Skip to main content
×
Home

Flavonoids: modulators of brain function?

  • Jeremy P. E. Spencer (a1)
Abstract

Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects on the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by improving cognitive function. It is likely that flavonoids exert such effects, through selective actions on different components of a number of protein kinase and lipid kinase signalling cascades, such as the phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase (MAPK) pathways. This review explores the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to underlie neurological effects through their ability to affect the activation state of target molecules and/or by modulating gene expression. Future research directions are outlined in relation to the precise site(s) of action of flavonoids within signalling pathways and the sequence of events that allow them to regulate neuronal function.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Flavonoids: modulators of brain function?
      Available formats
      ×
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Flavonoids: modulators of brain function?
      Available formats
      ×
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Flavonoids: modulators of brain function?
      Available formats
      ×
Copyright
Corresponding author
*Corresponding author: Dr J. P. E. Spencer, fax +44 118 931 0080, email j.p.e.spencer@reading.ac.uk
References
Hide All
1Youdim KA & Joseph JA (2001) A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: a multiplicity of effects. Free Radic Biol Med 30, 583594.
2Youdim KA, Spencer JP, Schroeter H & Rice-Evans C (2002) Dietary flavonoids as potential neuroprotectants. Biol Chem 383, 503519.
3Galli RL, Shukitt-Hale B, Youdim KA & Joseph JA (2002) Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits. Ann N Y Acad Sci 959, 128132.
4Unno K, Takabayashi F, Kishido T & Oku N (2004) Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol 39, 10271034.
5Haque AM, Hashimoto M, Katakura M, Tanabe Y, Hara Y & Shido O (2006) Long-term administration of green tea catechins improves spatial cognition learning ability in rats. J Nutr 136, 10431047.
6Kuriyama S, Hozawa A, Ohmori K, Shimazu T, Matsui T, Ebihara S, Awata S, Nagatomi R, Arai H & Tsuji I (2006) Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am J Clin Nutr 83, 355361.
7Wang Y, Wang L, Wu J & Cai J (2006) The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats. Br J Pharmacol 148, 147153.
8Inanami O, Watanabe Y, Syuto B, Nakano M, Tsuji M & Kuwabara M (1998) Oral administration of ( − )catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil. Free Radic Res 29, 359365.
9Luo Y, Smith JV, Paramasivam V, Burdick A, Curry KJ, Buford JP, Khan I, Netzer WJ, Xu H & Butko P (2002) Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc Natl Acad Sci U S A 99, 1219712202.
10Bastianetto S, Zheng WH & Quirion R (2000) The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: involvement of its flavonoid constituents and protein kinase C. J Neurochem 74, 22682277.
11Zimmermann M, Colciaghi F, Cattabeni F & Di Luca M (2002) Ginkgo biloba extract: from molecular mechanisms to the treatment of Alzhelmer's disease. Cell Mol Biol (Noisy-le-grand) 48, 613623.
12Datla KP, Christidou M, Widmer WW, Rooprai HK & Dexter DT (2001) Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson's disease. Neuroreport 12, 38713875.
13Rice-Evans CA, Miller NJ & Paganga G (1996) Structure–antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20, 933956.
14Williams RJ, Spencer JPE & Rice-Evans C (2004) Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 36, 838849.
15Spencer JPE, Rice-Evans C & Williams RJ (2003) Modulation of pro-survival Akt/PKB and ERK1/2 signalling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J Biol Chem 278, 3478334793.
16Schroeter H, Boyd C, Spencer JPE, Williams RJ, Cadenas E & Rice-Evans C (2002) MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging 23, 861880.
17Manach C, Scalbert A, Morand C, Remesy C & Jimenez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79, 727747.
18Rice-Evans C (2001) Flavonoid antioxidants. Curr Med Chem 8, 797807.
19Rice-Evans C (1995) Plant polyphenols: free radical scavengers or chain-breaking antioxidants? Biochem Soc Symp 61, 103116.
20Spencer JPE, Schroeter H, Rechner AR & Rice-Evans C (2001) Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid Redox Signal 3, 10231039.
21Spencer JPE, Srai SK & Rice-Evans C (2003) Metabolism in the small intestine and gastrointestinal tract. In Flavonoids in Health and Disease, pp. 363390 [Rice-Evans C and Packer L, editors]. New York: Marcel Dekker.
22Walle T, Walgren RA, Walle UK, Galijatovic A & Vaidyanathan JB (2003) Understanding the bioavailability of flavanoids through studies in Caco-2 cells. In Flavonoids in Health and Disease, pp. 349362 [Rice-Evans C and Packer L, editors]. New York: Marcel Dekker.
23Day AJ & Williamson G (2003) Absorption of quercetin glycosides. In Flavonoids in Health and Disease, pp. 391412 [Rice-Evans C and Packer L, editors]. New York: Marcel Dekker.
24Donovan JL & Waterhouse AL (2003) Bioavailability of flavanol monomers. In Flavonoids in Health and Disease, pp. 413440 [Rice-Evans C and Packer L, editors]. New York: Marcel Dekker.
25Spencer JPE, Chowrimootoo G, Choudhury R, Debnam ES, Srai SK & Rice-Evans C (1999) The small intestine can both absorb and glucuronidate luminal flavonoids. FEBS Lett 458, 224230.
26Scheline RR (1999) Metabolism of oxygen heterocyclic compounds. In CRC Handbook of Mammalian Metabolism of Plant Compounds, pp. 243295Boca Ranton: CRC Press.
27Spencer JPE, Kuhnle GG, Williams RJ & Rice-Evans C (2003) Intracellular metabolism and bioactivity of quercetin and its in vivo metabolites. Biochem J 372, 173181.
28Spencer JPE, Schroeter H, Crossthwaithe AJ, Kuhnle G, Williams RJ & Rice-Evans C (2001) Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts. Free Radic Biol Med 31, 11391146.
29Miyake Y, Shimoi K, Kumazawa S, Yamamoto K, Kinae N & Osawa T (2000) Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agric Food Chem 48, 32173224.
30Terao J, Yamaguchi S, Shirai M, Miyoshi M, Moon JH, Oshima S, Inakuma T, Tsushida T & Kato Y (2001) Protection by quercetin and quercetin 3-O-beta-d-glucuronide of peroxynitrite-induced antioxidant consumption in human plasma low-density lipoprotein. Free Radic Res 35, 925931.
31Shirai M, Moon JH, Tsushida T & Terao J (2001) Inhibitory effect of a quercetin metabolite, quercetin 3-O-beta-d-glucuronide, on lipid peroxidation in liposomal membranes. J Agric Food Chem 49, 56025608.
32Yamamoto N, Moon JH, Tsushida T, Nagao A & Terao J (1999) Inhibitory effect of quercetin metabolites and their related derivatives on copper ion-induced lipid peroxidation in human low-density lipoprotein. Arch Biochem Biophys 372, 347354.
33da Silva EL, Piskula MK, Yamamoto N, Moon JH & Terao J (1998) Quercetin metabolites inhibit copper ion-induced lipid peroxidation in rat plasma. FEBS Lett 430, 405408.
34Abbott NJ (2002) Astrocyte–endothelial interactions and blood–brain barrier permeability. J Anat 200, 629638.
35Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ & Rice-Evans C (2003) Interaction between flavonoids and the blood–brain barrier: in vitro studies. J Neurochem 85, 180192.
36Youdim KA, Shukitt-Hale B & Joseph JA (2004) Flavonoids and the brain: interactions at the blood–brain barrier and their physiological effects on the central nervous system. Free Radic Biol Med 37, 16831693.
37Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA & Abbott NJ (2004) Flavonoid permeability across an in situ model of the blood–brain barrier. Free Radic Biol Med 36, 592604.
38Aasmundstad TA, Morland J & Paulsen RE (1995) Distribution of morphine 6-glucuronide and morphine across the blood–brain barrier in awake, freely moving rats investigated by in vivo microdialysis sampling. J Pharmacol Exp Ther 275, 435441.
39Sperker B, Backman JT & Kroemer HK (1997) The role of beta-glucuronidase in drug disposition and drug targeting in humans. Clin Pharmacokinet 33, 1831.
40Kroemer HK & Klotz U (1992) Glucuronidation of drugs. A re-evaluation of the pharmacological significance of the conjugates and modulating factors. Clin Pharmacokinet 23, 292310.
41Lin JH & Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42, 5998.
42Suganuma M, Okabe S, Oniyama M, Tada Y, Ito H & Fujiki H (1998) Wide distribution of [3H]( − )-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 19, 17711776.
43Abd El Mohsen MM, Kuhnle G, Rechner AR, Schroeter H, Rose S, Jenner P & Rice-Evans CA (2002) Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic Biol Med 33, 16931702.
44Talavera S, Felgines C, Texier O, Besson C, Gil-Izquierdo A, Lamaison JL & Remesy C (2005) Anthocyanin metabolism in rats and their distribution to digestive area, kidney, and brain. J Agric Food Chem 53, 39023908.
45El Mohsen MA, Marks J, Kuhnle G, Moore K, Debnam E, Kaila SS, Rice-Evans C & Spencer JP (2006) Absorption, tissue distribution and excretion of pelargonidin and its metabolites following oral administration to rats. Br J Nutr 95, 5158.
46Andres-Lacueva C, Shukitt-Hale B, Galli RL, Jauregui O, Lamuela-Raventos RM & Joseph JA (2005) Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci 8, 111120.
47Halliwell B, Zhao K & Whiteman M (2000) The gastrointestinal tract: a major site of antioxidant action? Free Radic Res 33, 819830.
48Joseph JA, Shukitt-Hale B, Denisova NA, Prior RL, Cao G, Martin A, Taglialatela G & Bickford PC (1998) Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. J Neurosci 18, 80478055.
49Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A, McEwen JJ & Bickford PC (1999) Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 19, 81148121.
50Casadesus G, Shukitt-Hale B, Stellwagen HM, Zhu X, Lee HG, Smith MA & Joseph JA (2004) Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci 7, 309316.
51Shukitt-Hale B, Smith DE, Meydani M & Joseph JA (1999) The effects of dietary antioxidants on psychomotor performance in aged mice. Exp Gerontol 34, 797808.
52Joseph JA, Shukitt-Hale B & Casadesus G (2005) Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. Am J Clin Nutr 81, 313S316S.
53Goyarzu P, Malin DH, Lau FC, et al. (2004) Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr Neurosci 7, 7583.
54Joseph JA, Denisova NA, Arendash G, Gordon M, Diamond D, Shukitt-Hale B & Morgan D (2003) Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci 6, 153162.
55Ramirez MR, Izquierdo I, do Carmo Bassols RM, Zuanazzi JA, Barros D & Henriques AT (2005) Effect of lyophilised Vaccinium berries on memory, anxiety and locomotion in adult rats. Pharmacol Res 52, 457462.
56Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK, Sies H, Kwik-Uribe C, Schmitz HH & Kelm M (2006) ( − )-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A 103, 10241029.
57Francis ST, Head K, Morris PG & Macdonald IA (2006) The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol 47, Suppl. 2, S215S220.
58Fisher ND, Sorond FA & Hollenberg NK (2006) Cocoa flavanols and brain perfusion. J Cardiovasc Pharmacol 47, Suppl. 2, S210S214.
59Gage FH (2000) Mammalian neural stem cells. Science 287, 14331438.
60Palmer TD, Willhoite AR & Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425, 479494.
61Harris KM & Kater SB (1994) Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci 17, 341371.
62Carew TJ (1996) Molecular enhancement of memory formation. Neuron 16, 58.
63Martin KC, Barad M & Kandel ER (2000) Local protein synthesis and its role in synapse-specific plasticity. Curr Opin Neurobiol 10, 587592.
64Kelleher RJ III, Govindarajan A & Tonegawa S (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44, 5973.
65Impey S, McCorkle SR, Cha-Molstad H, Dwyer JM, Yochum GS, Boss JM, McWeeney S, Dunn JJ, Mandel G & Goodman RH (2004) Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119, 10411054.
66Barco A, Bailey CH & Kandel ER (2006) Common molecular mechanisms in explicit and implicit memory. J Neurochem 97, 15201533.
67Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G & Silva AJ (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 5968.
68Tully T, Bourtchouladze R, Scott R & Tallman J (2003) Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2, 267277.
69Pham TA, Impey S, Storm DR & Stryker MP (1999) CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period. Neuron 22, 6372.
70Impey S, Smith DM, Obrietan K, Donahue R, Wade C & Storm DR (1998) Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci 1, 595601.
71Impey S, Mark M, Villacres EC, Poser S, Chavkin C & Storm DR (1996) Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16, 973982.
72Schroeter H, Spencer JP, Rice-Evans C & Williams RJ (2001) Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J 358, 547557.
73Schroeter H, Bahia P, Spencer JPE, Sheppard O, Rattray M, Rice-Evans C & Williams RJ (2007) ( − )-Epicatechin stimulates ERK-dependent cyclic AMP response element activity and upregulates GLUR2 in cortical neurons J Neurochem 101, 15961606..
74Maher P, Akaishi T & Abe K (2006) Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A 103, 1656816573.
75Conkright MD, Guzman E, Flechner L, Su AI, Hogenesch JB & Montminy M (2003) Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. Mol Cell 11, 11011108.
76Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ & Greenberg ME (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709726.
77Shieh PB, Hu SC, Bobb K, Timmusk T & Ghosh A (1998) Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20, 727740.
78Bramham CR & Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76, 99125.
79Patterson SL, Grover LM, Schwartzkroin PA & Bothwell M (1992) Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9, 10811088.
80Thomas K & Davies A (2005) Neurotrophins: a ticket to ride for BDNF. Curr Biol 15, R262R264.
81Peng S, Wuu J, Mufson EJ & Fahnestock M (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem 93, 14121421.
82Michalski B & Fahnestock M (2003) Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer's disease. Brain Res Mol Brain Res 111, 148154.
83Egan MF, Kojima M, Callicott JH, et al. (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257269.
84Linnarsson S, Bjorklund A & Ernfors P (1997) Learning deficit in BDNF mutant mice. Eur J Neurosci 9, 25812587.
85Mu JS, Li WP, Yao ZB & Zhou XF (1999) Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res 835, 259265.
86Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T & Klein R (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401414.
87Wullschleger S, Loewith R & Hall MN (2006) TOR signaling in growth and metabolism. Cell 124, 471484.
88Schratt GM, Nigh EA, Chen WG, Hu L & Greenberg ME (2004) BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci 24, 73667377.
89Yin Y, Edelman GM & Vanderklish PW (2002) The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A 99, 23682373.
90Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, Bundman M & Kuhl D (2001) Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J Neurosci 21, 54845493.
91Soule J, Messaoudi E & Bramham CR (2006) Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain. Biochem Soc Trans 34, 600604.
92Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Gilbert DJ, Jenkins NA, Lanahan AA & Worley PF (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14, 433445.
93Reznichenko L, Amit T, Youdim MB & Mandel S (2005) Green tea polyphenol ( − )-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem 93, 11571167.
94Hirsch EC, Hunot S & Hartmann A (2005) Neuroinflammatory processes in Parkinson's disease. Parkinsonism Relat Disord 11, Suppl. 1, S9S15.
95McGeer EG & McGeer PL (2003) Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 27, 741749.
96Zheng Z, Lee JE & Yenari MA (2003) Stroke: molecular mechanisms and potential targets for treatment. Curr Mol Med 3, 361372.
97Casper D, Yaparpalvi U, Rempel N & Werner P (2000) Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro. Neurosci Lett 289, 201204.
98Chen H, Zhang SM, Hernan MA, Schwarzschild MA, Willett WC, Colditz GA, Speizer FE & Ascherio A (2003) Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol 60, 10591064.
99McGeer EG & McGeer PL (1997) The role of the immune system in neurodegenerative disorders. Mov Disord 12, 855858.
100Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teismann P, Choi DK, Tieu K & Przedborski S (2001) The role of glial cells in Parkinson's disease. Curr Opin Neurol 14, 483489.
101Kim YS & Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp Mol Med 38, 333347.
102Allan SM & Rothwell NJ (2003) Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci 358, 16691677.
103Stewart VC & Heales SJ (2003) Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration. Free Radic Biol Med 34, 287303.
104Moncada S & Bolanos JP (2006) Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 97, 16761689.
105Kozuka N, Itofusa R, Kudo Y & Morita M (2005) Lipopolysaccharide and proinflammatory cytokines require different astrocyte states to induce nitric oxide production. J Neurosci Res 82, 717728.
106Bal-Price A, Matthias A & Brown GC (2002) Stimulation of the NADPH oxidase in activated rat microglia removes nitric oxide but induces peroxynitrite production. J Neurochem 80, 7380.
107Fiebich BL, Lieb K, Engels S & Heinrich M (2002) Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J Neuroimmunol 132, 1824.
108Bhat NR, Zhang P, Lee JC & Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18, 16331641.
109Marcus JS, Karackattu SL, Fleegal MA & Sumners C (2003) Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: role of Erk mitogen-activated protein kinase and NF-kappaB. Glia 41, 152160.
110Pawate S & Bhat NR (2006) C-Jun N-terminal kinase (JNK) regulation of iNOS expression in glial cells: predominant role of JNK1 isoform. Antioxid Redox Signal 8, 903909.
111Li R, Huang YG, Fang D & Le WD (2004) ( − )-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury. J Neurosci Res 78, 723731.
112Huang Q, Wu LJ, Tashiro S, Gao HY, Onodera S & Ikejima T (2005) (+)-Catechin, an ingredient of green tea, protects murine microglia from oxidative stress-induced DNA damage and cell cycle arrest. J Pharmacol Sci 98, 1624.
113Lee H, Kim YO, Kim H, Kim SY, Noh HS, Kang SS, Cho GJ, Choi WS & Suk K (2003) Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia. FASEB J 17, 19431944.
114Shen SC, Lee WR, Lin HY, Huang HC, Ko CH, Yang LL & Chen YC (2002) In vitro and in vivo inhibitory activities of rutin, wogonin, and quercetin on lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production. Eur J Pharmacol 446, 187194.
115Woo KJ, Lim JH, Suh SI, Kwon YK, Shin SW, Kim SC, Choi YH, Park JW & Kwon TK (2006) Differential inhibitory effects of baicalein and baicalin on LPS-induced cyclooxygenase-2 expression through inhibition of C/EBPbeta DNA-binding activity. Immunobiology 211, 359368.
116Kim H, Kim YS, Kim SY & Suk K (2001) The plant flavonoid wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production. Neurosci Lett 309, 6771.
117Chen CJ, Raung SL, Liao SL & Chen SY (2004) Inhibition of inducible nitric oxide synthase expression by baicalein in endotoxin/cytokine-stimulated microglia. Biochem Pharmacol 67, 957965.
118Chen JC, Ho FM, Pei-Dawn LC, Chen CP, Jeng KC, Hsu HB, Lee ST, Wen TW & Lin WW (2005) Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. Eur J Pharmacol 521, 920.
119Matter WF, Brown RF & Vlahos CJ (1992) The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs. Biochem Biophys Res Commun 186, 624631.
120Vlahos CJ, Matter WF, Hui KY & Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269, 52415248.
121Agullo G, Gamet-Payrastre L, Manenti S, Viala C, Remesy C, Chap H & Payrastre B (1997) Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem Pharmacol 53, 16491657.
122Gamet-Payrastre L, Manenti S, Gratacap MP, Tulliez J, Chap H & Payrastre B (1999) Flavonoids and the inhibition of PKC and PI 3-kinase. Gen Pharmacol 32, 279286.
123Kong AN, Yu R, Chen C, Mandlekar S & Primiano T (2000) Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Arch Pharm Res 23, 116.
124Lin CH, Yeh SH, Lin CH, Lu KT, Leu TH, Chang WC & Gean PW (2001) A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 31, 841851.
125Sweatt JD (2001) Memory mechanisms: the yin and yang of protein phosphorylation. Curr Biol 11, R391R394.
126Conseil G, Baubichon-Cortay H, Dayan G, Jault JM, Barron D & Di Pietro A (1998) Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc Natl Acad Sci U S A 95, 98319836.
127Di Pietro A, Godinot C, Bouillant ML & Gautheron DC (1975) Pig heart mitochondrial ATPase: properties of purified and membrane-bound enzyme. Effects of flavonoids. Biochimie 57, 959967.
128Barzilai A & Rahamimoff H (1983) Inhibition of Ca2+-transport ATPase from synaptosomal vesicles by flavonoids. Biochim Biophys Acta 730, 245254.
129Revuelta MP, Cantabrana B & Hidalgo A (1997) Depolarization-dependent effect of flavonoids in rat uterine smooth muscle contraction elicited by CaCl2. Gen Pharmacol 29, 847857.
130Lee SF & Lin JK (1997) Inhibitory effects of phytopolyphenols on TPA-induced transformation, PKC activation, and c-jun expression in mouse fibroblast cells. Nutr Cancer 28, 177183.
131Ursini F, Maiorino M, Morazzoni P, Roveri A & Pifferi G (1994) A novel antioxidant flavonoid (IdB 1031) affecting molecular mechanisms of cellular activation. Free Radic Biol Med 16, 547553.
132Kantengwa S & Polla BS (1991) Flavonoids, but not protein kinase C inhibitors, prevent stress protein synthesis during erythrophagocytosis. Biochem Biophys Res Commun 180, 308314.
133Rosenblat M, Belinky P, Vaya J, Levy R, Hayek T, Coleman R, Merchav S & Aviram M (1999) Macrophage enrichment with the isoflavan glabridin inhibits NADPH oxidase-induced cell-mediated oxidation of low density lipoprotein. A possible role for protein kinase C. J Biol Chem 274, 1379013799.
134Boege F, Straub T, Kehr A, Boesenberg C, Christiansen K, Andersen A, Jakob F & Kohrle J (1996) Selected novel flavones inhibit the DNA binding or the DNA religation step of eukaryotic topoisomerase I. J Biol Chem 271, 22622270.
135Medina JH, Viola H, Wolfman C, Marder M, Wasowski C, Calvo D & Paladini AC (1997) Overview—flavonoids: a new family of benzodiazepine receptor ligands. Neurochem Res 22, 419425.
136Dekermendjian K, Kahnberg P, Witt MR, Sterner O, Nielsen M & Liljefors T (1999) Structure–activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABA(A) receptor complex. J Med Chem 42, 43434350.
137Fischer PM & Lane DP (2000) Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem 7, 12131245.
138Huang YT, Hwang JJ, Lee PP, Ke FC, Huang JH, Huang CJ, Kandaswami C, Middleton E Jr & Lee MT (1999) Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol 128, 9991010.
139So FV, Guthrie N, Chambers AF, Moussa M & Carroll KK (1996) Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 26, 167181.
140Green DR & Reed JC (1998) Mitochondria and apoptosis. Science 281, 13091312.
141Tatton WG & Olanow CW (1999) Apoptosis in neurodegenerative diseases: the role of mitochondria. Biochim Biophys Acta 1410, 195213.
142Goyal L (2001) Cell death inhibition: keeping caspases in check. Cell 104, 805808.
143Srinivasula SM, Hegde R, Saleh A, et al. (2001) A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 410, 112116.
144Cobb MH & Goldsmith EJ (1995) How MAP kinases are regulated. J Biol Chem 270, 1484314846.
145Goldsmith EJ & Cobb MH (1994) Protein kinases. Curr Opin Struct Biol 4, 833840.
146Marshall CJ (1994) Signal transduction. Hot lips and phosphorylation of protein kinases. Nature 367, 686.
147Karin M (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270, 1648316486.
148Xia Z, Dickens M, Raingeaud J, Davis RJ & Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 13261331.
149Anderson CN & Tolkovsky AM (1999) A role for MAPK/ERK in sympathetic neuron survival: protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J Neurosci 19, 664673.
150Bonni A, Brunet A, West AE, Datta SR, Takasu MA & Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 13581362.
151Kaplan DR & Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10, 381391.
152Crossthwaite AJ, Hasan S & Williams RJ (2002) Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. J Neurochem 80, 2435.
153Mielke K & Herdegen T (2000) JNK and p38 stresskinases—degenerative effectors of signal-transduction-cascades in the nervous system. Prog Neurobiol 61, 4560.
154Yuan J & Yankner BA (2000) Apoptosis in the nervous system. Nature 407, 802809.
155Behrens A, Sibilia M & Wagner EF (1999) Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 21, 326329.
156Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239252.
157Kobuchi H, Roy S, Sen CK, Nguyen HG & Packer L (1999) Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol 277, C403C411.
158Herdegen T, Skene P & Bahr M (1997) The c-Jun transcription factor—bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 20, 227231.
159Castagne V & Clarke PG (1999) Inhibitors of mitogen-activated protein kinases protect axotomized developing neurons. Brain Res 842, 215219.
160Castagne V, Gautschi M, Lefevre K, Posada A & Clarke PG (1999) Relationships between neuronal death and the cellular redox status. Focus on the developing nervous system. Prog Neurobiol 59, 397423.
161Hung SP, Hsu JR, Lo CP, Huang HJ, Wang JP & Chen ST (2005) Genistein-induced neuronal differentiation is associated with activation of extracellular signal-regulated kinases and upregulation of p21 and N-cadherin. J Cell Biochem 96, 10611070.
162Llorens F, Garcia L, Itarte E & Gomez N (2002) Apigenin and LY294002 prolong EGF-stimulated ERK1/2 activation in PC12 cells but are unable to induce full differentiation. FEBS Lett 510, 149153.
163Dudley DT, Pang L, Decker SJ, Bridges AJ & Saltiel AR (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A 92, 76867689.
164Pang L, Sawada T, Decker SJ & Saltiel AR (1995) Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J Biol Chem 270, 1358513588.
165Alessi DR, Cuenda A, Cohen P, Dudley DT & Saltiel AR (1995) PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270, 2748927494.
166Lazar DF, Wiese RJ, Brady MJ, Mastick CC, Waters SB, Yamauchi K, Pessin JE, Cuatrecasas P & Saltiel AR (1995) Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem 270, 2080120807.
167Levites Y, Amit T, Youdim MB & Mandel S (2002) Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol ( − )-epigallocatechin 3-gallate neuroprotective action. J Biol Chem 277, 3057430580.
168Reznichenko L, Amit T, Youdim MB & Mandel S (2005) Green tea polyphenol ( − )-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem 93, 11571167.
169Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP & Williams RL (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6, 909919.
170Perkinton MS, Sihra TS & Williams RJ (1999) Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signaling cascade in neurons. J Neurosci 19, 58615874.
171Jacobson KA, Moro S, Manthey JA, West PL & Ji XD (2002) Interactions of flavones and other phytochemicals with adenosine receptors. Adv Exp Med Biol 505, 163171.
172Johnston GA (2005) GABA(A) receptor channel pharmacology. Curr Pharm Des 11, 18671885.
173Adachi N, Tomonaga S, Tachibana T, Denbow DM & Furuse M (2006) ( − )-Epigallocatechin gallate attenuates acute stress responses through GABAergic system in the brain. Eur J Pharmacol 531, 171175.
174Han YS, Bastianetto S, Dumont Y & Quirion R (2006) Specific plasma membrane binding sites for polyphenols, including resveratrol, in the rat brain. J Pharmacol Exp Ther 318, 238245.
175Nifli AP, Bosson-Kouame A, Papadopoulou N, Kogia C, Kampa M, Castagnino C, Stournaras C, Vercauteren J & Castanas E (2005) Monomeric and oligomeric flavanols are agonists of membrane androgen receptors. Exp Cell Res 309, 329339.
176Klinge CM, Blankenship KA, Risinger KE, Bhatnagar S, Noisin EL, Sumanasekera WK, Zhao L, Brey DM & Keynton RS (2005) Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J Biol Chem 280, 74607468.
177Camps M, Nichols A & Arkinstall S (2000) Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J 14, 616.
178Kim Y, Rice AE & Denu JM (2003) Intramolecular dephosphorylation of ERK by MKP3. Biochemistry 42, 1519715207.
179Davis RJ (1999) Signal transduction by the c-Jun N-terminal kinase. Biochem Soc Symp 64, 112.
180Leppa S & Bohmann D (1999) Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene 18, 61586162.
181Ichijo H (1999) From receptors to stress-activated MAP kinases. In Oncogene 18, pp. 60876093.
182Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K & Gotoh Y (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 9094.
183Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H, Zukowski M & Yao Z (1996) Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J Biol Chem 271, 3160731611.
184Matsuzawa A & Ichijo H (2001) Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signal-regulating kinase 1. J Biochem (Tokyo) 130, 18.
185Schroeter H, Williams RJ, Matin R, Iversen L & Rice-Evans CA (2000) Phenolic antioxidants attenuate neuronal cell death following uptake of oxidized low-density lipoprotein. Free Radic Biol Med 29, 12221233.
186Spencer JPE, Schroeter H, Kuhnle G, Srai SK, Tyrrell RM, Hahn U & Rice-Evans C (2001) Epicatechin and its in vivo metabolite, 3′-O-methyl epicatechin, protect human fibroblasts from oxidative-stress-induced cell death involving caspase-3 activation. Biochem J 354, 493500.
187Wang L, Matsushita K, Araki I & Takeda M (2002) Inhibition of c-Jun N-terminal kinase ameliorates apoptosis induced by hydrogen peroxide in the kidney tubule epithelial cells (NRK-52E). Nephron 91, 142147.
188Ishikawa Y & Kitamura M (2000) Anti-apoptotic effect of quercetin: intervention in the JNK- and ERK-mediated apoptotic pathways. Kidney Int 58, 10781087.
189Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y & Osawa T (1999) Activation of stress signaling pathways by the end product of lipid peroxidation. 4-Hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem 274, 22342242.
190Zhang L, Chen J & Fu H (1999) Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins. Proc Natl Acad Sci U S A 96, 85118515.
191Park HS, Park E, Kim MS, Ahn K, Kim IY & Choi EJ (2000) Selenite inhibits the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) through a thiol redox mechanism. J Biol Chem 275, 25272531.
192Adler V, Yin Z, Fuchs SY, et al. (1999) Regulation of JNK signaling by GSTp. EMBO J 18, 13211334.
193Adler V, Yin Z, Tew KD & Ronai Z (1999) Role of redox potential and reactive oxygen species in stress signaling. Oncogene 18, 61046111.
194Monaco R, Friedman FK, Hyde MJ, Chen JM, Manolatus S, Adler V, Ronai Z, Koslosky W & Pincus MR (1999) Identification of a glutathione-S-transferase effector domain for inhibition of jun kinase, by molecular dynamics. J Protein Chem 18, 859866.
195Yin Z, Ivanov VN, Habelhah H, Tew K & Ronai Z (2000) Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases. Cancer Res 60, 40534057.
196Spencer JPE, Abd El, Mohsen MM & Rice-Evans C (2003) Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch Biochem Biophys 423, 148161.
197Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN & Hay N (1997) The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev 11, 701713.
198Coffer PJ, Jin J & Woodgett JR (1998) Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 335, [Pt 1], 113.
199Miller FD & Kaplan DR (2001) Neurotrophin signalling pathways regulating neuronal apoptosis. Cell Mol Life Sci 58, 10451053.
200Crowder RJ & Freeman RS (1998) Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. J Neurosci 18, 29332943.
201Carpenter CL & Cantley LC (1990) Phosphoinositide kinases. Biochemistry 29, 1114711156.
202Simpson L & Parsons R (2001) PTEN: life as a tumor suppressor. Exp Cell Res 264, 2941.
203Neri LM, Borgatti P, Capitani S & Martelli AM (2002) The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system. Biochim Biophys Acta 1584, 7380.
204Franke TF, Kaplan DR & Cantley LC (1997) PI3K: downstream AKTion blocks apoptosis. Cell 88, 435437.
205Burgering BM & Coffer PJ (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599602.
206Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR & Tsichlis PN (1995) The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81, 727736.
207Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S & Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 13181321.
208Burgering BM & Kops GJ (2002) Cell cycle and death control: long live Forkheads. Trends Biochem Sci 27, 352360.
209Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J & Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857868.
210Zha J, Harada H, Yang E, Jockel J & Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87, 619628.
211Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P & Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15, 65416551.
212Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y & Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231241.
213del Peso L, Gonzalez-Garcia M, Page C, Herrera R & Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278, 687689.
214Ferriola PC, Cody V & Middleton E Jr (1989) Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure–activity relationships. Biochem Pharmacol 38, 16171624.
215Cao F, Jin TY & Zhou YF (2006) Inhibitory effect of isoflavones on prostate cancer cells and PTEN gene. Biomed Environ Sci 19, 3541.
216Gulati N, Laudet B, Zohrabian VM, Murali R & Jhanwar-Uniyal M (2006) The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway. Anticancer Res 26, 11771181.
217Dave B, Eason RR, Till SR, Geng Y, Velarde MC, Badger TM & Simmen RC (2005) The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN. Carcinogenesis 26, 17931803.
218Cantley LC & Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 96, 42404245.
219Myers MP, Pass I, Batty IH, Van der KJ KJ, Stolarov JP, Hemmings BA, Wigler MH, Downes CP & Tonks NK (1998) The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A 95, 1351313518.
220Wu X, Senechal K, Neshat MS, Whang YE & Sawyers CL (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 95, 1558715591.
221Wild AC, Moinova HR & Mulcahy RT (1999) Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 274, 3362733636.
222Moinova HR & Mulcahy RT (1999) Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element. Biochem Biophys Res Commun 261, 661668.
223Venugopal R & Jaiswal AK (1998) Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17, 31453156.
224Venugopal R & Jaiswal AK (1996) Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci U S A 93, 1496014965.
225Kang KW, Lee SJ & Kim SG (2005) Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal 7, 16641673.
226Itoh K, Tong KI & Yamamoto M (2004) Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 36, 12081213.
227Leung L, Kwong M, Hou S, Lee C & Chan JY (2003) Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J Biol Chem 278, 4802148029.
228Bloom D, Dhakshinamoorthy S & Jaiswal AK (2002) Site-directed mutagenesis of cysteine to serine in the DNA binding region of Nrf2 decreases its capacity to upregulate antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene 21, 21912200.
229Andreadi CK, Howells LM, Atherfold PA & Manson MM (2006) Involvement of Nrf2, p38, B-Raf, and nuclear factor-kappaB, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols. Mol Pharmacol 69, 10331040.
230Banning A, Deubel S, Kluth D, Zhou Z & Brigelius-Flohe R (2005) The GI-GPx gene is a target for Nrf2. Mol Cell Biol 25, 49144923.
231Hernandez-Montes E, Pollard SE, Vauzour D, Jofre-Montseny L, Rota C, Rimbach G, Weinberg PD & Spencer JP (2006) Activation of glutathione peroxidase via Nrf1 mediates genistein's protection against oxidative endothelial cell injury. Biochem Biophys Res Commun 346, 851859.
232Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD & Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13, 7686.
233Hayes JD & McMahon M (2001) Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett 174, 103113.
234Alcaraz MJ, Vicente AM, Araico A, Dominguez JN, Terencio MC & Ferrandiz ML (2004) Role of nuclear factor-kappaB and heme oxygenase-1 in the mechanism of action of an anti-inflammatory chalcone derivative in RAW 264.7 cells. Br J Pharmacol 142, 11911199.
235Kobayashi M & Yamamoto M (2005) Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal 7, 385394.
236Nguyen T, Sherratt PJ, Huang HC, Yang CS & Pickett CB (2003) Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem 278, 45364541.
237Nguyen T, Huang HC & Pickett CB (2000) Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. J Biol Chem 275, 1546615473.
238Sherratt PJ, Huang HC, Nguyen T & Pickett CB (2004) Role of protein phosphorylation in the regulation of NF-E2-related factor 2 activity. Methods Enzymol 378, 286301.
239Yu R, Mandlekar S, Lei W, Fahl WE, Tan TH & Kong AN (2000) p38 mitogen-activated protein kinase negatively regulates the induction of phase II drug-metabolizing enzymes that detoxify carcinogens. J Biol Chem 275, 23222327.
240Shen G, Hebbar V, Nair S, Xu C, Li W, Lin W, Keum YS, Han J, Gallo MA & Kong AN (2004) Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein. J Biol Chem 279, 2305223060.
241Kang KW, Lee SJ, Park JW & Kim SG (2002) Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress. Mol Pharmacol 62, 10011010.
242Nakaso K, Yano H, Fukuhara Y, Takeshima T, Wada-Isoe K & Nakashima K (2003) PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett 546, 181184.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords:

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 69
Total number of PDF views: 341 *
Loading metrics...

Abstract views

Total abstract views: 1634 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 23rd November 2017. This data will be updated every 24 hours.