Cocoa Phytochemicals: Recent Advances in Molecular Mechanisms on Health

Critical Reviews in Food Science and Nutrition

Volumn 54, Issue 11, 2014, Pages 1458-1472

  Kim, Jiyoung ^a,b,c   Kim, Jaekyoon ^a   Shim, Jaesung ^a   Lee, Chang Yong ^d   Lee, Ki Won ^a,b,c,e   Lee, Hyong Joo ^a,b,c  

^a Seoul National University   (South Korea)

^b Seoul National University   (South Korea)

^c Seoul National University   (South Korea)

^d Department of Obstetrics Gynecology   (United States)

^e Seoul National University   (South Korea)

Author keywords

cancer; cardiovascular diseases; Cocoa; neurodegeneration; obesity and diabetes; skin aging

Indexed keywords

CAFFEINE; DISEASES; FLAVONOIDS; HEALTH; NUTRITION; PHENOLS; VITAMINS;

CANCER; CARDIO-VASCULAR DISEASE; HUMAN DISEASE; MOLECULAR MECHANISM; MOLECULAR TARGETS; NEURODEGENERATION; PHYTOCHEMICALS; SKIN AGING;

COCOA;

CAFFEINE; FLAVONOID; PLANT MEDICINAL PRODUCT; PROANTHOCYANIDIN; THEOBROMINE;

ANIMAL; BIOAVAILABILITY; CACAO; CARDIOVASCULAR DISEASE; CHEMISTRY; CUTANEOUS PARAMETERS; DEGENERATIVE DISEASE; DIABETES MELLITUS; DRUG EFFECT; HEALTH PROMOTION; HUMAN; NEOPLASM; OBESITY; REVIEW;

ANIMALS; BIOLOGICAL AVAILABILITY; CACAO; CAFFEINE; CARDIOVASCULAR DISEASES; DIABETES MELLITUS; FLAVONOIDS; HEALTH PROMOTION; HUMANS; NEOPLASMS; NEURODEGENERATIVE DISEASES; OBESITY; PHYTOCHEMICALS; PROANTHOCYANIDINS; SKIN AGING; THEOBROMINE;

EID: 84896807803     PISSN: 10408398     EISSN: 15497852     Source Type: Journal    
DOI: 10.1080/10408398.2011.641041     Document Type: Review

References (147)

1. Abd El Mohsen, M. M., Kuhnle, G., Rechner, A. R., Schroeter, H., Rose, S., Jenner, P. and Rice-Evans, C. A. 2002. Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic. Biol. Med., 33: 1693 - 1702.
2. Andres-Lacueva, C., Monagas, M., Khan, N., Izquierdo-Pulido, M., Urpi-Sarda, M., Permanyer, J. and Lamuela-Raventos, R. M. 2008. Flavanol and flavonol contents of cocoa powder products: Influence of the manufacturing process. J. Agric. Food Chem, 56: 3111 - 3117.
3. Arteel, G. E., Schroeder, P. and Sies, H. 2000. Reactions of peroxynitrite with cocoa procyanidin oligomers. J. Nutr, 130: 2100S - 2104S.
4. Baba, S., Natsume, M., Yasuda, A., Nakamura, Y., Tamura, T., Osakabe, N., Kanegae, M. and Kondo, K. 2007a. Plasma LDL and HDL cholesterol and oxidized LDL concentrations are altered in normo- and hypercholesterolemic humans after intake of different levels of cocoa powder. J. Nutr, 137: 1436 - 1441.
5. Baba, S., Osakabe, N., Kato, Y., Natsume, M., Yasuda, A., Kido, T., Fukuda, K., Muto, Y. and Kondo, K. 2007b. Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. Am. J. Clin. Nutr., 85: 709 - 717.
6. Baba, S., Osakabe, N., Yasuda, A., Natsume, M., Takizawa, T., Nakamura, T. and Terao, J. 2000. Bioavailability of (-)-epicatechin upon intake of chocolate and cocoa in human volunteers. Free Radic. Res., 33: 635 - 641.
7. Barcz, E., Sommer, E., Sokolnicka, I., Gawrychowski, K., Roszkowska-Purska, K., Janik, P. and Skopinska-Rozewska, E. 1998. The influence of theobromine on angiogenic activity and proangiogenic cytokines production of human ovarian cancer cells. Oncol. Rep, 5: 517 - 520.
8. Berliner, J. A. and Heinecke, J. W. 1996. The role of oxidized lipoproteins in atherogenesis. Free Radic. Biol. Med, 20: 707 - 727.
9. Biessels, G. J. 2010. Caffeine, diabetes, cognition, and dementia. J. Alzheimers Dis, 20 (Suppl. 1): S143 - S150.
10. Bisson, J. F., Nejdi, A., Rozan, P., Hidalgo, S., Lalonde, R. and Messaoudi, M. 2008. Effects of long-term administration of a cocoa polyphenolic extract (Acticoa powder) on cognitive performances in aged rats. Br. J. Nutr., 100: 94 - 101.
11. Brothers, H. M., Marchalant, Y. and Wenk, G. L. 2010. Caffeine attenuates lipopolysaccharide-induced neuroinflammation. Neurosci. Lett., 480: 97 - 100.
12. Buijsse, B., Feskens, E. J., Kok, F. J. and Kromhout, D. 2006. Cocoa intake, blood pressure, and cardiovascular mortality: The Zutphen Elderly Study. Arch. Intern. Med., 166: 411 - 417.
13. Caligiani, A., Cirlini, M., Palla, G., Ravaglia, R. and Arlorio, M. 2007. GC-MS detection of chiral markers in cocoa beans of different quality and geographic origin. Chirality, 19: 329 - 334.
14. Carnesecchi, S., Schneider, Y., Lazarus, S. A., Coehlo, D., Gosse, F. and Raul, F. 2002. Flavanols and procyanidins of cocoa and chocolate inhibit growth and polyamine biosynthesis of human colonic cancer cells. Cancer Lett, 175: 147 - 155.
15. Chavez-Valdez, R., Wills-Karp, M., Ahlawat, R., Cristofalo, E. A., Nathan, A. and Gauda, E. B. 2009. Caffeine modulates TNF-alpha production by cord blood monocytes: The role of adenosine receptors. Pediatr. Res, 65: 203 - 208.
16. Chen, X., Ghribi, O. and Geiger, J. D. 2010. Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's and Parkinson's diseases. J. Alzheimers Dis, 20 (Suppl. 1): S127 - S141.
17. Cho, E. S., Jang, Y. J., Kang, N. J., Hwang, M. K., Kim, Y. T., Lee, K. W. and Lee, H. J. 2009. Cocoa procyanidins attenuate 4-hydroxynonenal-induced apoptosis of PC12 cells by directly inhibiting mitogen-activated protein kinase kinase 4 activity. Free Radic. Biol. Med, 46: 1319 - 1327.
18. Cho, E. S., Lee, K. W. and Lee, H. J. 2008. Cocoa procyanidins protect PC12 cells from hydrogen-peroxide-induced apoptosis by inhibiting activation of p38 MAPK and JNK. Mutat. Res, 640: 123 - 130.
19. Cooper, K. A., Campos-Gimenez, E., Jimenez Alvarez, D., Nagy, K., Donovan, J. L. and Williamson, G. 2007. Rapid reversed phase ultra-performance liquid chromatography analysis of the major cocoa polyphenols and inter-relationships of their concentrations in chocolate. J. Agric. Food Chem., 55: 2841 - 2847.
20. Cooper, K. A., Donovan, J. L., Waterhouse, A. L. and Williamson, G. 2008. Cocoa and health: A decade of research. Br. J. Nutr, 99: 1 - 11.
21. Corti, R., Flammer, A. J., Hollenberg, N. K. and Luscher, T. F. 2009. Cocoa and cardiovascular health. Circulation, 119: 1433 - 1441.
22. Counet, C., Callemien, D. and Collin, S. 2006. Chocolate and cocoa: New sources of trans-resveratrol and trans-piceid. Food Chem, 98: 649 - 657.
23. Cuevas, E., Limon, D., Perez-Severiano, F., Diaz, A., Ortega, L., Zenteno, E. and Guevara, J. 2009. Antioxidant effects of epicatechin on the hippocampal toxicity caused by amyloid-beta 25-35 in rats. Eur. J. Pharmacol, 616: 122 - 127.
24. de Mendonca, A. and Cunha, R. A. 2010. Therapeutic opportunities for caffeine in Alzheimer's disease and other neurodegenerative disorders. J. Alzheimers Dis., 20 (Suppl. 1): S1 - S2.
25. Deprez, S., Brezillon, C., Rabot, S., Philippe, C., Mila, I., Lapierre, C. and Scalbert, A. 2000. Polymeric proanthocyanidins are catabolized by human colonic microflora into low-molecular-weight phenolic acids. J. Nutr, 130: 2733 - 2738.
26. Deprez, S., Mila, I., Huneau, J. F., Tome, D. and Scalbert, A. 2001. Transport of proanthocyanidin dimer, trimer, and polymer across monolayers of human intestinal epithelial Caco-2 cells. Antioxid. Redox. Signal, 3: 957 - 967.
27. Dillinger, T. L., Barriga, P., Escarcega, S., Jimenez, M., Salazar Lowe, D. and Grivetti, L. E. 2000. Food of the gods: Cure for humanity? A cultural history of the medicinal and ritual use of chocolate. J. Nutr, 130: 2057S - 2072S.
28. Donovan, J. L., Manach, C., Rios, L., Morand, C., Scalbert, A. and Remesy, C. 2002. Procyanidins are not bioavailable in rats fed a single meal containing a grapeseed extract or the procyanidin dimer B3. Br. J. Nutr, 87: 299 - 306.
29. Dray, C., Daviaud, D., Guigne, C., Valet, P. and Castan-Laurell, I. 2007. Caffeine reduces TNFalpha up-regulation in human adipose tissue primary culture. J. Physiol. Biochem, 63: 329 - 336.
30. Echeverri, D., Montes, F. R., Cabrera, M., Galan, A. and Prieto, A. 2010. Caffeine's vascular mechanisms of action. Int. J. Vasc. Med., 2010: 834060
31. Engler, M. B. and Engler, M. M. 2006. The emerging role of flavonoid-rich cocoa and chocolate in cardiovascular health and disease. Nutr. Rev, 64: 109 - 118.
32. Engler, M. B., Engler, M. M., Chen, C. Y., Malloy, M. J., Browne, A., Chiu, E. Y., Kwak, H. K., Milbury, P., Paul, S. M., Blumberg, J. and Mietus-Snyder, M. L. 2004. Flavonoid-rich dark chocolate improves endothelial function and increases plasma epicatechin concentrations in healthy adults. J. Am. Coll. Nutr., 23: 197 - 204.
33. Eskelinen, M. H. and Kivipelto, M. 2010. Caffeine as a protective factor in dementia and Alzheimer's disease. J. Alzheimers Dis, 20 (Suppl. 1): S167 - S174.
34. Fisher, N. D. and Hollenberg, N. K. 2006. Aging and vascular responses to flavanol-rich cocoa. J. Hypertens, 24: 1575 - 1580.
35. Fisher, N. D., Hughes, M., Gerhard-Herman, M. and Hollenberg, N. K. 2003. Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J. Hypertens, 21: 2281 - 2286.
36. Forsyth, W. G. 1952. Cacao polyphenolic substances. I. Fractionation of the fresh bean. Biochem. J, 51: 511 - 516.
37. Fraga, C. G., Actis-Goretta, L., Ottaviani, J. I., Carrasquedo, F., Lotito, S. B., Lazarus, S., Schmitz, H. H. and Keen, C. L. 2005. Regular consumption of a flavanol-rich chocolate can improve oxidant stress in young soccer players. Clin. Dev. Immunol, 12: 11 - 17.
38. Francis, S. T., Head, K., Morris, P. G. and Macdonald, I. A. 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): S215 - S220.
39. Gasser, P., Lati, E., Peno-Mazzarino, L., Bouzoud, D., Allegaert, L. and Bernaert, H. 2008. Cocoa polyphenols and their influence on parameters involved in ex vivo skin restructuring. Int. J. Cosmet Sci, 30: 339 - 345.
40. Gil, M., Skopinska-Rozewska, E., Radomska, D., Demkow, U., Skurzak, H., Rochowska, M., Beuth, J. and Roszkowski, K. 1993. Effect of purinergic receptor antagonists suramin and theobromine on tumor-induced angiogenesis in BALB/c mice. Folia Biol. (Praha)., 39: 63 - 68.
41. Gordon, D. J., Probstfield, J. L., Garrison, R. J., Neaton, J. D., Castelli, W. P., Knoke, J. D., Jacobs, D. R. Jr., Bangdiwala, S. and Tyroler, H. A. 1989. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation, 79: 8 - 15.
42. Gotti, R., Furlanetto, S., Pinzauti, S. and Cavrini, V. 2006. Analysis of catechins in Theobroma cacao beans by cyclodextrin-modified micellar electrokinetic chromatography. J. Chromatogr. A., 1112: 345 - 352.
43. Grassi, D., Lippi, C., Necozione, S., Desideri, G. and Ferri, C. 2005. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am. J. Clin. Nutr., 81: 611 - 614.
44. Gu, L., House, S. E., Wu, X., Ou, B. and Prior, R. L. 2006. Procyanidin and catechin contents and antioxidant capacity of cocoa and chocolate products. J. Agric. Food Chem., 54: 4057 - 4061.
45. Heinrich, U., Neukam, K., Tronnier, H., Sies, H. and Stahl, W. 2006. Long-term ingestion of high flavanol cocoa provides photoprotection against UV-induced erythema and improves skin condition in women. J. Nutr., 136: 1565 - 1569.
46. Heiss, C., Dejam, A., Kleinbongard, P., Schewe, T., Sies, H. and Kelm, M. 2003. Vascular effects of cocoa rich in flavan-3-ols. JAMA, 290: 1030 - 1031.
47. Heiss, C., Finis, D., Kleinbongard, P., Hoffmann, A., Rassaf, T., Kelm, M. and Sies, H. 2007. Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1 week. J. Cardiovasc. Pharmacol, 49: 74 - 80.
48. Heiss, C., Kleinbongard, P., Dejam, A., Perre, S., Schroeter, H., Sies, H. and Kelm, M. 2005. Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J. Am. Coll. Cardiol., 46: 1276 - 1283.
49. Heiss, C., Schroeter, H., Balzer, J., Kleinbongard, P., Matern, S., Sies, H. and Kelm, M. 2006. Endothelial function, nitric oxide, and cocoa flavanols. J. Cardiovasc. Pharmacol., 47 (Suppl. 2): S128 - S135. discussion S172- S176
50. Heo, H. J. and Lee, C. Y. 2005. Epicatechin and catechin in cocoa inhibit amyloid beta protein induced apoptosis. J. Agric. Food Chem, 53: 1445 - 1448.
51. Heptinstall, S., May, J., Fox, S., Kwik-Uribe, C. and Zhao, L. 2006. Cocoa flavanols and platelet and leukocyte function: Recent in vitro and ex vivo studies in healthy adults. J. Cardiovasc. Pharmacol, 47 (Suppl. 2): S197 - S205. discussion S206-S209
52. Hermann, F., Spieker, L. E., Ruschitzka, F., Sudano, I., Hermann, M., Binggeli, C., Luscher, T. F., Riesen, W., Noll, G. and Corti, R. 2006. Dark chocolate improves endothelial and platelet function. Heart, 92: 119 - 120.
53. Hollenberg, N. K., Martinez, G., McCullough, M., Meinking, T., Passan, D., Preston, M., Rivera, A., Taplin, D. and Vicaria-Clement, M. 1997. Aging, acculturation, salt intake, and hypertension in the Kuna of Panama. Hypertension, 29: 171 - 176.
54. Holt, R. R., Lazarus, S. A., Sullards, M. C., Zhu, Q. Y., Schramm, D. D., Hammerstone, J. F., Fraga, C. G., Schmitz, H. H. and Keen, C. L. 2002. Procyanidin dimer B2 [epicatechin-(4beta-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa. Am. J. Clin. Nutr., 76: 798 - 804.
55. Innes, A. J., Kennedy, G., McLaren, M., Bancroft, A. J. and Belch, J. J. 2003. Dark chocolate inhibits platelet aggregation in healthy volunteers. Platelets, 14: 325 - 327.
56. Jourdain, C., Tenca, G., Deguercy, A., Troplin, P. and Poelman, D. 2006. In-vitro effects of polyphenols from cocoa and beta-sitosterol on the growth of human prostate cancer and normal cells. Eur. J. Cancer Prev., 15: 353 - 361.
57. Kang, N. J., Lee, K. W., Lee, D. E., Rogozin, E. A., Bode, A. M., Lee, H. J. and Dong, Z. 2008. Cocoa procyanidins suppress transformation by inhibiting mitogen-activated protein kinase kinase. J. Biol. Chem, 283: 20664 - 20673.
58. Kang, S. S., Han, K. S., Ku, B. M., Lee, Y. K., Hong, J., Shin, H. Y., Almonte, A. G., Woo, D. H., Brat, D. J., Hwang, E. M., Yoo, S. H., Chung, C. K., Park, S. H., Paek, S. H., Roh, E. J., Lee, S. J., Park, J. Y., Traynelis, S. F. and Lee, C. J. 2010. Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival. Cancer Res., 70: 1173 - 1183.
59. Kenny, D., Coughlan, M. G., Pagel, P. S., Kampine, J. P. and Warltier, D. C. 1994. Transforming growth factor beta 1 preserves endothelial function after multiple brief coronary artery occlusions and reperfusion. Am. Heart J, 127: 1456 - 1461.
60. Kenny, T. P., Keen, C. L., Jones, P., Kung, H. J., Schmitz, H. H. and Gershwin, M. E. 2004. Pentameric procyanidins isolated from Theobroma cacao seeds selectively downregulate ErbB2 in human aortic endothelial cells. Exp. Biol. Med. (Maywood)., 229: 255 - 263.
61. Kim, J. E., Son, J. E., Jung, S. K., Kang, N. J., Lee, C. Y., Lee, K. W. and Lee, H. J. 2010. Cocoa polyphenols suppress TNF-alpha-induced vascular endothelial growth factor expression by inhibiting phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase kinase-1 (MEK1) activities in mouse epidermal cells. Br. J. Nutr., 104: 957 - 964.
62. Kobayashi-Hattori, K., Mogi, A., Matsumoto, Y. and Takita, T. 2005. Effect of caffeine on the body fat and lipid metabolism of rats fed on a high-fat diet. Biosci. Biotechnol. Biochem., 69: 2219 - 2223.
63. Kostyuk, V. A., Kraemer, T., Sies, H. and Schewe, T. 2003. Myeloperoxidase/ nitrite-mediated lipid peroxidation of low-density lipoprotein as modulated by flavonoids. FEBS Lett, 537: 146 - 150.
64. Kraemer, T., Prakosay, I., Date, R. A., Sies, H. and Schewe, T. 2004. Oxidative modification of low-density lipoprotein: Lipid peroxidation by myeloperoxidase in the presence of nitrite. Biol. Chem, 385: 809 - 818.
65. Ku, B. M., Lee, Y. K., Jeong, J. Y., Ryu, J., Choi, J., Kim, J. S., Cho, Y. W., Roh, G. S., Kim, H. J., Cho, G. J., Choi, W. S. and Kang, S. S. 2010. Caffeine inhibits cell proliferation and regulates PKA/GSK3beta pathways in U87MG human glioma cells. Mol. Cells, 31: 275 - 279.
66. Lee, C. 2000. Antioxidant ability of caffeine and its metabolites based on the study of oxygen radical absorbing capacity and inhibition of LDL peroxidation. Clin. Chim. Acta, 295: 141 - 154.
67. Lee, D. E., Kang, N. J., Lee, K. M., Lee, B. K., Kim, J. H., Lee, K. W. and Lee, H. J. 2010. Cocoa polyphenols attenuate hydrogen peroxide-induced inhibition of gap-junction intercellular communication by blocking phosphorylation of connexin 43 via the MEK/ERK signaling pathway. J. Nutr. Biochem., 21: 680 - 686.
68. Lee, K. W., Kang, N. J., Oak, M. H., Hwang, M. K., Kim, J. H., Schini-Kerth, V. B. and Lee, H. J. 2008. Cocoa procyanidins inhibit expression and activation of MMP-2 in vascular smooth muscle cells by direct inhibition of MEK and MT1-MMP activities. Cardiovasc. Res, 79: 34 - 41.
69. Lee, K. W., Kim, Y. J., Lee, H. J. and Lee, C. Y. 2003. Cocoa has more phenolic phytochemicals and a higher antioxidant capacity than teas and red wine. J. Agric. Food Chem, 51: 7292 - 7295.
70. Lee, K. W., Kundu, J. K., Kim, S. O., Chun, K. S., Lee, H. J. and Surh, Y. J. 2006. Cocoa polyphenols inhibit phorbol ester-induced superoxide anion formation in cultured HL-60 cells and expression of cyclooxygenase-2 and activation of NF-kappaB and MAPKs in mouse skin in vivo. J. Nutr, 136: 1150 - 1155.
71. Lijnen, P. J., Petrov, V. V. and Fagard, R. H. 2000. Induction of cardiac fibrosis by transforming growth factor-beta(1). Mol. Genet Metab, 71: 418 - 435.
72. Loke, W. M., Hodgson, J. M., Proudfoot, J. M., McKinley, A. J., Puddey, I. B. and Croft, K. D. 2008. Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am. J. Clin. Nutr., 88: 1018 - 1025.
73. Lopez-Garcia, E., van Dam, R. M., Rajpathak, S., Willett, W. C., Manson, J. E. and Hu, F. B. 2006. Changes in caffeine intake and long-term weight change in men and women. Am. J. Clin. Nutr., 83: 674 - 680.
74. Lv, X., Chen, Z., Li, J., Zhang, L., Liu, H., Huang, C. and Zhu, P. 2010. Caffeine protects against alcoholic liver injury by attenuating inflammatory response and oxidative stress. Inflamm. Res, 59: 635 - 645.
75. Mackenzie, G. G., Carrasquedo, F., Delfino, J. M., Keen, C. L., Fraga, C. G. and Oteiza, P. I. 2004. Epicatechin, catechin, and dimeric procyanidins inhibit PMA-induced NF-kappaB activation at multiple steps in Jurkat T cells. Faseb. J., 18: 167 - 169.
76. Mackenzie, G. G. and Oteiza, P. I. 2006. Modulation of transcription factor NF-kappaB in Hodgkin's lymphoma cell lines: Effect of (-)-epicatechin. Free Radic. Res., 40: 1086 - 1094.
77. Manach, C., Scalbert, A., Morand, C., Remesy, C. and Jimenez, L. 2004. Polyphenols: Food sources and bioavailability. Am. J. Clin. Nutr, 79: 727 - 747.
78. Manach, C., Williamson, G., Morand, C., Scalbert, A. and Remesy, C. 2005. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr., 81: 230S - 242S.
79. Mao, T., Van De Water, J., Keen, C. L., Schmitz, H. H. and Gershwin, M. E. 2000. Cocoa procyanidins and human cytokine transcription and secretion. J. Nutr., 130: 2093S - 2099S.
80. Mao, T. K., Van De Water, J., Keen, C. L., Schmitz, H. H. and Gershwin, M. E. 2002. Modulation of TNF-alpha secretion in peripheral blood mononuclear cells by cocoa flavanols and procyanidins. Dev. Immunol., 9: 135 - 141.
81. Mao, T. K., Van De Water, J., Keen, C. L., Schmitz, H. H. and Gershwin, M. E. 2003. Cocoa flavonols and procyanidins promote transforming growth factor-beta1 homeostasis in peripheral blood mononuclear cells. Exp. Biol. Med. (Maywood)., 228: 93 - 99.
82. Merighi, S., Benini, A., Mirandola, P., Gessi, S., Varani, K., Simioni, C., Leung, E., Maclennan, S., Baraldi, P. G. and Borea, P. A. 2007. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol. Pharmacol., 72: 395 - 406.
83. Miller, K. B., Hurst, W. J., Flannigan, N., Ou, B., Lee, C. Y., Smith, N. and Stuart, D. A. 2009. Survey of commercially available chocolate- and cocoa-containing products in the United States. 2. Comparison of flavan-3-ol content with nonfat cocoa solids, total polyphenols, and percent cacao. J. Agric. Food Chem, 57: 9169 - 9180.
84. Miller, K. B., Stuart, D. A., Smith, N. L., Lee, C. Y., McHale, N. L., Flanagan, J. A., Ou, B. and Hurst, W. J. 2006. Antioxidant activity and polyphenol and procyanidin contents of selected commercially available cocoa-containing and chocolate products in the United States. J. Agric. Food Chem, 54: 4062 - 4068.
85. Mumford, G. K., Benowitz, N. L., Evans, S. M., Kaminski, B. J., Preston, K. L., Sannerud, C. A. and Silverman, K. Griffiths, R. R. 1996. Absorption rate of methylxanthines following capsules, cola and chocolate. Eur. J. Clin. Pharmacol., 51: 319 - 325.
86. Muniyappa, R., Hall, G., Kolodziej, T. L., Karne, R. J., Crandon, S. K. and Quon, M. J. 2008. Cocoa consumption for 2 wk enhances insulin-mediated vasodilatation without improving blood pressure or insulin resistance in essential hypertension. Am. J. Clin. Nutr., 88: 1685 - 1696.
87. Murphy, K. J., Chronopoulos, A. K., Singh, I., Francis, M. A., Moriarty, H., Pike, M. J., Turner, A. H., Mann, N. J. and Sinclair, A. J. 2003. Dietary flavanols and procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function. Am. J. Clin. Nutr., 77: 1466 - 1473.
88. Mursu, J., Voutilainen, S., Nurmi, T., Rissanen, T. H., Virtanen, J. K., Kaikkonen, J., Nyyssonen, K. and Salonen, J. T. 2004. Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans. Free Radic. Biol. Med, 37: 1351 - 1359.
89. Nakabayashi, H., Hashimoto, T., Ashida, H., Nishiumi, S. and Kanazawa, K. 2008. Inhibitory effects of caffeine and its metabolites on intracellular lipid accumulation in murine 3T3-L1 adipocytes. Biofactors., 34: 293 - 302.
90. Natsume, M., Osakabe, N., Oyama, M., Sasaki, M., Baba, S., Nakamura, Y., Osawa, T. and Terao, J. 2003. Structures of (-)-epicatechin glucuronide identified from plasma and urine after oral ingestion of (-)-epicatechin: Differences between human and rat. Free Radic. Biol. Med., 34: 840 - 849.
91. Nazaruddin, R., Seng, L. K., Hassan, O. and Said, M. 2006. Effect of pulp preconditioning on the content of polyphenols in cocoa beans (Theobroma cacao) during fermentation. Industr. Crops Prod, 24: 87 - 94.
92. Nehlig, A., Daval, J. L. and Debry, G. 1992. Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res. Brain Res. Rev., 17: 139 - 170.
93. Okano, J., Nagahara, T., Matsumoto, K. and Murawaki, Y. 2008. Caffeine inhibits the proliferation of liver cancer cells and activates the MEK/ERK/EGFR signalling pathway. Basic Clin. Pharmacol. Toxicol, 102: 543 - 551.
94. Osakabe, N., Baba, S., Yasuda, A., Iwamoto, T., Kamiyama, M., Takizawa, T., Itakura, H. and Kondo, K. 2001. Daily cocoa intake reduces the susceptibility of low-density lipoprotein to oxidation as demonstrated in healthy human volunteers. Free Radic. Res., 34: 93 - 99.
95. Osakabe, N., Yamagishi, M., Sanbongi, C., Natsume, M., Takizawa, T. and Osawa, T. 1998. The antioxidative substances in cacao liquor. J. Nutr. Sci. Vitaminol. (Tokyo)., 44: 313 - 321.
96. Ottaviani, J. I., Carrasquedo, F., Keen, C. L., Lazarus, S. A., Schmitz, H. H. and Fraga, C. G. 2002. Influence of flavan-3-ols and procyanidins on UVC-mediated formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine in isolated DNA. Arch. Biochem. Biophys, 406: 203 - 208.
97. Pan, T., Jankovic, J. and Le, W. 2003. Potential therapeutic properties of green tea polyphenols in Parkinson's disease. Drugs Aging, 20: 711 - 721.
98. Pearson, D. A., Paglieroni, T. G., Rein, D., Wun, T., Schramm, D. D., Wang, J. F., Holt, R. R., Gosselin, R., Schmitz, H. H. and Keen, C. L. 2002. The effects of flavanol-rich cocoa and aspirin on ex vivo platelet function. Thromb. Res, 106: 191 - 197.
99. Peng, L., Khan, N., Afaq, F., Ye, C. and Mukhtar, H. 2010. In vitro and in vivo effects of water extract of white cocoa tea (Camellia ptilophylla) against human prostate cancer. Pharm. Res, 27: 1128 - 1137.
100. Pettipher, G. L. 1986. An improved method for the extraction and quantitation of anthocyanins in cocoa beans and its use as an index of the degree of fermentation. J. Sci. Food Agric, 37: 289 - 296.
101. Podrez, E. A., Abu-Soud, H. M. and Hazen, S. L. 2000. Myeloperoxidase-generated oxidants and atherosclerosis. Free Radic. Biol. Med, 28: 1717 - 1725.
102. Prediger, R. D. 2010. Effects of caffeine in Parkinson's disease: From neuroprotection to the management of motor and non-motor symptoms. J. Alzheimers Dis, 20 (Suppl. 1): S205 - S220.
103. Ptolemy, A. S., Tzioumis, E., Thomke, A., Rifai, S. and Kellogg, M. 2010. Quantification of theobromine and caffeine in saliva, plasma and urine via liquid chromatography-tandem mass spectrometry: A single analytical protocol applicable to cocoa intervention studies. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci, 878: 409 - 416.
104. Naik, J. 2001. Improved high-performance liquid chromatography method to determine theobromine and caffeine in cocoa and cocoa products. J. Agric. Food Chem, 49: 3579 - 3583. Pura
105. Ramiro, E., Franch, A., Castellote, C., Perez-Cano, F., Permanyer, J., Izquierdo-Pulido, M. and Castell, M. 2005. Flavonoids from Theobroma cacao down-regulate inflammatory mediators. J. Agric. Food Chem., 53: 8506 - 8511.
106. Ramiro-Puig, E. and Castell, M. 2009. Cocoa: Antioxidant and immunomodulator. Br. J. Nutr, 101: 931 - 940.
107. Rein, D., Lotito, S., Holt, R. R., Keen, C. L., Schmitz, H. H. and Fraga, C. G. 2000. Epicatechin in human plasma: In vivo determination and effect of chocolate consumption on plasma oxidation status. J. Nutr, 130: 2109S - 2114S.
108. Richelle, M., Tavazzi, I., Enslen, M. and Offord, E. A. 1999. Plasma kinetics in man of epicatechin from black chocolate. Eur. J. Clin. Nutr, 53: 22 - 26.
109. Rios, L. Y., Gonthier, M. P., Remesy, C., Mila, I., Lapierre, C., Lazarus, S. A., Williamson, G. and Scalbert, A. 2003. Chocolate intake increases urinary excretion of polyphenol-derived phenolic acids in healthy human subjects. Am. J. Clin. Nutr, 77: 912 - 918.
110. Ritchie, K., Carriere, I., de Mendonca, A., Portet, F., Dartigues, J. F., Rouaud, O., Barberger-Gateau, P. and Ancelin, M. L. 2007. The neuroprotective effects of caffeine: A prospective population study (the Three City Study). Neurology, 69: 536 - 545.
111. Ross, R. 1999. Atherosclerosis-an inflammatory disease. N. Engl. J. Med, 340: 115 - 126.
112. Ruzaidi, A., Amin, I., Nawalyah, A. G., Hamid, M. and Faizul, H. A. 2005. The effect of Malaysian cocoa extract on glucose levels and lipid profiles in diabetic rats. J. Ethnopharmacol, 98: 55 - 60.
113. Schewe, T., Steffen, Y. and Sies, H. 2008. How do dietary flavanols improve vascular function? A position paper. Arch. Biochem. Biophys, 476: 102 - 106.
114. Scholey, A. B., French, S. J., Morris, P. J., Kennedy, D. O., Milne, A. L. and Haskell, C. F. 2010. Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J. Psychopharmacol, 24: 1505 - 1514.
115. Schramm, D. D., Karim, M., Schrader, H. R., Holt, R. R., Kirkpatrick, N. J., Polagruto, J. A., Ensunsa, J. L., Schmitz, H. H. and Keen, C. L. 2003. Food effects on the absorption and pharmacokinetics of cocoa flavanols. Life Sci, 73: 857 - 869.
116. Schroeter, H., Heiss, C., Balzer, J., Kleinbongard, P., Keen, C. L., Hollenberg, N. K., Sies, H., Kwik-Uribe, C., Schmitz, H. H. and Kelm, M. 2006. (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc. Natl. Acad. Sci. USA, 103: 1024 - 1029.
117. Schroeter, H., Williams, R. J., Matin, R., Iversen, L. and Rice-Evans, C. A. 2000. Phenolic antioxidants attenuate neuronal cell death following uptake of oxidized low-density lipoprotein. Free Radic. Biol. Med, 29: 1222 - 1233.
118. Selmi, C., Cocchi, C. A., Lanfredini, M., Keen, C. L. and Gershwin, M. E. 2008. Chocolate at heart: The anti-inflammatory impact of cocoa flavanols. Mol. Nutr. Food Res, 52: 1340 - 1348.
119. Selmi, C., Mao, T. K., Keen, C. L., Schmitz, H. H. and Eric Gershwin, M. 2006. The anti-inflammatory properties of cocoa flavanols. J. Cardiovasc. Pharmacol, 47 (Suppl. 2): S163 - S171. discussion S172- S176
120. Shah, Z. A., Li, R. C., Ahmad, A. S., Kensler, T. W., Yamamoto, M., Biswal, S. and Dore, S. 2010. The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. J. Cereb. Blood Flow Metab, 30: 1951 - 1961.
121. Shepherd, J., Cobbe, S. M., Ford, I., Isles, C. G., Lorimer, A. R., MacFarlane, P. W., McKillop, J. H. and Packard, C. J. 1995. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N. Engl. J. Med., 333: 1301 - 1307.
122. Sies, H., Schewe, T., Heiss, C. and Kelm, M. 2005. Cocoa polyphenols and inflammatory mediators. Am. J. Clin. Nutr, 81: 304S - 312S.
123. Skopinska-Rozewska, E., Janik, P., Przybyszewska, M., Sommer, E. and Bialas-Chromiec, B. 1998. Inhibitory effect of theobromine on induction of angiogenesis and VEGF mRNA expression in v-raf transfectants of human urothelial cells HCV-29. Int. J. Mol. Med, 2: 649 - 652.
124. Smit, H. J. and Blackburn, R. J. 2005. Reinforcing effects of caffeine and theobromine as found in chocolate. Psychopharmacology (Berl)., 181: 101 - 106.
125. Smit, H. J., Gaffan, E. A. and Rogers, P. J. 2004. Methylxanthines are the psycho-pharmacologically active constituents of chocolate. Psychopharmacology (Berl)., 176: 412 - 419.
126. Smit, H. J. and Rogers, P. J. 2000. Effects of low doses of caffeine on cognitive performance, mood and thirst in low and higher caffeine consumers. Psychopharmacology (Berl)., 152: 167 - 173.
127. Spencer, J. P. 2009. Flavonoids and brain health: Multiple effects underpinned by common mechanisms. Genes Nutr, 4: 243 - 250.
128. Stamler, J., Wentworth, D. and Neaton, J. D. 1986. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA, 256: 2823 - 2828.
129. Steinberg, F. M., Bearden, M. M. and Keen, C. L. 2003. Cocoa and chocolate flavonoids: Implications for cardiovascular health. J. Am. Diet Assoc, 103: 215 - 223.
130. Tarka, S. M. Jr. 1982. The toxicology of cocoa and methylxanthines: A review of the literature. Crit. Rev. Toxicol., 9: 275 - 312.
131. Taubert, D., Roesen, R. and Schomig, E. 2007. Effect of cocoa and tea intake on blood pressure: A meta-analysis. Arch. Intern. Med, 167: 626 - 634.
132. Tomaru, M., Takano, H., Osakabe, N., Yasuda, A., Inoue, K., Yanagisawa, R., Ohwatari, T. and Uematsu, H. 2007. Dietary supplementation with cacao liquor proanthocyanidins prevents elevation of blood glucose levels in diabetic obese mice. Nutrition, 23: 351 - 355.
133. Umemura, T., Ueda, K., Nishioka, K., Hidaka, T., Takemoto, H., Nakamura, S., Jitsuiki, D., Soga, J., Goto, C., Chayama, K., Yoshizumi, M. and Higashi, Y. 2006. Effects of acute administration of caffeine on vascular function. Am. J. Cardiol, 98: 1538 - 1541.
134. Van Praag, H., Lucero, M. J., Yeo, G. W., Stecker, K., Heivand, N., Zhao, C., Yip, E., Afanador, M., Schroeter, H., Hammerstone, J. and Gage, F. H. 2007. Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in mice. J. Neurosci., 27: 5869 - 5878.
135. Vlachopoulos, C., Aznaouridis, K., Alexopoulos, N., Economou, E., Andreadou, I. and Stefanadis, C. 2005. Effect of dark chocolate on arterial function in healthy individuals. Am. J. Hypertens, 18: 785 - 791.
136. Wan, Y., Vinson, J. A., Etherton, T. D., Proch, J., Lazarus, S. A. and Kris-Etherton, P. M. 2001. Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans. Am. J. Clin. Nutr, 74: 596 - 602.
137. Wang, J. F., Schramm, D. D., Holt, R. R., Ensunsa, J. L., Fraga, C. G., Schmitz, H. H. and Keen, C. L. 2000. A dose-response effect from chocolate consumption on plasma epicatechin and oxidative damage. J. Nutr, 130: 2115S - 2119S.
138. Wang-Polagruto, J. F., Villablanca, A. C., Polagruto, J. A., Lee, L., Holt, R. R., Schrader, H. R., Ensunsa, J. L., Steinberg, F. M., Schmitz, H. H. and Keen, C. L. 2006. Chronic consumption of flavanol-rich cocoa improves endothelial function and decreases vascular cell adhesion molecule in hypercholesterolemic postmenopausal women. J. Cardiovasc. Pharmacol, 47 (Suppl. 2): S177 - S186. discussion S206- S209
139. Waterhouse, A. L., Shirley, J. R. and Donovan, J. L. 1996. Antioxidants in chocolate. Lancet., 348: 834
140. Weisburger, J. H. 2001. Chemopreventive effects of cocoa polyphenols on chronic diseases. Exp. Biol. Med. (Maywood)., 226: 891 - 897.
141. Wollgast, J. and Anklam, E. 2000. Review on polyphenols in Theobroma cacao: Changes in composition during the manufacture of chocolate and methodology for identification and quantification. Food Res. Int., 33: 423 - 447.
142. Yamada, T., Yamada, Y., Okano, Y., Terashima, T. and Yokogoshi, H. 2009. Anxiolytic effects of short- and long-term administration of cacao mass on rat elevated T-maze test. J. Nutr. Biochem., 20: 948 - 955.
143. Yamagishi, M., Natsume, M., Osakabe, N., Nakamura, H., Furukawa, F., Imazawa, T., Nishikawa, A. and Hirose, M. 2002. Effects of cacao liquor proanthocyanidins on PhIP-induced mutagenesis in vitro, and in vivo mammary and pancreatic tumorigenesis in female Sprague-Dawley rats. Cancer Lett., 185: 123 - 130.
144. Yamagishi, M., Natsume, M., Osakabe, N., Okazaki, K., Furukawa, F., Imazawa, T., Nishikawa, A. and Hirose, M. 2003. Chemoprevention of lung carcinogenesis by cacao liquor proanthocyanidins in a male rat multi-organ carcinogenesis model. Cancer Lett, 191: 49 - 57.
145. Yamagishi, M., Osakab, N., Takizawa, T. and Osawa, T. 2001. Cacao liquor polyphenols reduce oxidative stress without maintaining alpha-tocopherol levels in rats fed a vitamin E-deficient diet. Lipids, 36: 67 - 71.
146. Yang, H., Rouse, J., Lukes, L., Lancaster, M., Veenstra, T., Zhou, M., Shi, Y., Park, Y. G. and Hunter, K. 2004. Caffeine suppresses metastasis in a transgenic mouse model: A prototype molecule for prophylaxis of metastasis. Clin. Exp. Metastasis., 21: 719 - 735.
147. Yasuda, A., Natsume, M., Sasaki, K., Baba, S., Nakamura, Y., Kanegae, M. and Nagaoka, S. 2008. Cacao procyanidins reduce plasma cholesterol and increase fecal steroid excretion in rats fed a high-cholesterol diet. Biofactors., 33: 211 - 223.