Action mechanism and cardiovascular effect of anthocyanins: A systematic review of animal and human studies

Journal of Translational Medicine

Volumn 14, Issue 1, 2016, Pages

  Reis, Jordano Ferreira ^a   Monteiro, Valter Vinicius Silva ^a   Souza Gomes, Rafaelli ^a   Carmo, Matheus Moraes ^a   Costa, Glauber Vilhena ^a   Ribera, Paula Cardoso ^a   Monteiro, Marta Chagas ^a  

^a FEDERAL UNIVERSITY OF PARÁ   (Brazil)

Author keywords

Animal models; Anthocyanins; Cardiovascular disease; Human study; Oxidative stress; Polyphenols

Indexed keywords

ANTHOCYANIN; ARACHIDONIC ACID; ASCORBIC ACID; CATALASE; COPPER; FREE RADICAL; GLUTATHIONE; HEME OXYGENASE 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERCELLULAR ADHESION MOLECULE 1; IRON; LOW DENSITY LIPOPROTEIN; MONOCYTE CHEMOTACTIC PROTEIN 1; NITRIC OXIDE; PHOSPHOLIPASE A2; SUPEROXIDE DISMUTASE; TRANSCRIPTION FACTOR NRF2; TUMOR NECROSIS FACTOR; VASCULAR CELL ADHESION MOLECULE 1; XANTHINE OXIDASE; ANTIOXIDANT; BIOLOGICAL MARKER;

ANTIOXIDANT ACTIVITY; BERRY; BLOOD PRESSURE REGULATION; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CEREAL; COMORBIDITY; DIET SUPPLEMENTATION; DISEASE MODEL; DRUG MECHANISM; DRUG STRUCTURE; DRUG TARGETING; DYSLIPIDEMIA; ENZYME INHIBITION; FLOWER; FRUIT; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; IRON CHELATION; LIPID OXIDATION; LIPID PEROXIDATION; MOUSE; NONHUMAN; PLANT LEAF; PROTEIN EXPRESSION; RABBIT; RAT; REVIEW; SYSTEMATIC REVIEW; VEGETABLE; ANIMAL; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; CHEMISTRY; DRUG EFFECTS; META ANALYSIS; METABOLISM; PATHOLOGY;

ANIMALS; ANTHOCYANINS; ANTIOXIDANTS; BIOMARKERS; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; DISEASE MODELS, ANIMAL; HUMANS;

EID: 84995581975     PISSN: None     EISSN: 14795876     Source Type: Journal    
DOI: 10.1186/s12967-016-1076-5     Document Type: Review

References (185)

1. WHO. Global status report on noncommunicable diseases 2014. Geneva: World Health Organization; 2014. p. 176.
2. Menotti A, Puddu PE, Maiani G, Catasta G. Lifestyle behaviour and lifetime incidence of heart diseases. Int J Cardiol. 2015;201:293-9.
3. Rushton CA, Kadam UT. Impact of non-cardiovascular disease comorbidity on cardiovascular disease symptom severity: a population-based study. Int J Cardiol. 2014;175:154-61.
4. Vauzour D, Rodriguez-Mateos A, Corona G, Oruna-Concha MJ, Spencer JPE. Polyphenols and human health: prevention of disease and mechanisms of action. Nutrients. 2010;2:1106-31.
5. Castaneda-Ovando A, de Lourdes Pacheco-Hernández M, Páez-Hernández ME, Rodríguez JA, Galán-Vidal CA. Chemical studies of anthocyanins: a review. Food Chem. 2009;113:859-71. doi: 10.1016/j.foodchem.2008.09.001.
6. Andersen ØM, Jordheim M, Byamukama R, Mbabazi A, Ogweng G, Skaar I, et al. Anthocyanins with unusual furanose sugar (apiose) from leaves of Synadenium grantii (Euphorbiaceae). Phytochemistry. 2010;71:1558-63.
7. de Pascual-Teresa S. Molecular mechanisms involved in the cardiovascular and neuroprotective effects of anthocyanins. Arch Biochem Biophys. 2014;559:68-74.
8. Goncharov NV, Avdonin PV, Nadeev AD, Zharkikh IL, Jenkins RO. Reactive oxygen species in pathogenesis of atherosclerosis. Curr Pharm Des. 2015;21:1134-46.
9. Camejo G, Lalaguna F, Lopez F, Starosta R. Characterization and properties of a lipoprotein-complexing proteoglycan from human aorta. Atherosclerosis. 1980;35:307-20.
10. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116:1832-44.
11. Chen C, Khismatullin DB. Oxidized low-density lipoprotein contributes to atherogenesis via co-activation of macrophages and mast cells. PLoS ONE. 2015;10:e0123088.
12. Lee SJ, Thien Quach CH, Jung K-H, Paik J-Y, Lee JH, Park JW, et al. Oxidized low-density lipoprotein stimulates macrophage 18F-FDG uptake via hypoxia-inducible factor-1α activation through Nox2-dependent reactive oxygen species generation. J Nucl Med. 2014;55:1699-705.
13. Frostegard J, Nilsson J, Haegerstrand A, Hamsten A, Wigzell H, Gidlund M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. Proc Natl Acad Sci USA. 1990;87:904-8.
14. Frostegard J, Wu R, Giscombe R, Holm G, Lefvert AK, Nilsson J. Induction of T-cell activation by oxidized low density lipoprotein. Arterioscler Thromb Vasc Biol. 1992;12:461-7.
15. Newton AH, Benedict SH. Low density lipoprotein promotes human naive T cell differentiation to Th1 cells. Hum Immunol. 2014;75:621-8.
16. Pandey D, Bhunia A, Oh YJ, Chang F, Bergman Y, Kim JH, et al. OxLDL triggers retrograde translocation of arginase2 in aortic endothelial cells via ROCK and mitochondrial processing peptidase. Circ Res. 2014;115:450-9.
17. Berliner JA, Territo MC, Sevanian A, Ramin S, Kim JA, Bamshad B, et al. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J Clin Investig. 1990;85:1260-6.
18. Lievens D, von Hundelshausen P. Platelets in atherosclerosis. Thromb Haemost. 2011;106:827-38.
19. Platt MO, Ankeny RF, Shi G-P, Weiss D, Vega JD, Taylor WR, et al. Expression of cathepsin K is regulated by shear stress in cultured endothelial cells and is increased in endothelium in human atherosclerosis. Am J Physiol Heart Circ Physiol. 2007;292:H1479-86.
20. Falk E. Pathogenesis of atherosclerosis. J Am Coll Cardiol. 2006;47:C7-12.
21. Lusis AJ. Atherosclerosis. Nature. 2000;407:233-41.
22. Libby P, Aikawa M. Stabilization of atherosclerotic plaques: New mechanisms and clinical targets. Nat Med. 2002;8:1257-62. doi: 10.1038/nm1102-1257.
23. Wolf D, Stachon P, Bode C, Zirlik A. Inflammatory mechanisms in atherosclerosis. Hamostaseologie. 2014;34:63-71.
24. Butler HR. Coronary disease. J Natl Med Assoc. 1933;25:110-5.
25. Ambrose JA, Singh M. Pathophysiology of coronary artery disease leading to acute coronary syndromes. F1000prime Rep. 2015;7:8.
26. McDowell HAJ. Stroke and occlusive cerebrovascular disease: review of surgical results in 383 patients. Am Surg. 1971;37:594-9.
27. Bogiatzi C, Hackam DG, McLeod AI, Spence JD. Secular trends in ischemic stroke subtypes and stroke risk factors. Stroke. 2014;45:3208-13.
28. Johansson BB. Hypertension mechanisms causing stroke. Clin Exp Pharmacol Physiol. 1999;26:563-5.
29. Chen Q, Shi Y, Wang Y, Li X. Patterns of disease distribution of lower extremity peripheral arterial disease. Angiology. 2015;66:211-8.
30. Tsimikas S. Oxidized low-density lipoprotein biomarkers in atherosclerosis. Curr Atheroscler Rep. 2006;8:55-61.
31. Karbiner MS, Sierra L, Minahk C, Fonio MC, de Bruno MP, Jerez S. The role of oxidative stress in alterations of hematological parameters and inflammatory markers induced by early hypercholesterolemia. Life Sci. 2013;93:503-8.
32. Kim JY, Kim OY, Paik JK, Kwon DY, Kim H-J, Lee JH. Association of age-related changes in circulating intermediary lipid metabolites, inflammatory and oxidative stress markers, and arterial stiffness in middle-aged men. Age. 2013;35:1507-19.
33. Zafrilla P, Losada M, Perez A, Caravaca G, Mulero J. Biomarkers of oxidative stress in patients with wet age related macular degeneration. J Nutr Health Aging. 2013;17:219-22.
34. Grassi D, Desideri G, Ferri L, Aggio A, Tiberti S, Ferri C. Oxidative stress and endothelial dysfunction: say NO to cigarette smoking! Curr Pharm Des. 2010;16:2539-50.
35. Zhao CT, Wang M, Siu CW, Hou YL, Wang T, Tse HF, et al. Myocardial dysfunction in patients with type 2 diabetes mellitus: role of endothelial progenitor cells and oxidative stress. Cardiovasc Diabetol. 2012;11:147.
36. Duarte JA, Carvalho F, Fernandes E, Remiao F, Bastos ML, Magalhaes J, et al. d-amphetamine-induced hydrogen peroxide production in skeletal muscle is modulated by monoamine oxidase inhibition. Int J Sports Med. 2004;25:446-9.
37. Carvalho F, Duarte JA, Neuparth MJ, Carmo H, Fernandes E, Remiao F, et al. Hydrogen peroxide production in mouse tissues after acute d-amphetamine administration. Influence of monoamine oxidase inhibition. Arch Toxicol. 2001;75:465-9.
38. Hafstad AD, Nabeebaccus AA, Shah AM. Novel aspects of ROS signalling in heart failure. Basic Res Cardiol. 2013;108:359.
39. Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS. Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol. 2002;34:379-88.
40. Giustarini D, Dalle-Donne I, Tsikas D, Rossi R. Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers. Crit Rev Clin Lab Sci. 2009;46:241-81.
41. Catala A. Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids. 2009;157:1-11.
42. Niki E. Lipid peroxidation: physiological levels and dual biological effects. Free Radic Biol Med. 2009;47:469-84.
43. Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11:81-128.
44. Daum G. Lipids of mitochondria. Biochim Biophys Acta. 1985;822:1-42.
45. Ardail D, Privat JP, Egret-Charlier M, Levrat C, Lerme F, Louisot P. Mitochondrial contact sites. Lipid composition and dynamics. J Biol Chem. 1990;265:18797-802.
46. Houtkooper RH, Vaz FM. Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci. 2008;65:2493-506.
47. Grammer TB, Kleber ME, Marz W, Silbernagel G, Siekmeier R, Wieland H, et al. Low-density lipoprotein particle diameter and mortality: the Ludwigshafen risk and cardiovascular health study. Eur Heart J. 2015;36:31-8.
48. Itabe H. Oxidative modification of LDL: its pathological role in atherosclerosis. Clin Rev Allergy Immunol. 2009;37:4-11.
49. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62:707-14.
50. Koppaka V, Silvestro L, Engler JA, Brouillette CG, Axelsen PH. The structure of human lipoprotein A-I. Evidence for the "belt" model. J Biol Chem. 1999;274:14541-4.
51. Maranhao RC, Carvalho PO, Strunz CC, Pileggi F. Lipoprotein (a): structure, pathophysiology and clinical implications. Arq Bras Cardiol. 2014;103:76-84.
52. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412-23.
53. Marcovina SM, Koschinsky ML. Lipoprotein(a) as a risk factor for coronary artery disease. Am J Cardiol. 1998;82:57U-66U (discussion 86U).
54. Poon M, Zhang X, Dunsky KG, Taubman MB, Harpel PC. Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells. Circulation. 1997;96:2514-9.
55. Di Napoli M, Elkind MSV, Godoy DA, Singh P, Papa F, Popa-Wagner A. Role of C-reactive protein in cerebrovascular disease: a critical review. Expert Rev Cardiovasc Ther. 2011;9:1565-84.
56. Sung K-C, Ryu S, Chang Y, Byrne CD, Kim SH. C-reactive protein and risk of cardiovascular and all-cause mortality in 268 803 East Asians. Eur Heart J. 2014;35:1809-16.
57. Anand SS, Yusuf S. C-reactive protein is a bystander of cardiovascular disease. Eur Heart J. 2010;31:2092-6.
58. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-9.
59. Singh SK, Suresh MV, Prayther DC, Moorman JP, Rusinol AE, Agrawal A. C-reactive protein-bound enzymatically modified low-density lipoprotein does not transform macrophages into foam cells. J Immunol. 2008;180:4316-22.
60. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-43.
61. Agrawal A, Hammond DJJ, Singh SK. Atherosclerosis-related functions of C-reactive protein. Cardiovasc Hematol Disord Drug Targets. 2010;10:235-40.
62. Khurana S, Venkataraman K, Hollingsworth A, Piche M, Tai TC. Polyphenols: benefits to the cardiovascular system in health and in aging. Nutrients. 2013;5:3779-827.
63. da Silva Santos VD, Bisen-Hersh E, Yu Y, Cabral ISR, Nardini V, Culbreth M, et al. Anthocyanin-rich acai (Euterpe oleracea Mart.) extract attenuates manganese-induced oxidative stress in rat primary astrocyte cultures. J Toxicol Environ Health A. 2014;77:390-404.
64. Alvarez-Suarez JM, Giampieri F, Tulipani S, Casoli T, Di Stefano G, Gonzalez-Paramas AM, et al. One-month strawberry-rich anthocyanin supplementation ameliorates cardiovascular risk, oxidative stress markers and platelet activation in humans. J Nutr Biochem. 2014;25:289-94.
65. Curtis PJ, Kroon PA, Hollands WJ, Walls R, Jenkins G, Kay CD, et al. Cardiovascular disease risk biomarkers and liver and kidney function are not altered in postmenopausal women after ingesting an elderberry extract rich in anthocyanins for 12weeks. J Nutr. 2009;139:2266-71.
66. Zapolska-Downar D, Bryk D, Małecki M, Hajdukiewicz K, Sitkiewicz D. Aronia melanocarpa fruit extract exhibits anti-inflammatory activity in human aortic endothelial cells. Eur J Nutr. 2012;51:563-72.
67. Di Stefano R. Advances in the study of secondary metabolites occurring in grapes and wines. Drugs Exp Clin Res. 1999;25:53-6.
68. Doughty J, Aljabri M, Scott RJ. Flavonoids and the regulation of seed size in Arabidopsis. Biochem Soc Trans. 2014;42:364-9.
69. Mouradov A, Spangenberg G. Flavonoids: a metabolic network mediating plants adaptation to their real estate. Front Plant Sci. 2014;5:620.
70. Juránek I, Bezek S. Controversy of free radical hypothesis: reactive oxygen species-cause or consequence of tissue injury? Gen Physiol Biophys. 2005;24:263-78.
71. Hori M, Nishida K. Oxidative stress and left ventricular remodelling after myocardial infarction. Cardiovasc Res. 2009;81:457-64.
72. Van den Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem. 1998;273:18092-8.
73. Bel A, Ricci M, Piquet J, Bruneval P, Perier M-C, Gagnieu C, et al. Prevention of postcardiopulmonary bypass pericardial adhesions by a new resorbable collagen membrane. Interact Cardiovasc Thorac Surg. 2012;14:469-73.
74. Zweier JL, Flaherty JT, Weisfeldt ML. Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sci USA. 1987;84:1404-7.
75. Guerra MC, Galvano F, Bonsi L, Speroni E, Costa S, Renzulli C, et al. Cyanidin-3-O-β-glucopyranoside, a natural free-radical scavenger against aflatoxin B1- and ochratoxin A-induced cell damage in a human hepatoma cell line (Hep G2) and a human colonic adenocarcinoma cell line (CaCo-2). Br J Nutr. 2005;94:211-20.
76. Cardoso LM, Viana Leite JP, Gouveia Peluzio MD. Efeitos biológicos das antocianinas no processo aterosclerótico. Revista Colombiana de Ciencias Químico-Farmacéuticas. 2011;40(1):116-38.
77. Rodrigo R, Guichard C, Charles R. Clinical pharmacology and therapeutic use of antioxidant vitamins. Fundam Clin Pharmacol. 2007;21:111-27.
78. Chen J, Sun H, Sun A, Hua Lin Q, Wang Y, Tao X. Studies of the protective effect and antioxidant mechanism of blueberry anthocyanins in a CC14-induced liver injury model in mice. Food Agric Immunol. 2012;23:352-62.
79. Paixão JIF. Papel das antocianinas no contexto da prevenção da aterosclerose: mecanismos moleculares de protecção contra a apoptose e inflamação em células endoteliais. 2012.
80. Chang Y-C, Huang K-X, Huang A-C, Ho Y-C, Wang C-J. Hibiscus anthocyanins-rich extract inhibited LDL oxidation and oxLDL-mediated macrophages apoptosis. Food Chem Toxicol. 2006;44:1015-23.
81. Kong J-M, Chia L-S, Goh N-K, Chia T-F, Brouillard R. Analysis and biological activities of anthocyanins. Phytochemistry. 2003;64:923-33.
82. Yi L, Chen C, Jin X, Mi M, Yu B, Chang H, et al. Structural requirements of anthocyanins in relation to inhibition of endothelial injury induced by oxidized low-density lipoprotein and correlation with radical scavenging activity. FEBS Lett. 2010;584:583-90.
83. Cook N. Flavonoids-chemistry, metabolism, cardioprotective effects, and dietary sources. J Nutr Biochem. 1996;7:66-76.
84. Galvez J, de la Cruz JP, Zarzuelo A, de la Cuesta FS. Flavonoid inhibition of enzymic and nonenzymic lipid peroxidation in rat liver differs from its influence on the glutathione-related enzymes. Pharmacology. 1995;51:127-33.
85. Heymes C, Bendall JK, Ratajczak P, Cave AC, Samuel J-L, Hasenfuss G, et al. Increased myocardial NADPH oxidase activity in human heart failure. J Am Coll Cardiol. 2003;41:2164-71.
86. Watson F, Robinson J, Edwards SW. Protein kinase C-dependent and -independent activation of the NADPH oxidase of human neutrophils. J Biol Chem. 1991;266:7432-9.
87. Sirker A, Zhang M, Shah AM. NADPH oxidases in cardiovascular disease: insights from in vivo models and clinical studies. Basic Res Cardiol. 2011;106:735-47.
88. Pagano PJ, Chanock SJ, Siwik DA, Colucci WS, Clark JK. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension. 1998;32:331-7.
89. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74(6):1141-8.
90. Bauldry SA, Nasrallah VN, Bass DA. Activation of NADPH oxidase in human neutrophils permeabilized with Staphylococcus aureus alpha-toxin. A lower Km when the enzyme is activated in situ. J Biol Chem. 1992;267:323-30.
91. Sag CM, Wagner S, Maier LS. Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radic Biol Med. 2013;63:338-49.
92. Byrne JA, Grieve DJ, Bendall JK, Li JM, Gove C, Lambeth JD, Cave AC, Shah AM. Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy. Circ Res. 2003;93(9):802-5.
93. Grieve DJ, Byrne JA, Siva A, Layland J, Johar S, Cave AC, et al. Involvement of the nicotinamide adenosine dinucleotide phosphate oxidase isoform Nox2 in cardiac contractile dysfunction occurring in response to pressure overload. J Am Coll Cardiol. 2006;47:817-26.
94. Eddy LJ, Stewart JR, Jones HP, Engerson TD, McCord JM, Downey JM. Free radical-producing enzyme, xanthine oxidase, is undetectable in human hearts. Am J Physiol. 1987;253:H709-11.
95. Ferrari R, Ceconi C, Curello S, Cargnoni A, Alfieri O, Pardini A, Marzollo P, Visioli O. Oxygen free radicals and myocardial damage: protective role of thiol-containing agents. Am J Med. 1991;91(3C):95S-105S.
96. Borges F, Fernandes E, Roleira F. Progress towards the discovery of xanthine oxidase inhibitors. Curr Med Chem. 2002;9:195-217.
97. Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res. 2000;47:446-56.
98. Saugstad OD, Aasen AO. Plasma hypoxanthine concentrations in pigs. A prognostic aid in hypoxia. Eur Surg Res. 1980;12:123-9.
99. Baldus S, Müllerleile K, Chumley P, Steven D, Rudolph V, Lund GK, et al. Inhibition of xanthine oxidase improves myocardial contractility in patients with ischemic cardiomyopathy. Free Radic Biol Med. 2006;41:1282-8.
100. Halliwell B, Gutteridge JM. Free radicals in biology and medicine. 3rd ed. Oxford: Oxford University Press; 2015.
101. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84.
102. Minhas KM, Saraiva RM, Schuleri KH, Lehrke S, Zheng M, Saliaris AP, Berry CE, Vandegaer KM, Li D, Hare JM. Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy. Circ Res. 2006;98(2):271-9.
103. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6:1191-7.
104. Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids. 2005;73:141-62.
105. Paixao J, Dinis TCP, Almeida LM. Malvidin-3-glucoside protects endothelial cells up-regulating endothelial NO synthase and inhibiting peroxynitrite-induced NF-ΚB activation. Chem Biol Interact. 2012;199:192-200.
106. Murakami M, Kudo I. Phospholipase A2. J Biochem. 2002;131:285-92.
107. Rosenson RS, Stafforini DM. Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2. J Lipid Res. 2012;53:1767-82.
108. Kanterman J, Sade-Feldman M, Baniyash M. New insights into chronic inflammation-induced immunosuppression. Semin Cancer Biol. 2012;22:307-18.
109. Wang H, Nair MG, Strasburg GM, Chang YC, Booren AM, Gray JI, et al. Antioxidant and antiinflammatory activities of anthocyanins and their aglycon, cyanidin, from tart cherries. J Nat Prod. 1999;62:294-6.
110. Seeram NP, Momin RA, Nair MG, Bourquin LD. Cyclooxygenase inhibitory and antioxidant cyanidin glycosides in cherries and berries. Phytomedicine. 2001;8:362-9.
111. Hou D-X, Yanagita T, Uto T, Masuzaki S, Fujii M. Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: structure-activity relationship and molecular mechanisms involved. Biochem Pharmacol. 2005;70:417-25.
112. Seeram NP, Zhang Y, Nair MG. Inhibition of proliferation of human cancer cells and cyclooxygenase enzymes by anthocyanidins and catechins. Nutr Cancer. 2003;46:101-6.
113. Muñoz-Espada AC, Watkins BA. Cyanidin attenuates PGE2 production and cyclooxygenase-2 expression in LNCaP human prostate cancer cells. J Nutr Biochem. 2006;17:589-96.
114. Mulabagal V, Lang GA, DeWitt DL, Dalavoy SS, Nair MG. Anthocyanin content, lipid peroxidation and cyclooxygenase enzyme inhibitory activities of sweet and sour cherries. J Agric Food Chem. 2009;57:1239-46.
115. Dreiseitel A, Korte G, Schreier P, Oehme A, Locher S, Hajak G, et al. sPhospholipase A(2) is inhibited by anthocyanidins. J Neural Transm. 2009;116:1071-7.
116. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, et al. Cyclooxygenase in biology and disease. FASEB J. 1998;12:1063-73.
117. Knaup B, Oehme A, Valotis A, Schreier P. Anthocyanins as lipoxygenase inhibitors. Mol Nutr Food Res. 2009;53:617-24.
118. Szymanowska U, Zlotek U, Karas M, Baraniak B. Anti-inflammatory and antioxidative activity of anthocyanins from purple basil leaves induced by selected abiotic elicitors. Food Chem. 2015;172:71-7.
119. Mashima R, Okuyama T. The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol. 2015;6:297-310.
120. Kuhn H, Banthiya S, van Leyen K. Mammalian lipoxygenases and their biological relevance. Biochim Biophys Acta. 2015;1851:308-30.
121. Zhang Y, Yang X, Bian F, Wu P, Xing S, Xu G, et al. TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: crosstalk between NF-ΚB and PPAR-γ. J Mol Cell Cardiol. 2014;72:85-94.
122. Huang W-Y, Wang J, Liu Y-M, Zheng Q-S, Li C-Y. Inhibitory effect of Malvidin on TNF-α-induced inflammatory response in endothelial cells. Eur J Pharmacol. 2014;723:67-72.
123. Yan X, Wu L, Li B, Meng X, Dai H, Zheng Y, et al. Cyanidin-3-O-glucoside induces apoptosis and inhibits migration of tumor necrosis factor-α-treated rat aortic smooth muscle cells. Toxicol: Cardiovascular; 2015.
124. Speciale A, Canali R, Chirafisi J, Saija A, Virgili F, Cimino F. Cyanidin-3-O-glucoside protection against TNF-α-induced endothelial dysfunction: involvement of nuclear factor-ΚB signaling. J Agric Food Chem. 2010;58:12048-54.
125. Luo X, Fang S, Xiao Y, Song F, Zou T, Wang M, et al. Cyanidin-3-glucoside suppresses TNF-α-induced cell proliferation through the repression of Nox activator 1 in mouse vascular smooth muscle cells: involvement of the STAT3 signaling. Mol Cell Biochem. 2012;362:211-8.
126. Zhang Y, Lian F, Zhu Y, Xia M, Wang Q, Ling W, et al. Cyanidin-3-O-β-glucoside inhibits LPS-induced expression of inflammatory mediators through decreasing IΚBα phosphorylation in THP-1 cells. Inflamm Res. 2010;59:723-30.
127. Ma M-M, Li Y, Liu X-Y, Zhu W-W, Ren X, Kong G-Q, et al. Cyanidin-3-O-glucoside ameliorates lipopolysaccharide-induced injury both in vivo and in vitro suppression of NF-ΚB and MAPK pathways. Inflammation. 2015;38:1669-82.
128. Limtrakul P, Yodkeeree S, Pitchakarn P, Punfa W. Suppression of inflammatory responses by black rice extract in RAW 264.7 macrophage cells via downregulation of NF-ΚB and AP-1 signaling pathways. Asian Pac J Cancer Prev. 2015;16:4277-83.
129. Serraino I, Dugo L, Dugo P, Mondello L, Mazzon E, Dugo G, et al. Protective effects of cyanidin-3-O-glucoside from blackberry extract against peroxynitrite-induced endothelial dysfunction and vascular failure. Life Sci. 2003;73:1097-114.
130. Pergola C, Rossi A, Dugo P, Cuzzocrea S, Sautebin L. Inhibition of nitric oxide biosynthesis by anthocyanin fraction of blackberry extract. Nitric Oxide. 2006;15:30-9.
131. Xu J-W, Ikeda K, Yamori Y. Upregulation of endothelial nitric oxide synthase by cyanidin-3-glucoside, a typical anthocyanin pigment. Hypertension. 2004;44:217-22.
132. Xu J-W, Ikeda K, Yamori Y. Cyanidin-3-glucoside regulates phosphorylation of endothelial nitric oxide synthase. FEBS Lett. 2004;574:176-80.
133. Paixao J, Dinis TCP, Almeida LM. Dietary anthocyanins protect endothelial cells against peroxynitrite-induced mitochondrial apoptosis pathway and Bax nuclear translocation: an in vitro approach. Apoptosis. 2011;16:976-89.
134. Martin S, Giannone G, Andriantsitohaina R, Martinez MC. Delphinidin, an active compound of red wine, inhibits endothelial cell apoptosis via nitric oxide pathway and regulation of calcium homeostasis. Br J Pharmacol. 2003;139:1095-102.
135. Chen B, Lu Y, Chen Y, Cheng J. The role of Nrf2 in oxidative stress-induced endothelial injuries. J Endocrinol. 2015;225:R83-99.
136. Aboonabi A, Singh I. Chemopreventive role of anthocyanins in atherosclerosis via activation of Nrf2-ARE as an indicator and modulator of redox. Biomed Pharmacother. 2015;72:30-6.
137. Murakami S, Motohashi H. Roles of Nrf2 in cell proliferation and differentiation. Free Radic Biol Med. 2015;88:168-78.
138. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med. 2004;10:549-57.
139. Sorrenti V, Mazza F, Campisi A, Di Giacomo C, Acquaviva R, Vanella L, et al. Heme oxygenase induction by cyanidin-3-O-β-glucoside in cultured human endothelial cells. Mol Nutr Food Res. 2007;51:580-6.
140. Parzonko A, Oswit A, Bazylko A, Naruszewicz M. Anthocyans-rich Aronia melanocarpa extract possesses ability to protect endothelial progenitor cells against angiotensin II induced dysfunction. Phytomedicine. 2015;22:1238-46.
141. Pantan R, Tocharus J, Suksamrarn A, Tocharus C. Synergistic effect of atorvastatin and cyanidin-3-glucoside on angiotensin II-induced inflammation in vascular smooth muscle cells. Exp Cell Res. 2016;342:104-12.
142. Shaughnessy KS, Boswall IA, Scanlan AP, Gottschall-Pass KT, Sweeney MI. Diets containing blueberry extract lower blood pressure in spontaneously hypertensive stroke-prone rats. Nutr Res. 2009;29:130-8.
143. Negishi H, Xu J-W, Ikeda K, Njelekela M, Nara Y, Yamori Y. Black and green tea polyphenols attenuate blood pressure increases in stroke-prone spontaneously hypertensive rats. J Nutr. 2004;134:38-42.
144. Ardiansyah, Shirakawa H, Koseki T, Ohinata K, Hashizume K, Komai M. Rice bran fractions improve blood pressure, lipid profile, and glucose metabolism in stroke-prone spontaneously hypertensive rats. J Agric Food Chem. 2006;54:1914-20.
145. Thandapilly SJ, LeMaistre JL, Louis XL, Anderson CM, Netticadan T, Anderson HD. Vascular and cardiac effects of grape powder in the spontaneously hypertensive rat. Am J Hypertens. 2012;25:1070-6.
146. Panchal SK, Brown L. Cardioprotective and hepatoprotective effects of ellagitannins from European oak bark (Quercus petraea L.) extract in rats. Eur J Nutr. 2013;52:397-408.
147. Zhang Y, Wang X, Wang Y, Liu Y, Xia M. Supplementation of cyanidin-3-O-β-glucoside promotes endothelial repair and prevents enhanced atherogenesis in diabetic apolipoprotein E-deficient mice. J Nutr. 2013;143:1248-53.
148. Kalea AZ, Clark K, Schuschke DA, Klimis-Zacas DJ. Vascular reactivity is affected by dietary consumption of wild blueberries in the Sprague-Dawley rat. J Med Food. 2009;12:21-8.
149. Cortes SF, Valadares YM, de Oliveira AB, Lemos VS, Barbosa MPT, Braga FC. Mechanism of endothelium-dependent vasodilation induced by a proanthocyanidin-rich fraction from Ouratea semiserrata. Planta Med. 2002;68:412-5.
150. Andriambeloson E, Magnier C, Haan-Archipoff G, Lobstein A, Anton R, Beretz A, et al. Natural dietary polyphenolic compounds cause endothelium-dependent vasorelaxation in rat thoracic aorta. J Nutr. 1998;128:2324-33.
151. Liu Y, Li D, Zhang Y, Sun R, Xia M. Anthocyanin increases adiponectin secretion and protects against diabetes-related endothelial dysfunction. Am J Physiol Endocrinol Metab. 2014;306:E975-88.
152. Luna-Vazquez FJ, Ibarra-Alvarado C, Rojas-Molina A, Rojas-Molina JI, Yahia EM, Rivera-Pastrana DM, et al. Nutraceutical value of black cherry Prunus serotina Ehrh. fruits: antioxidant and antihypertensive properties. Molecules. 2013;18:14597-612.
153. Graf D, Seifert S, Jaudszus A, Bub A, Watzl B. Anthocyanin-rich juice lowers serum cholesterol, leptin, and resistin and improves plasma fatty acid composition in fischer rats. PLoS ONE. 2013;8:e66690.
154. Mahmoud MY. Natural antioxidants effect of mulberry fruits (Morus nigra and Morus alba L.) on lipids profile and oxidative stress in hypercholestrolemic rats. Pakistan J Nutr. 2013;12:665-72.
155. Sankhari JM, Thounaojam MC, Jadeja RN, Devkar RV, Ramachandran AV. Anthocyanin-rich red cabbage (Brassica oleracea L.) extract attenuates cardiac and hepatic oxidative stress in rats fed an atherogenic diet. J Sci Food Agric. 2012;92:1688-93.
156. Zawistowski J, Kopec A, Kitts DD. Effects of a black rice extract (Oryza sativa L. indica) on cholesterol levels and plasma lipid parameters in Wistar Kyoto rats. J Funct Foods. 2012;1:50-6. doi: 10.1016/j.jff.2008.09.008.
157. Yang Y, Andrews MC, Hu Y, Wang D, Qin Y, Zhu Y, et al. Anthocyanin extract from black rice significantly ameliorates platelet hyperactivity and hypertriglyceridemia in dyslipidemic rats induced by high fat diets. J Agric Food Chem. 2011;59:6759-64.
158. Valcheva-Kuzmanova S, Kuzmanov K, Mihova V, Krasnaliev I, Borisova P, Belcheva A. Antihyperlipidemic effect of Aronia melanocarpa fruit juice in rats fed a high-cholesterol diet. Plant Foods Hum Nutr. 2007;62:19-24.
159. Peng C-H, Liu L-K, Chuang C-M, Chyau C-C, Huang C-N, Wang C-J. Mulberry water extracts possess an anti-obesity effect and ability to inhibit hepatic lipogenesis and promote lipolysis. J Agric Food Chem. 2011;59:2663-71.
160. Brader L, Overgaard A, Christensen LP, Jeppesen PB, Hermansen K. Polyphenol-rich bilberry ameliorates total cholesterol and LDL-cholesterol when implemented in the diet of Zucker diabetic fatty rats. Rev Diabet Stud. 2013;10:270-82.
161. Mauray A, Milenkovic D, Besson C, Caccia N, Morand C, Michel F, et al. Atheroprotective effects of bilberry extracts in apo E-deficient mice. J Agric Food Chem. 2009;57:11106-11.
162. Mauray A, Felgines C, Morand C, Mazur A, Scalbert A, Milenkovic D. Bilberry anthocyanin-rich extract alters expression of genes related to atherosclerosis development in aorta of apo E-deficient mice. Nutr Metab Cardiovasc Dis. 2012;22:72-80.
163. Wang Y, Zhang Y, Wang X, Liu Y, Xia M. Supplementation with cyanidin-3-O-β-glucoside protects against hypercholesterolemia-mediated endothelial dysfunction and attenuates atherosclerosis in apolipoprotein E-deficient mice. J Nutr. 2012;142:1033-7.
164. Xia X, Ling W, Ma J, Xia M, Hou M, Wang Q, et al. An anthocyanin-rich extract from black rice enhances atherosclerotic plaque stabilization in apolipoprotein E-deficient mice. J Nutr. 2006;136:2220-5.
165. Wu T, Qi X, Liu Y, Guo J, Zhu R, Chen W, et al. Dietary supplementation with purified mulberry (Morus australis Poir) anthocyanins suppresses body weight gain in high-fat diet fed C57BL/6 mice. Food Chem. 2013;141:482-7.
166. Wang D, Wei X, Yan X, Jin T, Ling W. Protocatechuic acid, a metabolite of anthocyanins, inhibits monocyte adhesion and reduces atherosclerosis in apolipoprotein E-deficient mice. J Agric Food Chem. 2010;58:12722-8.
167. Seymour EM, Lewis SK, Urcuyo-Llanes DE, Tanone II, Kirakosyan A, Kaufman PB, et al. Regular tart cherry intake alters abdominal adiposity, adipose gene transcription, and inflammation in obesity-prone rats fed a high fat diet. J Med Food. 2009;12:935-42.
168. Yamakoshi J, Kataoka S, Koga T, Ariga T. Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Atherosclerosis. 1999;142:139-49.
169. Finne Nielsen IL, Elbol Rasmussen S, Mortensen A, Ravn-Haren G, Ma HP, Knuthsen P, et al. Anthocyanins increase low-density lipoprotein and plasma cholesterol and do not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits. Mol Nutr Food Res. 2005;49:301-8.
170. Kabiri N, Asgary S, Setorki M. Lipid lowering by hydroalcoholic extracts of Amaranthus caudatus L. induces regression of rabbits atherosclerotic lesions. Lipids Health Dis. 2011;10:89.
171. Abdel-Moemin AR. Switching to black rice diets modulates low-density lipoprotein oxidation and lipid measurements in rabbits. Am J Med Sci. 2011;341:318-24.
172. Sozanski T, Kucharska AZ, Szumny A, Magdalan J, Bielska K, Merwid-Lad A, et al. The protective effect of the Cornus mas fruits (cornelian cherry) on hypertriglyceridemia and atherosclerosis through PPARα activation in hypercholesterolemic rabbits. Phytomedicine. 2014;21:1774-84.
173. Qin Y, Xia M, Ma J, Hao Y, Liu J, Mou H, et al. Anthocyanin supplementation improves serum LDL- and HDL-cholesterol concentrations associated with the inhibition of cholesteryl ester transfer protein in dyslipidemic subjects. Am J Clin Nutr. 2009;90:485-92.
174. Zhu Y, Xia M, Yang Y, Liu F, Li Z, Hao Y, et al. Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin Chem. 2011;57:1524-33.
175. Hassellund SS, Flaa A, Sandvik L, Kjeldsen SE, Rostrup M. Effects of anthocyanins on blood pressure and stress reactivity: a double-blind randomized placebo-controlled crossover study. J Hum Hypertens. 2012;26:396-404.
176. Hassellund SS, Flaa A, Kjeldsen SE, Seljeflot I, Karlsen A, Erlund I, et al. Effects of anthocyanins on cardiovascular risk factors and inflammation in pre-hypertensive men: a double-blind randomized placebo-controlled crossover study. J Hum Hypertens. 2013;27:100-6.
177. Basu A, Du M, Leyva MJ, Sanchez K, Betts NM, Wu M, et al. Blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome. J Nutr. 2010;140:1582-7.
178. Basu A, Betts NM, Ortiz J, Simmons B, Wu M, Lyons TJ. Low-energy cranberry juice decreases lipid oxidation and increases plasma antioxidant capacity in women with metabolic syndrome. Nutr Res. 2011;31:190-6.
179. Dohadwala MM, Holbrook M, Hamburg NM, Shenouda SM, Chung WB, Titas M, et al. Effects of cranberry juice consumption on vascular function in patients with coronary artery disease. Am J Clin Nutr. 2011;93:934-40.
180. Cassidy A, Bertoia M, Chiuve S, Flint A, Forman J, Rimm EB. Habitual intake of anthocyanins and flavanones and risk of cardiovascular disease in men. Am J Clin Nutr. 2016;104:587-94.
181. Cassidy A, Mukamal KJ, Liu L, Franz M, Eliassen AH, Rimm EB. High anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women. Circulation. 2013;127:188-96.
182. Mink PJ, Scrafford CG, Barraj LM, Harnack L, Hong C-P, Nettleton JA, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr. 2007;85:895-909.
183. Naruszewicz M, Łaniewska I, Millo B, Dłužniewski M. Combination therapy of statin with flavonoids rich extract from chokeberry fruits enhanced reduction in cardiovascular risk markers in patients after myocardial infraction (MI). Atherosclerosis. 2007;194:179-84.
184. Ryszawa N, Kawczýska-Drózdz A, Pryjma J, Czesnikiewicz-Guzik M, Adamek-Guzik T, Naruszewicz M, et al. Effects of novel plant antioxidants on platelet superoxide production and aggregation in atherosclerosis. J Physiol Pharmacol. 2006;57:611-26.
185. Kokotkiewicz A, Jaremicz Z, Luczkiewicz M. Aronia plants: a review of traditional use, biological activities, and perspectives for modern medicine. J Med Food. 2010;13:255-69.