Masquelier's grape seed extract: from basic flavonoid research to a well-characterized food supplement with health benefits

Nutrition Journal

Volumn 16, Issue 1, 2017, Pages 1-19

  Weseler, Antje R ^a   Bast, Aalt ^a  

^a MAASTRICHT UNIVERSITY   (Netherlands)

Author keywords

Cardiovascular; Flavanols; Food; Grape seed; Health; Inflammation; Masquelier; Nutraceutical; Oxidative stress; Proanthocyanidins

Indexed keywords

EPICATECHIN; FLAVONOID; FLAVONOL; GRAPE SEED EXTRACT; NUTRACEUTICAL; PLACEBO; PROCYANIDOL OLIGOMER; ANTIOXIDANT;

ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; BIOSYNTHESIS; CAPILLARY PERMEABILITY; CARRAGEENAN-INDUCED PAW EDEMA; CHEMICAL COMPOSITION; COLLAGEN FIBER; COLORIMETRY; DRUG BIOAVAILABILITY; DRUG ELIMINATION; DRUG METABOLISM; EDEMA; ELASTIC FIBER; GENE EXPRESSION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; MASS SPECTROMETRY; MORNING DOSAGE; NONHUMAN; PETECHIA; PROTON NUCLEAR MAGNETIC RESONANCE; REVIEW; SINGLE DRUG DOSE; STANDARDIZATION; VARICOSIS; ANIMAL; BIOAVAILABILITY; CELL LINE; CHEMISTRY; DIETARY SUPPLEMENT; DISEASE MODEL; RANDOMIZED CONTROLLED TRIAL (TOPIC); VITIS;

ANIMALS; ANTIOXIDANTS; BIOLOGICAL AVAILABILITY; CELL LINE; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DIETARY SUPPLEMENTS; DISEASE MODELS, ANIMAL; FLAVONOIDS; GRAPE SEED EXTRACT; HUMANS; RANDOMIZED CONTROLLED TRIALS AS TOPIC; VITIS;

EID: 85009971921     PISSN: None     EISSN: 14752891     Source Type: Journal    
DOI: 10.1186/s12937-016-0218-1     Document Type: Review

References (115)

1. Nassiri-Asl M, Hosseinzadeh H. Review of the pharmacological effects of Vitis vinifera (grape) and its bioactive constituents: an update. Phytother Res. 2016;30(9):1392-403.
2. Olaku OO, Ojukwu MO, Zia FZ, White JD. The role of grape seed extract in the treatment of chemo/radiotherapy induced toxicity: a systematic review of preclinical studies. Nutr Cancer. 2015;67:730-40.
3. Kasdagly M, Radhakrishnan S, Reddivari L, Veeramachaneni DN, Vanamala J. Colon carcinogenesis: influence of Western diet-induced obesity and targeting stem cells using dietary bioactive compounds. Nutrition. 2014;30:1242-56.
4. Ting H, Deep G, Agarwal C, Agarwal R. The strategies to control prostate cancer by chemoprevention approaches. Mutat Res. 2014;760:1-15.
5. Tong LX, Young LC. Nutrition: the future of melanoma prevention? J Am Acad Dermatol. 2014;71:151-60.
6. Feringa HH, Laskey DA, Dickson JE, Coleman CI. The effect of grape seed extract on cardiovascular risk markers: a meta-analysis of randomized controlled trials. J Am Diet Assoc. 2011;111:1173-81.
7. Ho L, Pasinetti GM. Polyphenolic compounds for treating neurodegenerative disorders involving protein misfolding. Expert Rev Proteomics. 2010;7:579-89.
8. Pasinetti GM, Ho L. Role of grape seed polyphenols in Alzheimer's disease neuropathology. Nutr Diet Suppl. 2010;2010:97-103.
9. Wu CD. Grape products and oral health. J Nutr. 2009;139:1818S-23S.
10. Baumann LS. Less-known botanical cosmeceuticals. Dermatol Ther. 2007;20:330-42.
11. Martinez-Zapata MJ, Vernooij RW, Uriona Tuma SM, Stein AT, Moreno RM, Vargas E, Capella D, Bonfill Cosp X. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2016;4:CD003229.
12. World Health Organization (WHO). Constitution of the World Health Organization - basic documents, vol. Supplement. 45th ed. 2006.
13. Michaud JMJRAM. Synthèse des procyanidines naturelles. Ann Pharm Fr. 1973;31:385-95.
14. Dewick PM. The Shikimate Pathway: Aromatic Amino Acids and Phenylpropanoids. In: Medicinal Natural Products. Hoboken: Wiley; 2009. p. 137-86.
15. Xie D-Y, Dixon RA. Proanthocyanidin biosynthesis - still more questions than answers? Phytochemistry. 2005;66:2127-44.
16. He F, Pan QH, Shi Y, Duan CQ. Biosynthesis and genetic regulation of proanthocyanidins in plants. Molecules. 2008;13:2674-703.
17. Dixon RA, Xie D-Y, Sharma SB. Proanthocyanidins - a final frontier in flavonoid research? New Phytol. 2005;165:9-28.
18. Vaughn KC, Lax AR, Duke SO. Polyphenol oxidase: The chloroplast oxidase with no established function. Physiol Plant. 1988;72:659-65.
19. Creasy LL, Swain T. Structure of condensed tannins. Nature. 1965;208:151-3.
20. Baxter IR, Young JC, Armstrong G, Foster N, Bogenschutz N, Cordova T, Peer WA, Hazen SP, Murphy AS, Harper JF. A plasma membrane H+-ATPase is required for the formation of proanthocyanidins in the seed coat endothelium of Arabidopsis thaliana. Proc Natl Acad Sci U S A. 2005;102:2649-54.
21. Hemingway RW, Foo LY, Porter LJ. Linkage isomerism in trimeric and polymeric 2,3-cis-procyanidins. J Chem Soc, Perkin Trans. 1982;1:1209-16.
22. St Leger AS, Cochrane AL, Moore F. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. Lancet. 1979;1:1017-20.
23. Prior RL, Gu L. Occurrence and biological significance of proanthocyanidins in the American diet. Phytochemistry. 2005;66:2264-80.
24. USDA database for the proanthocyanidin content of selected foods - 2004, available at https://www.ars.usda.gov/northeast-area/beltsville-md/beltsville-human-nutrition-research-center/nutrient-data-laboratory/docs/usda-database-for-the-proanthocyanidin-content-of-selected-foods-2004/accessed. Accessed 30 June 2016.
25. 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.
26. Zamora-Ros R, Knaze V, Rothwell J, Hémon B, Moskal A, Overvad K, Tjønneland A, Kyrø C, Fagherazzi G, Boutron-Ruault M-C, et al. Dietary polyphenol intake in Europe: the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Eur J Nutr. 2015;55:1-17.
27. Vogiatzoglou A, Mulligan AA, Luben RN, Lentjes MAH, Heiss C, Kelm M, Merx MW, Spencer JPE, Schroeter H, Kuhnle GGC. Assessment of the dietary intake of total flavan-3-ols, monomeric flavan-3-ols, proanthocyanidins and theaflavins in the European Union. Br J Nutr. 2014;111:1463-73.
28. Knaze V, Zamora-Ros R, Lujan-Barroso L, Romieu I, Scalbert A, Slimani N, Riboli E, van Rossum CT, Bueno-de-Mesquita HB, Trichopoulou A, et al. Intake estimation of total and individual flavan-3-ols, proanthocyanidins and theaflavins, their food sources and determinants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Br J Nutr. 2012;108:1095-108.
29. Sebastian RS, Wilkinson Enns C, Goldman JD, Martin CL, Steinfeldt LC, Murayi T, Moshfegh AJ. A New database facilitates characterization of flavonoid intake, sources, and positive associations with diet quality among US adults. J Nutr. 2015;145:1239-48.
30. Wang Y, Chung S-J, Song WO, Chun OK. Estimation of daily proanthocyanidin intake and major food sources in the U.S. diet. J Nutr. 2011;141:447-52.
31. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer. 2006;55:1-12.
32. Chan SG, Ho SC, Kreiger N, Darlington G, Adlaf EM, So KF, Chong PY. Validation of a food frequency questionnaire for assessing dietary soy isoflavone intake among midlife Chinese women in Hong Kong. J Nutr. 2008;138:567-73.
33. Chan SG, Ho SC, Kreiger N, Darlington G, So KF, Chong PY. Dietary sources and determinants of soy isoflavone intake among midlife Chinese Women in Hong Kong. J Nutr. 2007;137:2451-5.
34. Kim J-S, Kwon C-S. Estimated dietary isoflavone intake of Korean population based on National Nutrition Survey. Nutr Res. 2001;21:947-53.
35. Li G, Zhu Y, Zhang Y, Lang J, Chen Y, Ling W. Estimated daily flavonoid and stilbene intake from fruits, vegetables, and nuts and associations with lipid profiles in Chinese adults. J Acad Nutr Diet. 2013;113:786-94.
36. Woo H, Lee J, Choi I, Kim C, Lee J, Kwon O, Kim J. Dietary flavonoids and gastric cancer risk in a Korean population. Nutrients. 2014;6:4961-73.
37. Otaki N, Kimira M, Katsumata S-i, Uehara M, Watanabe S, Suzuki K. Distribution and major sources of flavonoid intakes in the middle-aged Japanese women. J Clin Biochem Nutr. 2009;44:231-8.
38. Johannot L, Somerset SM. Age-related variations in flavonoid intake and sources in the Australian population. Public Health Nutr. 2006;9:1045-54.
39. Ivey KL, Lewis JR, Lim WH, Lim EM, Hodgson JM, Prince RL. Associations of proanthocyanidin intake with renal function and clinical outcomes in elderly women. PLoS One. 2013;8:e71166.
40. Arabbi PR, Genovese MI, Lajolo FM. Flavonoids in vegetable foods commonly consumed in brazil and estimated ingestion by the Brazilian Population. J Agric Food Chem. 2004;52:1124-31.
41. Corrêa VG, Tureck C, Locateli G, Peralta RM, Koehnlein EA. Estimate of consumption of phenolic compounds by Brazilian population. Rev Nutr. 2015;28:185-96.
42. Neveu V, Perez-Jiménez J, Vos F, Crespy V, du Chaffaut L, Mennen L, Knox C, Eisner R, Cruz J, Wishart D, Scalbert A. Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database (Oxford). 2010;2010:bap024.
43. World Health Organization (WHO). Diet, nutrition and the prevention of chronic diseases In: WHO Tech Rep Ser, vol. No. 916 (TRS 916). Geneva: WHO; 2003.
44. Bauer R. Quality criteria and standardization of phytopharmaceuticals: Can acceptable drug standards be achieved? Drug Inf J. 1998;32:101-10.
45. Singleton VL, Rossi JA. Colorimetry of total phenolics with phosphomolybdic-phosphotungstic acid reagents. Am J Enol Vitic. 1965;16:144-58.
46. Stalikas CD. Extraction, separation, and detection methods for phenolic acids and flavonoids. J Sep Sci. 2007;30:3268-95.
47. Bate-Smith EC. Phytochemistry of proanthocyanidins. Phytochemistry. 1975;14:1107-13.
48. Porter LJ, Hrstich LN, Chan BG. The conversion of procyanidins and prodelphinidins to cyanidin and delphinidin. Phytochemistry. 1985;25:223-30.
49. Schofield P, Mbugua DM, Pell AN. Analysis of condensed tannins: a review. Anim Feed Sci Technol. 2001;91:21-40.
50. Sun B, Ricardo-da-Silva JM, Spranger I. Critical factors of vanillin assay for catechins and proanthocyanidins. J Agric Food Chem. 1998;46:4267-74.
51. Naczk M, Shahidi F. Phenolics in cereals, fruits and vegetables: occurrence, extraction and analysis. J Pharm Biomed Anal. 2006;41:1523-42.
52. Ignat I, Volf I, Popa VI. A critical review of methods for characterisation of polyphenolic compounds in fruits and vegetables. Food Chem. 2011;126:1821-35.
53. Khoddami A, Wilkes MA, Roberts TH. Techniques for analysis of plant phenolic compounds. Molecules. 2013;18:2328-75.
54. Dumon M, Michaud J, Masquelier J. Dosages des procyanidols dans les extraits végétaux destinés a la préparation de médicaments. Bull Soc Pharm Bord. 1990;129:51-65.
55. Dumon M. Recherches analytiques sur les pycnogenols. PhD thesis. Bordeaux: Université de Bordeaux II, UFR des Sciences Pharmaceutiques; 1990.
56. de Haan B, Achanta G, Post JA. A potential role for oligomeric proanthocyanidins (OPCs) in delaying senescence in human endothelial cells. Free Radic Biol Med. 2008;45:S78.
57. Krishnan P, Kruger NJ, Ratcliffe RG. Metabolite fingerprinting and profiling in plants using NMR. J Exp Bot. 2005;56:255-65.
58. Hylands PJN, JK, Holmes E, Dunn MJ. Process for quality control and standardization of medicinal plant products. In Google patent, vol. US6806090 B1. USA; 2004.
59. Laparra J, Michaud J, Masquelier J. Étude pharmacocinétique des oligomères flavanoliques. Plantes Medicinales Phytotherapie. 1977;9:133-42.
60. Laparra J, Michaud J, Lesca MF, Blanquet P, Masquelier J. Étude pharmacocinetique des oligomeres procyanidoliques totaux du raisin. Acta Ther. 1978;4:233-46.
61. Jacobs H, Koek GH, Peters R, Moalin M, Tack J, van der Vijgh WJ, Bast A, Haenen GR. Differences in pharmacological activities of the antioxidant flavonoid monoHER in humans and mice are caused by variations in its metabolic profile. Clin Pharmacol Ther. 2011;90:852-9.
62. Benakis A, Schopfer C, Ritschard J. Disposition of 14C-labelled ENDOTELON in humans. Eur J Drug Metab Pharmacokinet. 2008;33:37-43.
63. Choy YY, Jaggers GK, Oteiza PI, Waterhouse AL. Bioavailability of intact proanthocyanidins in the rat colon after ingestion of grape seed extract. J Agric Food Chem. 2013;61:121-7.
64. Prasain JK, Peng N, Dai Y, Moore R, Arabshahi A, Wilson L, Barnes S, Michael Wyss J, Kim H, Watts RL. Liquid chromatography tandem mass spectrometry identification of proanthocyanidins in rat plasma after oral administration of grape seed extract. Phytomedicine. 2009;16:233-43.
65. Serra A, Macia A, Romero MP, Salvado MJ, Bustos M, Fernandez-Larrea J, Motilva MJ. Determination of procyanidins and their metabolites in plasma samples by improved liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877:1169-76.
66. Tsang C, Auger C, Mullen W, Bornet A, Rouanet JM, Crozier A, Teissedre PL. The absorption, metabolism and excretion of flavan-3-ols and procyanidins following the ingestion of a grape seed extract by rats. Br J Nutr. 2005;94:170-81.
67. Actis-Goretta L, Leveques A, Rein M, Teml A, Schafer C, Hofmann U, Li H, Schwab M, Eichelbaum M, Williamson G. Intestinal absorption, metabolism, and excretion of (-)-epicatechin in healthy humans assessed by using an intestinal perfusion technique. Am J Clin Nutr. 2013;98:924-33.
68. Ottaviani JI, Momma TY, Kuhnle GK, Keen CL, Schroeter H. Structurally related (−)-epicatechin metabolites in humans: Assessment using de novo chemically synthesized authentic standards. Free Radic Biol Med. 2012;52:1403-12.
69. Holt RR, Lazarus SA, Sullards MC, Zhu QY, Schramm DD, Hammerstone JF, Fraga CG, Schmitz HH, Keen CL. Procyanidin dimer B2 [epicatechin-(4β-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa. Am J Clin Nutr. 2002;76:798-804.
70. Sano A, Yamakoshi J, Tokutake S, Tobe K, Kubota Y, Kikuchi M. Procyanidin B1 is detected in human serum after intake of proanthocyanidin-rich grape seed extract. Biosci Biotechnol Biochem. 2003;67:1140-3.
71. Deprez S, Mila I, Huneau JF, Tome D, Scalbert A. Transport of proanthocyanidin dimer, trimer, and polymer across monolayers of human intestinal epithelial Caco-2 cells. Antioxid Redox Signal. 2001;3:957-67.
72. Rios LY, Gonthier M-P, Rémésy C, Mila I, Lapierre C, Lazarus SA, Williamson G, Scalbert A. Chocolate intake increases urinary excretion of polyphenol-derived phenolic acids in healthy human subjects. Am J Clin Nutr. 2003;77:912-8.
73. Appeldoorn MM, Vincken JP, Aura AM, Hollman PC, Gruppen H. Procyanidin dimers are metabolized by human microbiota with 2-(3,4-dihydroxyphenyl)acetic acid and 5-(3,4-dihydroxyphenyl)-gamma-valerolactone as the major metabolites. J Agric Food Chem. 2009;57:1084-92.
74. Stoupi S, Williamson G, Drynan JW, Barron D, Clifford MN. Procyanidin B2 catabolism by human fecal microflora: Partial characterization of ‘dimeric' intermediates. Arch Biochem Biophys. 2010;501:73-8.
75. Wiese S, Esatbeyoglu T, Winterhalter P, Kruse H-P, Winkler S, Bub A, Kulling SE. Comparative biokinetics and metabolism of pure monomeric, dimeric, and polymeric flavan-3-ols: A randomized cross-over study in humans. Mol Nutr Food Res. 2015;59:610-21.
76. Nakamura Y, Tsuji S, Tonogai Y. Analysis of proanthocyanidins in grape seed extracts, health foods and grape seed oils. J Health Sci. 2003;49:45-54.
77. Masquelier J, Dumon M, Dumas J. Stabilisation du collagene par les oligomeres procyanidoliques. Acta Ther. 1981;7:101-5.
78. Pfister A, Simon M, Gazave J. Sites de fixation des oligomeres procyanidoliques dans la paroi des capillaires sanguins du poumon de cobaye. Acta Ther. 1982;8:223-37.
79. Tixier JM, Godeau G, Robert AM, Hornebeck W. Evidence by in vivo and in vitro studies that binding of pycnogenols to elastin affects its rate of degradation by elastases. Biochem Pharmacol. 1984;33:3933-9.
80. Gavignet-Jeannin C, Groult N, Godeau G, Robert A, Robert L. Mode d'action des oligomeres procyanidoliques sur la paroi vasculaire. Toulouse: Congrès International d'Angiologie, symposium satellite Endotelon et unite circulatoire; 1988.
81. Robert AM. Substrate-protecting antiproteolytic agents for the prevention of pathological degradation of connective tissues. A review. Pathol Biol (Paris). 2012;60:48-57.
82. Oligomeric proanthocyanidins (OPCs). Monograph Altern Med Rev 2003, 8:442-450.
83. Bast A, Haenen GRMM. Ten misconceptions about antioxidants. Trends Pharmacol Sci. 2013;34:430-6.
84. Weseler AR, Bast A. Oxidative stress and vascular function: implications for pharmacologic treatments. Curr Hypertens Rep. 2010;12:154-61.
85. Masquelier J. Action comparee de divers facteurs vitaminiques P sur l'oxydation de l'acide ascorbique par les ions cuivriques. Bull Soc Chim Biol (Paris). 1951;33:302-5.
86. Masquelier J. Plant extract with a proanthocyanidins content as therapeutic agent having radical scavenger effect and use thereof, vol. US4698360 A. USA; 1987.
87. van Acker SA, de Groot MJ, van den Berg DJ, Tromp MN, Donne-Op den Kelder G, van der Vijgh WJ, Bast A. A quantum chemical explanation of the antioxidant activity of flavonoids. Chem Res Toxicol. 1996;9:1305-12.
88. Barbier AM, JP, Savi P, Unkovic J, Vilain P. Activité angioprotectrice des oligomères procyanidoliques chez l'animal. Toulouse: Congrès International d'Angiologie; 1988.
89. Meunier M, Duroux E, Bastide P. Activite antiradicalaire d'oligomeres procyanidolique et d'anthocyanosides vis-a-vis de l'anion superoxyde et vis-a-vis de la lipoperoxydation. Plantes Medicinales Phytotherapie. 1989;13:267-74.
90. Masquelier J. Effets physiologiques du vin - Sa part dans l'alcoolisme. Bulletin de l'OIV. 1988;689:555-78.
91. de Haan B, Babat S, Post JA. Protection of vascular endothelial cells from oxidative damage by oligomeric proanthocyanidins. In: Oxidants and antioxidants in biology. Santa Barbara: Oxygen Club of California; 2006.
92. de Haan B, Babat S, Post JA. Oligomeric proanthocyanidins protect vascular endothelial cells from lipid oxidation. Inflamm Res. 2006;Supplement 2:S116.
93. Bos MA, Vennat B, Meunier MT, Pouget MP, Pourrat A, Fialip J. Procyanidins from tormentil: antioxidant properties towards lipoperoxidation and anti-elastase activity. Biol Pharm Bull. 1996;19:146-8.
94. Ruijters EJ, Weseler AR, Kicken C, Haenen GR, Bast A. The flavanol (-)-epicatechin and its metabolites protect against oxidative stress in primary endothelial cells via a direct antioxidant effect. Eur J Pharmacol. 2013;715:147-53.
95. Granado-Serrano AB, Martin MA, Haegeman G, Goya L, Bravo L, Ramos S. Epicatechin induces NF-kappaB, activator protein-1 (AP-1) and nuclear transcription factor erythroid 2p45-related factor-2 (Nrf2) via phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and extracellular regulated kinase (ERK) signalling in HepG2 cells. Br J Nutr. 2010;103:168-79.
96. Rodriguez-Ramiro I, Ramos S, Bravo L, Goya L, Martin MA. Procyanidin B2 induces Nrf2 translocation and glutathione S-transferase P1 expression via ERKs and p38-MAPK pathways and protect human colonic cells against oxidative stress. Eur J Nutr. 2012;51:881-92.
97. Ohnuma T, Anzai E, Suzuki Y, Shimoda M, Saito S, Nishiyama T, Ogura K, Hiratsuka A. Selective antagonization of activated Nrf2 and inhibition of cancer cell proliferation by procyanidins from Cinnamomi Cortex extract. Arch Biochem Biophys. 2015;585:17-24.
98. Krajka-Kuzniak V, Paluszczak J, Oszmianski J, Baer-Dubowska W. Hawthorn (Crataegus oxyacantha L.) bark extract regulates antioxidant response element (ARE)-mediated enzyme expression via Nrf2 pathway activation in normal hepatocyte cell line. Phytother Res. 2014;28:593-602.
99. Bak MJ, Jun M, Jeong WS. Procyanidins from wild grape (Vitis amurensis) seeds regulate ARE-mediated enzyme expression via Nrf2 coupled with p38 and PI3K/Akt pathway in HepG2 cells. Int J Mol Sci. 2012;13:801-18.
100. Nazimabashir, Manoharan V, Miltonprabu S. Cadmium induced cardiac oxidative stress in rats and its attenuation by GSP through the activation of Nrf2 signaling pathway. Chem Biol Interact. 2015;242:179-93.
101. Chen S, Zhu Y, Liu Z, Gao Z, Li B, Zhang D, Zhang Z, Jiang X, Liu Z, Meng L, et al. Grape seed proanthocyanidin extract ameliorates diabetic bladder dysfunction via the activation of the Nrf2 pathway. PLoS One. 2015;10:e0126457.
102. Blazso G, Gabor M. Oedema-inhibiting effect of procyanidin. Acta Physiol Acad Sci Hung. 1980;56:235-40.
103. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2:725-34.
104. Milenkovic D, Vanden Berghe W, Boby C, Leroux C, Declerck K, Szarc vel Szic K, Heyninck K, Laukens K, Bizet M, Defrance M, et al. Dietary flavanols modulate the transcription of genes associated with cardiovascular pathology without changes in their DNA methylation state. PLoS One. 2014;9:e95527.
105. Ruijters EJ, Haenen GR, Weseler AR, Bast A. The cocoa flavanol (-)-epicatechin protects the cortisol response. Pharmacol Res. 2014;79:28-33.
106. Ruijters EJ, Haenen GR, Willemsen M, Weseler AR, Bast A. Food-derived bioactives can protect the anti-inflammatory activity of cortisol with antioxidant-dependent and -independent mechanisms. Int J Mol Sci. 2016;17:239-48.
107. Weseler AR, Bast A. Pleiotropic-acting nutrients require integrative investigational approaches: the example of flavonoids. J Agric Food Chem. 2012;60:8941-6.
108. Dartenuc J, Marache P, Choussat H. Resistance capillaire en geriatrie: etude d'un microangioprotecteur endotelon. Bordeaux Med. 1980;13:903-7.
109. Dubos G, Durst G, Hugonot R. Evolution de la resistance capillaire, spontanement ou artificiellement diminuee par l'action d'un substance capillaro-toxique chez des personnes agees. Revue Geriatr. 1980;5:302-5.
110. Paitel D. Etude rheographique et thermographic des effets d'un endotheliotrophique sur l'hemodynamique peripherique. Vie Med. 1981;11:776-83.
111. Beylot C, Bioulac P. Essai therapeutique d'un angioprotecteur peripherique, l'Endotelon. Gaz Med (Paris). 1980;87:2919-22.
112. Elbaz C, Reinharez D, Sapin G, Brami C, Boschet P, Gounon P, Roure M, Tragit R, Vergoz L. Etude multicentrique controlee de l'endotelon dans les manifestations fonctionelles de l'insufficance veineuse chronique des membres inferieurs. Le Praticien. 1981;400:63-8.
113. Thebaut J-F, Thebaut P, Vin F. Etude de l'endotelon dans les manifestations functionelles de l'insufficisance veineuse peripherique. Resultats d'une etude en double aveugle portant sur 92 patients. Gaz Med (Paris). 1985;92:96-100.
114. Weseler AR, Ruijters EJ, Drittij-Reijnders MJ, Reesink KD, Haenen GR, Bast A. Pleiotropic benefit of monomeric and oligomeric flavanols on vascular health - a randomized controlled clinical pilot study. PLoS One. 2011;6:e28460.
115. Aragones G, Suarez M, Ardid-Ruiz A, Vinaixa M, Rodriguez MA, Correig X, Arola L, Blade C. Dietary proanthocyanidins boost hepatic NAD(+) metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats. Sci Rep. 2016;6:24977.