A Double-Edged Sword with Therapeutic Potential: An Updated Role of Autophagy in Ischemic Cerebral Injury

CNS Neuroscience and Therapeutics

Volumn 18, Issue 11, 2012, Pages 879-886

  Wei, Kai ^a   Wang, Pei ^a   Miao, Chao Yu ^a  

^a SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

Autophagy; Cell death; Cerebral ischemia

Indexed keywords

3 METHYLADENINE; AMLODIPINE; ATORVASTATIN; BECLIN 1; RAPAMYCIN;

AUTOPHAGOSOME; AUTOPHAGY; BRAIN ISCHEMIA; BRAIN NERVE CELL; CENTRAL NERVOUS SYSTEM; ELECTRON MICROSCOPE; ELECTRON MICROSCOPY; HYPERBARIC OXYGEN; IN VITRO STUDY; IN VIVO STUDY; ISCHEMIC PRECONDITIONING; NEUROPROTECTION; NONHUMAN; REVIEW;

ANIMALS; AUTOPHAGY; BRAIN INJURIES; BRAIN ISCHEMIA; HUMANS; ISCHEMIC PRECONDITIONING; NEURONS;

EID: 84868196007     PISSN: 17555930     EISSN: 17555949     Source Type: Journal    
DOI: 10.1111/cns.12005     Document Type: Review

References (146)

1. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lancet 2008;371:1612-1623.
2. Yepes M, Roussel BD, Ali C, Vivien D. Tissue-type plasminogen activator in the ischemic brain: More than a thrombolytic. Trends Neurosci 2009;32:48-55.
3. Liang BA, Lew R, Zivin JA. Review of tissue plasminogen activator, ischemic stroke, and potential legal issues. Arch Neurol 2008;65:1429-1433.
4. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: Mechanisms in search of treatments. Neuron 2010;67:181-198.
5. Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke 2009;40:e331-e339.
6. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008;132:27-42.
7. Le Bot N. Autophagy: A new regulator of development. Nat Cell Biol 2007;9:741.
8. Mortensen M, Simon AK. Nonredundant role of Atg7 in mitochondrial clearance during erythroid development. Autophagy 2011;6:423-425.
9. Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol 2010;12:823-830.
10. Qu X, Zou Z, Sun Q, et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 2007;128:931-946.
11. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 2011;469:323-335.
12. Lenz HD, Haller E, Melzer E, Gust AA, Nurnberger T. Autophagy controls plant basal immunity in a pathogenic lifestyle-dependent manner. Autophagy 2011;7:773-774.
13. Deretic V, Levine B. Autophagy, immunity, and microbial adaptations. Cell Host Microbe 2009;5:527-549.
14. Virgin HW, Levine B. Autophagy genes in immunity. Nat Immunol 2009;10:461-470.
15. Rabinowitz JD, White E. Autophagy and metabolism. Science 2010;330:1344-1348.
16. Gonzalez CD, Lee MS, Marchetti P, et al. The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy 2011;7:2-11.
17. Xiao S, Chye ML. The Arabidopsis thaliana ACBP3 regulates leaf senescence by modulating phospholipid metabolism and ATG8 stability. Autophagy 2010;6:802-804.
18. Kovsan J, Bashan N, Greenberg AS, Rudich A. Potential role of autophagy in modulation of lipid metabolism. Am J Physiol Endocrinol Metab 2010;298:E1-E7.
19. Kang R, Livesey KM, Zeh HJ 3rd, Lotze MT, Tang D. Metabolic regulation by HMGB1-mediated autophagy and mitophagy. Autophagy 2011;7:1256-1258.
20. Rubinsztein DC, Marino G, Kroemer G. Autophagy and aging. Cell 2011;146:682-695.
21. Lipinski MM, Zheng B, Lu T, et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proc Natl Acad Sci U S A 2010;107:14164-14169.
22. Isaka Y, Kimura T, Takabatake Y. The protective role of autophagy against aging and acute ischemic injury in kidney proximal tubular cells. Autophagy 2011;7:1085-1087.
23. Bartlett BJ, Isakson P, Lewerenz J, et al. p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects. Autophagy 2011;7:572-583.
24. Harris H, Rubinsztein DC. Control of autophagy as a therapy for neurodegenerative disease. Nat Rev Neurol 2012;8:108-117.
25. Wang Y, Martinez-Vicente M, Kruger U, et al. Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation. Autophagy 2010;6:182-183.
26. Scheper W, Nijholt DA, Hoozemans JJ. The unfolded protein response and proteostasis in Alzheimer disease: Preferential activation of autophagy by endoplasmic reticulum stress. Autophagy 2011;7:910-911.
27. Vila M, Bove J, Dehay B, Rodriguez-Muela N, Boya P. Lysosomal membrane permeabilization in Parkinson disease. Autophagy 2011;7:98-100.
28. Gray SG. Targeting histone deacetylases for the treatment of Huntington's disease. CNS Neurosci Ther 2010;16:348-361.
29. Chen ZF, Li YB, Han JY, et al. The double-edged effect of autophagy in pancreatic beta cells and diabetes. Autophagy 2011;7:12-16.
30. Ost A, Svensson K, Ruishalme I, et al. Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol Med 2010;16:235-246.
31. Xie Z, He C, Zou MH. AMP-activated protein kinase modulates cardiac autophagy in diabetic cardiomyopathy. Autophagy 2011;7:1254-1255.
32. Goldman S, Zhang Y, Jin S. Autophagy and adipogenesis: Implications in obesity and type II diabetes. Autophagy 2010;6:179-181.
33. Zhou L, Liu F. Autophagy: Roles in obesity-induced ER stress and adiponectin downregulation in adipocytes. Autophagy 2010;6:1196-1197.
34. Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 2005;5:726-734.
35. Dewaele M, Maes H, Agostinis P. ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy. Autophagy 2010;6:838-854.
36. Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B. Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy 2010;6:322-329.
37. Gargini R, Garcia-Escudero V, Izquierdo M. Therapy mediated by mitophagy abrogates tumor progression. Autophagy 2011;7:466-476.
38. Guo JY, Chen HY, Mathew R, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 2011;25:460-470.
39. Abdulrahman BA, Khweek AA, Akhter A, et al. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy 2011;7:1359-1370.
40. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 2011;333:1109-1112.
41. Luciani A, Villella VR, Esposito S, et al. Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition. Nat Cell Biol 2010;12:863-875.
42. Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 2007;100:914-922.
43. Przyklenk K, Undyala VV, Wider J, Sala-Mercado JA, Gottlieb RA, Mentzer RM Jr. Acute induction of autophagy as a novel strategy for cardioprotection: Getting to the heart of the matter. Autophagy 2011;7:432-433.
44. Zhang Y, Ren J. Autophagy in ALDH2-elicited cardioprotection against ischemic heart disease: Slayer or savior? Autophagy 2010;6:1212-1213.
45. Esposti DD, Domart MC, Sebagh M, et al. Autophagy is induced by ischemic preconditioning in human livers formerly treated by chemotherapy to limit necrosis. Autophagy 2010;6:172-174.
46. Wang JH, Ahn IS, Fischer TD, et al. Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice. Gastroenterology 2011;141(2188-2199):e2186.
47. Uchiyama Y, Koike M, Shibata M. Autophagic neuron death in neonatal brain ischemia/hypoxia. Autophagy 2008;4:404-408.
48. 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.
49. Zhang X, Li L, Chen S, et al. Rapamycin treatment augments motor neuron degeneration in SOD1 (G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 2011;7:412-425.
50. Jaeger PA, Wyss-Coray T. All-you-can-eat: Autophagy in neurodegeneration and neuroprotection. Mol Neurodegener 2009;4:16.
51. Madeo F, Eisenberg T, Kroemer G. Autophagy for the avoidance of neurodegeneration. Genes Dev 2009;23:2253-2259.
52. Medeiros R, Baglietto-Vargas D, LaFerla FM. The role of tau in Alzheimer's disease and related disorders. CNS Neurosci Ther 2011;17:514-524.
53. Balin B, Abrams JT, Schrogie J. Toward a unifying hypothesis in the development of Alzheimer's disease. CNS Neurosci Ther 2011;17:587-589.
54. Berezniuk I, Fricker LD. A defect in cytosolic carboxypeptidase 1 (Nna1) causes autophagy in Purkinje cell degeneration mouse brain. Autophagy 2010;6:558-559.
55. Chu CT. Eaten alive: Autophagy and neuronal cell death after hypoxia-ischemia. Am J Pathol 2008;172:284-287.
56. Smith CM, Chen Y, Sullivan ML, Kochanek PM, Clark RS. Autophagy in acute brain injury: Feast, famine, or folly? Neurobiol Dis 2011;43:52-59.
57. Xu M, Zhang HL. Death and survival of neuronal and astrocytic cells in ischemic brain injury: A role of autophagy. Acta Pharmacol Sin 2011;32:1089-1099.
58. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67-93.
59. Yang Z, Klionsky DJ. Eaten alive: A history of macroautophagy. Nat Cell Biol 2010;12:814-822.
60. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011;13:1016-1023.
61. Loffler AS, Alers S, Dieterle AM, et al. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy 2011;7:696-706.
62. Hardie DG. AMPK and autophagy get connected. EMBO J 2011;30:634-635.
63. Shang L, Wang X. AMPK and mTOR coordinate the regulation of Ulk1 and mammalian autophagy initiation. Autophagy 2011;7:924-926.
64. Djavaheri-Mergny M, Maiuri MC, Kroemer G. Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 2010;29:1717-1719.
65. Proikas-Cezanne T, Codogno P. Beclin 1 or not Beclin 1. Autophagy 2011;7:671-672.
66. Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 2004;36:2503-2518.
67. Pankiv S, Clausen TH, Lamark T, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 2007;282:24131-24145.
68. Mathew R, Karp CM, Beaudoin B, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 2009;137:1062-1075.
69. Komatsu M, Ichimura Y. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett 2010;584:1374-1378.
70. Larsen KB, Lamark T, Øvervatn A, Harneshaug I, Johansen T, Bjørkøy G. A reporter cell system to monitor autophagy based on p62/SQSTM1. Autophagy 2010;6:784-793.
71. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011;13:132-141.
72. Jung CH, Seo M, Otto NM, Kim DH. ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 2011;7:1212-1221.
73. Dunlop EA, Hunt DK, Acosta-Jaquez HA, Fingar DC, Tee AR. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 2011;7:737-747.
74. Lee JW, Park S, Takahashi Y, Wang HG. The association of AMPK with ULK1 regulates autophagy. PLoS One 2010;5:e15394.
75. Dice JF. Chaperone-mediated autophagy. Autophagy 2007;3:295-299.
76. Mijaljica D, Prescott M, Devenish RJ. Microautophagy in mammalian cells: Revisiting a 40-year-old conundrum. Autophagy 2011;7:673-682.
77. Santambrogio L, Cuervo AM. Chasing the elusive mammalian microautophagy. Autophagy 2011;7:652-654.
78. Rosello A, Warnes G, Meier UC. Cell death pathways and autophagy in the central nervous system and its involvement in neurodegeneration, immunity and central nervous system infection: To die or not to die-that is the question. Clin Exp Immunol 2012;168:52-57.
79. Haapasalo A, Viswanathan J, Bertram L, Soininen H, Tanzi RE, Hiltunen M. Emerging role of Alzheimer's disease-associated ubiquilin-1 in protein aggregation. Biochem Soc Trans 2010;38:150-155.
80. Eskelinen EL, Reggiori F, Baba M, Kovacs AL, Seglen PO. Seeing is believing: The impact of electron microscopy on autophagy research. Autophagy 2011;7:935-956.
81. Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008;4:151-175.
82. Nitatori T, Sato N, Waguri S, et al. Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 1995;15:1001-1011.
83. Adhami F, Liao G, Morozov YM, et al. Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol 2006;169:566-583.
84. Liu C, Gao Y, Barrett J, Hu B. Autophagy and protein aggregation after brain ischemia. J Neurochem 2010;115:68-78.
85. Wang JY, Xia Q, Chu KT, et al. Severe global cerebral ischemia-induced programmed necrosis of hippocampal CA1 neurons in rat is prevented by 3-methyladenine: A widely used inhibitor of autophagy. J Neuropathol Exp Neurol 2011;70:314-322.
86. Carloni S, Girelli S, Scopa C, Buonocore G, Longini M, Balduini W. Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy 2010;6:366-377.
87. Grishchuk Y, Ginet V, Truttmann AC, Clarke PG, Puyal J. Beclin 1-independent autophagy contributes to apoptosis in cortical neurons. Autophagy 2010;7:1115-1131.
88. Puyal J, Vaslin A, Mottier V, Clarke PG. Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann Neurol 2009;66:378-389.
89. Zheng YQ, Liu JX, Li XZ, Xu L, Xu YG. RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats. Acta Pharmacol Sin 2009;30:919-927.
90. Qin AP, Liu CF, Qin YY, et al. Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy 2010;6:738-753.
91. Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 2000;19:5720-5728.
92. Ginet V, Puyal J, Clarke PG, Truttmann AC. Enhancement of autophagic flux after neonatal cerebral hypoxia-ischemia and its region-specific relationship to apoptotic mechanisms. Am J Pathol 2009;175:1962-1974.
93. Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis 2008;32:329-339.
94. Koike M, Shibata M, Tadakoshi M, et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol 2008;172:454-469.
95. 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.
96. Yan W, Zhang H, Bai X, Lu Y, Dong H, Xiong L. Autophagy activation is involved in neuroprotection induced by hyperbaric oxygen preconditioning against focal cerebral ischemia in rats. Brain Res 2011;1402:109-121.
97. Wang YC, Zhang S, Du TY, Wang B, Sun XQ. Hyperbaric oxygen preconditioning reduces ischemia-reperfusion injury by stimulating autophagy in neurocyte. Brain Res 2010;1323:149-151.
98. Tian F, Deguchi K, Yamashita T, et al. In vivo imaging of autophagy in a mouse stroke model. Autophagy 2010;6:1107-1114.
99. Komatsu M, Waguri S, Ueno T, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 2005;169:425-434.
100. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006;441:880-884.
101. Uchiyama Y. Autophagic cell death and its execution by lysosomal cathepsins. Arch Histol Cytol 2001;64:233-246.
102. Wen YD, Sheng R, Zhang LS, et al. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 2008;4:762-769.
103. Kubota C, Torii S, Hou N, et al. Constitutive reactive oxygen species generation from autophagosome/lysosome in neuronal oxidative toxicity. J Biol Chem 2010;285:667-674.
104. Shang J, Deguchi K, Yamashita T, et al. Antiapoptotic and antiautophagic effects of glial cell line-derived neurotrophic factor and hepatocyte growth factor after transient middle cerebral artery occlusion in rats. J Neurosci Res 2010;88:2197-2206.
105. Zheng C, Han J, Xia W, Shi S, Liu J, Ying W. NAD(+) administration decreases ischemic brain damage partially by blocking autophagy in a mouse model of brain ischemia. Neurosci Lett 2012;512:67-71.
106. Cui D, Wang L, Qi A, Zhou Q, Zhang X, Jiang W. Propofol prevents autophagic cell death following oxygen and glucose deprivation in PC12 cells and cerebral ischemia-reperfusion injury in rats. PLoS One 2012;7:e35324.
107. Liu L, Fang YQ, Xue ZF, He YP, Fang RM, Li L. Beta-asarone attenuates ischemia-reperfusion-induced autophagy in rat brains via modulating JNK, p-JNK, Bcl-2 and Beclin 1. Eur J Pharmacol 2012;680:34-40.
108. Li Q, Li H, Roughton K, et al. Lithium reduces apoptosis and autophagy after neonatal hypoxia-ischemia. Cell Death Dis 2010;1:e56.
109. Li L, Khatibi NH, Hu Q, et al. Transmembrane protein 166 regulates autophagic and apoptotic activities following focal cerebral ischemic injury in rats. Exp Neurol 2012;234:181-190.
110. Lu T, Jiang Y, Zhou Z, et al. Intranasal ginsenoside Rb1 targets the brain and ameliorates cerebral ischemia/reperfusion injury in rats. Biol Pharm Bull 2011;34:1319-1324.
111. Xin XY, Pan J, Wang XQ, et al. 2-methoxyestradiol attenuates autophagy activation after global ischemia. Can J Neurol Sci 2011;38:631-638.
112. Tyagi N, Qipshidze N, Munjal C, et al. Tetrahydrocurcumin ameliorates homocysteinylated cytochrome-c mediated autophagy in hyperhomocysteinemia mice after cerebral ischemia. J Mol Neurosci 2012;47:128-138.
113. Liu N, Shang J, Tian F, Nishi H, Abe K. In vivo optical imaging for evaluating the efficacy of edaravone after transient cerebral ischemia in mice. Brain Res 2011;1397:66-75.
114. Mehta SL, Kumari S, Mendelev N, Li PA. Selenium preserves mitochondrial function, stimulates mitochondrial biogenesis, and reduces infarct volume after focal cerebral ischemia. BMC Neurosci 2012;13:79.
115. Zhang T, Liu X, Li Q, Wang J, Jia W, Sun X. Exacerbation of ischemia-induced amyloid-beta generation by diabetes is associated with autophagy activation in mice brain. Neurosci Lett 2010;479:215-220.
116. Zhang T, Yan W, Li Q, et al. 3-n-Butylphthalide (NBP) attenuated neuronal autophagy and amyloid-beta expression in diabetic mice subjected to brain ischemia. Neurol Res 2011;33:396-404.
117. Zhang X, Deguchi S, Deguchi K, et al. Amlodipine and atorvastatin exert protective and additive effects via antiapoptotic and antiautophagic mechanisms after transient middle cerebral artery occlusion in Zucker metabolic syndrome rats. J Neurosci Res 2011;89:1228-1234.
118. Mehta SL, Lin Y, Chen W, et al. Superoxide dismutase deficiency exacerbates ischemic brain damage under hyperglycemic conditions by altering autophagy. Transl Stroke Res 2011;2:42-50.
119. Zhou X, Zhou J, Li X, Guo C, Fang T, Chen Z. GSK-3beta inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury. Biochem Biophys Res Commun 2011;411:271-275.
120. Tanabe F, Yone K, Kawabata N, et al. Accumulation of p62 in degenerated spinal cord under chronic mechanical compression: Functional analysis of p62 and autophagy in hypoxic neuronal cells. Autophagy 2011;7:1462-1471.
121. Guo Y, Wang J, Wang Z, Yang Y, Wang X, Duan Q. Melatonin protects N2a against ischemia/reperfusion injury through autophagy enhancement. J Huazhong Univ Sci Technolog Med Sci 2010;30:1-7.
122. Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 2006;7:437-448.
123. Huang C, Yitzhaki S, Perry CN, et al. Autophagy induced by ischemic preconditioning is essential for cardioprotection. J Cardiovasc Transl Res 2010;3:365-373.
124. Yeh CH, Hsu SP, Yang CC, Chien CT, Wang NP. Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy. Life Sci 2010;86:115-123.
125. Wu BX, Darden AG, Laser M, et al. The rat Apg3p/Aut1p homolog is upregulated by ischemic preconditioning in the retina. Mol Vis 2006;12:1292-1302.
126. Park HK, Chu K, Jung KH, et al. Autophagy is involved in the ischemic preconditioning. Neurosci Lett 2009;451:16-19.
127. Sheng R, Zhang LS, Han R, Liu XQ, Gao B, Qin ZH. Autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioning. Autophagy 2010;6:482-494.
128. Sheng R, Liu XQ, Zhang LS, et al. Autophagy regulates endoplasmic reticulum stress in ischemic preconditioning. Autophagy 2012;8:310-325.
129. Balduini W, Carloni S, Buonocore G. Autophagy in hypoxia-ischemia induced brain injury. J Matern Fetal Neonatal Med 2012;25(Suppl 1):30-34.
130. Matchett GA, Martin RD, Zhang JH. Hyperbaric oxygen therapy and cerebral ischemia: Neuroprotective mechanisms. Neurol Res 2009;31:114-121.
131. Klionsky DJ. Autophagy: From phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007;8:931-937.
132. Hu G, Hacham M, Waterman SR, et al. PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans. J Clin Invest 2008;118:1186-1197.
133. Wu YT, Tan HL, Huang Q, Ong CN, Shen HM. Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy. Autophagy 2009;5:824-834.
134. Cheng Y, Yan L, Ren X, Yang JM. eEF-2 kinase, another meddler in the "yin and yang" of Akt-mediated cell fate? Autophagy 2011;7:660-661.
135. Qin L, Wang Z, Tao L, Wang Y. ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 2010;6:239-247.
136. Fan QW, Weiss WA. Autophagy and Akt promote survival in glioma. Autophagy 2011;7:536-538.
137. Barre B, Perkins ND. The Skp2 promoter integrates signaling through the NF-kappaB, p53, and Akt/GSK3beta pathways to regulate autophagy and apoptosis. Mol Cell 2010;38:524-538.
138. Fan QW, Cheng C, Hackett C, et al. Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 2010;3:ra81.
139. Dutta S, Baehrecke EH. Warts is required for PI3K-regulated growth arrest, autophagy, and autophagic cell death in Drosophila. Curr Biol 2008;18:1466-1475.
140. Duronio V. The life of a cell: Apoptosis regulation by the PI3K/PKB pathway. Biochem J 2008;415:333-344.
141. Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 2011;1813:1978-1986.
142. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471-484.
143. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009;10:307-318.
144. Menzies FM, Rubinsztein DC. Broadening the therapeutic scope for rapamycin treatment. Autophagy 2010;6:286-287.
145. Galluzzi L, Aaronson SA, Abrams J, et al. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ 2009;16:1093-1107.
146. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell 2010;140:313-326.