Flavanols
Özet
Flavanols, which are widely distributed in plant sources, constitute an important subclass of flavonoids. Cocoa, various types of tea, and several fruits (such as apples, grapes, apricots, peaches, and blueberries) are rich in these compounds. In recent years, these compounds have attracted considerable attention due to their potential beneficial effects on cardiovascular, neurological, and metabolic health. Their biological effects arise not only from their inherent antioxidant capacity but also from their influence on cellular signaling, gene regulation, and enzyme functions. The health-promoting potential of flavanols is closely linked to their chemical structure and metabolism. While early research emphasized their antioxidant role in neutralizing reactive oxygen species, recent findings have revealed more complex physiological effects involving interactions with endothelial cells, gut microbiota, and the immune system. This chapter provides a comprehensive evaluation of the chemical structure, dietary sources, and bioavailability of flavan-3-ols, as well as their biological activities, including antioxidant, cardiovascular, anti-inflammatory, neuroprotective, anticancer, and metabolic regulatory effects. The chapter concludes with an examination of clinical evidence supporting these health benefits and a discussion of future research directions.
Referanslar
Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79(5):727–47.
Luo Y, Jian Y, Liu Y, Jiang S, Muhammad D, Wang W. Flavanols from Nature: A Phytochemistry and Biological Activity Review. Molecules. 2022;27(3):719.
Fraga CG, Oteiza PI. Dietary flavonoids: Role of (−)-epicatechin and related procyanidins in cell signaling. Free Radic Biol Med. 2011;51(4):813–23.
Garcia JP, Santana A, Baruqui DL, Suraci N. The cardiovascular effects of chocolate. Vol. 19, Reviews in Cardiovascular Medicine. 2018;19:123–7.
Vlachojannis J, Erne P, Zimmermann B, Chrubasik-Hausmann S. The Impact of Cocoa Flavanols on Cardiovascular Health. Phyther Res. 2016;30(10):1641–57.
Mahdipour R, Ebrahimzadeh-Bideskan A, Hosseini M, Shahba S, Lombardi G, Malvandi AM, et al. The benefits of grape seed extract in neurological disorders and brain aging. Nutritional Neuroscience. 2023;26(5):369–83.
Salaish Kumar S, Mhd Jalil AM, Hussin N, Mat Daud ZA, Ismail A. Effects of flavanols and procyanidins-rich cocoa consumption on metabolic syndrome: an update review (2013-2023). Vol. 88, Bioscience, Biotechnology and Biochemistry. 2024;88(4):352–360.
Wang J, Yu Z, Wu W, He S, Xie B, Wu M, et al. Molecular mechanism of epicatechin gallate binding with carboxymethyl β-glucan and its effect on antibacterial activity. Carbohydr Polym. 2022;298:120105.
Anitha S, Saranya V, Shankar R, Sasirekha V. Structural exploration of interactions of (+) catechin and (−) epicatechin with bovine serum albumin: Insights from molecular dynamics and spectroscopic methods. J Mol Liq. 2022;348:118026.
Lee K, Bharadwaj S, Yadava U, Kang S. Computational and In Vitro Investigation of (-)-Epicatechin and Proanthocyanidin B2 as Inhibitors of Human Matrix Metalloproteinase 1. Biomolecules. 2020;10(10):1379.
Ramirez-Sanchez I, Nogueira L, Moreno A, Murphy A, Taub P, Perkins G, et al. Stimulatory effects of the flavanol (-)-epicatechin on cardiac angiogenesis: Additive effects with exercise. J Cardiovasc Pharmacol. 2012;60(5):429–38.
Sorrenti V, Ali S, Mancin L, Davinelli S, Paoli A, Scapagnini G. Cocoa Polyphenols and Gut Microbiota Interplay: Bioavailability, Prebiotic Effect, and Impact on Human Health. Nutrients. 2020;12(7):1908.
Azam S, Jakaria M, Kim IS, Kim J, Haque ME, Choi DK. Regulation of Toll-Like Receptor (TLR) Signaling Pathway by Polyphenols in the Treatment of Age-Linked Neurodegenerative Diseases: Focus on TLR4 Signaling. Front Immunol. 2019;10(MAY):1000.
Flores MEJ. Cocoa flavanols: Natural agents with attenuating effects on metabolic syndrome risk factors. Nutrients. 2019;11(4):751.
Amoah I, Lim JJ, Osei EO, Arthur M, Tawiah P, Oduro IN, et al. Effect of Cocoa Beverage and Dark Chocolate Consumption on Blood Pressure in Those with Normal and Elevated Blood Pressure: A Systematic Review and Meta‐Analysis. Foods. 2022; 11(13): 1962.
Chen TS, Liao WY, Huang CW, Chang CH. Adipose-Derived Stem Cells Preincubated with Green Tea EGCG Enhance Pancreatic Tissue Regeneration in Rats with Type 1 Diabetes through ROS/Sirt1 Signaling Regulation. Int J Mol Sci. 2022 Mar 15;23(6):3165.
Wang YQ, Li QS, Zheng XQ, Lu JL, Liang YR. Antiviral Effects of Green Tea EGCG and Its Potential Application against COVID-19. Molecules. 2021;26(13):3962.
Tang G, Xu Y, Zhang C, Wang N, Li H, Feng Y. Green tea and epigallocatechin gallate (Egcg) for the management of nonalcoholic fatty liver diseases (nafld): Insights into the role of oxidative stress and antioxidant mechanism. Antioxidants. 2021;10(7):1076.
Hackman RM, Polagruto JA, Zhu QY, Sun B, Fujii H, Keen CL. Flavanols: digestion, absorption and bioactivity. Phytochem Rev. 2007;7(1):195–208.
Taubert D, Roesen R, Lehmann C, Jung N, Schömig E. Effects of Low Habitual Cocoa Intake on Blood Pressure and Bioactive Nitric Oxide. JAMA. 2007;298(1):49.
Manach C, Williamson G, Morand C, Scalbert A, Rémésy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005;81(1):230S-242S.
Mena P, Bresciani L, Brindani N, Ludwig IA, Pereira-Caro G, Angelino D, et al. Phenyl-γ-valerolactones and phenylvaleric acids, the main colonic metabolites of flavan-3-ols: synthesis, analysis, bioavailability, and bioactivity. Nat Prod Rep. 2019;36(5):714–52.
Fernandes I, Nave F, Gonçalves R, de Freitas V, Mateus N. On the bioavailability of flavanols and anthocyanins: Flavanol–anthocyanin dimers. Food Chem. 2012;135(2):812–8.
Di Lorenzo C, Colombo F, Biella S, Stockley C, Restani P. Polyphenols and Human Health: The Role of Bioavailability. Nutrients. 2021;13(1):273.
Payne A, Taka E, Adinew GM, Soliman KFA. Molecular Mechanisms of the Anti-Inflammatory Effects of Epigallocatechin 3-Gallate (EGCG) in LPS-Activated BV-2 Microglia Cells. Brain Sci. 2023;13(4):632.
Cheng Z, Zhang Z, Han Y, Wang J, Wang Y, Chen X, et al. A review on anti-cancer effect of green tea catechins. Journal of Functional Foods. 2020;74:104172.
Perron NR, Brumaghim JL. A review of the antioxidant mechanisms of polyphenol compounds related to iron binding. Cell Biochem Biophys. 2009;53(2):75–100.
Su J, Liao T, Ren Z, Kuang Y, Yu W, Qiao Q, et al. Polydopamine nanoparticles coated with a metal-polyphenol network for enhanced photothermal/chemodynamic cancer combination therapy. Int J Biol Macromol. 2023;238:124088.
Han J, Wang M, Jing X, Shi H, Ren M, Lou H. (-)-Epigallocatechin gallate protects against cerebral ischemia-induced oxidative stress via Nrf2/ARE signaling. Neurochem Res. 2014;39(7):1292–9.
Sun W, Liu X, Zhang H, Song Y, Li T, Liu X, et al. Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1. Free Radic Biol Med. 2017;108:840–57.
Heiss C, Keen CL, Kelm M. Flavanols and cardiovascular disease prevention. European Heart Journal. 2010; 31(21):2583-2592.
Steffen Y, Gruber C, Schewe T, Sies H. Mono-O-methylated flavanols and other flavonoids as inhibitors of endothelial NADPH oxidase. Arch Biochem Biophys. 2008;469(2):209–19.
Actis-Goretta L, Ottaviani JI, Keen CL, Fraga CG. Inhibition of angiotensin converting enzyme (ACE) activity by flavan‐3‐ols and procyanidins. FEBS Lett. 2003;555(3):597–600.
Wolfram S. Effects of green tea and egcg on cardiovascular and metabolic health. J Am Coll Nutr. 2007;26(4):373S-388S.
Ottaviani JI, Heiss C, Spencer JPE, Kelm M, Schroeter H. Recommending flavanols and procyanidins for cardiovascular health: Revisited. Mol Aspects Med. 2018;61:63–75.
Sharifi-Rad M, Pezzani R, Redaelli M, Zorzan M, Imran M, Ahmed Khalil A, et al. Preclinical Activities of Epigallocatechin Gallate in Signaling Pathways in Cancer. Molecules. 2020;25(3):467.
Xu T, Liu R, Zhu H, Zhou Y, Pei T, Yang Z. The Inhibition of LPS-Induced Oxidative Stress and Inflammatory Responses Is Associated with the Protective Effect of (-)-Epigallocatechin-3-Gallate on Bovine Hepatocytes and Murine Liver. Antioxidants. 2022;11(5):914.
Kim JS, Kim JM, O JJ, Jeon BS. Inhibition of inducible nitric oxide synthase expression and cell death by (−)-epigallocatechin-3-gallate, a green tea catechin, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J Clin Neurosci. 2010;17(9):1165–8.
Yoshida S, Inaba H, Nomura R, Nakano K, Matsumoto-Nakano M. Green tea catechins inhibit Porphyromonas gulae LPS-induced inflammatory responses in human gingival epithelial cells. J Oral Biosci. 2022;64(3):352–8.
Han Y, Pei D, Li W, Luo B, Jiang Q. Epigallocatechin gallate attenuates tumor necrosis factor (TNF)-α-induced inhibition of osteoblastic differentiation by up-regulating lncRNA TUG1 in osteoporosis. Bioengineered. 2022;13(4):8950–61.
Ranjith-Kumar CT, Lai Y, Sarisky RT, Kao CC. Green tea catechin, epigallocatechin gallate, suppresses signaling by the dsRNA innate immune receptor RIG-I. Cheriyath V, editor. PLoS One. 2010;5(9):1–11.
Narita K, Hisamoto M, Okuda T, Takeda S. Differential neuroprotective activity of two different grape seed extracts. Ikeda K, editor. PLoS One. 2011;6(1):e14575.
Ratnawati R, Arofah AN, Novitasari A, Utami SD, Hariningsih MA, Rahayu M, et al. Catechins decrease neurological severity score through apoptosis and neurotropic factor pathway in rat traumatic brain injury. Universa Med. 2017;36(2):110–22.
Pervin M, Unno K, Takagaki A, Isemura M, Nakamura Y. Function of Green Tea Catechins in the Brain: Epigallocatechin Gallate and its Metabolites. Int J Mol Sci. 2019;20(15):3630.
Özduran G, Becer E, Vatansever HS. The Role and Mechanisms of Action of Catechins in Neurodegenerative Diseases. Vol. 42, Journal of the American Nutrition Association. 2023;42(1):67–74.
Fernandes L, Cardim-Pires TR, Foguel D, Palhano FL. Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases. Frontiers in Neuroscience. 2021;15: 718188.
Ding ML, Ma H, Man YG, Lv HY. Protective effects of a green tea polyphenol, epigallocatechin- 3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Can J Physiol Pharmacol. 2017;95(12):1396–405.
Almaguer G, Almaguer-Vargas G, Molina-Trinidad EM, Becerril-Flores MA, Montejano B, Madrigal-Santillan E, et al. Antitumor Effect of Epigallocatechin Gallate and Vincristine in Mice with L5178Y Lymphoma. Plants. 2023;12(21):3757.
Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Rajaratnam V, Al-Hendy A. Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Fertil Steril. 2010;94(5):1887–93.
Gu JW, Makey KL, Tucker KB, Chinchar E, Mao X, Pei I, et al. EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression. Vasc Cell. 2013;5(1):9.
Shimizu M, Shirakami Y, Sakai H, Yasuda Y, Kubota M, Adachi S, et al. (-)-Epigallocatechin gallate inhibits growth and activation of the VEGF/VEGFR axis in human colorectal cancer cells. Chem Biol Interact. 2010;185(3):247–52.
García-Cordero J, Martinez A, Blanco-Valverde C, Pino A, Puertas-Martín V, San Román R, et al. Regular Consumption of Cocoa and Red Berries as a Strategy to Improve Cardiovascular Biomarkers via Modulation of Microbiota Metabolism in Healthy Aging Adults. Nutrients. 2023;15(10).
Goya L, Martín M, Sarriá B, Ramos S, Mateos R, Bravo L. Effect of Cocoa and Its Flavonoids on Biomarkers of Inflammation: Studies of Cell Culture, Animals and Humans. Nutrients. 2016;8(4):212.
Li F, Gao C, Yan P, Zhang M, Wang Y, Hu Y, et al. EGCG reduces obesity and white adipose tissue gain partly through AMPK activation in mice. Front Pharmacol. 2018;9:389872.
Sampath C, Rashid MR, Sang S, Ahmedna M. Green tea epigallocatechin 3-gallate alleviates hyperglycemia and reduces advanced glycation end products via nrf2 pathway in mice with high fat diet-induced obesity. Biomed Pharmacother. 2017;87:73–81.
Heiss C. Vascular Effects of Cocoa Rich in Flavan-3-ols. JAMA J Am Med Assoc. 2003;290(8):1030–1.
Grosso G, Godos J, Currenti W, Micek A, Falzone L, Libra M, et al. The Effect of Dietary Polyphenols on Vascular Health and Hypertension: Current Evidence and Mechanisms of Action. Nutrients. 2022;14(3):545.
Akhlaghi M, Ghobadi S, Mohammad Hosseini M, Gholami Z, Mohammadian F. Flavanols are potential anti-obesity agents, a systematic review and meta-analysis of controlled clinical trials. Nutr Metab Cardiovasc Dis. 2018;28(7):675–90.
Bazyar H, Hosseini SA, Saradar S, Mombaini D, Allivand M, Labibzadeh M, et al. Effects of epigallocatechin-3-gallate of Camellia sinensis leaves on blood pressure, lipid profile, atherogenic index of plasma and some inflammatory and antioxidant markers in type 2 diabetes mellitus patients: a clinical trial. J Complement Integr Med. 2021;18(2):405–11.
Gratton G, Weaver SR, Burley C V., Low KA, Maclin EL, Johns PW, et al. Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults. Sci Rep. 2020;10(1):19409.
Vyas CM, Manson JAE, Sesso HD, Rist PM, Weinberg A, Kim E, et al. Effect of cocoa extract supplementation on cognitive function: results from the clinic subcohort of the COSMOS trial. Am J Clin Nutr. 2024;119(1).
Brickman AM, Yeung LK, Alschuler DM, Ottaviani JI, Kuhnle GGC, Sloan RP, et al. Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption. Proc Natl Acad Sci. 2023;120(23).
Akyürek EG, Altınok A, Karabay A. Concurrent consumption of cocoa flavanols and caffeine does not acutely modulate working memory and attention. Eur J Nutr. 2025;64(1):1–17.
