A review on the structure–activity relationship of dietary flavonoids for protecting vascular endothelial function: Current understanding and future issues

Journal of Food Biochemistry

Volumn 42, Issue 5, 2018, Pages

  Zhang, Di ^a   Du, Mingzhao ^b   Wei, Ying ^c   Wang, Chengtao ^d   Shen, Lingqin ^a  

^a JIANGSU UNIVERSITY   (China)

^b AFFILIATED HOSPITAL OF JIANGSU UNIVERSITY   (China)

^c NATIONAL RESEARCH INSTITUTE FOR FAMILY PLANNING   (China)

^d BEIJING TECHNOLOGY AND BUSINESS UNIVERSITY   (China)

Author keywords

endothelial nitric oxide synthase; flow mediated dilation; metabolism; quercetin; structure activity relationship

Indexed keywords

BIOCHEMISTRY; ENDOTHELIAL CELLS; METABOLISM; NITRIC OXIDE; NUTRITION; STRUCTURES (BUILT OBJECTS);

CARDIO-VASCULAR DISEASE; ENDOTHELIAL FUNCTION; ENDOTHELIAL NITRIC OXIDE SYNTHASE; FLOW MEDIATED DILATION; PHARMACEUTICAL INDUSTRY; QUERCETIN; STRUCTURAL CHARACTERISTICS; STRUCTURE ACTIVITY RELATIONSHIPS;

FLAVONOIDS;

EID: 85046406136     PISSN: 01458884     EISSN: 17454514     Source Type: Journal    
DOI: 10.1111/jfbc.12557     Document Type: Review

References (118)

1. Agewall, S., Wright, S., Doughty, R. N., Whalley, G. A., Duxbury, M., & Sharpe, N. (2000). Does a glass of red wine improve endothelial function? European Heart Journal, 21(1), 74–78
2. Aprotosoaie, A. C., Miron, A., Trifan, A., Luca, V. S., & Costache, I. I. (2016). The cardiovascular effects of cocoa polyphenols-an overview. Diseases, 4(4), 39. pii:
3. Awika, J. M., Dykes, L., Gu, L., Rooney, L. W., & Prior, R. L. (2003). Processing of sorghum (Sorghum bicolor) and sorghum products alters procyanidin oligomer and polymer distribution and content. Journal of Agricultural and Food Chemistry, 51(18), 5516–5521
4. Ayer, A., Zarjou, A., Agarwal, A., & Stocker, R. (2016). Heme oxygenases in cardiovascular health and disease. Physiological Reviews, 96(4), 1449–1508
5. Balestra, C., Cimino, F., Theunissen, S., Snoeck, T., Provyn, S., Canali, R., … Virgili, F. (2016). A red orange extract modulates the vascular response to a recreational dive: A pilot study on the effect of anthocyanins on the physiological consequences of scuba diving. Natural Product Research, 30(18), 2101–2106
6. Balzer, J., Rassaf, T., Heiss, C., Kleinbongard, P., Lauer, T., Merx, M., … Kelm, M. (2008). Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients: A double-masked, randomized, controlled trial. Journal of the American College of Cardiology, 51(22), 2141–2149
7. Beecher, G. R. (2003). Overview of dietary flavonoids: Nomenclature, occurrence and intake. The Journal of Nutrition, 133(10), 3248S–3254S
8. Bondonno, N. P., Bondonno, C. P., Blekkenhorst, L. C., Considine, M. J., Maghzal, G., Stocker, R., … Croft, K. D. (2017). Flavonoid-rich apple improves endothelial function in individuals at risk for cardiovascular disease: A randomised controlled clinical trial. Molecular Nutrition & Food Research, 62, 2018
9. Bredsdorff, L., Nielsen, I. L., Rasmussen, S. E., Cornett, C., Barron, D., Bouisset, F., … Williamson, G. (2010). Absorption, conjugation and excretion of the flavanones, naringenin and hesperetin from alpha-rhamnosidase-treated orange juice in human subjects. British Journal of Nutrition, 103(11), 1602–1609
10. Cassidy, A., & Minihane, A. M. (2017). The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. The American Journal of Clinical Nutrition, 105(1), 10–22
11. Chan, Y. H., Lau, K. K., Yiu, K. H., Li, S. W., Chan, H. T., Fong, D. Y., … Tse, H. F. (2008). Reduction of C-reactive protein with isoflavone supplement reverses endothelial dysfunction in patients with ischaemic stroke. European Heart Journal, 29(22), 2800–2807
12. Chanet, A., Milenkovic, D., Claude, S., Maier, J. A., Kamran Khan, M., Rakotomanomana, N., … Morand, C. (2013). Flavanone metabolites decrease monocyte adhesion to TNF-α-activated endothelial cells by modulating expression of atherosclerosis-related genes. The British Journal of Nutrition, 110(4), 587–598
13. Chen, B., Lu, Y., Chen, Y., & Cheng, J. (2015). The role of Nrf2 in oxidative stress-induced endothelial injuries. Journal of Endocrinology, 225(3), R83–R99
14. Choi, E. Y., Lee, H., Woo, J. S., Jang, H. H., Hwang, S. J., Kim, H. S., … Kim, W. (2015). Effect of onion peel extract on endothelial function and endothelial progenitor cells in overweight and obese individuals. Nutrition, 31(9), 1131–1135
15. Claude, S., Boby, C., Rodriguez-Mateos, A., Spencer, J. P., Gérard, N., Morand, C., & Milenkovic, D. (2014). Flavanol metabolites reduce monocyte adhesion to endothelial cells through modulation of expression of genes via p38-MAPK and p65-Nf-kB pathways. Molecular Nutrition & Food Research, 58(5), 1016–1027
16. Clifford, M. N., van der Hooft, J. J., & Crozier, A. (2013). Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols. The American Journal of Clinical Nutrition, 98(6), 1619S–1630S
17. Croft, K. D., Zhang, D., Jiang, R., Ayer, A., Shengule, S., Payne, R. J., … Stocker, R. (2017). Structural requirements of flavonoids to induce heme oxygenase-1 expression. Free radical Biology & Medicine, 113, 165–175
18. Crozier, A., Jaganath, I. B., & Clifford, M. N. (2009). Dietary phenolics: Chemistry, bioavailability and effects on health. Natural Product Reports, 26(8), 1001–1043
19. Cutler, B. R., Petersen, C., & Anandh Babu, P. V. (2017). Mechanistic insights into the vascular effects of blueberries: Evidence from recent studies. Molecular Nutrition & Food Research, 61(6), 1600271
20. De Ferrars, R. M., Cassidy, A., Curtis, P., & Kay, C. D. (2014). Phenolic metabolites of anthocyanins following a dietary intervention study in postmenopausal women. Molecular Nutrition & Food Research, 58(3), 490–502
21. De Ferrars, R. M., Czank, C., Zhang, Q., Botting, N. P., Kroon, P. A., Cassidy, A., & Kay, C. D. (2014). The pharmacokinetics of anthocyanins and their metabolites in humans. British Journal of Pharmacology, 171(13), 3268–3282
22. De Taeye, C., Cibaka, M. L., Jerkovic, V., & Collin, S. (2014). Degradation of (−)-epicatechin and procyanidin b2 in aqueous and lipidic model systems. first evidence of “chemical” flavan-3-ol oligomers in processed cocoa. Journal of Agricultural and Food Chemistry, 62(36), 9002–9016
23. Del Rio, D., Rodriguez-Mateos, A., Spencer, J. P., Tognolini, M., Borges, G., & Crozier, A. (2013). Dietary (poly)phenolics in human health: Structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxidants & Redox Signaling, 18(14), 1818–1892
24. Donovan, J. M. C., Faulks, R. M., & Kroon, P. A. (2006). Absorption and metabolism of dietary plant secondary metabolites. In A. Crozier, M. N. Clifford, & H. Ashihara (Eds.), Plant secondary metabolites: Occurrence, structure and role in the human diet (pp. 303–351). Oxford: Blackwell Publishing
25. Dorenkott, M. R., Griffin, L. E., Goodrich, K. M., Thompson-Witrick, K. A., Fundaro, G., Ye, L., … Neilson, A. P. (2014). Oligomeric cocoa procyanidins possess enhanced bioactivity compared to monomeric and polymeric cocoa procyanidins for preventing the development of obesity, insulin resistance, and impaired glucose tolerance during high-fat feeding. Journal of Agricultural and Food Chemistry, 62(10), 2216–2227
26. Edwards, M., Czank, C., Woodward, G. M., Cassidy, A., & Kay, C. D. (2015). Phenolic metabolites of anthocyanins modulate mechanisms of endothelial function. Journal of Agricultural and Food Chemistry, 63(9), 2423–2431
27. Erlund, I., Silaste, M. L., Alfthan, G., Rantala, M., Kesäniemi, Y. A., & Aro, A. (2002). Plasma concentrations of the flavonoids hesperetin, naringenin and quercetin in human subjects following their habitual diets, and diets high or low in fruit and vegetables. European Journal of Clinical Nutrition, 56(9), 891–898
28. Farouque, H. M., Leung, M., Hope, S. A., Baldi, M., Schechter, C., Cameron, J. D., & Meredith, I. T. (2006). Acute and chronic effects of flavanol-rich cocoa on vascular function in subjects with coronary artery disease: A randomized double-blind placebo-controlled study. Clinical Science (London, England : 1979), 111(1), 71–80
29. Forman, H. J., Davies, K. J., & Ursini, F. (2014). How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radical Biology and Medicine, 66, 24–35
30. Fratantonio, D., Speciale, A., Ferrari, D., Cristani, M., Saija, A., & Cimino, F. (2015). Palmitate-induced endothelial dysfunction is attenuated by cyanidin-3-O-glucoside through modulation of Nrf2/Bach1 and NF-kappa B pathways. Toxicology Letters, 239(3), 152–160
31. Giménez-Bastida, J. A., González-Sarrías, A., Vallejo, F., Espín, J. C., & Tomás-Barberán, F. A. (2016). Hesperetin and its sulfate and glucuronide metabolites inhibit TNF-α induced human aortic endothelial cell migration and decrease plasminogen activator inhibitor-1 (PAI-1) levels. Food & Function, 7(1), 118–126
32. Hallund, J., Bügel, S., Tholstrup, T., Ferrari, M., Talbot, D., Hall, W. L., … Wiinberg, N. (2006). Soya isoflavone-enriched cereal bars affect markers of endothelial function in postmenopausal women. British Journal of Nutrition, 95(06), 1120–1126
33. Haenen, G. R., Arts, M. J., Bast, A., & Coleman, M. D. (2006). Structure and activity in assessing antioxidant activity in vitro and in vivo A critical appraisal illustrated with the flavonoids. Environmental Toxicology and Pharmacology, 21(2), 191–198
34. Han, S. G., Han, S. S., Toborek, M., & Hennig, B. (2012). EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes. Toxicology and Applied Pharmacology, 261(2), 181–188
35. Harborne, J. B., & Baxter, H. (1999). The handbook of natural flavonoids (Volume 1 and Volume 2). New York, NY: John Wiley & Sons
36. Haseeb, S., Alexander, B., & Baranchuk, A. (2017). Wine and cardiovascular health: A comprehensive review. Circulation, 136(15), 1434–1448
37. Heart Protection Study Collaborative Group. (2002). MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,356 high-risk individuals: A randomised placebo-controlled trial. Lancet, 360(9326), 23–33
38. Heiss, C., Finis, D., Kleinbongard, P., Hoffmann, A., Rassaf, T., Kelm, M., Sies, H. (2007). Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1 week. Journal of Cardiovascular Pharmacology, 49(2), 74–80
39. Hooper, L., Kay, C., Abdelhamid, A., Kroon, P. A., Cohn, J. S., Rimm, E. B., & Cassidy, A. (2012). Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: A systematic review and meta-analysis of randomized trials. The American Journal of Clinical Nutrition, 95(3), 740–751
40. Hooper, L., Kroon, P. A., Rimm, E. B., Cohn, J. S., Harvey, I., Le Cornu, K. A., … Cassidy, A. (2008). Flavonoids, flavonoid-rich foods, and cardiovascular risk: A meta-analysis of randomized controlled trials. The American Journal of Clinical Nutrition, 88(1), 38–50
41. Hosoda, K., Furuta, T., & Ishii, K. (2011). Metabolism and disposition of iosflavone conjugated metabolites in humans after ingestion of Kinako. Drug Metabolism & Disposition, 39(9), 1762–1767
42. Ichiyanagi, T., Rahman, M. M., Kashiwada, Y., Ikeshiro, Y., Shida, Y., Hatano, Y., … Konishi, T. (2004). Absorption and metabolism of delphinidin 3-O-β-D-glucopyranoside in rats. Free Radical Biology and Medicine, 36(7), 930–937
43. Ichiyanagi, T., Shida, Y., Rahman, M. M., Hatano, Y., Matsumoto, H., Hirayama, M., & Konishi, T. (2005a). Metabolic pathway of cyanidin 3-O-β-D-glucopyranoside in rats. Journal of Agricultural and Food Chemistry, 53(1), 145–150
44. Ichiyanagi, T., Shida, Y., Rahman, M. M., Hatano, Y., & Konishi, T. (2005b). Extended glucuronidation is another major path of cyanidin 3-O-β-D-glucopyranoside metabolism in rats. Journal of Agricultural and Food Chemistry, 53(18), 7312–7319
45. Ikeda, I., Tsuda, K., Suzuki, Y., Kobayashi, M., Unno, T., Tomoyori, H., … Kakuda, T. (2005). Tea catechins with gallolyl moiety suppress postprandial hypetriacyloglycerolemia by delaying lymphatic transport of dietary fat in rats. The Journal of Nutrition, 135(2), 155–159
46. Irace, C., Marini, H., Bitto, A., Altavilla, D., Polito, F., Adamo, E. B., … Squadrito, F. (2013). Genistein and endothelial function in postmenopausal women with metabolic syndrome. European Journal of Clinical Investigation, 43(10), 1025–1031
47. Jin, R. C., & Loscalzo, J. (2010). Vascular nitric oxide: Formation and function. Journal of Blood Medicine, 2010(1), 147–162
48. Kawai, Y., Nishikawa, T., Shiba, Y., Saito, S., Murota, K., Shibata, N., … Terao, J. (2008). Macrophage as a target of quercetin glucuronides in human atherosclerotic arteries: Implication in the anti-atherosclerotic mechanism of dietary flavonoids. Journal of Biological Chemistry, 283(14), 9424–9434
49. Kawanishi, S., Oikawa, S., & Murata, M. (2005). Evaluation for safety of antioxidant chemopreventive agents. Antioxidants & Redox Signaling, 7, 1728–1739
50. Kay, C. D., Hooper, L., Kroon, P. A., Rimm, E. B., & Cassidy, A. (2012). Relative impact of flavonoid composition, dose and structure on vascular function: A systematic review of randomised controlled trials of flavonoid-rich food products. Molecular Nutrition & Food Research, 56(11), 1605–1616
51. Kay, C. D., Kroon, P. A., & Cassidy, A. (2009). The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products. Molecular Nutrition & Food Research, 53(S1), S92–101
52. Kim, J. H., Auger, C., & Schini-Kerth, V. B. (2014). Activation of eNOS by polyphenol-rich products and polyphenolic compounds. Current Pharmaceutical Design, 20(22), 3521–3529
53. Kuhnert, N., Clifford, M. N., & Muller, A. (2010). Oxidative cascade reactions yielding polyhydroxy-theaflavins and theacitrins in the formation of black tea thearubigins: Evidence by tandem LC-MS. Food & Function, 1(2), 180–199
54. Lee, C. C., Dudonné, S., Kim, J. H., Kim, J. S., Dubé, P., Kim, J. E., … Lee, C. Y. (2018). A major daidzin metabolite 7,8,4′-trihydroxyisoflavone found in the plasma of soybean extract-fed rats attenuates monocyte-endothelial cell adhesion. Food Chemistry, 240, 607–614
55. Lee, S. M., Kim, C. W., Kim, J. K., Shin, H. J., & Baik, J. H. (2008). GCG-rich tea catechins are effective in lowering cholesterol and triglyceride concentrations in hyperlipidemicrats. Lipids, 43(5), 419–429
56. Lee-Hilz, Y. Y., Boerboom, A. M., Westphal, A. H., Berkel, W. J., Aarts, J. M., & Rietjens, I. M. (2006). Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression. Chemical Research in Toxicology, 19(11), 1499–1505
57. Ley, K., & Huo, Y. (2001). VCAM-1 is critical in atherosclerosis. The Journal of Clinical Investigation, 107(10), 1209–1210
58. Li, J. Y., Zhao, H. W., & Huang, W. D. (2015). Yeast-induced changes in the concentration and structure of oligomeric proanthocyanidins during simulated wine fermentation. Australian Journal of Grape & Wine Research, 21(3), 404–410
59. Liu, Y., Li, D., Zhang, Y., Sun, R., & Xia, M. (2014). Anthocyanin increases adiponectin secretion and protects against diabetes-related endothelial dysfunction. American Journal of Physiology. Endocrinology and Metabolism, 306(8), E975–E988
60. Lodi, F., Jimenez, R., Moreno, L., Kroon, P. A., Needs, P. W., Hughes, D. A., … Perez-Vizcaino, F. (2009). Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasorelaxant effects in rat aorta. Atherosclerosis, 204(1), 34–39
61. Loke, W. M., Proudfoot, J. M., Hodgson, J. M., McKinley, A. J., Hime, N., Magat, M., … Croft, K. D. (2010). Specific dietary polyphenols attenuate atherosclerosis in apolipoprotein E-knockout mice by alleviating inflammation and endothelial dysfunction. Arteriosclerosis Thrombosis and Vascular Biology, 30(4), 749–757
62. Loscalzo, J., & Welch, G. (1995). Nitric oxide and its role in the cardiovascular system. Progress in Cardiovascular Diseases, 38(2), 87–104
63. Lotito, S. B., & Frei, B. (2006). Dietary flavonoids attenuate tumor necrosis factor alpha-induced adhesion molecule expression in human aortic endothelial cells. Structure-function relationships and activity after first pass metabolism. Journal of Biological Chemistry, 281(48), 37102–37110
64. Manach, C., Mazur, A., & Scalbert, A. (2005). Polyphenols and prevention of cardiovascular diseases. Current Opinion in Lipidology, 16(1), 77–84
65. Martin, S., Andriambeloson, E., Takeda, K., & Andriantsitohaina, R. (2002). Red wine polyphenols increase calcium in bovine aortic endothelial cells: A basis to elucidate signalling pathways leading to nitric oxide production. British Journal of Pharmacology, 135(6), 1579–1587
66. Martínez-Fernández, L., Pons, Z., Margalef, M., Arola-Arnal, A., & Muguerza, B. (2015). Regulation of vascular endothelial genes by dietary flavonoids: Structure-expression relationship studies and the role of the transcription factor KLF-2. The Journal of Nutritional Biochemistry, 26(3), 277–284
67. Menendez, C., Dueñas, M., Galindo, P., González-Manzano, S., Jimenez, R., Moreno, L., … Perez-Vizcaino, F. (2011). Vascular deconjugation of quercetin glucuronide: The flavonoid paradox revealed. Molecular Nutrition & Food Research, 55(12), 1780–1790
68. Meng, X., Sang, S., Zhu, N., Lu, H., Sheng, S., Lee, M. J., … Yang, C. S. (2002). Identification and characterization of methylated and ring-fission metabolites of tea catechins formed in humans, mice, and rats. Chemical Research in Toxicology, 15(8), 1042–1050
69. Mensah, G. A. (2007). Healthy endothelium: The scientific basis for cardiovascular health promotion and chronic disease prevention. Vascular Pharmacology, 46(5), 310–314
70. Mika, M., Kostogrys, R. B., Franczyk-Żarów, M., Wikiera, A., & Maślak, E. (2015). Anti-atherosclerotic activity of catechins depends on their Stereoisomerism. Atherosclerosis, 240(1), 125–130
71. Mishra, S. K., Abbot, S. E., Choudhury, Z., Cheng, M., Khatab, N., Maycock, N. J., … Aaronson, P. I. (2000). Endothelium-dependent relaxation of rat aorta and main pulmonary artery by the phytoestrogens genistein and daidzein. Cardiovascular Research, 46(3), 539–546
72. Mladenka, P., Zatloukalová, L., Filipský, T., & Hrdina, R. (2010). Cardiovascular effects of flavonoids are not caused only by direct antioxidant activity. Free Radical Biology & Medicine, 49(6), 963–975
73. Morand, C., Dubray, C., Milenkovic, D., Lioger, D., Martin, J. F., Scalbert, A., & Mazur, A. (2011). Hesperidin contributes to the vascular protective effects of orange juice: A randomized crossover study in healthy volunteers. The American Journal of Clinical Nutrition, 93(1), 73–80
74. Muzolf-Panek, M., Gliszczyńska-świgło, A., de Haan, L., Aarts, J. M. M. J. G., Szymusiak, H., Vervoort, J. M., … Rietjens, I. M. C. M. (2008). Role of catechin quinones in the induction of EpRE-mediated gene expression. Chemical Research in Toxicology, 21((12), 2352–2360
75. Nakayama, H., Tsuge, N., Sawada, H., & Higashi, Y. (2013). Chronic intake of onion extract containing quercetin improved postprandial endothelial dysfunction in healthy men. The Journal of the American College of Nutrition, 32(3), 160–164
76. Nayak, B., Liu, R. H., & Tang, J. (2015). Effect of processing on phenolic antioxidants of fruits, vegetables, and grains–A review. Critical Reviews in Food Science & Nutrition, 55(7), 887–919
77. Novakovic, A., Marinko, M., Vranic, A., Jankovic, G., Milojevic, P., Stojanovic, I., … He, G. W. (2015). Mechanisms underlying the vasorelaxation of human internal mammary artery induced by (-)-epicatechin. European Journal of Pharmacology, 762, 306–312
78. Panche, A. N., Diwan, A. D., & Chandra, S. R. (2016). Flavonoids: An overview. Journal of Nutritional Science, 5, e47
79. Perez-Vizcaino, F., Duarte, J., & Santos-Buelga, C. (2012). The flavonoid paradox: Conjugation and deconjugation as key steps for the biological activity of flavonoids. Journal of the Science of Food and Agriculture, 92(9), 1822–1825
80. Pullikotil, P., Chen, H., Muniyappa, R., Greenberg, C. C., Yang, S. T., Reiter, C. E. N., … Quon, M. J. (2012). Epigallocatechin gallate induces expression of heme oxygenase-1 in endothelial cells via p38 MAPK and Nrf-2 that suppresses proinflammatory actions of TNF-alpha. Journal of Nutritional Biochemistry, 23(9), 1134–1145
81. Qian, Y., Babu, P. V. A., Symons, J. D., & Jalili, T. (2017). Metabolites of flavonoid compounds preserve indices of endothelial cell nitric oxide bioavailability under glucotoxic conditions. Nutrition & Diabetes, 7(9), e286
82. Ras, R. T., Streppel, M. T., Draijer, R., & Zock, P. L. (2013). Flow-mediated dilation and cardiovascular risk prediction: A systematic review with meta-analysis. International Journal of Cardiology, 168, 344–351
83. Ren, B., Qin, W., Wu, F., Wang, S., Pan, C., Wang, L., … Liang, J. (2016). Apigenin and naringenin regulate glucose and lipid metabolism, and ameliorate vascular dysfunction in type 2 diabetic rats. European Journal of Pharmacology, 773, 13–23
84. Rendeiro, C., Dong, H., Saunders, C., Harkness, L., Blaze, M., Hou, Y., … Spencer, J. P. (2016). Flavanone-rich citrus beverages counteract the transient decline in postprandial endothelial function in humans: A randomised, controlled, double-masked, cross-over intervention study. British Journal of Nutrition, 116(12), 1999–2010
85. Rizza, S., Muniyappa, R., Iantorno, M., Kim, J. A., Chen, H., Pullikotil, P., … Cardillo, C. (2011). Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. The Journal of Clinical Endocrinology and Metabolism, 96(5), E782–E792
86. Ruijters, E. J., Weseler, A. R., Kicken, C., Haenen, G. R., & Bast, A. (2013). The flavanol (-)-epicatechin and its metabolites protect against oxidative stress in primary endothelial cells via a direct antioxidant effect. European Journal of Pharmacology, 715(1–3), 147–153
87. Saarenhovi, M., Salo, P., Scheinin, M., Lehto, J., Lovró, Z., Tiihonen, K., … Raitakari, O. T. (2017). The effect of an apple polyphenol extract rich in epicatechin and flavan-3-ol oligomers on brachial artery flow-mediated vasodilatory function in volunteers with elevated blood pressure. Nutrition Journal, 16(1), 73
88. Sansone, R., Rodriguez-Mateos, A., Heuel, J., Falk, D., Schuler, D., Wagstaff, R., … Heiss, C. (2015). Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: A randomised, controlled, double-masked trial: The Flaviola Health Study. The British Journal of Nutrition, 114(8), 1246–1255
89. Schroeter, H., Heiss, C., Balzer, J., Kleinbongard, P., Keen, C. L., Hollenberg, N. K., … Kelm, M. (2006). (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proceedings of the National Academy of Sciences of United States of America, 103(4), 1024–1029
90. Serra, A., Macià, A., Romero, M., Reguant, J., Ortega, N., & Motilva, M.-J. (2012). Metabolic pathways of the colonic metabolism of flavonoids (flavonols, flavones and flavanones) and phenolic acids. Food Chemistry, 130(2), 383–393
91. Sesink, A. L. A., O'Leary, K. A., & Hollman, P. C. H. (2001). Quercetin glucuronides but not glucosides are present in human plasma after consumption of quercetin-3-glucoside or quercetin-4′glucoside. The Journal of Nutrition, 131(7), 1938–1941
92. Shen, Y., Croft, K. D., Hodgson, J. M., Kyle, R., Lee, I. L., Wang, Y., … Ward, N. C. (2012). Quercetin and its metabolites improve vessel function by inducing eNOS activity via phosphorylation of AMPK. Biochemical Pharmacology, 84(8), 1036–1044
93. Shen, Y., Ward, N. C., Hodgson, J. M., Puddey, I. B., Wang, Y., Zhang, D., … Croft, K. D. (2013). Dietary quercetin attenuates oxidant-induced endothelial dysfunction and atherosclerosis in apolipoprotein E knockout mice fed a high-fat diet: A critical role for heme oxygenase-1. Free Radical Biology & Medicine, 65, 908–915
94. Sorrenti, V., Mazza, F., Campisi, A., Di Giacomo, C., Acquaviva, R., Vanella, L., & Galvano, F. (2007). Heme oxygenase induction by cyanidin-3-O-beta-glucoside in cultured human endothelial cells. Molecular Nutrition & Food Research, 51(5), 580–586
95. Stocker, R. (2016). Antioxidant defenses in human blood plasma and extra-cellular fluids. Archives of Biochemistry and Biophysics, 595, 136–139
96. Stocker, R., & Keaney, J. F. Jr. (2004). Role of oxidative modifications in atherosclerosis. Physiological Reviews, 84(4), 1381–1478
97. Tanigawa, S., Fujii, M., & Hou, D. X. (2007). Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radical Biology & Medicine, 42(11), 1690–1703
98. Taubert, D., Berkels, R., Klaus, W., & Roesen, R. (2002). Nitric oxide formation and corresponding relaxation of porcine coronary arteries induced by plant phenols: Essential structural features. Journal of Cardiovascular Pharmacology, 40(5), 701–713
99. Terao, J. (2017). Factors modulating bioavailability of quercetin-related flavonoids and the consequences of their vascular function. Biochemical Pharmacology, 139, 15–23
100. Tribolo, S., Lodi, F., Winterbone, M. S., Saha, S., Needs, P. W., Hughes, D. A., & Kroon, P. A. (2013). Human metabolic transformation of quercetin blocks its capacity to decrease endothelial nitric oxide synthase (enos) expression and endothelin–1 secretion by human endothelial cells. Journal of Agricultural and Food Chemistry, 61(36), 8589–8596
101. Tsao, R., & McCallum, J. (2009). Chemistry of flavonoids. In L. A. de la Rosa, E. Alvarez-Parrilla, & G. Gonzalez-Aguilar (Eds.), Fruit and vegetable phytochemicals: Chemistry, nutritional value and stability (Chapter 5, pp. 131–153). Ames, IA: Blackwell Publishing
102. Tsuji, P. A., Stephenson, K. K., Wade, K. L., Liu, H., & Fahey, J. W. (2013). Structure-activity analysis of flavonoids: Direct and indirect antioxidant, and antiinflammatory potencies and toxicities. Nutrition and Cancer, 65(7), 1014–1025
103. Vitaglione, P., Donnarumma, G., Napolitano, A., Galvano, F., Gallo, A., Scalfi, L., & Fogliano, V. (2007). Protocatechuic acid is the major human metabolite of cyanidin-glucosides. The Journal of Nutrition, 137(9), 2043–2048
104. Wang, H., & Helliwell, K. (2000). Epimerisation of catechins in green tea infusions. Food Chemistry, 70(3), 337–344
105. Wang, D., Wei, X., Yan, X., Jin, T., & Ling, W. (2010). Protocatechuic acid, a metabolite of anthocyanins, inhibits monocyte adhesion and reduces atherosclerosis in apolipoprotein E-deficient mice. Journal of Agricultural and Food Chemistry, 58(24), 12722–12728
106. Warner, E. F., Zhang, Q., Raheem, K. S., O'Hagan, D., O'Connell, M. A., & Kay, C. D. (2016). Common phenolic metabolites of flavonoids, but not their unmetabolized precursors, reduce the secretion of vascular cellular adhesion molecules by human endothelial cells. The Journal of Nutrition, 146(3), 465–473
107. WHO. (2011). Global status report on noncommunicable diseases 2010. Geneva: World Health Organization
108. Williams, C. A. (2006). Flavone and flavonol O-glycosides. In O. M. Anderson, & K. R. Markham (Eds.), Flavonoids: Chemistry, biochemistry and applications (pp. 749–856). Boca Raton, FL: CRC Press/Taylor & Francis Group
109. Williamson, G., & Clifford, M. N. (2017). Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols. Biochemical Pharmacology, 139, 24–39
110. Xu, J. W., Ikeda, K., & Yamori, Y. (2007). Inhibitory effect of polyphenol cyanidin on TNF-α-induced apoptosis through multiple signaling pathways in endothelial cells. Atherosclerosis, 193(2), 299–308
111. Yamagata, K., Tagami, M., & Yamori, Y. (2015). Dietary polyphenols regulate endothelial function and prevent cardiovascular disease. Nutrition, 31(1), 28–37
112. 2. Plant Physiology, 115(4), 1405–1412
113. Yi, L., Chen, C. Y., Jin, X., Zhang, T., Zhou, Y., Zhang, Q. Y., … Mi, M. T. (2012). Differential suppression of intracellular reactive oxygen species-mediated signaling pathway in vascular endothelial cells by several subclasses of flavonoids. Biochimie, 94(9), 2035–2044
114. Zaheer, K., & Humayoun Akhtar, M. (2017). An updated review of dietary isoflavones: Nutrition, processing, bioavailability and impacts on human health. Critical Reviews in Food Science and Nutrition, 57(6), 1280–1293
115. Zeng, X., Su, W., Bai, Y., Chen, T., Yan, Z., Wang, J., … Yao, H. (2017). Urinary metabolite profiling of flavonoids in Chinese volunteers after consumption of orange juice by UFLC-Q-TOF-MS/MS. Journal of Chromatography B Analytical Technologies in the Biomedical & Life Sciences, 1061–1062, 79–88
116. Zhang, L., Zuo, Z., & Lin, G. (2007). Intestinal and hepatic glucuronidation of flavonoids. Molecular Pharmaceutics, 4(6), 833–845
117. Zheng, Y., Morris, A., Sunkara, M., Layne, J., Toborek, M., & Hennig, B. (2012). Epigallocatechin-gallate stimulates NF-E2-related factor and heme oxygenase-1 via caveolin-1 displacement. Journal of Nutritional Biochemistry, 23(2), 163–168
118. Zhu, Y., Xia, M., Yang, Y., Liu, F., Li, Z., Hao, Y., … Ling, W. (2011). Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clinical Chemistry, 57(11), 1524–1533