Activators of AMPK: Not just for Type II diabetes

Future Medicinal Chemistry

Volumn 6, Issue 11, 2014, Pages 1325-1353

  Zaks, Ilana ^a   Getter, Tamar ^a   Gruzman, Arie ^a  

^a BAR ILAN UNIVERSITY   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

2 AZETIDINONE DERIVATIVE; 2 OCTYNOIC ACID; 6,7 DIHYDRO 4 HYDROXY 3 (2' HYDROXY 1,1' BIPHENYL 4 YL) 6 OXOTHIENO[2,3 B]PYRIDINE 5 CARBONITRILE; BAICALEIN; BELINOSTAT; BETULIC ACID; CELASTROL; DAMULIN; DIMEBON; EPIGALLOCATECHIN GALLATE; ETC 1002; FATTY ACID DERIVATIVE; GAMBOGIC ACID; GINGEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE ACTIVATOR; LICOCACHALCONE A; METFORMIN; NATURAL PRODUCT; NECTADRIN B; PARA COUMARIC ACID; PHOSPHONIC ACID DERIVATIVE; PT 1; QUERCETIN; RESVERATROL; RILUZOLE; RSVA 314; SALICYLIC ACID; SOPHOCARPINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ENZYME ACTIVATOR;

AMYOTROPHIC LATERAL SCLEROSIS; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; BIOLOGICAL ACTIVITY; CELL METABOLISM; CHEMICAL STRUCTURE; DIABETES MELLITUS; DRUG DESIGN; DRUG MECHANISM; ENZYME ACTIVATION; HEPATITIS C; HUMAN; HYPERLIPIDEMIA; NEUROPROTECTION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; TREATMENT INDICATION; DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; ENERGY METABOLISM; PHYSIOLOGY;

AMP-ACTIVATED PROTEIN KINASES; DIABETES MELLITUS, TYPE 2; ENERGY METABOLISM; ENZYME ACTIVATORS; HUMANS;

EID: 84906727366     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.14.74     Document Type: Review

References (196)

1. Hardie DG. AMPK: A target for drugs and natural products with effects on both diabetes and cancer. Diabetes 62, 2164-2172 (2013).
2. Stark R, Ashley SE, Andrews ZB. AMPK and the neuroendocrine regulation of appetite and energy expenditure. Mol. Cell Endocrinol. 366, 215-223 (2013).
3. Hardie DG, Ross FA, Hawley SA. AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 22, 251-262 (2012).
4. Gruzman A, Babai G, Sasson S. Adenosine monophosphate-Activated protein kinase (AMPK) as a new target for antidiabetic drugs: A review on metabolic, pharmacological and chemical considerations. Rev. Diabet. Stud. 6, 13-36 (2009).
5. Sinnett SE, Brenman JE. Past strategies and future directions for identifying AMP-Activated protein kinase (AMPK) modulators. Pharmacol. Ther. 143, 111-118 (2014).
6. Davies SP, Hawley SA, Woods A et al. Purification of the AMP-Activated protein kinase on ATP-gamma-sepharose and analysis of its subunit structure. Eur. J. Biochem. 223, 351-357 (1994).
7. Beri RK, Marley AE, See CG et al. Molecular cloning, expression and chromosomal localisation of human AMP-Activated protein kinase. FEBS Lett. 356, 117-21 (1994).
8. Stephenne X, Foretz M, Taleux N et al. Metformin activates AMP-Activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 54, 3101-3110 (2011).
9. Wu J, Puppala D, Feng X et al. Chemoproteomic analysis of intertissue and interspecies isoform diversity of AMP-Activated protein kinase (AMPK). J. Biol. Chem. 288, 35904-35912 (2013).
10. Xiao B, Sanders MJ, Underwood E et al. Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230-233 (2011).
11. Protein Data Bank Japan. http://service.pdbj.org/mine/Search?position= 1&resultSize =16&query=human+AMPK
12. Day P, Sharff A, Parra L et al. Structure of a CBS-domain pair from the regulatory gamma1 subunit of human AMPK in complex with AMP and ZMP. Acta Crystallogr. D. Biol. Crystallogr. 63, 587-596 (2007).
13. Handa N, Takagi T, Saijo S et al. Structural basis for compound C inhibition of the human AMP-Activated protein kinase a2 subunit kinase domain. Acta Crystallogr. D. Biol. Crystallogr. 67, 480-487 (2011).
14. Littler DR, Walker JR, Davis T et al. A conserved mechanism of autoinhibition for the AMPK kinase domain: ATP-binding site and catalytic loop refolding as a means of regulation. Acta Crystallog. Sect. F Struct. Biol. Cryst. Commun. 66, 143-151 (2010)
15. Iseli TJ, Walter M, van Denderen BJ et al. AMP-Activated protein kinase beta subunit tethers alpha and gamma subunits via its C-Terminal sequence (186-270). J. Biol Chem. 280, 13395-13400 (2005).
16. Wang ZL, Huo JX, Sun LD et al. Computer-Aided drug design for AMP-Activated protein kinase activators. Curr. Comput. Aided Drug Des. 7, 214-227 (2011)
17. Russo GL, Russo M, Ungaro P. AMP-Activated protein kinase: A target for old drugs against diabetes and cancer. Biochem. Pharmacol. 86, 339-350 (2013).
18. Dandapani M, Hardie DG. AMPK: Opposing the metabolic changes in both tumor cells and inflammatory cells? Biochem. Soc. Trans. 41, 687-693 (2013).
19. Hardie DG, Salt IP, Hawley SA et al. AMP activated protein kinase: An ultrasensitive system for monitoring cellular energy charge. Biochem. J. 338, 717-722 (1999).
20. Hawley SA, Davison M, Woods A et al. Characterization of the AMP-Activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-Activated protein kinase. J. Biol. Chem. 271, 27879-27887 (1996).
21. Park S, Scheffler TL, Rossie SS et al. AMPK activity is regulated by calcium-mediated protein phosphatase 2A activity. Cell Calcium. 53, 217-223 (2013).
22. Kottakis F, Bardeesy N. LKB1-AMPK axis revisited. Cell Res. 22, 1617-1620 (2012).
23. Suter M, Riek U, Tuerk R et al. Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMP-Activated protein kinase. J. Biol. Chem. 281, 32207-32216 (2006).
24. Peng C, Head-Gordon T. The dynamical mechanism of auto-inhibition of AMP-Activated protein kinase. PLoS Comput. Biol. 7, e1002082 (2011).
25. Sanchez AM, Candau RB, Csibi A et al. The role of AMP-Activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis. Am. J. Physiol. Cell Physiol. 303, C475-C485 (2012).
26. Scheffler TL, Scheffler JM, Park S et al. Fiber hypertrophy and increased oxidative capacity can occur simultaneously in pig glycolytic skeletal muscle. Am. J. Physiol. Cell Physiol. 306, C354-363 (2014).
27. Tanner CB, Madsen SR, Hallowell DM et al. Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1 Am. J. Physiol. Endocrinol. Metab. 305, 1018-29 (2013).
28. Richter EA, Hargreaves M. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol. Rev. 93, 993-1017 (2013).
29. Friedrichsen M, Mortensen B, Pehmøller C et al. Exercise-induced AMPK activity in skeletal muscle: Role in glucose uptake and insulin sensitivity. Mol. Cell Endocrinol. 366, 204-214 (2013).
30. Mu J, T. Brozinick J, Valladares O et al. A role for AMP-Activated protein kinase in contraction-And hypoxia-regulated glucose transport in skeletal muscles. Mol. Cell, 7, 1085-1094 (2001).
31. Lefort N, St.-Amand E, Morasse S et al. The a-subunit of AMPK is essential for submaximal contraction-mediated glucose transport in skeletal muscle in vitro. Am. J. Physiol. Endocrinol. Metab. 295, E1447-E1454 (2008).
32. Fujii N, Hirshman M, Kane E et al. AMP-Activated protein kinase alpha 2 activity is not essential for contraction-And hyperosmolarity-induced glucose transport in skeletal muscle. J. Biol. Chem. 280, 39033-39041 (2005).
33. Bijland S, Mancini SJ, Salt IP. Role of AMP-Activated protein kinase in adipose tissue metabolism and inflammation. Clin. Sci. (Lond.) 124, 491-507 (2013).
34. Daval M, Foufelle F, Ferre P. Functions of AMP-Activated protein kinase in adipose tissue. J. Physiol. 574, 55-62 (2006).
35. Dzamko NL, Steinberg GR. AMPK-dependent hormonal regulation of whole-body energy metabolism. Acta Physiol. (Oxf.) 196, 115-27 (2009).
36. Lustig Y, Hemi R, Kanety H. Regulation and function of adiponectin receptors in skeletal muscle. Vitam. Horm. 90, 95-123 (2012).
37. Hasenour CM, Berglund ED, Wasserman DH. Emerging role of AMP-Activated protein kinase in endocrine control of metabolism in the liver. Mol. Cell Endocrinol. 366, 152-162 (2013).
38. Miller R, Chu O, Xie J et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494, 256-261 (2013).
39. Miller RA, Birnbaum MJ. An energetic tale of AMPK-independent effects of metformin. J. Clin. Invest. 120, 2267-2269 (2010).
40. Jenkins Y, Sun T, Markovtsov V et al. AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes. PLoS ONE 8, e81870 (2013).
41. Edgerton DS, Johnson KM, Cherrington AD. Current strategies for the inhibition of hepatic glucose production in type 2 diabetes. Front. Biosci. 14, 1169-1181 (2009).
42. Foretz M, Hébrard S, Leclerc J et al. Metformin inhibits hepatic gluconeogenesisin mice independently of the LKB1/ AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355-2369 (2010).
43. Pfeifer A, Kilić A, Hoffmann LS. Regulation of metabolism by cGMP. Pharmacol. Ther. 140, 81-91 (2013).
44. Viollet B, Mounier R, Leclerc J et al. Targeting AMP-Activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab. 33, 395-402 (2007).
45. Hawley SA, Ross FA, Chevtzoff C et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11, 554-565 (2010).
46. Guigas B, Bertrand L, Taleux N et al. 5-Aminoimidazole-4-carboxamide-1- beta-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-Activated protein kinase-independent effect on glucokinase translocation. Diabetes 55, 865-874 (2006).
47. Farghali H, Kutinová Canová N, Lekić N. Resveratrol and related compounds as antioxidants with an allosteric mechanism of action in epigenetic drug targets. Physiol. Res. 62, 1-13 (2013).
48. Nguyen PH, Gauhar R, Hwang SL et al. New dammarane-Type glucosides as potential activators of AMP-Activated protein kinase (AMPK) from Gynostemma pentaphyllum Bioorg. Med. Chem. 19, 6254-6260 (2011).
49. Quan HY, Kim DY, Kim SJ et al. Betulinic acid alleviates non-Alcoholic fatty liver by inhibiting SREBP1 activity via the AMPK-mTOR-SREBP signaling pathway. Biochem. Pharmacol. 85, 1330-1340 (2013).
50. Guo H, Liu G, Zhong R et al. Cyanidin-3-O-β-glucoside regulates fatty acid metabolism via an AMP-Activated protein kinase-dependent signaling pathway in human HepG2 cells. Lipids Health Dis. 11, 10 (2012).
51. He Y, Li Y, Zhao T et al. Ursolic acid inhibits adipogenesis in 3T3-L1 adipocytes through LKB1/AMPK pathway. PLoS ONE 8, e70135, (2013).
52. Pu P, Wang XA, Salim M et al. Baicalein, a natural product, selectively activating AMPKa2 and ameliorates metabolic disorder in diet-induced mice. Mol. Cell Endocrinol. 362, 128-138 (2012).
53. Yoon SA, Kang SI, Shin HS et al. p-coumaric acid modulates glucose and lipid metabolism via AMP-Activated protein kinase in L6 skeletal muscle cells. Biochem. Biophys. Res. Commun. 432, 553-557 (2013).
54. Kubra IR, Rao LJ. An impression on current developments in the technology, chemistry, and biological activities of ginger. Crit. Rev. Food Sci. Nutr. 52, 651-88 (2012).
55. Quan HY, Kim SJ, Kim DY et al. Licochalcone A regulates hepatic lipid metabolism through activation of AMP-Activated protein kinase. Fitoterapia 86, 208-216 (2013).
56. Zhou R. Wang L. Xu X et al. Danthron activates AMP-Activated protein kinase and regulates lipid and glucose metabolism in vitro. Acta Pharmacol. Sin. 34, 1061-1069 (2013).
57. Guo H, Zhao H, Kanno Y et al. A dihydrochalcone and several homoisoflavonoids from Polygonatum odoratum are activators of adenosine monophosphate-Activated protein kinase. Bioorg. Med. Chem. Lett. 23, 3137-3139 (2013).
58. Singhal SS, Figarola J, Singhal J et al. 1, 3-bis(3,5-dichlorophenyl) urea compound 'COH-SR4' inhibits proliferation and activates apoptosis in melanoma. Biochem. Pharmacol. 84, 1419-1427 (2012).
59. Figarola J, Rahbar S. Small molecule COH-SR4 inhibits adipocyte differentiation via AMPK activation. Int. J. Mol. Med. 31, 1166-1176 (2013).
60. Lian Z, Li Y, Gao J et al. A novel AMPK activator, WS070117, improves lipid metabolism discords in hamsters and HepG2 cells. Lipids Health Dis. 10, 67 (2011).
61. Oh S, Kim SJ, Hwang JH et al. Effects of ampkinone (6f ), a novel small molecule activator of amp-Activated protein kinase. J. Med. Chem. 53, 7405-7413 (2010).
62. Shen S, Zhuang J, Chen Y et al. Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK Bioorg. Med. Chem. 21, 3882-3893 (2013).
63. Tripodi F, Pagliarin R, Fumagalli G et al. Synthesis and biological evaluation of 1,4-diaryl-2-Azetidinones as specific anticancer agents: Activation of adenosine monophosphate activated protein kinase and induction of apoptosis. J. Med. Chem. 55, 2112-2124 (2012)
64. Sviripa V, Zhang W, Conroy MD et al. Fluorinated N, N-diarylureas as AMPK activators. Bioorg. Med. Chem. Lett. 23, 1600-1603 (2013)
65. Chen D, Pamu S, Cui Q et al. Novel epigallocatechin gallate (EGCG) analogs activate AMP-Activated protein kinase pathway and target cancer stem cells. Bioorg. Med. Chem. 20, 3031-3037 (2012).
66. Shieh JM, Chen YH, Lin YC et al. Demethoxycurcumin inhibits energy metabolic and oncogenic signaling pathways through AMPK activation in triple-negative breast cancer cells. J. Agric. Food Chem. 61, 6366-6375 (2013).
67. Kim JH, Lee JO, Lee SK et al. Celastrol suppresses breast cancer MCF-7 cell viability via the AMP-Activated protein kinase (AMPK)-induced p53-polo like kinase 2 (PLK-2) pathway. Cell. Signal. 25, 805-813 (2013).
68. Wang B, Wang XB, Chen LY et al. Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis. Biochem. Biophys. Res. Commun. 437, 1-6 (2013).
69. He XY, Liu XJ, Chen X et al. Gambogic acid induces EGFR degradation and Akt/mTORC1 inhibitionthrough AMPK dependent-LRIG1 upregulation in cultured U87 glioma cells. Biochem. Biophys. Res. Commun. 435, 397-402 (2013).
70. Ding D, Zhang B, Meng T et al. Novel synthetic baicalein derivatives caused apoptosis and activated AMP-Activated protein kinase in human tumor cells. Org. Biomol. Chem. 9, 7287-7291 (2011).
71. Lu J, Wu D-M, Zheng Y-L et al. Quercetin activates AMP-Activated protein kinase by reducing PP2C expression protecting old mouse brain against high cholesterol-induced neurotoxicity. J. Pathol. 222, 199-212 (2010).
72. Daniel B, Green O, Viskind O et al. Riluzole increases the rate of glucose transport in L6 myotubes and NSC-34motor neuron-like cells via AMPK pathway activation. Amyotroph. Lateral. Scler. Frontotemporal Degener. 14, 434-443 (2013).
73. Weisova P, Alvarez SP, Kilbride SM et al. Latrepirdine is a potent activator of AMP-Activated protein kinase and reduces neuronal excitability. Transl. Psychiatry 3, e317 (2013)
74. Xie L, Li W, Winters A et al. Methylene blue induces macroautophagy through 5′-Adenosine monophosphate activated protein kinase pathway to protect neurons from serum deprivation. Front. Cell. Neurosci. 7, 56 (2013).
75. Jang DH, Nelson LS, Hoffman RS. Methylene blue for distributive shock: A potential new use of an old antidote. J. Med. Toxicol. 9, 242-249.(2013).
76. Vingtdeux V, Chandakkar P, Zhao H et al. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-peptide degradation. FASEB J. 25, 219-231 (2011).
77. Vingtdeux V, Chandakkar P, Zhao H et al. Small-molecule activators of AMP-Activated protein kinase (AMPK), RSVA314 and RSVA405, inhibit adipogenesis. Mol. Med. 17, 1022-1030 (2011).
78. Nguyen PH, Le TV, Kang HW et al. Protective effect of nectandrin B, a potent AMPK activator on neointima formation: Inhibition of Pin1 expression through AMPK activation. Br. J. Pharmacol. 168, 932-945 (2013).
79. Song CY, Shi J, Zeng X et al. Sophocarpine alleviates hepatocyte steatosis through activating AMPK signaling pathway. Toxicol. In Vitro 27, 1065-1071 (2013).
80. Guh JH, Chang WL, Yang J et al. Development of novel adenosine monophosphate-Activated protein kinase activators. J. Med. Chem. 53, 2552-2561 (2010)
81. Filipov S, Pinkosky SL, Lister RJ et al. ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK. J. Lipid Res. 54, 2095-2108 (2013).
82. Ballantyne CM, Davidson M, MacDougall M et al. ETC-1002 lowers LDL-C and beneficially modulates other cardio-metabolic risk factors in hypercholesterolemic subjects with either normal or elevated triglycerides. J. Am. Coll. Cardiol. 59, E1625-E1625 (2012).
83. Park SH, Huh TL, Kim SY et al. Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): A randomized, double-blind, placebo-controlled trial. Obesity 22, 63-71 (2014).
84. Han R. Highlight on the studies of anticancer drugs derived from plants in China. Stem Cells 12, 53-63 (1994).
85. Pakrashi A, Pakrasi P. Biological profile of p-coumaric acid isolated from Aristolochia indica Linn. Indian J. Exp. Biol. 16, 1285-1287 (1978).
86. Quinde-Axtell Z, Baik BK. Phenolic compounds of barley grain and their implication in food product discoloration. J. Agric. Food Chem. 54, 9978-9984 (2006).
87. Stojkovic D, Petrovic J, Sokovic M et al. In situ antioxidant and antimicrobial activities of naturally occurring caffeic acid, p-coumaric acid and rutin, using food systems. J. Sci. Food Agric. 93, 3205-3208 (2013).
88. Gomez-Zorita S, Tréguer K, Mercader J et al. Resveratrol directly affects in vitro lipolysis and glucose transport in human fat cells. J. Physiol. Biochem. 69, 585-593 (2013).
89. Ferguson L, Zhu S, Harris P. Antioxidant and antigenetic effects of plant cell wall hydroxyl cinnamic acid in cultured HT-29 cells. Mol. Nutr. Food Res. 49, 585-593 (2005).
90. Roy AJ, Prince SM. Preventive effects of p-coumaric acid on lysosomal dysfunction and myocardial infarct size in experimentally induced myocardial infarction. Eur. J. Pharm. 699, 33-39 (2013).
91. An SM, Lee SI, Choi SW et al. p-coumaric acid, a constituent of Sasa quelpaertensis Nakai, inhibits cellular melanogenesis stimulated by alpha-melanocyte stimulating hormone. Br. J. Dermatol. 159, 292-299 (2008).
92. Lee SI, An SM, Mun GI et al. Protective effect of Sasa quelpaertensis and p-coumaric acid on ethanol-induced hepatotoxicity in mice. J. Appl. Biol. Chem. 51, 148-154 (2008).
93. Leiherer A, Mündlein A, Drexel H. Phytochemicals and their impact on adipose tissue inflammation and diabetes. Vascul. Pharmacol. 58, 3-20 (2013).
94. Chakraborty D, Mukherjee A, Sikdar S et al. [6]-Gingerol isolated from ginger attenuates sodium arsenite induced oxidative stress and plays a corrective role in improving insulin signaling in mice. Toxicol. Lett. 210, 34-43 (2012).
95. Li Y, Tran VH, Duke CC et al. Gingerols of Zingiber officinale enhance glucose uptake by increasing cell surface GLUT4 in cultured L6 myotubes. Planta Med. 78, 1549-1555 (2012).
96. Li Y, Tran VH, Koolaji N et al. (S)-[6]-Gingerol enhances glucose uptake in L6 myotubes by activation of AMPK in response to [Ca2+] J. Pharm. Pharm. Sci. 16, 304-312, (2013).
97. Mullauer FB, Kessler JH, Medema JP. Betulinic acid, a natural compound with potent anticancer effects. Anticancer Drugs 21, 215-27 (2010).
98. Fulda S, Scaffidi C, Susin SA et al. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J. Biol. Chem. 273, 33942-33948 (1998).
99. Fulda S, Kroemer G. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov. Today 14, 885-890 (2009).
100. Viollet B, Guigas B, Leclerc J et al. AMP-Activated protein kinase in the regulation of hepatic energy metabolism: From physiology to therapeutic perspectives. Acta Physiol. 196, 81-98 (2009).
101. Mosqueda-Garcia R. Adenosine as a therapeutic agent. Clin. Invest. Med. 15, 445-455 (1992).
102. Labuzek K, Liber S, Gabryel B et al. Metformin has adenosine- monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures. Pharmacol. Rep. 62, 827-848 (2010)
103. Ben Sahra I, Regazzetti C, Robert G et al Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1 Cancer Res. 71, 4366-4372 (2011).
104. Ouyang J, Parakhia RA, Ochs RS. Metformin activates AMP kinase through inhibition of AMP deaminase. J. Biol. Chem. 286, 1-11 (2011).
105. Kola B. Role of AMP-Activated protein kinase in the control of appetite. J. Neuroendocrinol. 20, 942-951 (2008).
106. Fu A, Eberhard CE, Screaton RA. Role of AMPK in pancreatic beta cell function. Mol. Cell Endocrinol. 366, 127-134 (2013).
107. Evans JM, Donnelly LA, Emslie-Smith AM et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 330(7503), 1304-1305 (2005).
108. Liang J, Gordon B, Mills GB. AMPK: A contextual oncogene or tumor suppressor? Cancer Res. 73, 2929-2935 (2013).
109. Dunlop EA, Tee AR. The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis. Biochem Soc Trans. 41, 939-943 (2013).
110. Lee CW, Wong LL, Tse EY et al. AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. Cancer Res. 72, 4394-4404 (2012).
111. Xu J, Ji J, Yan XH. Cross-Talk between AMPK and mTOR in regulating energy balance. Crit. Rev. Food Sci. Nutr. 52, 373-381 (2012).
112. Li C, Liu VW, Chiu PM et al. Over-expressions of AMPK subunits in ovarian carcinomas with significant clinical implications. BMC Cancer 12, 357 (2012).
113. Kato K, Ogura T, Kishimoto A et al. Critical roles of AMP-Activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene 21, 6082-6090 (2002).
114. Park HU, Suy S, Danner M et al. AMP-Activated protein kinase promotes human prostate cancer cell growth and survival. Mol. Cancer Ther. 8, 733-741 (2009).
115. Kim YH, Liang H, Liu X et al. AMPK alpha modulation in cancer progression: Multilayer integrative analysis of the whole transcriptome in Asian gastric cancer. Cancer Res. 72, 2512-2521 (2012).
116. Shackelford DB, Abt E, Gerken L et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143-58 (2013).
117. Faubert B, Vincent EE, Poffenberger NC et al. The AMP-Activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer Lett. doi:10.1016/j. canlet.2014.01.018 (2014) (Epub ahead of print).
118. Lettieri BD, Vegliante R, Desideri E et al. Managing lipid metabolism in proliferating cells: New perspective for metformin usage in cancer therapy. Biochim. Biophys. Acta 1845(2), 317-324 (2014).
119. Faubert B, Boily G, Izreig S et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 17, 113-24 (2012).
120. Banik BK, Banik I, Becker FF. Novel anticancer-lactams. Top. Heterocycl. Chem. 22, 349-373 (2010).
121. Smith DM, Kazi A, Smith L et al. A novel beta-lactam antibiotic activates tumor cell apoptotic program by inducing DNA damage. Mol. Pharmacol. 61, 1348-1358 (2002).
122. Wu CL, Qiang L, Han W et al. Role of AMPK in UVB-induced DNA damage repair and growth control. Oncogene 32, 2682-2689 (2013).
123. McKeown E, Nelson DW, Johnson EK et al. Current approaches and challenges for monitoring treatment response in colon and rectal cancer. J. Cancer 5, 31-43 (2014).
124. Shirakami Y, Shimizu M, Moriwaki H. Cancer chemoprevention with green tea catechins: From bench to bed. Curr. Drug Targets 13, 1842-1857 (2012).
125. Lee JH, Won YS, Park KH et al. Celastrol inhibits growth and induces apoptotic cell deathin melanoma cells via the activation ROS-dependent mitochondrial pathway and the suppression of PI3K/AKT signaling. Apoptosis 17, 1275-1286 (2012).
126. Madhunapantula SV, Mosca PJ, Robertson GP. The Akt signaling pathway: An emerging therapeutic target in malignant melanoma. Cancer Biol. Ther. 12, 1032-1049 (2011).
127. Tozawa K, Sagawa M, Kizaki M. Quinone methide tripterine, celastrol, induces apoptosis in human myeloma cells via NF-?B pathway. Int. J. Oncol. 39, 1117-1122 (2011).
128. Aggarwal B, Prasad S, Sung B et al. Prevention and treatment of colorectal cancer by natural agents from mother nature. Curr. Colorectal Cancer Rep. 9, 37-56 (2013).
129. O'Toole SA, Beith JM, Millar EK et al. Therapeutic targets in triple negative breast cancer. J. Clin. Pathol. 66, 530-542 (2013).
130. Arendos M, Bihan C, Delaloge S et al. Triple-negative breast cancer: Are we making headway at least? Ther. Adv. Med. Oncol. 4, 195-210 (2012).
131. Ajibade AA, Wang HY, Wang RF. Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol. 34, 307-316 (2013).
132. Nagpal K, Singh SK, Mishra DN. Drug targeting to brain: A systematic approach to study the factors, parameters and approaches for prediction of permeability of drugs across BBB. Expert Opin. Drug Deliv. 10, 927-955 (2013).
133. Liu X, Chhipa RR, Pooya S et al. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc. Natl Acad. Sci. USA 111, E435-E444 (2014).
134. Dienel DA, Hertz L. Glucose and lactate metabolism during brain activation. J. Neurosci. Res. 66, 824-838 (2001).
135. Culmsee C, Monnig J, Kemp BE et al. AMP-Activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J. Mol. Neurosci. 17, 45-58 (2001).
136. Gadalla AE, Pearson T, Currie AJ et al. AICA riboside both activates AMP-Activated protein kinase and competes with adenosine for the nucleoside transporter in the CA1 region of the rat hippocampus. J. Neurochem. 88, 1272-1282 (2004).
137. McCullough LD, Zeng Z, Li H et al. Pharmacological inhibition of AMP-Activated protein kinase provides neuroprotection in stroke. J. Biol. Chem. 280, 20493-20502 (2005).
138. Ramamurthy S, Ronnett G. AMP-Activated protein kinase (AMPK) and energy-sensing in the brain. Exp. Neurobiol. 21, 52-60 (2012).
139. Spasic MR, Callaerts P, Norga KK. AMP-Activated protein kinase (AMPK) molecular crossroad for metabolic control and survival of neurons. Neuroscientist 15, 309-316 (2009).
140. Hageman SA, Ellis TK, Fu LJ et al. Trans-(-)-viniferin increases mitochondrial Sirtuin 3 (SIRT3), activates AMP-Activated protein kinase (AMPK), and protects cells in models of Huntington disease. J. Biol. Chem. 287, 24460-24472 (2012).
141. Vingtdeux V, Davies P, Dickson DW et al. AMPK is abnormally activated in tangle-And pre-Tangle-bearing neurons in Alzheimer's disease and other tauopathies. Acta Neuropathol. 121, 337-349 (2011).
142. Morentin PB, Gonzalez CR, Lopez M. AMP-Activated protein kinase: 'a cup of tea' against cholesterol-induced neurotoxicity. J. Pathol. 222, 329-334 (2010).
143. Zhu K, Chen X, Liu J et al. AMPK interacts with DSCAM and plays an important role in Netrin-1 induced neurite outgrowth. Protein Cell 4, 155-161 (2013).
144. Kima J, Parka YL, Janga Y et al. AMPK activation inhibits apoptosis and tau hyperphosphorylation mediated by palmitate in SH-SY5Y cells. Brain Res. 1418, 42-51 (2011).
145. Paintlia AS, Paintlia MK, Mohan S et al. AMP-Activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model. Am. J. Pathol. 183, 526-541 (2013).
146. Choi IY, Ju C, Jalin A et al. Activation of cannabinoid CB2 receptore mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am. J. Pathol. 182, 928-939 (2013).
147. Kim SJ, Lee JH, Chung HS et al. Neuroprotective effects of AMP-Activated protein kinase on scopolamine induced memory impairment. Korean J. Physiol. Pharmacol. 17, 331-338 (2013).
148. Kwon KJ, Kim HJ, Shin CY et al. Melatonin potentiates the neuroprotective properties of Resveratrol against beta-Amyloid-induced neurodegeneration by modulating AMP-Activated protein kinase pathways. J. Clin. Neurol. 6, 127-137 (2010).
149. Ju TH, Chen HM, Lin JT et al. Nuclear translocation of AMPK-a1 potentiates striatal neurodegeneration in Huntington's disease. J. Cell Biol. 194, 209-227 (2011).
150. Cardaci S, Filomeni G, Ciriolo MR et al. Redox implications of AMPK-mediated signal transduction beyond energetic clues. J. Cell Sci. 125, 2115-2125 (2012).
151. Manwani B, McCullough LD. Function of the master energy regulator adenosine monophosphate-Activated protein kinase in stroke. J. Neurosci. Res. 91, 1018-1029 (2013).
152. Lee Y, Morrison BM, Li Y et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443-448 (2012).
153. Dajas F. Life or death: Neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol. 143, 383-396 (2012).
154. Ferry DR, Smith A, Malkhandi J et al. Phase I clinical trial of the flavonoid quercetin: Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin. Cancer Res.2, 659-668 (1996).
155. Cifra A, Mazzone GL, Nistri A. Riluzole: What it does to spinal and brainstem neurons and how it does it. Neuroscientist 19, 137-144 (2013).
156. Vannucci SJ, Reinhart R, Maher F et al. Alterations in GLUT1 and GLUT3 glucose transporter gene expression following unilateral hypoxia-ischaemia in the immature rat brain. Brain Res. Dev. Brain Res. 107, 255-264 (1998).
157. Delgado-Esteban M, Almeida A, Bolaños JP. D-glucose prevents glutathione oxidation and mitochondrial damage after glutamate receptor stimulation in rat cortical primary neurons. J. Neurochem. 75, 1618-1624 (2000).
158. Vergun O, Han YY, Reynolds IJ. Glucose deprivation produces a prolonged increase in sensitivity to glutamate in cultured rat cortical neurons. Exp. Neurol. 183, 682-694 (2003).
159. Lu DY, Huang BR, Yeh WL et al. Anti-neuroinflammatory effect of a novel caffeamide derivative, KS370G, in microglial cells. Mol. Neurobiol. 48, 863-874 (2013).
160. Benarroch EE. Microglia: Multiple roles in surveillance, circuit shaping, and response to injury. Neurology 81, 1079-1088 (2013).
161. Pallàs M, Camins A. Molecular and biochemical features in Alzheimer's disease. Curr. Pharm. Des. 12, 4389-4408 (2006).
162. Culmsee C, Monnig J, Kemp BE et al. AMP-Activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J. Mol. Neurosci. 17, 45-58 (2001).
163. Dagon Y, Avraham Y, Magen I et al. Nutritional status, cognition, and survival: A new role for leptin and AMP kinase. J. Biol. Chem. 280, 42142-42148 (2005).
164. Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl Acad. Sci. USA 104, 7217-7222 (2007).
165. Capiralla H, Vingtdeux V, Zhao H et al. Resveratrol mitigates lipopolysaccharide-And Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-?B/STAT signaling cascade. J. Neurochem. 120, 461-472 (2012).
166. Davies P. A very incomplete comprehensive theory of Alzheimer's disease. Ann. NY Acad. Sci. 924, 8-16 (2000).
167. Racioppi L, Means AR. Calcium/calmoduli-dependent protein kinase kinase 2: Roles in signaling and pathophysiology. J. Biol. Chem. 287, 31658-31665 (2012).
168. Nguyen PH, Le TV, Kang HW et al. AMP-Activated protein kinase (AMPK) activators from Myristica fragrans (nutmeg) and their anti-obesity effect. Bioorg. Med. Chem. Lett. 20, 4128-4131 (2010).
169. Hien TT, Ki SH, Yang JW et al. Nectandrin B suppresses the expression of adhesion molecules in endothelial cells: Role of AMP-Activated protein kinase activation. Food Chem. Toxicol. 66, 286-294 (2014).
170. Silvestre-Roig C, Fernández P, Esteban V et al. Inactivation of nuclear factor-Y inhibits vascular smooth muscle cell proliferation and neointima formation. Arterioscler. Thromb. Vasc. Biol. 33, 1036-1045 (2013).
171. Lihn AS, Pedersen SB, Lund S et al. The antidiabetic AMPK activator AICAR reduces IL-6 and IL-8 in human adipose tissue and skeletal muscle cells. Mol. Cell. Endocrinol. 292, 36-41 (2008).
172. Sag D, Carling D, Stout RD et al. Adenosine 5'-monophosphate-Activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181, 8633-8641 (2008).
173. Yang D, Xue B, Wang X et al. 2-octynoic acid inhibits hepatitis C virus infection through activation of AMP-Activated protein kinase. PLoS ONE 8, e64932 (2013).
174. Zhang Y, Wang Y, Bao C et al. Metformin interacts with AMPK through binding to subunit. Mol. Cell Biochem. 368, 69-76 (2012).
175. Wang Z, Wang X, Qu K et al. Binding of cordycepin monophosphate to AMP-Activated protein kinase and its effect on AMP-Activated protein kinase activation. Chem. Biol. Drug Des. 76, 340-344 (2010).
176. Hawley SA, Fullerton MD, Ross FA et al. The ancient drug salicylate directly activates AMP-Activated protein kinase. Science 336, 918-922 (2012).
177. Cool B, Zinker B, Chiou W et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403-416 (2006).
178. Treebak JT, Birk JB, Hansen BF et al. A-769662 activates AMPK 1-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle. Am. J. Physiol. Cell Physiol. 297, C1041-C1052 (2009).
179. Liu Y, Oh SG, Chang KH et al. Antiplatelet effect of AMP-Activated protein kinase activator and its potentiation by the phosphodiesterase inhibitor dipyridamole. Biochem. Pharmacol. 86, 914-925 (2013).
180. Pang T, Zhang ZS, Gu M et al. Small molecule antagonizes autoinhibition and activates AMP-Activated protein kinase in cells. J. Biol. Chem. 283, 16051-1660 (2008).
181. Meltzer-Mats E, Babai G, Pasternak L et al. Synthesis and mechanism of anti-hyperglycemic activity of benzothiazole derivatives. J. Med. Chem. 56, 5335-5350 (2013)
182. Yu LF, Li YY, Su MB et al. Development of novel alkene oxindole derivatives as orally efficacious AMP-Activated Protein Kinase activators. ACS Med. Chem. Lett. 4, 475-480 (2013).
183. Mirguet O, Sautet S, Clément CA et al. Discovery of pyridones as oral AMPK direct activators. ACS Med. Chem. Lett. 4, 632-636 (2013).
184. Gomez-Galeno GE, Dang Q, Nguyen TH et al. A potent and selective AMPK activator that inhibits de novo lipogenesis. ACS Med. Chem. Lett. 1, 478-482 (2010).
185. Choi J, He N, Sung MK et al. Sanguinarine is an allosteric activator of AMP-Activated protein kinase. Biochem. Biophys. Res. Comm. 413, 259-263 (2011).
186. Paterson RR. Cordyceps: A traditional Chinese medicine and another fungal therapeutic biofactory? Phytochemistry 69, 1469-1495 (2008).
187. Tuli HS, Sharma AK, Sandhu SS et al. Cordycepin: A bioactive metabolite with therapeutic potential. Life Sci. 93, 863-869 (2013).
188. Alpert E, Gruzman A, Tennenbaum T et al. Selective cyclooxygenase-2 inhibitors stimulate glucose transport in L6 myotubes in a protein kinase C-dependent manner. Biochem. Pharmacol. 73, 368-377 (2007).
189. Fleischman A, Shoelson SE, Bernier R et al. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31, 289-294 (2008).
190. Goldfine AB, Fonseca V, Jablonski KA et al. The effects of salsalate on glycemic control in patients with type 2 diabetes: A randomized trial. Ann. Intern. Med. 152, 346-357 (2010).
191. Xiao B, Sanders MJ, Carmena D et al. Structural basis of AMPK regulation by small molecule activators. Nat. Commun. 4, 3017 (2013).
192. Foukas LC, Withers DJ. Phosphoinositide signaling pathways in metabolic regulation. Curr. Top Microbiol. Immunol. 346, 115-141 (2013).
193. Kim AS, Miller EJ, Wright TM et al. A small molecule AMPK activator protects the heart against ischemia-reperfusion injury. J. Mol. Cell. Cardiol. 51, 24-32 (2011).
194. Chen L, Jiao ZH, Zheng LS et al. Structural insight into the autoinhibition mechanism of AMP-Activated protein kinase. Nature 459, 1146-1149 (2009).
195. Pang T, Xiong B, Li JY et al. Conserved alpha-helix acts as autoinhibitory sequence in AMP-Activated protein kinase alpha subunits. J. Biol. Chem. 282, 495-506 (2007).
196. Mackraj I, Govender T, Gathiram P. Sanguinarine. Cardiovasc. Ther. 26, 75-83 (2008).