295
Views
0
CrossRef citations to date
0
Altmetric
Review

Activators of AMPK: Not Just for Type II Diabetes

, &
Pages 1325-1353 | Published online: 27 Aug 2014

References

  • Hardie DG . AMPK: a target for drugs and natural products with effects on both diabetes and cancer. Diabetes62, 2164–2172 (2013).
  • Stark R , AshleySE, AndrewsZB. AMPK and the neuroendocrine regulation of appetite and energy expenditure. Mol. Cell Endocrinol.366, 215–223 (2013).
  • Hardie DG , RossFA, HawleySA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol.22, 251–262 (2012).
  • Gruzman A , BabaiG, SassonS. 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).
  • Sinnett SE , BrenmanJE. Past strategies and future directions for identifying AMP-activated protein kinase (AMPK) modulators. Pharmacol. Ther.143, 111–118 (2014).
  • Davies SP , HawleySA, WoodsAet 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).
  • Beri RK , MarleyAE, SeeCGet al. Molecular cloning, expression and chromosomal localisation of human AMP-activated protein kinase. FEBS Lett.356, 117–21 (1994).
  • Stephenne X , ForetzM, TaleuxNet al. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia54, 3101–3110 (2011).
  • Wu J , PuppalaD, FengXet al. Chemoproteomic analysis of intertissue and interspecies isoform diversity of AMP-activated protein kinase (AMPK). J. Biol. Chem.288, 35904–35912 (2013).
  • Xiao B , SandersMJ, UnderwoodEet al. Structure of mammalian AMPK and its regulation by ADP. Nature472, 230–233 (2011).
  • Protein Data Bank Japan . http://service.pdbj.org/mine/Search?position=1&resultSize=16&query=human+AMPK
  • Day P , SharffA, ParraLet 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).
  • Handa N , TakagiT, SaijoSet al. Structural basis for compound C inhibition of the human AMP-activated protein kinase α2 subunit kinase domain. Acta Crystallogr. D. Biol. Crystallogr.67, 480–487 (2011).
  • Littler DR , WalkerJR, DavisTet 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)
  • Iseli TJ , WalterM, van DenderenBJet 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).
  • Wang ZL , HuoJX, SunLDet al. Computer-aided drug design for AMP-activated protein kinase activators. Curr. Comput. Aided Drug Des.7, 214–227 (2011)
  • Russo GL , RussoM, UngaroP. AMP-activated protein kinase: A target for old drugs against diabetes and cancer. Biochem. Pharmacol.86, 339–350 (2013).
  • Dandapani M , HardieDG. AMPK: opposing the metabolic changes in both tumor cells and inflammatory cells?Biochem. Soc. Trans.41, 687–693 (2013).
  • Hardie DG , SaltIP, HawleySAet al. AMP activated protein kinase: an ultrasensitive system for monitoring cellular energy charge. Biochem. J.338, 717–722 (1999).
  • Hawley SA , DavisonM, WoodsAet 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).
  • Park S , SchefflerTL, RossieSSet al. AMPK activity is regulated by calcium-mediated protein phosphatase 2A activity. Cell Calcium.53, 217–223 (2013).
  • Kottakis F , BardeesyN. LKB1–AMPK axis revisited. Cell Res.22, 1617–1620 (2012).
  • Suter M , RiekU, TuerkRet 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).
  • Peng C , Head-GordonT. The dynamical mechanism of auto-inhibition of AMP-activated protein kinase. PLoS Comput. Biol.7, e1002082 (2011).
  • Sanchez AM , CandauRB, CsibiAet 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).
  • Scheffler TL , SchefflerJM, ParkSet al. Fiber hypertrophy and increased oxidative capacity can occur simultaneously in pig glycolytic skeletal muscle. Am. J. Physiol. Cell Physiol.306, C354–363 (2014).
  • Tanner CB , MadsenSR, HallowellDMet al. Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1 Am. J. Physiol. Endocrinol. Metab. 305, 1018–29 (2013).
  • Richter EA , HargreavesM. Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol. Rev.93, 993–1017 (2013).
  • Friedrichsen M , MortensenB, Pehm⊘llerCet al. Exercise-induced AMPK activity in skeletal muscle: role in glucose uptake and insulin sensitivity. Mol. Cell Endocrinol.366, 204–214 (2013).
  • Mu J, T. BrozinickJ, ValladaresOet al. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscles. Mol. Cell, 7, 1085–1094  (2001).
  • Lefort N , St.-AmandE, MorasseSet al. The α-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).
  • Fujii N , HirshmanM, KaneEet 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).
  • Bijland S , ManciniSJ, SaltIP. Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin. Sci. (Lond.)124, 491–507 (2013).
  • Daval M , FoufelleF, FerreP. Functions of AMP-activated protein kinase in adipose tissue. J. Physiol.574, 55–62 (2006).
  • Dzamko NL , SteinbergGR. AMPK-dependent hormonal regulation of whole-body energy metabolism. Acta Physiol. (Oxf.)196, 115–27 (2009).
  • Lustig Y , HemiR, KanetyH. Regulation and function of adiponectin receptors in skeletal muscle. Vitam. Horm.90, 95–123 (2012).
  • Hasenour CM , BerglundED, WassermanDH. Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver. Mol. Cell Endocrinol.366, 152–162 (2013).
  • Miller R , ChuO, XieJet al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature494, 256–261 (2013).
  • Miller RA , BirnbaumMJ. An energetic tale of AMPK-independent effects of metformin. J. Clin. Invest.120, 2267–2269 (2010).
  • Jenkins Y , SunT, MarkovtsovVet al. AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes. PLoS ONE8, e81870 (2013).
  • Edgerton DS , JohnsonKM, CherringtonAD. Current strategies for the inhibition of hepatic glucose production in type 2 diabetes. Front. Biosci.14, 1169–1181 (2009).
  • Foretz M , HébrardS, LeclercJet 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).
  • Pfeifer A , KilićA, HoffmannLS. Regulation of metabolism by cGMP. Pharmacol. Ther.140, 81–91 (2013).
  • Viollet B , MounierR, LeclercJet al. Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab.33, 395–402 (2007).
  • Hawley SA , RossFA, ChevtzoffCet al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab.11, 554–565 (2010).
  • Guigas B , BertrandL, TaleuxNet 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. Diabetes55, 865–874 (2006).
  • Farghali H , Kutinová CanováN, LekićN. Resveratrol and related compounds as antioxidants with an allosteric mechanism of action in epigenetic drug targets. Physiol. Res.62, 1–13 (2013).
  • Nguyen PH , GauharR, HwangSLet al. New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum Bioorg. Med. Chem. 19, 6254–6260 (2011).
  • Quan HY , KimDY, KimSJet 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).
  • Guo H , LiuG, ZhongRet 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).
  • He Y , LiY, ZhaoTet al. Ursolic acid inhibits adipogenesis in 3T3-L1 adipocytes through LKB1/AMPK pathway. PLoS ONE8, e70135, (2013).
  • Pu P , WangXA, SalimMet al. Baicalein, a natural product, selectively activating AMPKa2 and ameliorates metabolic disorder in diet-induced mice. Mol. Cell Endocrinol.362, 128–138 (2012).
  • Yoon SA , KangSI, ShinHSet 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).
  • Kubra IR , RaoLJ. An impression on current developments in the technology, chemistry, and biological activities of ginger. Crit. Rev. Food Sci. Nutr.52, 651–88 (2012).
  • Quan HY , KimSJ, KimDYet al. Licochalcone A regulates hepatic lipid metabolism through activation of AMP-activated protein kinase. Fitoterapia86, 208–216 (2013).
  • Zhou R . WangL. XuXet al. Danthron activates AMP-activated protein kinase and regulates lipid and glucose metabolism in vitro. Acta Pharmacol. Sin.34, 1061–1069 (2013).
  • Guo H , ZhaoH, KannoYet 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).
  • Singhal SS , FigarolaJ, SinghalJet al. 1, 3-bis(3,5-dichlorophenyl) urea compound ‘COH-SR4’ inhibits proliferation and activates apoptosis in melanoma. Biochem. Pharmacol.84, 1419–1427 (2012).
  • Figarola J , RahbarS. Small molecule COH-SR4 inhibits adipocyte differentiation via AMPK activation. Int. J. Mol. Med.31, 1166–1176 (2013).
  • Lian Z , LiY, GaoJet al. A novel AMPK activator, WS070117, improves lipid metabolism discords in hamsters and HepG2 cells. Lipids Health Dis.10, 67 (2011).
  • Oh S , KimSJ, HwangJHet al. Effects of ampkinone (6f), a novel small molecule activator of amp-activated protein kinase. J. Med. Chem.53, 7405–7413 (2010).
  • Shen S , ZhuangJ, ChenYet al. Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK Bioorg. Med. Chem.21, 3882–3893 (2013).
  • Tripodi F , PagliarinR, FumagalliGet 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)
  • Sviripa V , ZhangW, ConroyMDet al. Fluorinated N, N-diarylureas as AMPK activators. Bioorg. Med. Chem. Lett.23, 1600–1603 (2013)
  • Chen D , PamuS, CuiQet al. Novel epigallocatechin gallate (EGCG) analogs activate AMP-activated protein kinase pathway and target cancer stem cells. Bioorg. Med. Chem.20, 3031–3037 (2012).
  • Shieh JM , ChenYH, LinYCet 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).
  • Kim JH , LeeJO, LeeSKet 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).
  • Wang B , WangXB, ChenLYet 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).
  • He XY , LiuXJ, ChenXet 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).
  • Ding D , ZhangB, MengTet al. Novel synthetic baicalein derivatives caused apoptosis and activated AMP-activated protein kinase in human tumor cells. Org. Biomol. Chem.9, 7287–7291 (2011).
  • Lu J , WuD-M, ZhengY-Let 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).
  • Daniel B , GreenO, ViskindOet 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).
  • Weisova P , AlvarezSP, KilbrideSMet al. Latrepirdine is a potent activator of AMP-activated protein kinase and reduces neuronal excitability. Transl. Psychiatry3, e317 (2013)
  • Xie L , LiW, WintersAet 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).
  • Jang DH , NelsonLS, HoffmanRS. Methylene blue for distributive shock: a potential new use of an old antidote. J. Med. Toxicol.9, 242–249 .(2013).
  • Vingtdeux V , ChandakkarP, ZhaoHet al. Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid- peptide degradation. FASEB J.25, 219–231 (2011).
  • Vingtdeux V , ChandakkarP, ZhaoHet al. Small-molecule activators of AMP- activated protein kinase (AMPK), RSVA314 and RSVA405, inhibit adipogenesis. Mol. Med.17, 1022–1030 (2011).
  • Nguyen PH , LeTV, KangHWet 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).
  • Song CY , ShiJ, ZengXet al. Sophocarpine alleviates hepatocyte steatosis through activating AMPK signaling pathway. Toxicol. In Vitro27, 1065–1071 (2013).
  • Guh JH , ChangWL, YangJet al. Development of novel adenosine monophosphate-activated protein kinase activators. J. Med. Chem.53, 2552–2561 (2010)
  • Filipov S , PinkoskySL, ListerRJet 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).
  • Ballantyne CM , DavidsonM, MacDougallMet 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).
  • Park SH , HuhTL, KimSYet al. Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial. Obesity22, 63–71 (2014).
  • Han R . Highlight on the studies of anticancer drugs derived from plants in China. Stem Cells12, 53–63 (1994).
  • Pakrashi A , PakrasiP. Biological profile of p-coumaric acid isolated from Aristolochia indica Linn. Indian J. Exp. Biol.16, 1285–1287 (1978).
  • Quinde-Axtell Z , BaikBK. Phenolic compounds of barley grain and their implication in food product discoloration. J. Agric. Food Chem.54, 9978–9984 (2006).
  • Stojkovic D , PetrovicJ, SokovicMet 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).
  • Gomez-Zorita S , TréguerK, MercaderJet al. Resveratrol directly affects in vitro lipolysis and glucose transport in human fat cells. J. Physiol. Biochem.69, 585–593 (2013).
  • Ferguson L , ZhuS, HarrisP. Antioxidant and antigenetic effects of plant cell wall hydroxyl cinnamic acid in cultured HT-29 cells. Mol. Nutr. Food Res.49, 585–593 (2005).
  • Roy AJ , PrinceSM. 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).
  • An SM , LeeSI, ChoiSWet 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).
  • Lee SI , AnSM, MunGIet al. Protective effect of Sasa quelpaertensis and p-coumaric acid on ethanol-induced hepatotoxicity in mice. J. Appl. Biol. Chem.51, 148–154 (2008).
  • Leiherer A , MündleinA, DrexelH. Phytochemicals and their impact on adipose tissue inflammation and diabetes. Vascul. Pharmacol.58, 3–20 (2013).
  • Chakraborty D , MukherjeeA, SikdarSet 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).
  • Li Y , TranVH, DukeCCet al. Gingerols of Zingiber officinale enhance glucose uptake by increasing cell surface GLUT4 in cultured L6 myotubes. Planta Med.78, 1549–1555 (2012).
  • Li Y , TranVH, KoolajiNet 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).
  • Mullauer FB , KesslerJH, MedemaJP. Betulinic acid, a natural compound with potent anticancer effects. Anticancer Drugs21, 215–27 (2010).
  • Fulda S , ScaffidiC, SusinSAet al. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J. Biol. Chem.273, 33942–33948 (1998).
  • Fulda S , KroemerG. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov. Today14, 885–890 (2009).
  • Viollet B , GuigasB, LeclercJet al. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol.196, 81–98 (2009).
  • Mosqueda-Garcia R . Adenosine as a therapeutic agent. Clin. Invest. Med.15, 445–455 (1992).
  • Łabuzek K , LiberS, GabryelBet al. Metformin has adenosine-monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures. Pharmacol. Rep.62, 827–848 (2010)
  • Ben Sahra I , RegazzettiC, RobertGet al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1 Cancer Res. 71, 4366–4372  (2011).
  • Ouyang J , ParakhiaRA, OchsRS. Metformin activates AMP kinase through inhibition of AMP deaminase. J. Biol. Chem.286, 1–11 (2011).
  • Kola B . Role of AMP-activated protein kinase in the control of appetite. J. Neuroendocrinol.20, 942–951  (2008).
  • Fu A , EberhardCE, ScreatonRA. Role of AMPK in pancreatic beta cell function. Mol. Cell Endocrinol.366, 127–134 (2013).
  • Evans JM , DonnellyLA, Emslie-SmithAMet al. Metformin and reduced risk of cancer in diabetic patients. BMJ330 (7503), 1304–1305 (2005).
  • Liang J , GordonB, MillsGB. AMPK: a contextual oncogene or tumor suppressor?Cancer Res.73, 2929–2935 (2013).
  • Dunlop EA , TeeAR. The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis. Biochem Soc Trans.41, 939–943 (2013).
  • Lee CW , WongLL, TseEYet al. AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells. Cancer Res.72, 4394–4404 (2012).
  • Xu J , JiJ, YanXH. Cross-talk between AMPK and mTOR in regulating energy balance. Crit. Rev. Food Sci. Nutr.52, 373–381 (2012).
  • Li C , LiuVW, ChiuPMet al. Over-expressions of AMPK subunits in ovarian carcinomas with significant clinical implications. BMC Cancer12, 357 (2012).
  • Kato K , OguraT, KishimotoAet al. Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation. Oncogene21, 6082–6090 (2002).
  • Park HU , SuyS, DannerMet al. AMP-activated protein kinase promotes human prostate cancer cell growth and survival. Mol. Cancer Ther.8, 733–741 (2009).
  • Kim YH , LiangH, LiuXet al. AMPK alpha modulation in cancer progression: multilayer integrative analysis of the whole transcriptome in Asian gastric cancer. Cancer Res.72, 2512–2521 (2012).
  • Shackelford DB , AbtE, GerkenLet al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell23, 143–58  (2013).
  • Faubert B , VincentEE, PoffenbergerNCet 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).
  • Lettieri BD , VeglianteR, DesideriEet al. Managing lipid metabolism in proliferating cells: New perspective for metformin usage in cancer therapy. Biochim. Biophys. Acta1845 (2), 317–324 (2014).
  • Faubert B , BoilyG, IzreigSet al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab.17, 113–24 (2012).
  • Banik BK , BanikI, BeckerFF. Novel anticancer-lactams. Top. Heterocycl. Chem.22, 349–373 (2010).
  • Smith DM , KaziA, SmithLet al. A novel beta-lactam antibiotic activates tumor cell apoptotic program by inducing DNA damage. Mol. Pharmacol.61, 1348–1358  (2002).
  • Wu CL , QiangL, HanWet al. Role of AMPK in UVB-induced DNA damage repair and growth control. Oncogene32, 2682–2689 (2013).
  • McKeown E , NelsonDW, JohnsonEKet al. Current approaches and challenges for monitoring treatment response in colon and rectal cancer. J. Cancer5, 31–43 (2014).
  • Shirakami Y , ShimizuM, MoriwakiH. Cancer chemoprevention with green tea catechins: from bench to bed. Curr. Drug Targets13, 1842–1857 (2012).
  • Lee JH , WonYS, ParkKHet 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. Apoptosis17, 1275–1286 (2012).
  • Madhunapantula SV , MoscaPJ, RobertsonGP. The Akt signaling pathway: an emerging therapeutic target in malignant melanoma. Cancer Biol. Ther.12, 1032–1049 (2011).
  • Tozawa K , SagawaM, KizakiM. Quinone methide tripterine, celastrol, induces apoptosis in human myeloma cells via NF-κB pathway. Int. J. Oncol.39, 1117–1122 (2011).
  • Aggarwal B , PrasadS, SungBet al. Prevention and treatment of colorectal cancer by natural agents from mother nature. Curr. Colorectal Cancer Rep.9, 37–56 (2013).
  • O'Toole SA , BeithJM, MillarEKet al. Therapeutic targets in triple negative breast cancer. J. Clin. Pathol.66, 530–542 (2013).
  • Arendos M , BihanC, DelalogeSet al. Triple-negative breast cancer: are we making headway at least? Ther. Adv. Med. Oncol. 4, 195–210 (2012).
  • Ajibade AA , WangHY, WangRF. Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol.34, 307–316 (2013).
  • Nagpal K , SinghSK, MishraDN. 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).
  • Liu X , ChhipaRR, PooyaSet al. Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. Proc. Natl Acad. Sci. USA111, E435–E444 (2014).
  • Dienel DA , HertzL. Glucose and lactate metabolism during brain activation. J. Neurosci. Res.66, 824–838 (2001).
  • Culmsee C , MonnigJ, KempBEet 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).
  • Gadalla AE , PearsonT, CurrieAJet 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).
  • McCullough LD , ZengZ, LiHet al. Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke. J. Biol. Chem.280, 20493–20502 (2005).
  • Ramamurthy S , RonnettG. AMP-activated protein kinase (AMPK) and energy- sensing in the brain. Exp. Neurobiol.21, 52–60 (2012).
  • Spasic MR , CallaertsP, NorgaKK. AMP-activated protein kinase (AMPK) molecular crossroad for metabolic control and survival of neurons. Neuroscientist15, 309–316 (2009).
  • Hageman SA , EllisTK, FuLJet 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).
  • Vingtdeux V , DaviesP, DicksonDWet 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).
  • Morentin PB , GonzalezCR, LopezM. AMP-activated protein kinase: ‘a cup of tea’ against cholesterol-induced neurotoxicity. J. Pathol.222, 329–334 (2010).
  • Zhu K , ChenX, LiuJet al. AMPK interacts with DSCAM and plays an important role in Netrin-1 induced neurite outgrowth. Protein Cell4, 155–161 (2013).
  • Kima J , ParkaYL, JangaYet al. AMPK activation inhibits apoptosis and tau hyperphosphorylation mediated by palmitate in SH-SY5Y cells. Brain Res.1418, 42–51 (2011).
  • Paintlia AS , PaintliaMK, MohanSet 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).
  • Choi IY , JuC, JalinAet al. Activation of cannabinoid CB2 receptore mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am. J. Pathol.182, 928–939 (2013).
  • Kim SJ , LeeJH, ChungHSet al. Neuroprotective effects of AMP-activated protein kinase on scopolamine induced memory impairment. Korean J. Physiol. Pharmacol.17, 331–338 (2013).
  • Kwon KJ , KimHJ, ShinCYet 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).
  • Ju TH , ChenHM, LinJTet al. Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington's disease. J. Cell Biol.194, 209–227 (2011).
  • Cardaci S , FilomeniG, CirioloMRet al. Redox implications of AMPK-mediated signal transduction beyond energetic clues. J. Cell Sci.125, 2115–2125 (2012).
  • Manwani B , McCulloughLD. Function of the master energy regulator adenosine monophosphate-activated protein kinase in stroke. J. Neurosci. Res.91, 1018–1029 (2013)
  • Lee Y , MorrisonBM, LiYet al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature487, 443–448 (2012).
  • Dajas F . Life or death: Neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol.143, 383–396 (2012).
  • Ferry DR , SmithA, MalkhandiJet 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).
  • Cifra A , MazzoneGL, NistriA. Riluzole: what it does to spinal and brainstem neurons and how it does it. Neuroscientist19, 137–144 (2013).
  • Vannucci SJ , ReinhartR, MaherFet 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).
  • Delgado-Esteban M , AlmeidaA, BolañosJP. D-glucose prevents glutathione oxidation and mitochondrial damage after glutamate receptor stimulation in rat cortical primary neurons. J. Neurochem.75, 1618–1624 (2000).
  • Vergun O , HanYY, ReynoldsIJ. Glucose deprivation produces a prolonged increase in sensitivity to glutamate in cultured rat cortical neurons. Exp. Neurol.183, 682–694 (2003).
  • Lu DY , HuangBR, YehWLet al. Anti-neuroinflammatory effect of a novel caffeamide derivative, KS370G, in microglial cells. Mol. Neurobiol.48, 863–874 (2013).
  • Benarroch EE . Microglia: multiple roles in surveillance, circuit shaping, and response to injury. Neurology81, 1079–1088 (2013).
  • Pallàs M , CaminsA. Molecular and biochemical features in Alzheimer's disease. Curr. Pharm. Des.12, 4389–4408 (2006).
  • Culmsee C , MonnigJ, KempBEet 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).
  • Dagon Y , AvrahamY, MagenIet al. Nutritional status, cognition, and survival: a new role for leptin and AMP kinase. J. Biol. Chem.280, 42142–42148 (2005).
  • Dasgupta B , MilbrandtJ. Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl Acad. Sci. USA104, 7217–7222 (2007).
  • Capiralla H , VingtdeuxV, ZhaoHet al. Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade. J. Neurochem.120, 461–472 (2012).
  • Davies P . A very incomplete comprehensive theory of Alzheimer's disease. Ann. NY Acad. Sci.924, 8–16 (2000).
  • Racioppi L , MeansAR. Calcium/calmoduli-dependent protein kinase kinase 2: roles in signaling and pathophysiology. J. Biol. Chem.287, 31658–31665 (2012).
  • Nguyen PH , LeTV, KangHWet al. AMP-activated protein kinase (AMPK) activators from Myristica fragrans (nutmeg) and their anti-obesity effect. Bioorg. Med. Chem. Lett.20, 4128–4131 (2010).
  • Hien TT , KiSH, YangJWet 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).
  • Silvestre-Roig C , FernándezP, EstebanVet al. Inactivation of nuclear factor-Y inhibits vascular smooth muscle cell proliferation and neointima formation. Arterioscler. Thromb. Vasc. Biol.33, 1036–1045 (2013).
  • Lihn AS , PedersenSB, LundSet 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).
  • Sag D , CarlingD, StoutRDet al. Adenosine 5'-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol.181, 8633–8641 (2008).
  • Yang D , XueB, WangXet al. 2-octynoic acid inhibits hepatitis C virus infection through activation of AMP-activated protein kinase. PLoS ONE8, e64932 (2013).
  • Zhang Y , WangY, BaoCet al. Metformin interacts with AMPK through binding to subunit. Mol. Cell Biochem.368, 69–76 (2012).
  • Wang Z , WangX, QuKet 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).
  • Hawley SA , FullertonMD, RossFAet al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science336, 918–922 (2012).
  • Cool B , ZinkerB, ChiouWet 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).
  • Treebak JT , BirkJB, HansenBFet 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).
  • Liu Y , OhSG, ChangKHet al. Antiplatelet effect of AMP-activated protein kinase activator and its potentiation by the phosphodiesterase inhibitor dipyridamole. Biochem. Pharmacol.86, 914–925 (2013).
  • Pang T , ZhangZS, GuMet al. Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J. Biol. Chem.283, 16051–1660 (2008).
  • Meltzer-Mats E , BabaiG, PasternakLet al. Synthesis and mechanism of anti- hyperglycemic activity of benzothiazole derivatives. J. Med. Chem.56, 5335–5350 (2013)
  • Yu LF , LiYY, SuMBet al. Development of novel alkene oxindole derivatives as orally efficacious AMP-activated protein kinase activators. ACS Med. Chem. Lett.4, 475–480 (2013).
  • Mirguet O , SautetS, ClémentCAet al. Discovery of pyridones as oral AMPK direct activators. ACS Med. Chem. Lett.4, 632–636 (2013).
  • Gomez-Galeno GE , DangQ, NguyenTHet al. A potent and selective AMPK activator that inhibits de novo lipogenesis. ACS Med. Chem. Lett.1, 478–482 (2010).
  • Choi J , HeN, SungMKet al. Sanguinarine is an allosteric activator of AMP- activated protein kinase. Biochem. Biophys. Res. Comm.413, 259–263 (2011).
  • Paterson RR . Cordyceps: a traditional Chinese medicine and another fungal therapeutic biofactory?Phytochemistry69, 1469–1495 (2008).
  • Tuli HS , SharmaAK, SandhuSSet al. Cordycepin: a bioactive metabolite with therapeutic potential. Life Sci.93, 863–869 (2013).
  • Alpert E , GruzmanA, TennenbaumTet al. Selective cyclooxygenase-2 inhibitors stimulate glucose transport in L6 myotubes in a protein kinase C -dependent manner. Biochem. Pharmacol.73, 368–377 (2007).
  • Fleischman A , ShoelsonSE, BernierRet al. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care31, 289–294 (2008).
  • Goldfine AB , FonsecaV, JablonskiKAet al. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med.152, 346–357 (2010).
  • Xiao B , SandersMJ, CarmenaDet al. Structural basis of AMPK regulation by small molecule activators. Nat. Commun.4, 3017 (2013).
  • Foukas LC , WithersDJ. Phosphoinositide signaling pathways in metabolic regulation. Curr. Top Microbiol. Immunol.346, 115–141 (2013).
  • Kim AS , MillerEJ, WrightTMet al. A small molecule AMPK activator protects the heart against ischemia–reperfusion injury. J. Mol. Cell. Cardiol.51, 24–32 (2011).
  • Chen L , JiaoZH, ZhengLSet al. Structural insight into the autoinhibition mechanism of AMP-activated protein kinase. Nature459, 1146–1149 (2009).
  • Pang T , XiongB, LiJYet al. Conserved alpha-helix acts as autoinhibitory sequence in AMP-activated protein kinase alpha subunits. J. Biol. Chem.282, 495–506 (2007).
  • Mackraj I , GovenderT, GathiramP. Sanguinarine. Cardiovasc. Ther.26, 75–83 (2008).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.