Cardiometabolic disorders are among the leading causes of mortality in the human population. Dietary polyphenols exert beneficial effects on cardiometabolic health in humans. Molecular mechanisms, however, are not completely understood. Aiming to conduct in-depth integrative bioinformatic analyses to elucidate molecular mechanisms underlying the protective effects of polyphenols on cardiometabolic health, we first conducted a systematic literature search to identify human intervention studies with polyphenols that demonstrate improvement of cardiometabolic risk factors in parallel with significant nutrigenomic effects. Applying the predefined inclusion criteria, we identified 58 differentially expressed genes at mRNA level and 5 miRNAs, analyzed in peripheral blood cells with RT-PCR methods. Subsequent integrative bioinformatic analyses demonstrated that polyphenols modulate genes that are mainly involved in the processes such as inflammation, lipid metabolism, and endothelial function. We also identified 37 transcription factors that are involved in the regulation of polyphenol modulated genes, including RELA/NFKB1, STAT1, JUN, or SIRT1. Integrative bioinformatic analysis of mRNA and miRNA-target pathways demonstrated several common enriched pathways that include MAPK signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, focal adhesion, or PPAR signaling pathway. These bioinformatic analyses represent a valuable source of information for the identification of molecular mechanisms underlying the beneficial health effects of polyphenols and potential target genes for future nutrigenetic studies.

Centre of Research Excellence in Nutrition and Metabolism Institute for Medical Research National Institute of Republic of Serbia University of Belgrade 11060 Belgrade Serbia

Department of Food Science Czech University of Life Sciences 16521 Prague Czech Republic

Department of Internal Medicine Division of Cardiovascular Medicine School of Medicine University of California Davis Davis CA 95616 USA

Department of Medicine Democritus University of Thrace Dragana 68100 Alexandroupolis Greece

Faculty of Medical Sciences Goce Delcev University 2000 Stip North Macedonia

Institute for Adriatic Crops and Karst Reclamation 21000 Split Croatia

Institute for Biological Research Siniša Stanković National Institute of Republic of Serbia University of Belgrade 11060 Belgrade Serbia

Institute of Biology and Immunology of Reproduction Bulgarian Academy of Sciences 1113 Sofia Bulgaria

National Research Council 73100 Lecce Italy

Norwich Medical School University of East Anglia Norwich NR4 7TJ UK

Nutrigenomics Research Group Departament de Bioquímica i Biotecnologia Universitat Rovira i Virgili 43007 Tarragona Spain

Unité de Nutrition Humaine Faculté de Médecine F 63000 Clermont Ferrand France

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Del Rio D., Rodriguez-Mateos A., Spencer J.P., Tognolini M., Borges G., Crozier A. Dietary (poly)phenolics in human health: Structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid. Redox Signal. 2013;18:1818–1892. doi: 10.1089/ars.2012.4581. PubMed DOI PMC

Tresserra-Rimbau A., Lamuela-Raventos R.M., Moreno J.J. Polyphenols, food and pharma. Current knowledge and directions for future research. Biochem. Pharmacol. 2018;156:186–195. doi: 10.1016/j.bcp.2018.07.050. PubMed DOI

Sharma A., Shahzad B., Rehman A., Bhardwaj R., Landi M., Zheng B. Response of Phenylpropanoid Pathway and the Role of Polyphenols in Plants under Abiotic Stress. Molecules. 2019;24:2452. doi: 10.3390/molecules24132452. PubMed DOI PMC

Cory H., Passarelli S., Szeto J., Tamez M., Mattei J. The Role of Polyphenols in Human Health and Food Systems: A Mini-Review. Front. Nutr. 2018;5:87. doi: 10.3389/fnut.2018.00087. PubMed DOI PMC

Neveu V., Perez-Jimenez J., Vos F., Crespy V., du Chaffaut L., Mennen L., Knox C., Eisner R., Cruz J., Wishart D., et al. Phenol-Explorer: An online comprehensive database on polyphenol contents in foods. Database. 2010;2010:bap024. doi: 10.1093/database/bap024. PubMed DOI PMC

Scalbert A., Williamson G. Dietary intake and bioavailability of polyphenols. J. Nutr. 2000;130:2073S–2085S. doi: 10.1093/jn/130.8.2073S. PubMed DOI

Miranda A.M., Steluti J., Fisberg R.M., Marchioni D.M. Dietary intake and food contributors of polyphenols in adults and elderly adults of Sao Paulo: A population-based study. Br. J. Nutr. 2016;115:1061–1070. doi: 10.1017/S0007114515005061. PubMed DOI

Grosso G., Stepaniak U., Topor-Madry R., Szafraniec K., Pajak A. Estimated dietary intake and major food sources of polyphenols in the Polish arm of the HAPIEE study. Nutrition. 2014;30:1398–1403. doi: 10.1016/j.nut.2014.04.012. PubMed DOI PMC

Hertog M.G., Feskens E.J., Hollman P.C., Katan M.B., Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: The Zutphen Elderly Study. Lancet. 1993;342:1007–1011. doi: 10.1016/0140-6736(93)92876-U. PubMed DOI

Wedick N.M., Pan A., Cassidy A., Rimm E.B., Sampson L., Rosner B., Willett W., Hu F.B., Sun Q., van Dam R.M. Dietary flavonoid intakes and risk of type 2 diabetes in US men and women. Am. J. Clin. Nutr. 2012;95:925–933. doi: 10.3945/ajcn.111.028894. PubMed DOI PMC

Loffredo L., Baratta F., Ludovica P., Battaglia S., Carnevale R., Nocella C., Novo M., Pannitteri G., Ceci F., Angelico F., et al. Effects of dark chocolate on endothelial function in patients with non-alcoholic steatohepatitis. Nutr. Metab. Cardiovasc. Dis. 2017;28:143–149. doi: 10.1016/j.numecd.2017.10.027. PubMed DOI

Grassi D., Desideri G., Necozione S., Lippi C., Casale R., Properzi G., Blumberg J.B., Ferri C. Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate. J. Nutr. 2008;138:1671–1676. doi: 10.1093/jn/138.9.1671. PubMed DOI

Park E., Edirisinghe I., Choy Y.Y., Waterhouse A., Burton-Freeman B. Effects of grape seed extract beverage on blood pressure and metabolic indices in individuals with pre-hypertension: A randomised, double-blinded, two-arm, parallel, placebo-controlled trial. Br. J. Nutr. 2016;115:226–238. doi: 10.1017/S0007114515004328. PubMed DOI

Hokayem M., Blond E., Vidal H., Lambert K., Meugnier E., Feillet-Coudray C., Coudray C., Pesenti S., Luyton C., Lambert-Porcheron S., et al. Grape polyphenols prevent fructose-induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients. Diabetes Care. 2013;36:1454–1461. doi: 10.2337/dc12-1652. PubMed DOI PMC

Pinto X., Fanlo-Maresma M., Corbella E., Corbella X., Mitjavila M.T., Moreno J.J., Casas R., Estruch R., Corella D., Bullo M., et al. A Mediterranean Diet Rich in Extra-Virgin Olive Oil Is Associated with a Reduced Prevalence of Nonalcoholic Fatty Liver Disease in Older Individuals at High Cardiovascular Risk. J. Nutr. 2019;149:1920–1929. doi: 10.1093/jn/nxz147. PubMed DOI

Storniolo C.E., Casillas R., Bullo M., Castaner O., Ros E., Saez G.T., Toledo E., Estruch R., Ruiz-Gutierrez V., Fito M., et al. A Mediterranean diet supplemented with extra virgin olive oil or nuts improves endothelial markers involved in blood pressure control in hypertensive women. Eur. J. Nutr. 2017;56:89–97. doi: 10.1007/s00394-015-1060-5. PubMed DOI

Menezes R., Rodriguez-Mateos A., Kaltsatou A., Gonzalez-Sarrias A., Greyling A., Giannaki C., Andres-Lacueva C., Milenkovic D., Gibney E.R., Dumont J., et al. Impact of Flavonols on Cardiometabolic Biomarkers: A Meta-Analysis of Randomized Controlled Human Trials to Explore the Role of Inter-Individual Variability. Nutrients. 2017;9:117. doi: 10.3390/nu9020117. PubMed DOI

Morand C., De Roos B., Garcia-Conesa M.T., Gibney E.R., Landberg R., Manach C., Milenkovic D., Rodriguez-Mateos A., Van de Wiele T., Tomas-Barberan F. Why interindividual variation in response to consumption of plant food bioactives matters for future personalised nutrition. Proc. Nutr. Soc. 2020;79:225–235. doi: 10.1017/S0029665120000014. PubMed DOI

Gibney E.R., Milenkovic D., Combet E., Ruskovska T., Greyling A., Gonzalez-Sarrias A., de Roos B., Tomas-Barberan F., Morand C., Rodriguez-Mateos A. Factors influencing the cardiometabolic response to (poly)phenols and phytosterols: A review of the COST Action POSITIVe activities. Eur. J. Nutr. 2019;58:37–47. doi: 10.1007/s00394-019-02066-6. PubMed DOI PMC

Milenkovic D., Morand C., Cassidy A., Konic-Ristic A., Tomas-Barberan F., Ordovas J.M., Kroon P., De Caterina R., Rodriguez-Mateos A. Interindividual Variability in Biomarkers of Cardiometabolic Health after Consumption of Major Plant-Food Bioactive Compounds and the Determinants Involved. Adv. Nutr. 2017;8:558–570. doi: 10.3945/an.116.013623. PubMed DOI PMC

Caradonna F., Consiglio O., Luparello C., Gentile C. Science and Healthy Meals in the World: Nutritional Epigenomics and Nutrigenetics of the Mediterranean Diet. Nutrients. 2020;12:1748. doi: 10.3390/nu12061748. PubMed DOI PMC

Caradonna F., Cruciata I., Luparello C. Nutrigenetics, nutrigenomics and phenotypic outcomes of dietary low-dose alcohol consumption in the suppression and induction of cancer development: Evidence from in vitro studies. Crit. Rev. Food Sci. Nutr. 2020;8:1–32. doi: 10.1080/10408398.2020.1850416. PubMed DOI

Ruskovska T., Maksimova V., Milenkovic D. Polyphenols in human nutrition: From the in vitro antioxidant capacity to the beneficial effects on cardiometabolic health and related inter-individual variability—An overview and perspective. Br. J. Nutr. 2020;123:241–254. doi: 10.1017/S0007114519002733. PubMed DOI

Krga I., Tamaian R., Mercier S., Boby C., Monfoulet L.E., Glibetic M., Morand C., Milenkovic D. Anthocyanins and their gut metabolites attenuate monocyte adhesion and transendothelial migration through nutrigenomic mechanisms regulating endothelial cell permeability. Free Radic. Biol. Med. 2018;124:364–379. doi: 10.1016/j.freeradbiomed.2018.06.027. PubMed DOI

Ruskovska T., Massaro M., Carluccio M.A., Arola-Arnal A., Muguerza B., Vanden Berghe W., Declerck K., Bravo F.I., Calabriso N., Combet E., et al. Systematic bioinformatic analysis of nutrigenomic data of flavanols in cell models of cardiometabolic disease. Food Funct. 2020;11:5040–5064. doi: 10.1039/D0FO00701C. PubMed DOI

Mitjavila M.T., Moreno J.J. The effects of polyphenols on oxidative stress and the arachidonic acid cascade. Implications for the prevention/treatment of high prevalence diseases. Biochem. Pharmacol. 2012;84:1113–1122. doi: 10.1016/j.bcp.2012.07.017. PubMed DOI

Tarragon E., Moreno J.J. Polyphenols and taste 2 receptors. Physiological, pathophysiological and pharmacological implications. Biochem. Pharmacol. 2020;178:114086. doi: 10.1016/j.bcp.2020.114086. PubMed DOI

Most J., Timmers S., Warnke I., Jocken J.W., van Boekschoten M., de Groot P., Bendik I., Schrauwen P., Goossens G.H., Blaak E.E. Combined epigallocatechin-3-gallate and resveratrol supplementation for 12 wk increases mitochondrial capacity and fat oxidation, but not insulin sensitivity, in obese humans: A randomized controlled trial. Am. J. Clin. Nutr. 2016;104:215–227. doi: 10.3945/ajcn.115.122937. PubMed DOI

Most J., Warnke I., Boekschoten M.V., Jocken J.W.E., de Groot P., Friedel A., Bendik I., Goossens G.H., Blaak E.E. The effects of polyphenol supplementation on adipose tissue morphology and gene expression in overweight and obese humans. Adipocyte. 2018;7:190–196. doi: 10.1080/21623945.2018.1469942. PubMed DOI PMC

Gaj S., Eijssen L., Mensink R.P., Evelo C.T. Validating nutrient-related gene expression changes from microarrays using RT(2) PCR-arrays. Genes Nutr. 2008;3:153–157. doi: 10.1007/s12263-008-0094-1. PubMed DOI PMC

Morey J.S., Ryan J.C., Van Dolah F.M. Microarray validation: Factors influencing correlation between oligonucleotide microarrays and real-time PCR. Biol. Proced. Online. 2006;8:175–193. doi: 10.1251/bpo126. PubMed DOI PMC

Moher D., Liberati A., Tetzlaff J., Altman D.G., Group P. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann. Intern. Med. 2009;151:264–269. doi: 10.7326/0003-4819-151-4-200908180-00135. PubMed DOI

Stockel D., Kehl T., Trampert P., Schneider L., Backes C., Ludwig N., Gerasch A., Kaufmann M., Gessler M., Graf N., et al. Multi-omics enrichment analysis using the GeneTrail2 web service. Bioinformatics. 2016;32:1502–1508. doi: 10.1093/bioinformatics/btv770. PubMed DOI

Shannon P., Markiel A., Ozier O., Baliga N.S., Wang J.T., Ramage D., Amin N., Schwikowski B., Ideker T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–2504. doi: 10.1101/gr.1239303. PubMed DOI PMC

Bindea G., Mlecnik B., Hackl H., Charoentong P., Tosolini M., Kirilovsky A., Fridman W.H., Pages F., Trajanoski Z., Galon J. ClueGO: A Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;25:1091–1093. doi: 10.1093/bioinformatics/btp101. PubMed DOI PMC

Bindea G., Galon J., Mlecnik B. CluePedia Cytoscape plugin: Pathway insights using integrated experimental and in silico data. Bioinformatics. 2013;29:661–663. doi: 10.1093/bioinformatics/btt019. PubMed DOI PMC

Szklarczyk D., Morris J.H., Cook H., Kuhn M., Wyder S., Simonovic M., Santos A., Doncheva N.T., Roth A., Bork P., et al. The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–D368. doi: 10.1093/nar/gkw937. PubMed DOI PMC

Chen E.Y., Tan C.M., Kou Y., Duan Q., Wang Z., Meirelles G.V., Clark N.R., Ma’ayan A. Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform. 2013;14:128. doi: 10.1186/1471-2105-14-128. PubMed DOI PMC

Kuleshov M.V., Jones M.R., Rouillard A.D., Fernandez N.F., Duan Q., Wang Z., Koplev S., Jenkins S.L., Jagodnik K.M., Lachmann A., et al. Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90–W97. doi: 10.1093/nar/gkw377. PubMed DOI PMC

Han H., Cho J.W., Lee S., Yun A., Kim H., Bae D., Yang S., Kim C.Y., Lee M., Kim E., et al. TRRUST v2: An expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res. 2018;46:D380–D386. doi: 10.1093/nar/gkx1013. PubMed DOI PMC

Su G., Morris J.H., Demchak B., Bader G.D. Biological network exploration with Cytoscape 3. Curr. Protoc. Bioinform. 2014;47:8–13. doi: 10.1002/0471250953.bi0813s47. PubMed DOI PMC

Kozomara A., Birgaoanu M., Griffiths-Jones S. miRBase: From microRNA sequences to function. Nucleic Acids Res. 2019;47:D155–D162. doi: 10.1093/nar/gky1141. PubMed DOI PMC

Koopmans F., van Nierop P., Andres-Alonso M., Byrnes A., Cijsouw T., Coba M.P., Cornelisse L.N., Farrell R.J., Goldschmidt H.L., Howrigan D.P., et al. SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse. Neuron. 2019;103:217–234.e214. doi: 10.1016/j.neuron.2019.05.002. PubMed DOI PMC

Heberle H., Meirelles G.V., da Silva F.R., Telles G.P., Minghim R. InteractiVenn: A web-based tool for the analysis of sets through Venn diagrams. BMC Bioinform. 2015;16:169. doi: 10.1186/s12859-015-0611-3. PubMed DOI PMC

Zhou Y., Zhou B., Pache L., Chang M., Khodabakhshi A.H., Tanaseichuk O., Benner C., Chanda S.K. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 2019;10:1523. doi: 10.1038/s41467-019-09234-6. PubMed DOI PMC

Krzywinski M., Schein J., Birol I., Connors J., Gascoyne R., Horsman D., Jones S.J., Marra M.A. Circos: An information aesthetic for comparative genomics. Genome Res. 2009;19:1639–1645. doi: 10.1101/gr.092759.109. PubMed DOI PMC

Zhou G., Xia J. OmicsNet: A web-based tool for creation and visual analysis of biological networks in 3D space. Nucleic Acids Res. 2018;46:W514–W522. doi: 10.1093/nar/gky510. PubMed DOI PMC

Zhou G., Xia J. Using OmicsNet for Network Integration and 3D Visualization. Curr. Protoc. Bioinform. 2019;65:e69. doi: 10.1002/cpbi.69. PubMed DOI

Stelzer G., Rosen N., Plaschkes I., Zimmerman S., Twik M., Fishilevich S., Stein T.I., Nudel R., Lieder I., Mazor Y., et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr. Protoc. Bioinform. 2016;54:1–30. doi: 10.1002/cpbi.5. PubMed DOI

UniProt Consortium UniProt: A worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47:D506–D515. doi: 10.1093/nar/gky1049. PubMed DOI PMC

Castaner O., Covas M.I., Khymenets O., Nyyssonen K., Konstantinidou V., Zunft H.F., de la Torre R., Munoz-Aguayo D., Vila J., Fito M. Protection of LDL from oxidation by olive oil polyphenols is associated with a downregulation of CD40-ligand expression and its downstream products in vivo in humans. Am. J. Clin. Nutr. 2012;95:1238–1244. doi: 10.3945/ajcn.111.029207. PubMed DOI

Farras M., Valls R.M., Fernandez-Castillejo S., Giralt M., Sola R., Subirana I., Motilva M.J., Konstantinidou V., Covas M.I., Fito M. Olive oil polyphenols enhance the expression of cholesterol efflux related genes in vivo in humans. A randomized controlled trial. J. Nutr. Biochem. 2013;24:1334–1339. doi: 10.1016/j.jnutbio.2012.10.008. PubMed DOI

Martin-Pelaez S., Castaner O., Konstantinidou V., Subirana I., Munoz-Aguayo D., Blanchart G., Gaixas S., de la Torre R., Farre M., Saez G.T., et al. Effect of olive oil phenolic compounds on the expression of blood pressure-related genes in healthy individuals. Eur. J. Nutr. 2017;56:663–670. doi: 10.1007/s00394-015-1110-z. PubMed DOI

Seyyedebrahimi S., Khodabandehloo H., Nasli Esfahani E., Meshkani R. The effects of resveratrol on markers of oxidative stress in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled clinical trial. Acta Diabetol. 2018;55:341–353. doi: 10.1007/s00592-017-1098-3. PubMed DOI

Khorshidi M., Moini A., Alipoor E., Rezvan N., Gorgani-Firuzjaee S., Yaseri M., Hosseinzadeh-Attar M.J. The effects of quercetin supplementation on metabolic and hormonal parameters as well as plasma concentration and gene expression of resistin in overweight or obese women with polycystic ovary syndrome. Phytother. Res. 2018;32:2282–2289. doi: 10.1002/ptr.6166. PubMed DOI

Barber-Chamoux N., Milenkovic D., Verny M.A., Habauzit V., Pereira B., Lambert C., Richard D., Boby C., Mazur A., Lusson J.R., et al. Substantial Variability Across Individuals in the Vascular and Nutrigenomic Response to an Acute Intake of Curcumin: A Randomized Controlled Trial. Mol. Nutr. Food Res. 2018;62 doi: 10.1002/mnfr.201700418. PubMed DOI

Tome-Carneiro J., Larrosa M., Yanez-Gascon M.J., Davalos A., Gil-Zamorano J., Gonzalvez M., Garcia-Almagro F.J., Ruiz Ros J.A., Tomas-Barberan F.A., Espin J.C., et al. One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol. Res. 2013;72:69–82. doi: 10.1016/j.phrs.2013.03.011. PubMed DOI

Tome-Carneiro J., Gonzalvez M., Larrosa M., Yanez-Gascon M.J., Garcia-Almagro F.J., Ruiz-Ros J.A., Tomas-Barberan F.A., Garcia-Conesa M.T., Espin J.C. Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: A triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc. Drugs Ther. 2013;27:37–48. doi: 10.1007/s10557-012-6427-8. PubMed DOI PMC

Lopez-Candales A., Hernandez Burgos P.M., Hernandez-Suarez D.F., Harris D. Linking Chronic Inflammation with Cardiovascular Disease: From Normal Aging to the Metabolic Syndrome. J. Nat. Sci. 2017;3:e341. PubMed PMC

Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542:177–185. doi: 10.1038/nature21363. PubMed DOI

Ormazabal V., Nair S., Elfeky O., Aguayo C., Salomon C., Zuniga F.A. Association between insulin resistance and the development of cardiovascular disease. Cardiovasc. Diabetol. 2018;17:122. doi: 10.1186/s12933-018-0762-4. PubMed DOI PMC

Caputo T., Gilardi F., Desvergne B. From chronic overnutrition to metaflammation and insulin resistance: Adipose tissue and liver contributions. FEBS Lett. 2017;591:3061–3088. doi: 10.1002/1873-3468.12742. PubMed DOI

Longo M., Zatterale F., Naderi J., Parrillo L., Formisano P., Raciti G.A., Beguinot F., Miele C. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications. Int. J. Mol. Sci. 2019;20:2358. doi: 10.3390/ijms20092358. PubMed DOI PMC

Ruskovska T., Bernlohr D.A. Oxidative stress and protein carbonylation in adipose tissue—Implications for insulin resistance and diabetes mellitus. J. Proteom. 2013;92:323–334. doi: 10.1016/j.jprot.2013.04.002. PubMed DOI PMC

Nandipati K.C., Subramanian S., Agrawal D.K. Protein kinases: Mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance. Mol. Cell. Biochem. 2017;426:27–45. doi: 10.1007/s11010-016-2878-8. PubMed DOI PMC

Khan H., Ullah H., Castilho P., Gomila A.S., D’Onofrio G., Filosa R., Wang F., Nabavi S.M., Daglia M., Silva A.S., et al. Targeting NF-kappaB signaling pathway in cancer by dietary polyphenols. Crit. Rev. Food Sci. Nutr. 2020;60:2790–2800. doi: 10.1080/10408398.2019.1661827. PubMed DOI

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. doi: 10.1371/journal.pone.0095527. PubMed DOI PMC

Milenkovic D., Berghe W.V., Morand C., Claude S., van de Sandt A., Gorressen S., Monfoulet L.E., Chirumamilla C.S., Declerck K., Szic K.S.V., et al. A systems biology network analysis of nutri(epi)genomic changes in endothelial cells exposed to epicatechin metabolites. Sci. Rep. 2018;8:15487. doi: 10.1038/s41598-018-33959-x. PubMed DOI PMC

Claude S., Boby C., Rodriguez-Mateos A., Spencer J.P., Gerard N., Morand C., Milenkovic D. Flavanol metabolites reduce monocyte adhesion to endothelial cells through modulation of expression of genes via p38-MAPK and p65-Nf-kB pathways. Mol. Nutr. Food Res. 2014;58:1016–1027. doi: 10.1002/mnfr.201300658. PubMed DOI

Moreno-Ulloa A., Mendez-Luna D., Beltran-Partida E., Castillo C., Guevara G., Ramirez-Sanchez I., Correa-Basurto J., Ceballos G., Villarreal F. The effects of (-)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER) Pharmacol. Res. 2015;100:309–320. doi: 10.1016/j.phrs.2015.08.014. PubMed DOI PMC

Yeung F., Hoberg J.E., Ramsey C.S., Keller M.D., Jones D.R., Frye R.A., Mayo M.W. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004;23:2369–2380. doi: 10.1038/sj.emboj.7600244. PubMed DOI PMC

Yoshizaki T., Milne J.C., Imamura T., Schenk S., Sonoda N., Babendure J.L., Lu J.C., Smith J.J., Jirousek M.R., Olefsky J.M. SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol. Cell. Biol. 2009;29:1363–1374. doi: 10.1128/MCB.00705-08. PubMed DOI PMC

Yoshizaki T., Schenk S., Imamura T., Babendure J.L., Sonoda N., Bae E.J., Oh D.Y., Lu M., Milne J.C., Westphal C., et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 2010;298:E419–E428. doi: 10.1152/ajpendo.00417.2009. PubMed DOI PMC

Zhou S., Tang X., Chen H.Z. Sirtuins and Insulin Resistance. Front. Endocrinol. 2018;9:748. doi: 10.3389/fendo.2018.00748. PubMed DOI PMC

Olmos Y., Sanchez-Gomez F.J., Wild B., Garcia-Quintans N., Cabezudo S., Lamas S., Monsalve M. SirT1 regulation of antioxidant genes is dependent on the formation of a FoxO3a/PGC-1alpha complex. Antioxid. Redox Signal. 2013;19:1507–1521. doi: 10.1089/ars.2012.4713. PubMed DOI PMC

Ren Z., He H., Zuo Z., Xu Z., Wei Z., Deng J. The role of different SIRT1-mediated signaling pathways in toxic injury. Cell. Mol. Biol. Lett. 2019;24:36. doi: 10.1186/s11658-019-0158-9. PubMed DOI PMC

Stein S., Matter C.M. Protective roles of SIRT1 in atherosclerosis. Cell. Cycle. 2011;10:640–647. doi: 10.4161/cc.10.4.14863. PubMed DOI

Kane A.E., Sinclair D.A. Sirtuins and NAD(+) in the Development and Treatment of Metabolic and Cardiovascular Diseases. Circ. Res. 2018;123:868–885. doi: 10.1161/CIRCRESAHA.118.312498. PubMed DOI PMC

Mazloom H., Alizadeh S., Esfahani E.N., Razi F., Meshkani R. Decreased expression of microRNA-21 is associated with increased cytokine production in peripheral blood mononuclear cells (PBMCs) of obese type 2 diabetic and non-diabetic subjects. Mol. Cell. Biochem. 2016;419:11–17. doi: 10.1007/s11010-016-2743-9. PubMed DOI

Hijmans J.G., Diehl K.J., Bammert T.D., Kavlich P.J., Lincenberg G.M., Greiner J.J., Stauffer B.L., DeSouza C.A. Association between hypertension and circulating vascular-related microRNAs. J. Hum. Hypertens. 2018;32:440–447. doi: 10.1038/s41371-018-0061-2. PubMed DOI PMC

Ling H.Y., Hu B., Hu X.B., Zhong J., Feng S.D., Qin L., Liu G., Wen G.B., Liao D.F. MiRNA-21 reverses high glucose and high insulin induced insulin resistance in 3T3-L1 adipocytes through targeting phosphatase and tensin homologue. Exp. Clin. Endocrinol. Diabetes. 2012;120:553–559. doi: 10.1055/s-0032-1311644. PubMed DOI

Luo A., Yan H., Liang J., Du C., Zhao X., Sun L., Chen Y. MicroRNA-21 regulates hepatic glucose metabolism by targeting FOXO1. Gene. 2017;627:194–201. doi: 10.1016/j.gene.2017.06.024. PubMed DOI

Wang S., Liang C., Ai H., Yang M., Yi J., Liu L., Song Z., Bao Y., Li Y., Sun L., et al. Hepatic miR-181b-5p Contributes to Glycogen Synthesis Through Targeting EGR1. Dig. Dis. Sci. 2019;64:1548–1559. doi: 10.1007/s10620-018-5442-4. PubMed DOI

Hori D., Dunkerly-Eyring B., Nomura Y., Biswas D., Steppan J., Henao-Mejia J., Adachi H., Santhanam L., Berkowitz D.E., Steenbergen C., et al. miR-181b regulates vascular stiffness age dependently in part by regulating TGF-beta signaling. PLoS ONE. 2017;12:e0174108. doi: 10.1371/journal.pone.0174108. PubMed DOI PMC

Witkowski M., Witkowski M., Saffarzadeh M., Friebel J., Tabaraie T., Ta Bao L., Chakraborty A., Dorner A., Stratmann B., Tschoepe D., et al. Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes. Cardiovasc. Diabetol. 2020;19:20. doi: 10.1186/s12933-020-0993-z. PubMed DOI PMC

Oses M., Margareto Sanchez J., Portillo M.P., Aguilera C.M., Labayen I. Circulating miRNAs as Biomarkers of Obesity and Obesity-Associated Comorbidities in Children and Adolescents: A Systematic Review. Nutrients. 2019;11:2890. doi: 10.3390/nu11122890. PubMed DOI PMC

Shen Y., Xu H., Pan X., Wu W., Wang H., Yan L., Zhang M., Liu X., Xia S., Shao Q. miR-34a and miR-125b are upregulated in peripheral blood mononuclear cells from patients with type 2 diabetes mellitus. Exp. Ther. Med. 2017;14:5589–5596. doi: 10.3892/etm.2017.5254. PubMed DOI PMC

Xu Y., Xu Y., Zhu Y., Sun H., Juguilon C., Li F., Fan D., Yin L., Zhang Y. Macrophage miR-34a Is a Key Regulator of Cholesterol Efflux and Atherosclerosis. Mol. Ther. 2020;28:202–216. doi: 10.1016/j.ymthe.2019.09.008. PubMed DOI PMC

Pan Y., Hui X., Hoo R.L.C., Ye D., Chan C.Y.C., Feng T., Wang Y., Lam K.S.L., Xu A. Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J. Clin. Investig. 2019;129:834–849. doi: 10.1172/JCI123069. PubMed DOI PMC

Scoditti E., Carpi S., Massaro M., Pellegrino M., Polini B., Carluccio M.A., Wabitsch M., Verri T., Nieri P., De Caterina R. Hydroxytyrosol Modulates Adipocyte Gene and miRNA Expression Under Inflammatory Condition. Nutrients. 2019;11:2493. doi: 10.3390/nu11102493. PubMed DOI PMC

Oldenburg J., de Rooij J. Mechanical control of the endothelial barrier. Cell Tissue Res. 2014;355:545–555. doi: 10.1007/s00441-013-1792-6. PubMed DOI

Chistiakov D.A., Orekhov A.N., Bobryshev Y.V. Endothelial Barrier and Its Abnormalities in Cardiovascular Disease. Front. Physiol. 2015;6:365. doi: 10.3389/fphys.2015.00365. PubMed DOI PMC

Clark A.R., Ohlmeyer M. Protein phosphatase 2A as a therapeutic target in inflammation and neurodegeneration. Pharmacol. Ther. 2019;201:181–201. doi: 10.1016/j.pharmthera.2019.05.016. PubMed DOI PMC

Afzal M., Redha A., AlHasan R. Anthocyanins Potentially Contribute to Defense against Alzheimer’s Disease. Molecules. 2019;24:4255. doi: 10.3390/molecules24234255. PubMed DOI PMC

Vauzour D. Dietary polyphenols as modulators of brain functions: Biological actions and molecular mechanisms underpinning their beneficial effects. Oxid. Med. Cell. Longev. 2012;2012:914273. doi: 10.1155/2012/914273. PubMed DOI PMC