Targeting disease through novel pathways of apoptosis and autophagy

Expert Opinion on Therapeutic Targets

Volumn 16, Issue 12, 2012, Pages 1203-1214

  Maiese, Kenneth ^a   Chong, Zhao Zhong ^a   Shang, Yan Chen ^a   Wang, Shaohui ^a  

^a RUTGERS CANCER INSTITUTE OF NEW JERSEY   (United States)

Author keywords

catenin; Akt; Alzheimer's disease; Apoptosis; Autophagy; Beclin 1; Cancer; Cardiovascular disease; Caspase; CCN family; Diabetes mellitus; Erythropoietin; Forkhead transcription factors; FoxO; Glycogen synthase kinase 3 ; Mammalian target of rapamycin; Neurodegenerative disease; Oxidative stress; Parkinson's disease; Phosphoinositide 3 kinase; Programmed cell death; Wnt1 inducible signaling pathway protein 1

Indexed keywords

ALPHA SYNUCLEIN; APOPTOTIC PROTEASE ACTIVATING FACTOR 1; BECLIN 1; BETA CATENIN; CASPASE 3; CASPASE 8; CASPASE 9; CELL PROTEIN; CYCLOPHILIN; CYTOCHROME C; DEOXYRIBONUCLEASE II; ENDONUCLEASE; FREE RADICAL; GENOMIC DNA; HYDROGEN PEROXIDE; INTERLEUKIN 1BETA CONVERTING ENZYME; MAMMALIAN TARGET OF RAPAMYCIN; NITRIC OXIDE; PEROXYNITRITE; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLSERINE; PROTEIN; PROTEIN BAX; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN BID; PROTEIN KINASE B; REACTIVE OXYGEN METABOLITE; SINGLET OXYGEN; UNCLASSIFIED DRUG; WNT1 INDUCIBLE SIGNALING PATHWAY PROTEIN 1;

ALZHEIMER DISEASE; APOPTOSIS; AUTOPHAGY; BONE INJURY; CANCER GROWTH; CELL DEATH; CELL FATE; DNA DAMAGE; DNA DEGRADATION; DNA FRAGMENTATION; DRUG TARGETING; HEART MUSCLE INJURY; HUMAN; IMMUNOPATHOLOGY; NONHUMAN; OXIDATIVE STRESS; PARKINSON DISEASE; REVIEW; SIGNAL TRANSDUCTION;

APOPTOSIS; AUTOPHAGY; BETA CATENIN; CCN INTERCELLULAR SIGNALING PROTEINS; DISEASE; HUMANS; OXIDATIVE STRESS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-AKT; TOR SERINE-THREONINE KINASES;

EID: 84869474312     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2012.719499     Document Type: Review

References (132)

1. Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 2005;75:207-46
2. Deretic V, Jiang S, Dupont N. Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation. Trends Cell Biol 2012;22(8):397-406
3. Kerr JF. A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J Pathol Bacteriol 1965;90:419-35
4. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239-57
5. Novikoff AB, Beaufay H, De Duve C. Electron microscopy of lysosomerich fractions from rat liver. J Biophys Biochem Cytol 1956;2:179-84
6. Clark SL Jr. Cellular differentiation in the kidneys of newborn mice studies with the electron microscope. J Biophys Biochem Cytol 1957;3:349-62
7. Maiese K, Chong ZZ, Shang YC, et al. Novel avenues of drug discovery and biomarkers for diabetes mellitus. J Clin Pharmacol 2011;51:128-52
8. Chong ZZ, Shang YC, Wang S, et al. SIRT1: new avenues of discovery for disorders of oxidative stress. Expert Opin Ther Targets 2012;16:167-78
9. Maiese K, Chong ZZ, Hou J, et al. The vitamin nicotinamide: translating nutrition into clinical care. Molecules 2009;14:3446-85
10. Suzen S, Cihaner SS, Coban T. Synthesis and comparison of antioxidant properties of indole-based melatonin analogue indole amino acid derivatives. Chem Biol Drug Des 2012;79:76-83
11. Yuan H, Wan J, Li L, et al. Therapeutic benefits of the group B3 vitamin nicotinamide in mice with lethal endotoxemia and polymicrobial sepsis. Pharmacol Res 2012;65:328-37
12. Pearl R. The rate of living. University of London Press; London:1928
13. Zengi A, Ercan G, Caglayan O, et al. Increased oxidative DNA damage in lean normoglycemic offspring of type 2 diabetic patients. Exp Clin Endocrinol Diabetes 2011;119:467-71
14. Vendelbo MH, Nair KS. Mitochondrial longevity pathways. Biochim Biophys Acta 2011;1813:634-44
15. Tupe RS, Tupe SG, Agte VV. Dietary nicotinic acid supplementation improves hepatic zinc uptake and offers hepatoprotection against oxidative damage. Br J Nutr 2011;1-9
16. Tanno M, Kuno A, Yano T, et al. Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. J Biol Chem 2010;285:8375-82
17. Hou J, Chong ZZ, Shang YC, et al. Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation. Curr Neurovasc Res 2010;7:95-112
18. Jourde-Chiche N, Dou L, Cerini C, et al. Vascular incompetence in dialysis patients-protein-bound uremic toxins and endothelial dysfunction. Semin Dial 2011;24:327-37
19. Nerurkar PV, Johns LM, Buesa LM, et al. Momordica charantia (bitter melon) attenuates high-fat diet-associated oxidative stress and neuroinflammation. J Neuroinflammation 2011;8:64
20. Shang YC, Chong ZZ, Hou J, et al. FoxO3a governs early microglial proliferation and employs mitochondrial depolarization with caspase 3, 8, and 9 cleavage during oxidant induced apoptosis. Curr Neurovasc Res 2009;6:223-38
21. Shang YC, Chong ZZ, Hou J, et al. Wnt1, FoxO3a, and NF-kappaB oversee microglial integrity and activation during oxidant stress. Cell Signal 2010;22:1317-29
22. Poulose SM, Bielinski DF, Carrihill-Knoll K, et al. Exposure to (16) O-particle radiation causes aging-like decrements in rats through increased oxidative stress, inflammation and loss of autophagy. Radiat Res 2011;176:761-9
23. Chong ZZ, Shang YC, Hou J, et al. Wnt1 neuroprotection translates into improved neurological function during oxidant stress and cerebral ischemia through AKT1 and mitochondrial apoptotic pathways. Oxid Med Cell Longev 2010;3:153-65
24. Raza SS, Khan MM, Ashafaq M, et al. Silymarin protects neurons from oxidative stress associated damages in focal cerebral ischemia: a behavioral, biochemical and immunohistological study in Wistar rats. J Neurol Sci 2011;309:45-54
25. Hou J, Chong ZZ, Shang YC, et al. FoxO3a governs early and late apoptotic endothelial programs during elevated glucose through mitochondrial and caspase signaling. Mol Cell Endocrinol 2010;321:194-206
26. Liu Z, Stanojevic V, Brindamour LJ, et al. GLP1-derived nonapeptide GLP1 (28-36)amide protects pancreatic beta-cells from glucolipotoxicity. J Endocrinol 2012;213:143-54
27. Cechetti F, Worm PV, Elsner VR, et al. Forced treadmill exercise prevents oxidative stress and memory deficits following chronic cerebral hypoperfusion in the rat. Neurobiol Learn Mem 2012;97:90-6
28. Bailey TJ, Fossum SL, Fimbel SM, et al. The inhibitor of phagocytosis, O-phospho-L-serine, suppresses Muller glia proliferation and cone cell regeneration in the light-damaged zebrafish retina. Exp Eye Res 2010;91:601-12
29. Chong ZZ, Kang J, Li F, et al. mGluRI targets microglial activation and selectively prevents neuronal cell engulfment through akt and caspase dependent pathways. Curr Neurovasc Res 2005;2:197-211
30. Koh PO. Nicotinamide attenuates the decrease of astrocytic phosphoprotein PEA-15 in focal cerebral ischemic injury. J Vet Med Sci 2012;74:377-80
31. Maiese K, Chong ZZ, Shang YC. "Sly as a FOXO": new paths with Forkhead signaling in the brain. Curr Neurovasc Res 2007;4:295-302
32. Aksu U, Demirci C, Ince C. The pathogenesis of acute kidney injury and the toxic triangle of oxygen, reactive oxygen species and nitric oxide. Contrib Nephrol 2011;174:119-28
33. Balan V, Miller GS, Kaplun L, et al. Life span extension and neuronal cell protection by Drosophila nicotinamidase. J Biol Chem 2008;283:27810-19
34. Chong ZZ, Li F, Maiese K. Cellular demise and inflammatory microglial activation during beta-amyloid toxicity are governed by Wnt1 and canonical signaling pathways. Cell Signal 2007;19:1150-62
35. Chong ZZ, Hou J, Shang YC, et al. EPO relies upon novel signaling of Wnt1 that requires Akt1, FoxO3a, GSK-3beta, and beta-catenin to foster vascular integrity during experimental diabetes. Curr Neurovasc Res 2011;8:103-20
36. Kook YH, Ka M, Um M. Neuroprotective cytokines repress PUMA induction in the 1-methyl-4-phenylpyridinium (MPP(+)) model of Parkinson's disease. Biochem Biophys Res Commun 2011;411:370-4
37. Ullah N, Lee HY, Naseer MI, et al. Nicotinamide inhibits alkylating agent-induced apoptotic neurodegeneration in the developing rat brain. PLoS One 2011;6:e27093
38. Troy CM, Akpan N, Jean YY. Regulation of caspases in the nervous system implications for functions in health and disease. Prog Mol Biol Transl Sci 2011;99:265-305
39. Salvesen GS, Riedl SJ. Caspase mechanisms. Adv Exp Med Biol 2008;615:13-23
40. Chong ZZ, Lin SH, Kang JQ, et al. Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspase 1, 3, and 8. J Neurosci Res 2003;71:659-69
41. Shang YC, Chong ZZ, Hou J, et al. The forkhead transcription factor FoxO3a controls microglial inflammatory activation and eventual apoptotic injury through caspase 3. Curr Neurovasc Res 2009;6:20-31
42. Broe M, Shepherd CE, Milward EA, et al. Relationship between DNA fragmentation, morphological changes and neuronal loss in Alzheimer's disease and dementia with Lewy bodies. Acta Neuropathol 2001;101:616-24
43. Louneva N, Cohen JW, Han LY, et al. Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer's disease. Am J Pathol 2008;173:1488-95
44. Grammas P, Tripathy D, Sanchez A, et al. Brain microvasculature and hypoxia-related proteins in Alzheimer's disease. Int J Clin Exp Pathol 2011;4:616-27
45. Tatton NA. Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease. Exp Neurol 2000;166:29-43
46. Narula J, Acio ER, Narula N, et al. Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat Med 2001;7:1347-52
47. Shang YC, Chong ZZ, Wang S, et al. Erythropoietin and Wnt1 Govern Pathways of mTOR, Apaf-1, and XIAP in Inflammatory Microglia. Curr Neurovasc Res 2011;198:270-85
48. Zhou X, Wang L, Wang M, et al. Emodin-induced microglial apoptosis is associated with TRB3 induction. Immunopharmacol Immunotoxicol 2011;33:594-602
49. Yamada E, Singh R. Mapping autophagy on to your metabolic radar. Diabetes 2012;61:272-80
50. Gumy LF, Tan CL, Fawcett JW. The role of local protein synthesis and degradation in axon regeneration. Exp Neurol 2010;223:28-37
51. Silva DF, Esteves AR, Oliveira CR, et al. Mitochondria: the common upstream driver of amyloid-beta and tau pathology in Alzheimer's disease. Curr Alzheimer Res 2011;8:563-72
52. Spencer B, Potkar R, Trejo M, et al. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci 2009;29:13578-88
53. Spilman P, Podlutskaya N, Hart MJ, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One 2010;5:e9979
54. Jeong JK, Moon MH, Bae BC, et al. Autophagy induced by resveratrol prevents human prion protein-mediated neurotoxicity. Neurosci Res 2012;73:99-105
55. Xilouri M, Vogiatzi T, Vekrellis K, et al. Aberrant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS ONE 2009;4:e5515
56. 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;6:738-53
57. Baba H, Sakurai M, Abe K, et al. Autophagy-mediated stress response in motor neuron after transient ischemia in rabbits. J Vasc Surg 2009;50:381-7
58. 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;70:314-22
59. Canu N, Tufi R, Serafino AL, et al. Role of the autophagic-lysosomal system on low potassium-induced apoptosis in cultured cerebellar granule cells. J Neurochem 2005;92:1228-42
60. Xue L, Fletcher GC, Tolkovsky AM. Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci 1999;14:180-98
61. Nopparat C, Porter JE, Ebadi M, et al. The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy. J Pineal Res 2010;49(4):382-9
62. Pattingre S, Tassa A, Qu X, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005;122:927-39
63. Carayol N, Vakana E, Sassano A, et al. Critical roles for mTORC2-and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci USA 2010;107:12469-74
64. Luo S, Rubinsztein DC. Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ 2010;17:268-77
65. Maiese K. The many facets of cell injury: angiogenesis to autophagy. Curr Neurovasc Res 2012;9:1-2
66. McPhee CK, Logan MA, Freeman MR, et al. Activation of autophagy during cell death requires the engulfment receptor Draper. Nature 2010;24465:1093-6
67. Davies SR, Davies ML, Sanders A, et al. Differential expression of the CCN family member WISP-1, WISP-2 and WISP-3 in human colorectal cancer and the prognostic implications. Int J Oncol 2010;36:1129-36
68. Desnoyers L, Arnott D, Pennica D. WISP-1 binds to decorin and biglycan. J Biol Chem 2001;276:47599-607
69. Colston JT, de la Rosa SD, Koehler M, et al. Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor. Am J Physiol Heart Circ Physiol 2007;293:H1839-46
70. Wang S, Chong ZZ, Shang YC, et al. Wnt1 inducible signaling pathway protein 1 (WISP1) blocks neurodegeneration through phosphoinositide 3 kinase/Akt1 and apoptotic mitochondrial signaling involving Bad, Bax, Bim, and Bcl-xL. Curr Neurovasc Res 2012;9:20-31
71. Wang S, Chong ZZ, Shang YC, et al. WISP1 (CCN4) autoregulates its expression and nuclear trafficking of beta-catenin during oxidant stress with limited effects upon neuronal autophagy. Curr Neurovasc Res 2012;9:89-99
72. Heise RL, Stober V, Cheluvaraju C, et al. Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity. J Biol Chem 2011;286:17435-44
73. French DM, Kaul RJ, D'Souza AL, et al. WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair. Am J Pathol 2004;165:855-67
74. Macsai CE, Georgiou KR, Foster BK, et al. Microarray expression analysis of genes and pathways involved in growth plate cartilage injury responses and bony repair. Bone 2012;50:1081-91
75. Maiese K, Li F, Chong ZZ, et al. The Wnt signaling pathway: aging gracefully as a protectionist? Pharmacol Ther 2008;118:58-81
76. Noguti J, CF DEM, Hossaka TA, et al. The role of canonical WNT signaling pathway in oral carcinogenesis: a comprehensive review. Anticancer Res 2012;32:873-8
77. Chong ZZ, Shang YC, Maiese K. Vascular injury during elevated glucose can be mitigated by erythropoietin and Wnt signaling. Curr Neurovasc Res 2007;4:194-204
78. Jiang YL, Ning Y, Ma XL, et al. Alteration of the proteome profile of the pancreas in diabetic rats induced by streptozotocin. Int J Mol Med 2011;28:153-60
79. Fernandez-Martos CM, Gonzalez-Fernandez C, Gonzalez P, et al. Differential expression of wnts after spinal cord contusion injury in adult rats. PLoS One 2011;6:e27000
80. L'Episcopo F, Tirolo C, Testa N, et al. Reactive astrocytes and Wnt/beta-catenin signaling link nigrostriatal injury to repair in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine model of Parkinson's disease. Neurobiol Dis 2011;41:508-27
81. Lee G, Goretsky T, Managlia E, et al. Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis. Gastroenterology 2010;139:869-81.81 e1-9
82. Marchand A, Atassi F, Gaaya A, et al. The Wnt/beta-catenin pathway is activated during advanced arterial aging in humans. Aging Cell 2011;10:220-32
83. Wexler EM, Rosen E, Lu D, et al. Genome-wide analysis of a wnt1-regulated transcriptional network implicates neurodegenerative pathways. Sci signal 2011;4:ra65
84. Chen JR, Lazarenko OP, Shankar K, et al. A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/beta-catenin signaling. J Bone Miner Res 2010;25(5):1117-27
85. L'Episcopo F, Tirolo C, Testa N, et al. Plasticity of subventricular zone neuroprogenitors in MPTP (1-Methyl-4-Phenyl-1, 2, 3, 6-Tetrahydropyridine) mouse model of Parkinson's disease involves cross talk between inflammatory and Wnt/beta-catenin signaling pathways: functional consequences for neuroprotection and repair. J Neurosci 2012;32:2062-85
86. Shang YC, Chong ZZ, Wang S, et al. Prevention of beta-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL. Aging (Albany NY) 2012;4:187-201.
87. Li F, Chong ZZ, Maiese K. Winding through the WNT pathway during cellular development and demise. Histol Histopathol 2006;21:103-24
88. Liu YL, Yang HP, Zhou XD, et al. The hypomethylation agent bisdemethoxycurcumin acts on the WIF-1 promoter, inhibits the canonical Wnt pathway and induces apoptosis in human non-small-cell lung cancer. Curr Cancer Drug Targets 2011;11(9):1098-110
89. Zhang Y, Wang F, Han L, et al. GABARAPL1 negatively regulates Wnt/beta-catenin signaling by mediating Dvl2 degradation through the autophagy pathway. Cell Physiol Biochem 2011;27:503-12
90. Su F, Overholtzer M, Besser D, et al. WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. Genes Dev 2002;16:46-57
91. Shanmugam P, Valente AJ, Prabhu SD, et al. Angiotensin-II type 1 receptor and NOX2 mediate TCF/LEF and CREB dependent WISP1 induction and cardiomyocyte hypertrophy. J Mol Cell Cardiol 2011;50:928-38
92. Reddy VS, Valente AJ, Delafontaine P, et al. Interleukin-18/WNT1- inducible signaling pathway protein-1 signaling mediates human saphenous vein smooth muscle cell proliferation. J Cell Physiol 2011;226:3303-15
93. Venkatesan B, Prabhu SD, Venkatachalam K, et al. WNT1-inducible signaling pathway protein-1 activates diverse cell survival pathways and blocks doxorubicin-induced cardiomyocyte death. Cell Signal 2010;22:809-20
94. Chong ZZ, Maiese K. The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histol Histopathol 2007;22:1251-67
95. Baryawno N, Sveinbjornsson B, Eksborg S, et al. Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res 2010;70:266-76
96. Chung CY, Park YL, Song YA, et al. Knockdown of RON Inhibits AP-1 activity and induces apoptosis and cell cycle arrest through the modulation of Akt/FoxO signaling in human colorectal cancer cells. Dig Dis Sci 2012;57:371-80
97. Fokas E, Yoshimura M, Prevo R, et al. NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity. Radiat Oncol 2012;7:48
98. Janku F, Wheler JJ, Westin SN, et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 2012;30:777-82
99. Kapoor V, Zaharieva MM, Das SN, et al. Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt-mTOR signaling pathway in oral squamous cell carcinoma. Cancer Lett 2012;319:39-48
100. Le XF, Mao W, Lu Z, et al. Dasatinib induces autophagic cell death in human ovarian cancer. Cancer 2010;116(21):4980-90
101. Li F, Chong ZZ, Maiese K. Microglial integrity is maintained by erythropoietin through integration of Akt and its substrates of glycogen synthase kinase-3beta, beta-catenin, and nuclear factor-kappaB. Curr Neurovasc Res 2006;3:187-201
102. Case N, Ma M, Sen B, et al. Beta-catenin levels influence rapid mechanical responses in osteoblasts. J Biol Chem 2008;283:29196-205
103. Nguyen TM, Subramanian IV, Xiao X, et al. Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and beta-catenin levels. J Cell Mol Med 2009;13:3687-98
104. Wang Y, Ding L, Wang X, et al. Pterostilbene simultaneously induces apoptosis, cell cycle arrest and cyto-protective autophagy in breast cancer cells. Am J Transl Res 2012;4:44-51
105. Chong ZZ, Maiese K. Mammalian target of rapamycin signaling in diabetic cardiovascular disease. Cardiovasc Diabetol 2012;11:45
106. Chong ZZ, Shang YC, Maiese K. Cardiovascular disease and mTOR signaling. Trends Cardiovasc Med 2011;21:151-5
107. Hwang SK, Kim HH. The functions of mTOR in ischemic diseases. BMB Rep 2011;44:506-11
108. Benjamin D, Colombi M, Moroni C, et al. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 2011;10:868-80
109. Chong ZZ, Shang YC, Zhang L, et al. Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. Oxid Med Cell Longev 2010;3:374-91
110. Chen L, Xu B, Liu L, et al. Hydrogen peroxide inhibits mTOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells. Lab Invest 2010;90:762-73
111. Chong ZZ, Li F, Maiese K. The pro-survival pathways of mTOR and protein kinase B target glycogen synthase kinase-3beta and nuclear factor-kappaB to foster endogenous microglial cell protection. Int J Mol Med 2007;19:263-72
112. Choi KC, Kim SH, Ha JY, et al. A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death. J Neurochem 2010;112:366-76
113. Wu X, Reiter CE, Antonetti DA, et al. Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner. J Biol Chem 2004;279:9167-75
114. Kim J, Jung Y, Sun H, et al. Erythropoietin mediated bone formation is regulated by mTOR signaling. J Cell Biochem 2012;113:220-8
115. Chong ZZ, Li F, Maiese K. Attempted cell cycle induction in post-mitotic neurons occurs in early and late apoptotic programs through Rb, E2F1, and caspase 3. Curr Neurovasc Res 2006;3:25-39
116. Yu Y, Ren QG, Zhang ZH, et al. Phospho-Rb mediating cell cycle reentry induces early apoptosis following oxygen-glucose deprivation in rat cortical neurons. Neurochem Res 2012;37:503-11
117. Bhaskar K, Miller M, Chludzinski A, et al. The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events. Mol Neurodegener 2009;4:14
118. Pastor MD, Garcia-Yebenes I, Fradejas N, et al. mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. J Biol Chem 2009;284:22067-78
119. Zhang D, Contu R, Latronico MV, et al. MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest 2010;120:2805-16
120. Dormond O, Madsen JC, Briscoe DM. The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. J Biol Chem 2007;282:23679-86
121. Thedieck K, Polak P, Kim ML, et al. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2007;2:e1217
122. Nascimento EB, Snel M, Guigas B, et al. Phosphorylation of PRAS40 on Thr246 by PKB/AKT facilitates efficient phosphorylation of Ser183 by mTORC1. Cell Signal 2010;22:961-7
123. Yu L, McPhee CK, Zheng L, et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 2010;465:942-6
124. Schips TG, Wietelmann A, Hohn K, et al. FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model. Cardiovasc Res 2011;91:587-97
125. Jaber N, Dou Z, Chen JS, et al. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc Natl Acad Sci USA 2012;109:2003-8
126. Ogura Y, Iemitsu M, Naito H, et al. Single bout of running exercise changes LC3-II expression in rat cardiac muscle. Biochem Biophys Res Commun 2011;414:756-60
127. Maiese K, Chong ZZ, Shang YC, et al. Rogue proliferation versus restorative protection: where do we draw the line for Wnt and forkhead signaling? Expert Opin Ther Targets 2008;12:905-16
128. Yeo W, Gautier J. Early neural cell death: dying to become neurons. Dev Biol 2004;274:233-44
129. Wang RH, Kim HS, Xiao C, et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest 2011;121:4477-90
130. Lafay-Chebassier C, Perault-Pochat MC, Page G, et al. The immunosuppressant rapamycin exacerbates neurotoxicity of Abeta peptide. J Neurosci Res 2006;84:1323-34
131. Hernandez G, Lal H, Fidalgo M, et al. A novel cardioprotective p38-MAPK/mTOR pathway. Exp Cell Res 2011;317:2938-49
132. Sinha SS, Pham MX, Vagelos RH, et al. Effect of rapamycin therapy on coronary artery physiology early after cardiac transplantation. Am Heart J 2008;155:889; e1-6