However, comprehensive understanding of the biological activity of flavanols including their mechanisms of action in humans is still enigmatic. Over the past years, in vitro and in vivo studies have shown that polyphenols modulate the activity of cell signalling proteins, transcription factors and consequently the expression of both, mRNA and miRNA. For example, in animal models, supplementation of a diet with quercetin, naringenin or curcumin at nutritionally relevant doses altered the expression of hundreds of genes in lung, aorta or liver. In vitro, polyphenols impact the expression of genes in various cell types. It has been demonstrated that flavanone metabolites at physiological concentrations can modulate the expression of genes involved in inflammation in tumor necrosis factor -astimulated human umbilical vein endothelial cells. Exposure of human monocytes to green tea polyphenols affected the expression of genes related to atherosclerosis development, such as CD36, LXR-a, MYC or LDL-R. In human hepatocytes polyphenols from red grape juice were able to counteract the LDL-induced changes in gene expression of the LDL receptor, hydroxymethylglutaryl-CoA reductase and the transcription factor sterol regulatory element-binding protein -1, a key regulator of lipid homeostasis. Also genes such as ICAM1, MCP1, IL6 or IL1b of which expression is controlled by nuclear factor kappa B and of which transcriptional activation is critical in a number of pathologies, including cardiovascular diseases, are differentially expressed in the presence of polyphenols. However, only a few studies have been published up to now describing the genomic impact of polyphenols and polyphenol-rich foods in humans. It has been observed that the daily intake of 150 mg quercetin for 2 weeks significantly affected the expression of 788 genes in CD14-positive monocytes, genes related to immune system, apoptosis or cell signalling pathways. Consumption of orange juice rich in hesperidin or hesperidin alone for 4 weeks by healthy, middleaged, moderately overweight men significantly affected over 3000 and 1800 genes respectively. These genes were involved in the regulation of chemotaxis, cell adhesion, lipid transport and their expression profile could be considered as anti-inflammatory and anti-atherogenic. More recently, in a double-bind, randomized cross-over trial in menopausal women isoflavones affected in peripheral blood mononuclear cells the expression of 357 genes which are involved in inflammation, oxidative phosphorylation and cell cycle. In addition to the impact of polyphenols on the expression of genes, recent data suggest that polyphenols could also modulate DNA methylation at multiple levels. Furthermore, different lifestyle factors such as diet and smoking have been associated with DNA methylation changes in cancer and chronic inflammation related diseases such as metabolic syndrome.