Neuroprotective effects of citrus flavonoids

Journal of Agricultural and Food Chemistry

Volumn 60, Issue 4, 2012, Pages 877-885

  Hwang, Sam Long ^a   Shih, Ping Hsiao ^b   Yen, Gow Chin ^b  

^a FOOD INDUSTRY RESEARCH AND DEVELOPMENT INSTITUTE   (Taiwan)

^b NATIONAL CHUNG HSING UNIVERSITY   (Taiwan)

Author keywords

antioxidant; citrus; flavonoids; neuroprotection; signaling

Indexed keywords

ADVERSE EFFECT; ANTI-INFLAMMATORIES; ANTIOXIDANT; BIOLOGICAL ACTIVITIES; BLOOD-BRAIN BARRIER; CHEMOPREVENTIVE; CITRUS; NEURODEGENERATION; NEURODEGENERATIVE DISORDERS; NEUROPROTECTION; NEUROPROTECTIVE EFFECTS; NEUROTOXICITY; SIGNALING MOLECULES; SIGNALING PATHWAYS;

BIOACTIVITY; CITRUS FRUITS; NEURODEGENERATIVE DISEASES; SIGNALING;

FLAVONOIDS;

ANTIOXIDANT; FLAVONOID; HESPERETIN; HESPERIDIN; NEUROPROTECTIVE AGENT;

BLOOD BRAIN BARRIER; CHEMISTRY; CITRUS; DEGENERATIVE DISEASE; DIET; DRUG EFFECT; FRUIT; HUMAN; METABOLISM; OXIDATIVE STRESS; REVIEW; SIGNAL TRANSDUCTION;

ANTIOXIDANTS; BLOOD-BRAIN BARRIER; CITRUS; DIET; FLAVONOIDS; FRUIT; HESPERIDIN; HUMANS; NEURODEGENERATIVE DISEASES; NEUROPROTECTIVE AGENTS; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

CITRUS;

EID: 84856557346     PISSN: 00218561     EISSN: 15205118     Source Type: Journal    
DOI: 10.1021/jf204452y     Document Type: Review

References (115)

1. Floyd, R. A.; Carney, J. M. Age influence on oxidative events during brain ischemia/reperfusion Arch. Gerontol. Geriatr. 1991, 12, 155-177
2. Floyd, R. A.; West, M.; Hensley, K. Oxidative biochemical markers clues to understanding aging in long-lived species Exp. Gerontol. 2001, 36, 619-640 (Pubitemid 32273408)
3. Halliwell, B. Reactive oxygen species and the central nervous system J. Neurochem. 1992, 59, 1609-1623
4. Hamilton, M. L.; Van Remmen, H.; Drake, J. A.; Yang, H.; Gou, Z.; Kewitt, K. Does oxidative damage to DNA increase with age? Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 10469-10474 (Pubitemid 32803043)
5. Aruoma, O. I. Neuroprotection by dietary antioxidants: New age of research Nahrung/Food 2002, 46, 381-382
6. Joseph, J. A.; Denisova, N.; Fisher, D.; Bickford, P.; Prior, R.; Cao, G. Age-related neuro-degeneration and oxidative stress: putative nutritional intervention Neurol. Clin. 1998, 16, 747-755 (Pubitemid 28408984)
7. Butterfield, D. A.; Howard, B.; Yatin, S.; Koppal, T.; Drake, J.; Hensley, K.; Aksenov, M.; Aksenova, M.; Subramaniam, R.; Varadarajan, S.; Harris-White, M. E.; Pedigo, N. W., Jr.; Carney, J. M. Elevated oxidative stress in models of normal brain aging and Alzheimer's disease Life Sci. 1999, 65, 1883-1892 (Pubitemid 29506923)
8. Yuan, J.; Yankner, B. A. Apoptosis in the nervous system Nature 2000, 407, 802-809
9. Annunziato, L.; Pannaccione, A.; Cataldi, M.; Secondo, A.; Castaldo, P.; Di Renzo, G. Modulation of ion channels by reactive oxygen and nitrogen species: a pathophysiological role in brain aging? Neurobiol. Aging 2002, 23, 819-834 (Pubitemid 35217706)
10. Mattson, M. P. Pathways towards and away from Alzheimer's disease Nature 2004, 430, 631-107
11. Warner, D. S.; Sheng, H.; Batinic-Haberle, I. Oxidants, antioxidants and the ischemic brain J. Exp. Biol. 2004, 207, 3221-3231 (Pubitemid 39275296)
12. Oikawa, S.; Hirosawa, I.; Tada-Oikawa, S.; Furukawa, A.; Nishiura, K.; Kawanishi, S. Mechanism for manganese enhancement of dopamine-induced oxidative DNA damage and neuronal cell death Free Radical Biol. Med. 2006, 41, 748-756 (Pubitemid 44163409)
13. Gómez-Pinilla, F. Brain foods: the effects of nutrients on brain function Nat. Rev. Neurosci. 2008, 9, 568-578 (Pubitemid 351873468)
14. González-Molina, E.; Domínguez-Perles, R.; Moreno, D. A.; García-Viguera, C. Natural bioactive compounds of Citrus limon for food and health J. Pharm. Biomed. Anal. 2010, 51, 327-345
15. Manthey, J. A.; Guthrie, N.; Grohmann, K. Biological properties of citrus flavonoids pertaining to cancer and inflammation Curr. Med. Chem. 2001, 8, 135-153 (Pubitemid 32421562)
16. Yu, J.; Wang, L.; Walzem, R. L.; Miller, E. G.; Pike, L. M.; Patil, B. S. Antioxidant activity of citrus limonoids, flavonoids, and coumarins J. Agric. Food Chem. 2005, 53, 2009-14 (Pubitemid 40395766)
17. Marder, M.; Viola, H.; Wasowski, C.; Fernández, S.; Medina, J. H.; Paladini, A. C. 6-Methylapigenin and hesperidin: new valeriana flavonoids with activity on the CNS Pharmacol., Biochem. Behav. 2003, 75, 537-545 (Pubitemid 36936888)
18. Hirata, A.; Murakami, Y.; Shoji, M.; Kadoma, Y.; Fujisawa, S. Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory activity on COX-2 expression Anticancer Res. 2005, 25, 3367-3374 (Pubitemid 41105213)
19. Youdim, K. A.; Dobbie, M. S.; Kuhnle, G.; Proteggente, A. R.; Abbott, N. J.; Rice-Evans, C. (2003. Interaction between flavonoids and the blood-brain barrier: in vitro studies. J. Neurochem. 2003, 85, 180-192. (Pubitemid 36389708)
20. Dimpfel, W. Different anticonvulsive effects of hesperidin and its aglycone hesperetin on electrical activity in the rat hippocampus in-vitro J. Pharm. Pharmacol. 2006) 58, 375-379 (Pubitemid 43344581)
21. Kong, A.-N. T.; Yu, R.; Chen, C.; Mandlekar, S.; Primiano, T. Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis Arch. Pharmacal Res. 2000, 23, 1-16
22. Williams, R. J.; Spencer, J. P. E; Rice-Evans, C. Flavonoids: antioxidants or signaling molecules? Free Radical Biol. Med. 2004, 36, 838-849
23. Spencer, J. P. Flavonoids: modulators of brain functions? Br. J. Nutr. 2008, 99 (E-Suppl. 1) ES60-ES77
24. Tapieo, H.; Tew, K. D.; Ba, G. N.; Mathe, G. Polyphenols: do they play a role in the prevention of human pathologies? Biomed. Pharmacother. 2002, 56, 200-207 (Pubitemid 34628383)
25. Scalbert, A.; Williamson, G. Dietary intake and bioavailability of polyphenols J. Nutr. 2000, 130, 2073S-2085S (Pubitemid 30619386)
26. Manach, C.; Morand, C.; Gil-Izquierdo, A.; Bouteloup-Demange, C.; Rémésy, C. Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice Eur. J. Clin. Nutr. 2003, 57, 235-242 (Pubitemid 36240474)
27. Rice-Evans, C. A.; Miller, N. J.; Bolwell, P. G.; Bramley, P. M.; Pridham, J. B. The relative antioxidant activities of plant-derived polyphenolic flavonoids Free Radical Res. 1995, 22, 375-383
28. Rice-Evans, C. A.; Miller, N. J.; Paganga, G.. Structure-antioxidant activity relationships of flavonoids and phenolic acids Free Radical Biol. Med. 1996, 20, 933-956 (Pubitemid 26157509)
29. Li, S.; Lo, C. Y.; Ho, C. T. Hydroxylated polymethoxyflavones and methylated flavonoids in sweet orange (Citrus sinensis) peel J. Agric. Food Chem. 2006, 54, 4176-4185 (Pubitemid 44013319)
30. Lin, C. M.; Chen, C. T.; Lee, H. H.; Lin, J. K. Prevention of cellular ROS damage by isovitexin and related flavonoids Planta Med. 2002, 68, 365-367
31. Miyake, Y.; Sakurai, C.; Usuda, M.; Fukumoto, S.; Hiramitsu, M.; Sakaida, K.; Osawa, T.; Kondo, K. Difference in plasma metabolite concentration after ingestion of lemon flavonoids and their aglycones in humans J. Nutr. Sci. Vitaminol. 2006, 52, 54-60
32. Bors, W.; Michel, C.; Stettmaier, K. Structure-activity relationships governing antioxidant capacities of plant polyphenols Methods Enzymol. 2001, 335, 166-180 (Pubitemid 32507236)
33. Kandaswami, K.; Middleton, E., Jr. Flavonoids as Antioxidants. In Natural Antioxidants: Chemistry, Health Effects, and Application; Shahidi, F., Ed.; AOCS Press: Champaign, IL, 1997; Chapter 10.
34. Sawa, T.; Nakao, M.; Akaike, T.; Ono, K.; Maeda, H. Alkylperoxyl radical-scavenging activity of various flavonoids and other phenolic compounds: implications for the anti-tumor-promoter effect of vegetables J. Agric. Food Chem. 1999, 47, 397-402 (Pubitemid 29185198)
35. Yokozawa, T.; Nakagawa, T.; Kitani, K. Antioxidative activity of green tea polyphenol in cholesterol-fed rats J. Agric. Food Chem. 2002, 50, 3549-3552 (Pubitemid 34579289)
36. Kim, J. Y.; Jung, K. J.; Choi, J. S.; Chung, H. Y. Hesperetin: a potent antioxidant against peroxynitrite Free Radical Res. 2004, 38, 761-769 (Pubitemid 38812094)
37. Jung, H. A.; Jung, M. J.; Kim, J. Y.; Chung, H. Y.; Choi, J. S. Inhibitory activity of flavonoids from Prunus davidiana and other flavonoids on total ROS and hydroxyl radical generation Arch. Pharmacal Res. 2003, 26, 809-815
38. Pollard, S. E.; Whiteman, M.; Spencer, J. P. E Modulation of peroxynitrite-induced fibroblast injury by hrsperetin: A role for intracellular scanvenging and modulation of ERK signaling Biochem. Biophys. Res. Commun. 2006, 347, 916-923 (Pubitemid 44118206)
39. Yokozawa, T.; Kim, H. Y.; Cho, E. J.; Choi, J. S.; Chung, H. Y. Antioxidant effects of isorhamnetin 3,7-di-O-beta-D-glucopyranoside isolated from mustard leaf (Brassica juncea) in rats with streptozotocin-induced diabetes J. Agric. Food Chem. 2002, 50, 5490-5495 (Pubitemid 35001316)
40. Morton, L. W.; Caccetta, R.; Puddey, I. B.; Croft, K. D. Chemistry and biological effects of dietary phenolic compounds: Relevance to cardiovascular disease Clin. Exp. Pharmacol. Physiol. 2000, 27, 152-159 (Pubitemid 30158926)
41. Spencer, J. P.; Rice-Evans, C.; Williams, R. J. Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability J. Biol. Chem. 2003, 278, 34783-34793 (Pubitemid 37102237)
42. Kelsey, N. A.; Wilkins, H. M.; Linseman, D. A. Netraceutical antioxidants as novel neuroprotective ahents Molecules 2010, 15, 7792-7814
43. Kang, S. S.; Lee, J. Y.; Choi, Y. K.; Kim, G. S.; Han, B. H. Neuroprotective effects of flavones on hydrogen peroxide-induced apoptosis in SH-SY5Y neuroblostoma cells Bioorg. Med. Chem. Lett 2004, 14, 2261-2264 (Pubitemid 38481402)
44. Suzuki, M.; Tabuchi, M.; Ikeda, M.; Umegaki, K.; Tomita, K. Protection effects of green tea catechins on cerebral ischemic damage Med. Sci. Monit. 2004, 10, BR 166-BR 174
45. Yoon, I.; Lee, K. H.; Cho, J. Gossypin protects primary cultured rat cortical cells from oxidative stress- and beta-amyloid-induced toxicity Arch. Pharmacal Res. 2004, 27, 454-459 (Pubitemid 43073744)
46. Zeng, H.; Chen, Q.; Zhao, B. Genistein ameliorates β-amyloid peptide (25-35)-induced hippocampal neuronal apoptosis Free Radical Biol. Med. 2004, 36, 180-188 (Pubitemid 38117236)
47. Bu, L.; Lephart, E. D. Soy isoflavones modulate the expression of BAD and neuro-specific beta III tubulin in male rat brain Neurosci. Lett. 2005, 385, 153-157 (Pubitemid 40961653)
48. Joseph, J. A.; Shukitt-Hale, B.; Denisova, N. A. Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits J. Neurosci. 1998, 18, 8047-8055 (Pubitemid 28441042)
49. Patil, C. S.; Singh, V. P.; Satyanarayan, P. S. Protective effect of flavonoids against aging- and lipopolysaccharide-induced cognitive impairment in mice Pharmacology 2003, 69, 59-67 (Pubitemid 37034425)
50. Shirai, N.; Suzuki, H. Effect of dietary docosahexaenoic acid and catechins on maze behavior in mice Ann. Nutr. Metab. 2004, 48, 51-58 (Pubitemid 38250504)
51. Unno, K.; Takabayayashi, F.; Kishido, T.; Oku, N. Suppressive effect of green tea catechins on morphological and functional regression of the brain in aged mice with accelerated senescence (SAMP10) Exp. Gerontol. 2004, 39, 1027-1034 (Pubitemid 38952883)
52. Singh, A.; Naidu, P. S.; Kulkarni, S. K. Reversal of aging and chronic ethanol-induced cognitive dysfunction by quercetin a bioflavonoid Free Radical Res. 2003, 37, 1245-1252 (Pubitemid 37322203)
53. Letenneur, L.; Proust-Lima, C.; Le Gouge, A.; Dartigues, J. F.; Barberger-Gateau, P. Flavonoid intake and cognitive decline over a 10-year period Am. J. Epidemiol. 2007, 165, 1364-1371 (Pubitemid 47234313)
54. Fernández, S. P.; Wasowski, C.; Losalzo, L. M.; Granger, R. E.; Johnston, G. A. R.; Paladini, A. C.; Marder, M. Central nervous system depressant action of flavonoid glycosides Eur. J. Pharmacol. 2006, 539, 168-176 (Pubitemid 44208813)
55. Kobayashi, S.; Tanabe, S. Evaluation of the anti-allergic activity of Citrus unshiu using rat basophilic leukemia RBL-2H3 cells as well as basophils of patients with seasonal allergic rhinitis to pollen Int. J. Mol. Med. 2006, 17, 511-515
56. Benavente-García, O.; Castillo, J. Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity J. Agric. Food Chem. 2008, 56, 6185-205
57. Manthey, J. A.; Guthrie, N. Antiproliferative activities of citrus flavonoids against six human cancer cell lines J. Agric. Food Chem. 2002, 50, 5837-5843 (Pubitemid 35155302)
58. Miller, E. G.; Peacock, J. J.; Bourland, T. C.; Taylor, S. E.; Wright, J. M.; Patil, B. S.; Miller, E. G. Inhibition of oral carcinogenesis by citrus flavonoids Nutr. Cancer 2008, 60, 69-74 (Pubitemid 351186217)
59. Tang, M. X.; Ogawa, K.; Asamoto, M.; Chewonarin, T.; Suzuki, S.; Tanaka, T.; Shirai, T. Effects of Nobiletin on PhIP-Induced Prostate and Colon Carcinogenesis in F344 Rats Nutr. Cancer 2011, 63, 227-233
60. Benavente-García, O.; Castillo, J.; Alcaraz, M.; Vicente, V.; Del Río, J. A.; Ortuño, A. Beneficial action of Citrus flavonoids on multiple cancer-related biological pathways Curr. Cancer Drug Targets 2007, 7, 795-809
61. Kawaii, S.; Tomono, Y.; Katase, E.; Ogawa, K.; Yano, M. Antiproliferative activity of flavonoids on several cancer cell lines Biosci., Biotechnol., Biochem. 1999, 63, 896-899 (Pubitemid 129562768)
62. Choi, E. J.; Ahn, W. S. Neuroprotective effects of chronic hesperetin administration in miceArch Arch. Pharmacal Res. 2008, 31, 1457-1462
63. Lee, S. J.; McEwen, B. S. Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications Annu. Rev. Pharmacol. Toxicol. 2001, 41, 569-591 (Pubitemid 32385899)
64. Wang, H. Q.; Smart, R. C. Overexpression of protein kinase C-alpha in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-alpha expression but not timor promotion J. Cell Sci. 1999, 112, 3497-3506
65. Landolfi, R.; Mower, R. L.; Steiner, M. Modification of platelet function and arachidonic acid metabolism by bioflavonoids. Structure-activity relations Biochem. Pharmacol. 1984, 33, 1525-1530 (Pubitemid 14105028)
66. Gil, B.; Sanz, M. J.; Terencio, M. C.; Ferrándiz, M. L.; Bustos, G.; Payá, M.; Gunasegaran, R.; Alcaraz, M. J. Effects of flavonoids on Naja naja and human recombinant synovial phospholipases A2 and inflammatory responses in mice Life Sci. 1994, 54, PL333-338
67. Rossi, F.; Romeo, D.; Patriarca, P. Metabolic perturbation of the inflammatory cells Agents Actions 1976, 6, 50-59
68. Dana, R.; Malech, H. L.; Levy, R. The requirement for phospholipase A2 for activation of the assembled NADPH oxidase in human neutrophils Biochem. J. 1994, 297, 217-723
69. Erratum in: Biochem. J. 1994, 298, 759.
70. Zallen, G.; Moore, E. E.; Johnson, J. L.; Tamura, D. Y.; Barkin, M.; Stockinger, H.; Silliman, C. C. New mechanisms by which secretory phospholipase A2 stimulates neutrophils to provoke the release of cytotoxic agents Arch. Surg. 1998, 133, 1229-1233 (Pubitemid 28516275)
71. Shanmugam, K.; Holmquist, L.; Steele, M.; Stuchbury, G.; Berbaum, K.; Schulz, O.; Benavente-García, O.; Castillo, J.; Burnell, J.; Garcia Rivas, V.; Dobson, G.; Münch, G. Plant-derived polyphenols attenuate lipopolysaccharide-induced nitric oxide and tumour necrosis factor production in murine microglia and macrophages Mol. Nutr. Food Res. 2008, 52, 427-438
72. Heo, H. J.; Kim, D. O.; Shin, S. C.; Kim, M. J.; Kim, B. G.; Shin, D. H. Effect of antioxidant flavanone, naringenin, from Citrus junoson neuroprotection J. Agric. Food Chem. 2004, 52, 1520-1525
73. Vauzour, D.; Vafeiadou, K.; Rice-Evans, C.; Williams, R. J.; Spencer, J. P. E Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavonones in cortical neurons J. Neurochem. 2007, 103, 1355-1367 (Pubitemid 47631805)
74. Cho, J. Antioxidant and neuroprotective effects of hesperidin and its aglycone hesperetin Arch. Pharmacal Res. 2006, 29, 699-706 (Pubitemid 44338469)
75. Heo, H. J.; Lee, C. Y. Strawberry and its anthocyanins reduce oxidative stress-induced apoptosis in PC12 cells J. Agric. Food Chem. 2005, 53, 1984-1989
76. Raza, S. S.; Khan, M. M.; Ahmad, A.; Ashafag, M.; Khuwaja, G.; Tabassum, R.; Javed, H.; Siddiqui, M. S.; safhi, M. M.; Islam, F. Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke Brain Res. 2011, 1420, 93-105
77. Spencer, J. P.; Schroeter, H.; Crossthwaithe, A. J.; Kuhnle, G.; Williams, R. J.; Rice-Evans, C. Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts Free Radical Biol. Med. 2001, 31, 1139-1146 (Pubitemid 33000135)
78. Schroeter, H.; Spencer, J. P.; Rice-Evans, C.; Williams, R. J. Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3 Biochem. J. 2001, 358 (Part 3) 547-557 (Pubitemid 32896942)
79. 2-induced cytotoxicity in PC12 cells J. Agric. Food Chem. 2008, 56, 859-864
80. Hwang, S. L.; Yen, G. C. Modulation of Akt, JNK, and p38 activation is involved in citrus flavonoids-mediated cytoprotection of PC12 cells challenged by hydrogen peroxide J. Agric. Food Chem. 2009, 57, 2576-2582
81. 2+ and PI3-kinase J. Neurochem. 2002, 80, 23-35
82. McGinnis, K. M.; Wang, K. W. Alternation of extracellular calcium elicits selective modes of cell death and protease activation in SH-SY5Y human neuroblastoma cells J. Neurochem. 1999, 72, 1853-1863 (Pubitemid 29185987)
83. Youdim, K. A.; Shukitt-Hale, B.; Joseph, J. A. Flavonoids and the brain: interactions at the blood-brain barrier and their physiological effects on the central nervous system Free Radical Biol. Med 2004, 37, 1683-1693 (Pubitemid 39441053)
84. Paulke, A.; Schubert-Zsilavecz, M.; Wurglics, M. Determination of St. John's wort flavonoid-metabolites in rat brain through high performance liquid chromatography coupled with fluorescence detection J. Chromatogr., B: Anal. Technol. Biomed. Life Sci. 2006, 832, 109-113 (Pubitemid 43213017)
85. Erlund, I.; Meririnne, E.; Alfthan, G.; Aro, A. Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice J. Nutr. 2001, 131, 235-241 (Pubitemid 32115362)
86. Erlund, I.; Silaste, M. L.; Alfthan, G.; Rantala, M.; Kesäniemi, Y. A.; Aro, A. Plasma concentrations of the flavonoids hesperetin, naringenin and quercetin in human subjects following their habitual diets, and diets high or low in fruit and vegetables Eur. J. Clin. Nutr. 2002, 56, 891-898
87. Kanaze, F. I.; Bounartzi, M. I.; Georgarakis, M.; Niopas, I. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects Eur. J. Clin. Nutr. 2007, 61, 472-477 (Pubitemid 46605217)
88. Su, Z. Z.; Leszczyniecka, M.; Kang, D. C.; Sarkar, D.; Chao, W.; Volsky, D. J.; Fisher, P. B. Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2) Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 1955-1960 (Pubitemid 36254555)
89. Lee, S. G.; Su, Z. Z.; Emdad, L.; Gupta, P.; Sarkar, D.; Borjabad, A.; Volsky, D. J.; Fisher, P. B. Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes J. Biol. Chem. 2008, 283, 13116-13123
90. Habauzit, D.; Flouriot, G.; Pakdel, F.; Saligaut, C. Effects of estrogens and endocrine-disrupting chemicals on cell differentiation-survival- proliferation in brain: contributions of neuronal cell lines J. Toxicol. Environ. Health, Part B 2011, 14, 300-327
91. Sarkar, S.; Ravikumar, B.; Floto, R. A.; Rubinsztein, D. C. Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine- expanded huntingtin and related proteinopathies Cell Death Differ. 2009, 16, 46-56
92. Wu, P.; Jiang, C.; Shen, Q.; Hu, Y. Systematic gene expression profile of hypothalamus in calorie-restricted mice implicates the involvement of mTOR signaling in neuroprotective activity Mech. Ageing Dev. 2009, 130, 602-610
93. Carloni, S.; Buonocore, G.; Longini, M.; Proietti, F.; Balduini, W. Inhibition of rapamycin-induced autophagy causes necrotic cell death associated with BAX/BAD mitochondrial translocation Neuroscience 2011, 10.1016/j. neuroscience.2011.12.021
94. Wollen, K. A. Alzheimer's disease: the pros and cons of pharmaceutical, nutritional, botanical, and stimulatory therapies, with a discussion of treatment strategies from the perspective of patients and practitioners Altern. Med. Rev. 2010, 15, 223-44
95. So, F. V.; Guthrie, N.; Chambers, A. F.; Moussa, M.; Carroll, K. K. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices Nutr. Cancer 1996, 26, 167-181 (Pubitemid 26300196)
96. Huang, Y. T.; Hwang, J. J.; Lee, P. P.; Ke, F. C.; Huang, J. H.; Huang, C. J.; Kandaswami, C.; Middleton., E., Jr.; Lee, M. T. 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. 1999, 128, 999-1010 (Pubitemid 29512033)
97. Walker, E.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann, M. P.; Williams, R. L. Structural determinants of phosphoinositide 3-kinase inhibition by wortmanin, LY294002, quercetin, myricetin, and saturosporine Mol. Cell 2000, 6, 909-919
98. Green, D. R.; Reed, J. C. Mitochondria and apoptosis Science 1998, 281, 1309-1312 (Pubitemid 28406816)
99. Goyal, L. Cell death inhibition: keeping caspases in check Cell 2001, 104, 805-808 (Pubitemid 32289272)
100. Srinivasula, S. M.; Hegde, R.; Saleh, A.; Datta, P.; Shiozaki, E.; Chai, J.; Lee, R. A.; Robbins, P. D.; Fernandes-Alnemri, T.; Shi, Y.; Alnemri, E. S. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis Nature 2001, 410, 112-116 (Pubitemid 32225846)
101. Matter, W. F.; Brown, R. F.; Vlahos, C. J. The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs Biochem. Biophys. Res. Commun. 1992, 186, 624-631
102. Spencer, J. P.; Schroeter, H.; Shenoy, B.; Srai, S. K.; Debnam, E. S.; Rice-Evans, C. Epicatechin is the primary bioavailable form of the procyanidin dimers B2 and B5 after transfer across the small intestine Biochem. Biophys. Res. Commun. 2001, 285, 588-593 (Pubitemid 32924810)
103. Spencer, J. P.; Schroeter, H.; Rechner, A. R.; Rice-Evans, C. Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo Antioxid. Redox Signaling 2001, 3, 1023-1039 (Pubitemid 34027360)
104. Levites, Y.; Amit, T.; Youdim, M. B.; Mandel, S. Involvement of protein kinase C activation and cell survival/ cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action J. Biol. Chem. 2002, 277, 30574-30580 (Pubitemid 34970751)
105. Liu, L.; Xu, D. M.; Cheng, Y. Y. Distinct effects of naringenin and hesperetin on nitric oxide production from endothelial cells J. Agric. Food Chem. 2008, 56, 824-829 (Pubitemid 351300251)
106. Bourque, M.; Dluzen, D. E.; Di Paolo, T. Neuroprotective actions of sex steroids in Parkinson's disease Front. Neuroendocrinol. 2009, 30, 142-157
107. Hwang, S. L.; Yen, G. C. Effect of hesperetin against oxidative stress via ER- and TrkA-Mediated actions in PC12 cells J. Agric. Food Chem. 2011, 59, 5779-5785
108. Greeve, I.; Hermans-Borgmeyer, I.; Brellinger, C.; Kasper, D.; Gomez-Isla, T.; Behl, C.; Levkau, B.; Nitsch, R. M. The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress J. Neurosci. 2000, 20, 7345-7352
109. Han, B. H.; D'Costa, A.; Back, S. A.; Parsadanian, M.; Patel, S.; Shah, A. R.; Gidday, J. M.; Srinivasan, A.; Deshmukh, M.; Holtzman, D. M. BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia Neurobiol. Dis. 2000, 7, 38-53 (Pubitemid 30141818)
110. St-Pierre, J.; Drori, S.; Uldry, M.; Silvaggi, J. M.; Rhee, J.; Jäger, S.; Handschin, C.; Zheng, K.; Lin, J.; Yang, W.; Simon, D. K.; Bachoo, R.; Spiegelman, B. M. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators Cell 2006, 127, 397-408 (Pubitemid 44572377)
111. Arévalo, J. C.; Wu, S. H. Neurotrophin signaling: many exciting surprises! Cell. Mol. Life Sci. 2006, 63, 1523-1537 (Pubitemid 44156749)
112. Vasudevan, N.; Pfaff, D. Membrane-initiated actions of estrogens in neuroendocrinology: emerging principles Endocr. Rev. 2007, 28, 1-19 (Pubitemid 46220848)
113. Hwang, S. L. Neuroprotection of hesperetin against oxidative damage and its underlying mechanisms in PC12 cells. Ph.D. Dissertation, National Chung Hsing University, Taichung, Taiwan, 2010.
114. Williams, R. J.; Spencer, J. P. E Flavonoids, cognition, and dementia: Actions, mechanisms, and potential therapeutic utility for Alzheimer disease Free Radical Biol. Med. 2012, 52, 35-45
115. Kong, A. N.; Owuor, E. D. Antioxidant and oxidants regulated signal transduction pathways Biochem. Pharmacol. 2002, 64, 675-670