC, Anderson CD. Autophagy is involved in endoplasmic reticulum stress-induced cell death of rat hepatocytes. J Surg Res. 2013;183:929-935. [PubMed] [DOI] |
29. | Wang JH, Behrns KE, Leeuwenburgh C, Kim JS. Critical role of autophage in ischemia/reperfusion injury to aged livers. Autophagy. 2012;8:140-141. [PubMed] [DOI] |
30. | Wu HH, Hsiao TY, Chien CT, Lai MK. Ischemic conditioning by short periods of reperfusion attenuates renal ischemia/reperfusion induced apoptosis and autophagy in the rat. J Biomed Sci. 2009;16:19. [PubMed] [DOI] |
31. | Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 2011;18:571-580. [PubMed] [DOI] |
32. | Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586-8596. [PubMed] |
33. | Oberstein A, Jeffrey PD, Shi Y. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem. 2007;282:13123-13132. [PubMed] [DOI] |
34. | Qin H, Tan W, Zhang Z, Bao L, Shen H, Wang F, Xu F, Wang Z. 15d-prostaglandin J2 protects cortical neurons against oxygen-glucose deprivation/reoxygenation injury: involvement of inhibiting autophagy through upregulation of Bcl-2. Cell Mol Neurobiol. 2015;35:303-312. [PubMed] [DOI] |
35. | Mendes-Braz M, Elias-Miró M, Jiménez-Castro MB, Casillas-Ramírez A, Ramalho FS, Peralta C. The current state of knowledge of hepatic ischemia-reperfusion injury based on its study in experimental models. J Biomed Biotechnol. 2012;2012:298657. [PubMed] [DOI] |
36. | Kobayashi K, Oshima K, Muraoka M, Akao T, Totsuka O, Shimizu H, Sato H, Tanaka K, Konno K, Matsumoto K. Effect of atrial natriuretic peptide on ischemia-reperfusion injury in a porcine total hepatic vascular exclusion model. World J Gastroenterol. 2007;13:3487-3492. [PubMed] [DOI] |
37. | Tuncer MC, Ozturk H, Buyukbayram H, Ozturk H. Interaction of L-arginine-methyl ester and Sonic hedgehog in liver ischemia-reperfusion injury in the rats. World J Gastroenterol. 2007;13:3841-3846. [PubMed] [DOI] |
39. | Kamada N, Calne RY. A surgical experience with five hundred thirty liver transplants in the rat. Surgery. 1983;93:64-69. [PubMed] |
40. | Gotoh K, Lu Z, Morita M, Shibata M, Koike M, Waguri S, Dono K, Doki Y, Kominami E, Sugioka A. Participation of autophagy in the initiation of graft dysfunction after rat liver transplantation. Autophagy. 2009;5:351-360. [PubMed] [DOI] |
42. | Yun N, Cho HI, Lee SM. Impaired autophagy contributes to hepatocellular damage during ischemia/reperfusion: heme oxygenase-1 as a possible regulator. Free Radic Biol Med. 2014;68:168-177. [PubMed] [DOI] |
43. | Shimada S, Fukai M, Wakayama K, Ishikawa T, Kobayashi N, Kimura T, Yamashita K, Kamiyama T, Shimamura T, Taketomi A. Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver. Surg Today. 2015;45:892-903. [PubMed] [DOI] |
44. | Cheng P, Wang F, Chen K, Shen M, Dai W, Xu L, Zhang Y, Wang C, Li J, Yang J. Hydrogen sulfide ameliorates ischemia/reperfusion-induced hepatitis by inhibiting apoptosis and autophagy pathways. Mediators Inflamm. 2014;2014:935251. [PubMed] [DOI] |
45. | Shen M, Lu J, Dai W, Wang F, Xu L, Chen K, He L, Cheng P, Zhang Y, Wang C. Ethyl pyruvate ameliorates hepatic ischemia-reperfusion injury by inhibiting intrinsic pathway of apoptosis and autophagy. Mediators Inflamm. 2013;2013:461536. [PubMed] [DOI] |
46. | Rickenbacher A, Jang JH, Limani P, Ungethüm U, Lehmann K, Oberkofler CE, Weber A, Graf R, Humar B, Clavien PA. Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice. J Hepatol. 2014;61:301-308. [PubMed] [DOI] |
47. | Kim JS, Wang JH, Biel TG, Kim DS, Flores-Toro JA, Vijayvargiya R, Zendejas I, Behrns KE. Carbamazepine suppresses calpain-mediated autophagy impairment after ischemia/reperfusion in mouse livers. Toxicol Appl Pharmacol. 2013;273:600-610. [PubMed] [DOI] |
48. | Li J, Wang F, Xia Y, Dai W, Chen K, Li S, Liu T, Zheng Y, Wang J, Lu W. Astaxanthin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy via the ROS/MAPK Pathway in Mice. Mar Drugs. 2015;13:3368-3387. [PubMed] [DOI] |
49. | Chandler WF. Sellar and parasellar lesions. Clin Neurosurg. 1991;37:514-527. [PubMed] [DOI] |
50. | Wirawan E, Vande Walle L, Kersse K, Cornelis S, Claerhout S, Vanoverberghe I, Roelandt R, De Rycke R, Verspurten J, Declercq W. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 2010;1:e18. [PubMed] [DOI] |