Red raspberries and their bioactive polyphenols: Cardiometabolic and neuronal health links

Advances in Nutrition

Volumn 7, Issue 1, 2016, Pages 44-65

  Burton Freeman, Britt M ^a,b   Sandhu, Amandeep K ^a   Edirisinghe, Indika ^a  

^a ILLINOIS INSTITUTE OF TECHNOLOGY   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Anthocyanins; Cardiovascular disease; Diabetes; Ellagic acid; Inflammation; Oxidative stress; Polyphenols; Red raspberries

Indexed keywords

PLANT EXTRACT; POLYPHENOL;

ALZHEIMER DISEASE; CARDIOVASCULAR DISEASES; CHEMISTRY; DIET THERAPY; FRUIT; HUMAN; METABOLIC DISEASES; PHYTOTHERAPY; RUBUS;

ALZHEIMER DISEASE; CARDIOVASCULAR DISEASES; FRUIT; HUMANS; METABOLIC DISEASES; PHYTOTHERAPY; PLANT EXTRACTS; POLYPHENOLS; RUBUS;

EID: 85000799347     PISSN: 21618313     EISSN: 21565376     Source Type: Journal    
DOI: 10.3945/an.115.009639     Document Type: Review

References (165)

1. USDA. Scientific report of the 2015 Dietary Guidelines Advisory Committee. Washington (DC): USDA; 2015. [cited 2015 Jan 2].Available from: http://www.health.gov/dietaryguidelines/2015-scientificreport/PDFs/Scientific-Report-of-the-2015-Dietary-Guidelines-Advisory-Committee.pdf.
2. Hunter C. Raspberry history, folklore, myth, and magic. The Practical Herba list [Internet] [cited 2015 May 3]. Available from: http://www.thepracticalherbalist.com/herbal-library/magical-herbs/raspberry-mythand-magic.
3. Rayment WJ. Raspberry history. In Depth Info [Internet]. [cited 2014Aug 10]. Available from: http://www.indepthinfo.com/raspberries/history.htm.
4. Washington Red Raspberry Commission. History. Lynden (WA):Washington Red Raspberry Commission; 2013. [cited 2014 May 6].Available from: http://www.red-raspberry.org/history.asp.
5. USDA. National Agriculture Statistics Service Quick Stats 2.0 [Internet][cited 2014 Jul 17]. Available from: http://www.nass.usda.gov/Quick_Stats.
6. Washington Red Raspberry Commission. Production statistics.Lynden (WA): Washington Red Raspberry Commission; 2013.[cited 2015 Mar 29]. Available from: http://www.red-raspberry.org/stats/2014ProdStats.pdf.
7. USDA. National nutrient database for standard reference service release27 and the flavonoid content of selected foods release 3.1 [Internet].Washington (DC): USDA Agricultural Research Services[cited 2015 Apr 10]. Available respectively from: http://ndb.nal.usda.gov/ndb/search/list and http://www.ars.usda.gov/News/docs.htm?docid=6231.
8. Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 1998;56:317-33.
9. Waterman PG, Mole S, editors. Analysis of phenolic plant metabolites.1st ed. Hoboken (NJ): Wiley-Blackwell; 1994.
10. Vainio H, Bianchini F. Definitions and classifications for fruit and vegetables. Vol. 8. In: IARC handbooks of cancer prevention: fruit and vegetables. Vainio H, Bianchini F, editors. Lyon, France: IARCPress; 2003. p. 1-19.
11. Arts IC, Hollman PC. Polyphenols and disease risk in epidemiologic studies. Am J Clin Nutr 2005;81(1 Suppl):317S-25S.
12. Kaur C, Kapoor HC. Antioxidants in fruits and vegetables-the millenium health. Int J Food Sci Technol 2001;36:703-25.
13. Prior RL, Wu X, Gu L, Hager TJ, Hager A, Howard LR. Whole berriesversus berry anthocyanins: interactions with dietary fat levels in the C57BL/6J mouse model of obesity. J Agric Food Chem 2008;56:647-53.
14. Beekwilder J, Jonker H, Meesters P, Hall RD, van der Meer IM, Ric deVos CH. Antioxidants in raspberry: on-line analysis links antioxidant activity to a diversity of individual metabolites. J Agric Food Chem2005;53:3313-20.
15. Kassim A, Poette J, Paterson A, Zait D, McCallum S, Woodhead M,Smith K, Hackett C, Graham J. Environmental and seasonal influences on red raspberry anthocyanin antioxidant contents and identification of quantitative traits loci (QTL). Mol Nutr Food Res 2009;53:625-34.
16. Määttä-Riihinen KR, Kamal-Eldin A, Torronen AR. Identification and quantification of phenolic compounds in berries of Fragaria and Rubusspecies (family Rosaceae). J Agric Food Chem 2004;52:6178-87.
17. Mullen W, Lean ME, Crozier A. Rapid characterization of anthocyaninsin red raspberry fruit by high-performance liquid chromatography coupled to single quadrupole mass spectrometry. J Chromatogr A2002;966:63-70.
18. Remberg SF, Sonsteby A, Aaby K, Heide OM. Influence of post flowering temperature on fruit size and chemical composition of Glen Ample raspberry (Rubus idaeus L.). J Agric Food Chem 2010;58:9120-8.
19. da Silva FL, Escribano-Bailón MT, Pérez Alonso JJ, Rivas-Gonzalo JC,Santos-Buelga C. Anthocyanin pigments in strawberry. LWT - Food Sci Technol (Campinas) 2007;40:374-82.
20. Dossett M, Lee J, Finn CE. Characterization of a novel anthocyanin profile in wild black raspberry mutants: an opportunity for studying the genetic control of pigment and color. J Funct Foods 2011;3:207-14.
21. Torre LC, Barritt BH. Quantitative evaluation of Rubus fruit anthocyanin pigments. J Food Sci 1977;42:488-90.
22. Wu X, Beecher GR, Holden JM, Haytowitz DB, Gebhardt SE, PriorRL. Concentrations of anthocyanins in common foods in the United States and estimation of normal consumption. J Agric Food Chem2006;54:4069-75.
23. Koponen JM, Happonen AM, Mattila PH, Torronen AR. Contents of anthocyanins and ellagitannins in selected foods consumed in Finland.J Agric Food Chem 2007;55:1612-9.
24. Mazur SP, Nes A, Wold AB, Remberg SF, Aaby K. Quality and chemical composition of ten red raspberry (Rubus idaeus L.) genotypesduring three harvest seasons. Food Chem 2014;160:233-40 10.1016/j.foodchem.2014.02.174.
25. Clifford MN, Scalbert A. Ellagitannins-nature, occurrence and dietaryburden. J Sci Food Agric 2000;80:1118-25.
26. Haddock EA, Gupta RK, Al-Shafi SMK, Layden K, Haslam E,Magnolato D. The metabolism of gallic acid and hexa hydroxydiphenic acid in plants: biogenetic and molecular taxonomic considerations.Phytochemistry 1982;21:1049-62.
27. Lipínska L, Klewicka E, Sojka M. The structure, occurrence and biological activity of ellagitannins: a general review. Acta Sci Pol Technol Aliment 2014;13:289-99.
28. Dincheva I, Badjakov I, Kondakova V, Dobson P, Mcdougall G, Stewart D. Identification of the phenolic components in Bulgarian raspberry cultivars by LC-ESI-MSn. Int J Agric Sci Res 2013;3:127-37.
29. Gasperotti M, Masuero D, Vrhovsek U, Guella G, Mattivi F. Profilingand accurate quantification of Rubus ellagitannins and ellagic acid conjugates using direct UPLC-Q-TOF HDMS and HPLC-DAD analysis.J Agric Food Chem 2010;58:4602-16.
30. Mullen W, Yokota T, Lean ME, Crozier A. Analysis of ellagitannins and conjugates of ellagic acid and quercetin in raspberry fruits by LC-MSn. Phytochemistry 2003;64:617-24.
31. Kähkönen M, Kylli P, Ollilainen V, Salminen JP, Heinonen M. Antioxidant activity of isolated ellagitannins from red raspberries and cloudberries.J Agric Food Chem 2012;60:1167-74.
32. Jakobek L, Seruga M, Novak I, Medvidovic-Kosanovic M. Flavonols,phenolic acids and antioxidant activity of some red fruits. Dtsch Lebensm Rundsch 2007;103:369-78.
33. Gu L, Kelm MA, Hammerstone JF, Beecher G, Holden J, Haytowitz D,Gebhardt S, Prior RL. Concentrations of proanthocyanidins in common foods and estimations of normal consumption. J Nutr 2004;134:613-7.
34. Bakkalbasi E, Mentes O, Artik N. Food ellagitannins-occurrence, effects of processing and storage. Crit Rev Food Sci Nutr 2009;49:283-98.
35. Barrett DM, Lloyd B. Advanced preservation methods and nutrient retention in fruits and vegetables. J Sci Food Agric 2012;92:7-22.
36. Mullen W, Stewart AJ, Lean ME, Gardner P, Duthie GG, Crozier A.Effect of freezing and storage on the phenolics, ellagitannins, flavonoids,and antioxidant capacity of red raspberries. J Agric Food Chem 2002;50:5197-201.
37. Wood RJ. Bioavailability: definition, general aspects and fortificants.2nd ed. In: Caballero B, Allen L, Prentice A, eds. Encyclopedia of human nutrition. Oxford (United Kingdom): Elsevier; 2005.p. 195-201.
38. Daniel EM, Ratnayake S, Kinstle T, Stoner GD. The effects of pH and rat intestinal contents on the liberation of ellagic acid from purified and crude ellagitannins. J Nat Prod 1991;54:946-52.
39. Laitinen LA, Tammela PS, Galkin A, Vuorela HJ, Marvola ML, VuorelaPM. Effects of extracts of commonly consumed food supplements and food fractions on the permeability of drugs across Caco-2 cell monolayers.Pharm Res 2004;21:1904-16.
40. McDougall GJ, Dobson P, Smith P, Blake A, Stewart D. Assessing potentialbio availability of raspberry anthocyanins using an in vitro digestion system. J Agric Food Chem 2005;53:5896-904.
41. Borges G, Roowi S, Rouanet JM, Duthie GG, Lean ME, Crozier A. Thebio availability of raspberry anthocyanins and ellagitannins in rats.Mol Nutr Food Res 2007;51:714-25.
42. Cerdá B, Periago P, Espin JC, Tomas-Barberan FA. Identification of urolithin a as a metabolite produced by human colon microflora from ellagic acid and related compounds. J Agric Food Chem 2005;53:5571-6.
43. Gill CI, McDougall GJ, Glidewell S, Stewart D, Shen Q, Tuohy K,Dobbin A, Boyd A, Brown E, Haldar S, et al. Profiling of phenols in human fecal water after raspberry supplementation. J Agric Food Chem 2010;58:10389-95.
44. González-Barrio R, Edwards CA, Crozier A. Colonic catabolism of ellagitannins,ellagic acid, and raspberry anthocyanins: in vivo and invitro studies. Drug Metab Dispos 2011;39:1680-8.
45. Cao G, Muccitelli HU, Sanchez-Moreno C, Prior RL. Anthocyaninsare absorbed in glycated forms in elderly women: a pharmacokinetic study. Am J Clin Nutr 2001;73:920-6.
46. Felgines C, Talavera S, Texier O, Gil-Izquierdo A, Lamaison JL,Remesy C. Blackberry anthocyanins are mainly recovered fromurine as methylated and glucuronidated conjugates in humans.J Agric Food Chem 2005;53:7721-7.
47. Wu X, Cao G, Prior RL. Absorption and metabolism of anthocyaninsin elderly women after consumption of elderberry or blueberry. J Nutr2002;132:1865-71.
48. van Duynhoven J, Vaughan EE, Jacobs DM, Kemperman RA, vanVelzen EJ, Gross G, Roger LC, Possemiers S, Smilde AK, Dore J,et al. Metabolic fate of polyphenols in the human super organism.Proc Natl Acad Sci USA 2011;108(Suppl 1):4531-8.
49. González-Barrio R, Borges G, Mullen W, Crozier A. Bioavailability of anthocyanins and ellagitannins following consumption of raspberriesby healthy humans and subjects with an ileostomy. J Agric Food Chem2010;58:3933-9.
50. Selma MV, Tomas-Barberan FA, Beltran D, Garcia-Villalba R, EspinJC. Gordonibacter urolithinfaciens sp. nov., a urolithin-producing bacterium isolated from the human gut. Int J Syst Evol Microbiol2014;64:2346-52.
51. Vitaglione P, Donnarumma G, Napolitano A, Galvano F, Gallo A,Scalfi L, Fogliano V. Protocatechuic acid is the major human metabolite of cyanidin-glucosides. J Nutr 2007;137:2043-8.
52. WHO. Cardiovascular diseases (CVDs) fact sheet [Internet] [cited 2015Mar 15]. Available from: http://www.who.int/mediacentre/factsheets/fs317/en.
53. Grundy SM, Pasternak R, Greenland P, Smith S, Jr., Fuster V. Assessmentof cardio vascular risk by use of multiple-risk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation1999;100:1481-92.
54. Reriani MK, Lerman LO, Lerman A. Endothelial function as a functional expression of cardio vascular risk factors. Biomark Med 2010;4:351-60.
55. Beekwilder J, Hall RD, de Vos CH. Identification and dietary relevance of antioxidants from raspberry. Biofactors 2005;23:197-205.
56. Prior RL, Cao G, Prior RL, Cao G. Analysis of botanicals and dietary supplements for antioxidant capacity: a review. J AOAC Int 2000;83:950-6.
57. Zafra-Stone S, Yasmin T, Bagchi M, Chatterjee A, Vinson JA, Bagchi D. Berry anthocyanins as novel antioxidants in human health and disease prevention. Mol Nutr Food Res 2007;51:675-83.
58. European Food Safety Authority Panel on Dietetic Products, Nutritionand Allergies. Guidance on the scientific requirements for health claims related to antioxidants, oxidative damage and cardio vascular health. EFSA J 2011;9:2474.
59. Stone NJ, Robinson J, Lichtenstein AH, Merz CNB, Blum CB, EckelRH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, et al. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardio vascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation 2014;129(25 Suppl 2):S1-45.
60. Sies H, Cadenas E. Oxidative stress: damage to intact cells and organs.Philos Trans R Soc Lond B Biol Sci 1985;311:617-31.
61. Sies H. Oxidative stress: from basic research to clinical application.Am J Med 1991;91(3C):31S-8S.
62. Morrow JD. Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans. Arterioscler Thromb Vasc Biol 2005;25:279-86.
63. Zhang ZJ. Systematic review on the association between F2-isoprostanes and cardio vascular disease. Ann Clin Biochem 2013;50:108-14.
64. Tsimikas S,Willeit P,Willeit J, Santer P,Mayr M, Xu Q,Mayr A,Witztum JL, Kiechl S. Oxidation-specific biomarkers, prospective 15-year cardio vascular and stroke outcomes, and net reclassification of cardio vascular events. J Am Coll Cardiol 2012;60(21):2218-29.
65. Singh U, Jialal I. Oxidative stress and atherosclerosis. Pathophysiology2006;13:129-42.
66. Stocker R, Keaney JF Jr. Role of oxidative modifications in atherosclerosis.Physiol Rev 2004;84(4):1381-478.
67. Dröge W. Free radicals in the physiological control of cell function.Physiol Rev 2002;82:47-95.
68. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Freeradicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39(1):44-84.
69. Csiszar A, Labinskyy N, Zhao X, Hu F, Serpillon S, Huang Z, Ballabh P, Levy RJ, Hintze TH, Wolin MS, et al. Vascular superoxide and hydrogen peroxide production and oxidative stress resistance in two closely related rodent species with disparate longevity. Aging Cell2007;6(6):783-97.
70. Donato AJ, Eskurza I, Silver AE, Levy AS, Pierce GL, Gates PE, SealsDR. Direct evidence of endothelial oxidative stress with aging in humans:relation to impaired endothelium-dependent dilation andupregulation of nuclear factor-kappaB. Circ Res 2007;100:1659-6610.1161/01.RES.0000269183.13937.e8.
71. Durrant JR, Seals DR, Connell ML, Russell MJ, Lawson BR, Folian BJ,Donato AJ, Lesniewski LA. Voluntary wheel running restores endothelial function in conduit arteries of old mice: direct evidence for reduced oxidative stress, increased superoxide dismutase activity and down-regulation of NADPH oxidase. J Physiol 2009;587:3271-85.
72. Hamilton CA, Brosnan MJ, Al-Benna S, Berg G, Dominiczak AF. NAD(P)H oxidase inhibition improves endothelial function in rat and human blood vessels. Hypertension 2002;40:755-62.
73. Ungvari Z, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith K,Csiszar A. Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 2007;293:H37-47.
74. Heinecke JW. Mass spectrometric quantification of amino acid oxidation products in proteins: insights into pathways that promote LDL oxidation in the human artery wall. FASEB J 1999;13:1113-20.
75. Savenkova ML, Mueller DM, Heinecke JW. Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipidperoxidation in low density lipoprotein. J Biol Chem 1994;269:20394-400.
76. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 1999;18:6853-66.
77. Kris-Etherton PM, Lefevre M, Beecher GR, Gross MD, Keen CL,Etherton TD. Bioactive compounds in nutrition and health-research methodologies for establishing biological function: the antioxidantand anti-inflammatory effects of flavonoids on atherosclerosis. Annu Rev Nutr 2004;24:511-38.
78. Kern M, Fridrich D, Reichert J, Skrbek S, Nussher A, Hofem S, Vatter S, Pahlke G, Rufer C, Marko D. Limited stability in cell culture medium and hydrogen peroxide formation affect the growth inhibitory properties of delphinidin and its degradation product gallic acid.Mol Nutr Food Res 2007;51:1163-72.
79. Kropat C, Mueller D, Boettler U, Zimmermann K, Heiss EH, DirschVM, Rogoll D, Melcher R, Richling E, Marko D. Modulation of Nrf2-dependent gene transcription by bilberry anthocyanins in vivo.Mol Nutr Food Res 2013;57:545-50.
80. Meyer AS, Heinonen M, Frankel EN. Antioxidant interactions of catechin,cyanidin, caffeic acid, quercetin, and ellagic acid on human LDL oxidation. Food Chem 1998;61:71-5.
81. Vuorela S, Kreander K, Karonen M, Nieminen R, Hamalainen M, Galkin A, Laitinen L, Salminen JP, Moilanen E, Pihlaja K, et al. Preclinical evaluation of rape seed, raspberry, and pine bark phenolics for health related effects. J Agric Food Chem 2005;53:5922-31.
82. Duthie SJ, Gardner PT, Morrice PC, Wood SG, Pirie L, Bestwick CC,Milne L, Duthie GG. DNA stability and lipid peroxidation in vitamin E-deficient rats in vivo and colon cells in vitro-modulation by thedietary anthocyanin, cyanidin-3-glycoside. Eur J Nutr 2005;44:195-203.
83. Festa F, Aglitti T, Duranti G, Ricordy R, Perticone P, Cozzi R. Strong antioxidant activity of ellagic acid in mammalian cells in vitro revealed by the comet assay. Anticancer Res 2001;21(6A):3903-8.
84. Godevac D, Tesevic V, Vajs V, Milosavljevic S, Stankovic M. Antioxidant properties of raspberry seed extracts on micronucleus distribution in peripheral blood lymphocytes. Food Chem Toxicol 2009;47(11):2853-9.
85. Sangiovanni E, Vrhovsek U, Rossoni G, Colombo E, Brunelli C, Brembati L, Trivulzio S, Gasperotti M, Mattivi F, Bosisio E, et al. Ellagitannins from Rubus berries for the control of gastric inflammation: in vitro and in vivostudies. PLoS One 2013;8(8):e71762.
86. Gauliard B, Grieve D, Wilson R, Crozier A, Jenkins C, Mullen WD,Lean M. The effects of dietary phenolic compounds on cytokineand antioxidant production by A549 cells. J Med Food 2008;11:382-4.
87. Jean-Gilles D, Li L, Ma H, Yuan T, Chichester CO III, Seeram NP.Anti-inflammatory effects of polyphenolic-enriched red raspberry extractin an antigen-induced arthritis rat model. J Agric Food Chem2012;60:5755-62.
88. Tsuda T. Regulation of adipocyte function by anthocyanins; possibility of preventing the metabolic syndrome. J Agric Food Chem 2008;56:642-6.
89. Wang J, Mazza G. Effects of anthocyanins and other phenolic compounds on the production of tumor necrosis factor alpha in LPS/IFN-gamma-activated RAW 264.7 macrophages. J Agric Food Chem 2002;50(15):4183.
90. Li L, Wang L, Wu Z, Yao L, Wu Y, Huang L, Liu K, Zhou X, Gou D.Anthocyanin-rich fractions from red raspberries attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis. SciRep 2014;4:6234.
91. Nasef NA,Mehta S,Murray P,Marlow G, Ferguson LR. Anti-inflammatory activity of fruit fractions in vitro, mediated through toll-like receptor 4and 2 in the context of inflammatory bowel disease. Nutrients 2014;6:5265-79.
92. Seeram NP, Momin RA, Nair MG, Bourquin LD. Cyclooxygenase inhibitoryand antioxidant cyanidin glycosides in cherries and berries.Phytomedicine 2001;8(5):362-9.
93. Gião MS, Pestana D, Faria A, Guimarães JT, Pintado ME, Calhau C,Azevedo I, Malcata FX. Effects of extracts of selected medicinal plants upon hepatic oxidative stress. J Med Food 2010;13:131-6.
94. Jakobsdottir G, Blanco N, Xu J, Ahrne S, Molin G, Sterner O, Nyman M. Formation of short-chain fatty acids, excretion of anthocyanins,and microbial diversity in rats fed blackcurrants, blackberries, and raspberries. J Nutr Metab 2013; unique ID: 202534.
95. Figueira ME, Camara MB, Direito R, Rocha J, Serra AT, Duarte CM,Fernandes A, Freitas M, Fernandes E, Marques MC, et al. Chemical characterization of a red raspberry fruit extract and evaluation of its pharmacological effects in experimental models of acute inflammation and collagen-induced arthritis. Food Funct 2014;5:3241-51.
96. Allen CT, Peden-Adams MM, EuDaly J, Keil DE. Subchronic exposureto ellagic acid impairs cytotoxic T-cell function and suppresses humoral immunity in mice. Immunopharmacol Immunotoxicol 2003;25:409-22.
97. Iino T, Tashima K, Umeda M, Ogawa Y, Takeeda M, Takata K, Takeuchi K. Effect of ellagic acid on gastric damage induced in ischemic rat stomachs following ammonia or reperfusion. Life Sci 2002;70:1139-50.
98. Rosillo MA, Sanchez-Hidalgo M, Cardeno A, de la Lastra CA. Protective effect of ellagic acid, a natural polyphenolic compound, in amurine model of Crohn's disease. Biochem Pharmacol 2011;82(7):737-45.
99. Ramirez-Tortosa C, Andersen OM, Cabrita L, Gardner PT, MorricePC, Wood SG, Duthie SJ, Collins AR, Duthie GG. Anthocyanin-rich extract decreases indices of lipid peroxidation and DNA damage in vitamin E-depleted rats. Free Radic Biol Med 2001;31(9):1033-7.
100. Carmen Ramirez-Tortosa M, Garcia-Alonso J, Luisa Vidal-Guevara M,Quiles JL, Jesus Periago M, Linde J, Dolores Mesa M, Ros G, Abellan P,Gil A. Oxidative stress status in an institutionalised elderly group after the intake of a phenolic-rich dessert. Br J Nutr 2004;91:943-50.
101. Morillas-Ruiz J, Zafrilla P, Almar M, Cuevas MJ, Lopez FJ, Abellan P,Villegas JA, Gonzalez-Gallego J. The effects of an antioxidant supplemented beverage on exercise-induced oxidative stress: results from a placebo-controlled double-blind study in cyclists. Eur J ApplPhysiol 2005;95:543-9.
102. Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S,Lerman A, Mancia G, Oliver JJ, Pessina AC, et al. Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.J Hypertens 2005;23(1):7-17.
103. Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM, Cockcroft J, Cosentino F, Deanfield J, Gallino A, Ikonomidis I, et al. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation.Eur J Cardiovasc Prev Rehabil 2011;18(6):775-89.
104. Tousoulis D, Kampoli AM, Tentolouris C, Papageorgiou N, Stefanadis C. The role of nitric oxide on endothelial function. Curr Vasc Pharmacol2012;10(1):4-18.
105. Yu YM, Wang ZH, Liu CH, Chen CS. Ellagic acid inhibits IL-1betainduced cell adhesion molecule expression in human umbilical veinendothelial cells. Br J Nutr 2007;97(4):692-8.
106. Chang WC, Yu YM, Chiang SY, Tseng CY. Ellagic acid suppresses oxidised low-density lipoprotein-induced aortic smooth muscle cell proliferation:studies on the activation of extracellular signal-regulated kinase 1/2 and proliferating cell nuclear antigen expression. Br JNutr 2008;99(4):709-14.
107. Rani UP, Kesavan R, Ganugula R, Avaneesh T, Kumar UP, Reddy GB,Dixit M. Ellagic acid inhibits PDGF-BB-induced vascular smooth musclecell proliferation and prevents atheroma formation in streptozotocin induced diabetic rats. J Nutr Biochem 2013;24:1830-9.
108. Ding Y, Zhang B, Zhou K, Chen M, Wang M, Jia Y, Song Y, Li Y, Wen A. Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: role of Nrf2 activation. Int J Cardiol 2014;175:508-14.
109. Chao PC, Hsu CC, Yin MC. Anti-inflammatory and anti-coagulatory activities of caffeic acid and ellagic acid in cardiac tissue of diabetic mice. Nutr Metab (Lond) 2009;6:33.
110. Yu YM, Chang WC, Wu CH, Chiang SY. Reduction of oxidative stress and apoptosis in hyperlipidemic rabbits by ellagic acid. J Nutr Biochem2005;16(11):675-81.
111. Lin MC, Yin MC. Preventive effects of ellagic acid against doxorubicin induced cardio-toxicity in mice. Cardiovasc Toxicol 2013;13:185-93.
112. Panchal SK, Ward L, Brown L. Ellagic acid attenuates high-carbohydrate,high-fat diet-induced metabolic syndrome in rats. Eur J Nutr 2013;52:559-68.
113. Torres-Urrutia C, Guzman L, Schmeda-Hirschmann G,Moore-Carrasco R, Alarcon M, Astudillo L, Gutierrez M, Carrasco G, Yuri JA, Aranda E,et al. Antiplatelet, anticoagulant, and fibrinolytic activity in vitro of extracts from selected fruits and vegetables. Blood Coagul Fibrinolysis2011;22:197-205.
114. Mullen W, McGinn J, Lean MEJ, MacLean MR, Gardner P, DuthieGG, Yokota T, Crozier A. Ellagitannins, flavonoids, and other phenolicsin red raspberries and their contribution to antioxidant capacity and vasorelaxation properties. J Agric Food Chem 2002;50:5191-6.
115. Suh JH, Romain C, Gonzalez-Barrio R, Cristol JP, Teissedre PL, Crozier A, Rouanet JM. Raspberry juice consumption, oxidative stress and reduction of atherosclerosis risk factors in hyper cholesterolemic golden Syrian hamsters. Food Funct 2011;2:400-5.
116. Jia H, Liu JW, Ufur H, He GS, Liqian H, Chen P. The anti hypertensive effect of ethyl acetate extract from red raspberry fruit in hyper tensiverats. Pharmacogn Mag 2011;7:19-24.
117. Pieszka M, Tombarkiewicz B, Roman A, Migda1 W, Niedzió1ka J. Effect of bioactive substances found in rape seed, raspberry and strawberry seed oils on blood lipid profile and selected parameters ofoxidative status in rats. Environ Toxicol Pharmacol 2013;36:1055-62.
118. Freese R, Vaarala O, Turpeinen AM, Mutanen M. No difference inplatelet activation or inflammation markers after diets rich or poor in vegetables, berries and apple in healthy subjects. Eur J Nutr 2004;43:175-82.
119. Puupponen-Pimiä R, Seppänen-Laakso T, Kankainen M, Maukonen J,Törrönen R, Kolehmainen M, Leppänen T, Moilanen E, Nohynek L,Aura A-M, et al. Effects of ellagitannin-rich berries on blood lipids,gut microbiota, and urolithin production in human subjects with symptoms of metabolic syndrome. Mol Nutr Food Res 2013;57:2258-63.
120. CDC. National diabetes statistics report [Internet] [cited 2014 Dec12]. Available from: http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf.
121. WHO. Diabetes factsheet [Internet] [cited 2015 Mar 5]. Availablefrom: http://www.who.int/mediacentre/factsheets/fs312/en.
122. CDC. Heart disease facts [Internet] [cited 2015 Feb 2]. Available from:http://www.cdc.gov/heartdisease/facts.htm.
123. Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism under lyinginsulin resistance, diabetes, and cardio vascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol2004;24(5):816-23.
124. Neumann M, Kretzschmar HA. [Molecular neuropathology of non-Alzheimer dementia]. Pathologe 2008;29:434-41.
125. Pessin JE, Saltiel AR. Signaling pathways in insulin action: moleculartargets of insulin resistance. J Clin Invest 2000;106:165-9.
126. Kellerer M, Haring HU. Pathogenesis of insulin resistance: modulation of the insulin signal at receptor level. Diabetes Res Clin Pract 1995;28:S173-7.
127. Rudich A, Tirosh A, Potashnik R, Hemi R, Kanety H, Bashan N. Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes 1998;47:1562-9.
128. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes.Endocr Rev 2002;23:599-622.
129. Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM,Vinicor F, Marks JS. Diabetes trends in the U.S.: 1990-1998. Diabetes Care 2000;23:1278-83.
130. Gonzalez-Campoy JM, Sachiko TSJ, Castorino K, Ebrahim A, Hurley D, Jovanovic L, Mechanick JI, Petak SM, Yu Y-H, Harris KA, et al.Clinical practice guidelines for healthy eating for the prevention of metabolic and endocrine diseases in adults. Endocr Pract 2013;19:1-82.
131. McDougall GJ, Shpiro F, Dobson P, Smith P, Blake A, Stewart D. Different polyphenolic components of soft fruits inhibit alpha-amylaseand alpha-glucosidase. J Agric Food Chem 2005;53:2760-6.
132. Grussu D, Stewart D, McDougall GJ. Berry polyphenols inhibita-amylase in vitro: identifying active components in rowanberry and raspberry. J Agric Food Chem 2011;59:2324-31.
133. Jayaprakasam B, Vareed SK, Olson LK, Nair MG. Insulin secretion by bioactive anthocyanins and anthocyanidins present in fruits. J Agric Food Chem 2005;53:28-31.
134. Tsuda T, Ueno Y, Aoki H, Koda T, Horio F, Takahashi N, Kawada T, Osawa T. Anthocyanin enhances adipocytokine secretion and adipocyte-specific gene expression in isolated rat adipocytes. Biochem Biophys Res Commun 2004;316(1):149-57.
135. Tsuda T, Ueno Y, Yoshikawa T, Kojo H, Osawa T. Microarray profiling of gene expression in human adipocytes in response to anthocyanins.Biochem Pharmacol 2006;71(8):1184-97.
136. Sasaki R, Nishimura N, Hoshino H, Isa Y, Kadowaki M, Ichi T, Tanaka A, Nishiumi S, Fukuda I, Ashida H, et al. Cyanidin 3-glucoside ameliorateshyperglycemia and insulin sensitivity due to down regulation of retinol binding protein 4 expression in diabetic mice. Biochem Pharmacol 2007;74:1619-27.
137. Guo H, Xia M, Zou T, Ling W, Zhong R, Zhang W. Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepaticsteatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1. J Nutr Biochem 2012;23(4):349-60.
138. Chao CY, Mong MC, Chan KC, Yin MC. Anti-glycative and anti inflammatory effects of caffeic acid and ellagic acid in kidney of diabetic mice. Mol Nutr Food Res 2010;54:388-95.
139. Clegg ME, Pratt M, Meade CM, Henry CJ. The addition of raspberries and blueberries to a starch-based food does not alter the glycaemic response.Br J Nutr 2011;106:335-8.
140. Törrönen R, Kolehmainen M, Sarkkinen E, Poutanen K, Mykkanen H, Niskanen L. Berries reduce postprandial insulin responses to wheat and rye breads in healthy women. J Nutr 2013;143:430-6.
141. Mathew AJ, Raj NN, Sugappriya M, Priyadarshini SM. Modeling of ATP-sensitive inward rectifier potassium channel 11 and inhibition mechanism of the natural ligand, ellagic acid, using molecular docking.Adv Exp Med Biol 2010;680:489-95.
142. WHO. Obesity and over weight fact sheet [Internet] [cited 2015Mar 29]. Available from: http://www.who.int/mediacentre/factsheets/fs311/en.
143. NIH. Do you know some of the health risks of being over weight? [Internet][cited 2015 Mar 29]. Available from: http://www.niddk.nih.gov/health-information/health-topics/weight-control/health_risks_being_overweight/Documents/hlthrisks1104.pdf.
144. Park KS. Raspberry ketone increases both lipolysis and fatty acid oxidationin 3T3-L1 adipocytes. Planta Med 2010;76:1654-8.
145. Park KS. Raspberry ketone, a naturally occurring phenolic compound,inhibits adipogenic and lipogenic gene expression in 3T3-L1 adipocytes.Pharm Biol 2015;53:870-5.
146. Morimoto C, Satoh Y, Hara M, Inoue S, Tsujita T, Okuda H. Antiobeseaction of raspberry ketone. Life Sci 2005;77(2):194-204.
147. Prior RL, Wilkes SE, Rogers RT, Khanal RC, Wu X, Howard LR. Purified blueberry anthocyanins and blueberry juice alter development of obesity inmice fed an obesogenic high-fat diet. J Agric Food Chem 2010;58:3970-6.
148. Wu T, Qi X, Liu Y, Guo J, Zhu R, Chen W, Zheng X, Yu T. Dietary supplementation with purified mulberry (Morus australis Poir)anthocyanins suppresses body weight gain in high-fat diet fedC57BL/6 mice. Food Chem 2013;141(1):482-7.
149. Burton-Freeman B. Dietary fiber and energy regulation. J Nutr 2000;130(2S Suppl):272S-5S.
150. Alzheimer's Association. Alzheimer's disease facts and figures. Alzheimers Dement 2014;10(2):e47-92.
151. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010;362(4):329-44.
152. Moreira PI, Honda K, Zhu X, Nunomura A, Casadesus G, Smith MA,Perry G. Brain and brawn: parallels in oxidative strength. Neurology2006;66(2 Suppl 1):S97-101.
153. Selkoe DJ. Alzheimer's disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis 2001;3:75-80.
154. NIH. What is metabolic syndrome? [Internet] [cited 2015 Mar 18].Available from: http://www.nhlbi.nih.gov/health/health-topics/topics/ms.
155. Cooper C, Sommerlad A, Lyketsos CG, Livingston G. Modifiable predictorsof dementia in mild cognitive impairment: a systematic review and meta-analysis. Am J Psychiatry 2015;172:323-34.
156. Lin F, Lo RY, Cole D, Ducharme S, Chen DG, Mapstone M,Porsteinsson A. Longitudinal effects of metabolic syndrome on Alzheimer and vascular related brain pathology. Dement Geriatr Cogn Dis Extra 2014;4(2):184-94.
157. Panza F, Frisardi V, Capurso C, Imbimbo BP, Vendemiale G, Santamato A, D'Onofrio G, Seripa D, Sancarlo D, Pilotto A, et al. Metabolic syndrome and cognitive impairment: current epidemiology and possible underlying mechanisms. J Alzheimers Dis 2010;21(3):691-724.
158. Luchsinger JA, Gustafson DR. Adiposity, type 2 diabetes, and Alzheimer'sdisease. J Alzheimers Dis 2009;16(4):693-704.
159. Spielman LJ, Little JP, Klegeris A. Inflammation and insulin/IGF-1 resistanceas the possible link between obesity and neurode generation. JNeuroimmunol 2014;273(1-2):8-21.
160. Shukitt-Hale B. The effects of aging and oxidative stress on psychomotor and cognitive behavior. Age (Omaha) 1999;22:9-17.
161. Shukitt-Hale B, Smith DE, Meydani M, Joseph JA. The effects of dietary antioxidants on psychomotor performance in aged mice. Exp Gerontol 1999;34(6):797-808.
162. Feng Y, Yang SG, Du XT, Zhang X, Sun XX, Zhao M, Sun GY, Liu RT.Ellagic acid promotes Abeta42 fibrillization and inhibits Abeta42-induced neurotoxicity. Biochem Biophys Res Commun 2009;390:1250-4.
163. Kim KT, Nam TK, Park YS, Kim YB, Park SW. Neuroprotective effect of anthocyanin on experimental traumatic spinal cord injury. J KoreanNeurosurg Soc 2011;49:205-11.
164. Farbood Y, Sarkaki A, Dianat M, Khodadadi A, Haddad MK,Mashhadizadeh S. Ellagic acid prevents cognitive and hippo campal long-term potentiation deficits and brain inflammation in rat with traumatic brain injury. Life Sci 2015;124:120-7.
165. Fortalezas S, Tavares L, Pimpao R, Tyagi M, Pontes V, Alves PM,McDougall G, Stewart D, Ferreira RB, Santos CN. Antioxidant properties and neuro protective capacity of strawberry tree fruit (Arbutusunedo). Nutrients 2010;2(2):214-29.