Systematic analysis of nutrigenomic effects of polyphenols related to cardiometabolic health in humans - Evidence from untargeted mRNA and miRNA studies.

Cardiovascular and metabolic disorders present major causes of mortality in the ageing population. Polyphenols present in human diets possess cardiometabolic protective properties, however their underlying molecular mechanisms in humans are still not well identified. Even though preclinical and in vitro studies advocate that these bioactives can modulate gene expression, most studies were performed using targeted approaches. With the objective to decipher the molecular mechanisms underlying polyphenols cardiometabolic preventive properties in humans, we performed integrative multi-omic bioinformatic analyses of published studies which reported improvements of cardiometabolic risk factors following polyphenol intake, together with genomic analyses performed using untargeted approach. We identified 5 studies within our criteria and nearly 5000 differentially expressed genes, both mRNAs and miRNAs, in peripheral blood cells. Integrative bioinformatic analyses (e.g. pathway and gene network analyses, identification of transcription factors, correlation of gene expression profiles with those associated with diseases and drug intake) revealed that these genes are involved in the processes such as cell adhesion and mobility, immune system, metabolism, or cell signaling. We also identified 27 miRNAs known to regulate processes such as cell cytoskeleton, chemotaxis, cell signaling, or cell metabolism. Gene expression profiles negatively correlated with expression profiles of cardiovascular disease patients, while a positive correlation was observed with gene expression profiles following intake of drugs against cardiometabolic disorders. These analyses further advocate for health protective effects of these bioactives against age-associated diseases. In conclusion, polyphenols can exert multi-genomic modifications in humans and use of untargeted methods coupled with bioinformatic analyses represent the best approach to decipher molecular mechanisms underlying healthy-ageing effects of these bioactives.

Dietary patterns, caloric restrictions for management of cardiovascular disease and cancer; a brief review.

Cardiovascular disease (CVD) and cancers are overall still identified as the two most prevalent non-communicable diseases globally. Their prevention and potential reversal (in particular CVD risk) was seen effective with the modification of dietary intake that was applied in several different populations. Although the findings from epidemiological studies provide support that adhering to dietary patterns such as the Mediterranean diet can reduce incidence and prevalence of CVD and some forms of cancer, the mechanistic aspects of disease modulation associated with both diseases can be seen in dietary management. Several studies have already explored the potential modes of action of certain nutrients in well controlled large clinical trials. However, the clinical trials designed to determine the effects of adhering to a particular diet are relatively hard to conduct and these studies are faced with several obstacles particularly in the populations that are identified with a high risk of CVD or different cancers. Therefore, it is important to understand potential underlying and shared mechanisms of action and to explore how healthy dietary patterns may modulate the occurrence, initiation, and progression of such diseases. The aim of this review is to summarise and conceptualize the current understanding relating to healthy dietary patterns, and briefly discuss the opportunities that epigenetic research may bring and how it may assist to further interpret epidemiological and clinical evidence.

Systematic Bioinformatic Analyses of Nutrigenomic Modifications by Polyphenols Associated with Cardiometabolic Health in Humans-Evidence from Targeted Nutrigenomic Studies.

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.

Molecular Determinants of the Cardiometabolic Improvements of Dietary Flavanols Identified by an Integrative Analysis of Nutrigenomic Data from a Systematic Review of Animal Studies.

SCOPE: Flavanols are important polyphenols of the human diet with extensive demonstrations of their beneficial effects on cardiometabolic health. They contribute to preserve health acting on a large range of cellular processes. The underlying mechanisms of action of flavanols are not fully understood but involve a nutrigenomic regulation. METHODS AND RESULTS: To further capture how the intake of dietary flavanols results in the modulation of gene expression, nutrigenomics data in response to dietary flavanols obtained from animal models of cardiometabolic diseases have been collected and submitted to a bioinformatics analysis. This systematic analysis shows that dietary flavanols modulate a large range of genes mainly involved in endocrine function, fatty acid metabolism, and inflammation. Several regulators of the gene expression have been predicted and include transcription factors, miRNAs and epigenetic factors. CONCLUSION: This review highlights the complex and multilevel action of dietary flavanols contributing to their strong potential to preserve cardiometabolic health. The identification of the potential molecular mediators and of the flavanol metabolites driving the nutrigenomic response in the target organs is still a pending question which the answer will contribute to optimize the beneficial health effects of dietary bioactives.

Is There a FADS2-Modulated Link between Long-Chain Polyunsaturated Fatty Acids in Plasma Phospholipids and Polyphenol Intake in Adult Subjects Who Are Overweight?

Dietary polyphenols promote cardiometabolic health and are linked with long-chain polyunsaturated fatty acids in plasma phospholipids (LC-PUFA). The FADS2 polymorphisms are associated with LC-PUFA metabolism and overweight/obesity. This 4-week study examined the link between polyphenol intake, FADS2 variants (rs174593, rs174616, rs174576) and obesity in 62 overweight adults (BMI ≥ 25), allocated to consume 100 mL daily of either: Aronia juice, a rich source of polyphenols, with 1177.11 mg polyphenols (expressed as gallic acid equivalents)/100 mL (AJ, n = 22), Aronia juice with 294.28 mg polyphenols/100 mL (MJ, n = 20), or nutritionally matched polyphenol-lacking placebo as a control (PLB, n = 20). We analyzed LC-PUFA (% of total pool) by gas chromatography and FADS2 variants by real-time PCR. Four-week changes in LC-PUFA, BMI, and body weight were included in statistical models, controlling for gender and PUFA intake. Only upon AJ and MJ, the presence of FADS2 variant alleles affected changes in linoleic, arachidonic, and eicosapentaenoic acid (EPA). Upon MJ treatment, changes in EPA were inversely linked with changes in BMI (ß= -0.73, p = 0.029) and weight gain (ß= -2.17, p = 0.024). Only in subjects drinking AJ, the link between changes in EPA and anthropometric indices was modified by the rs174576 variant allele. Our results indicate the interaction between FADS2, fatty acid metabolism, and polyphenol intake in overweight subjects.

Aronia juice consumption prior to half-marathon race can acutely affect platelet activation in recreational runners.

Long-distance running, especially in non-professional runners, can increase cardiac arrest risk by enhancing platelet activation and aggregation. Polyphenols can exert cardioprotective effects by positively influencing platelet function. This study aimed to examine the acute effects of polyphenol-rich aronia juice consumption, before simulation of a half-marathon race, on platelet activation and aggregation with leukocytes in recreational runners. In this acute crossover study,10 healthy male runners (age 30.8 ± 2.3 years) consumed breakfast with 200 mL of aronia juice or 200 mL of placebo. They warmed-up and ran a simulated half-marathon race (21.1 km). Blood was collected at baseline, and at 15 min, 1 h, and 24 h after the run. All variables were analyzed with 4 (time) × 2 (group) ANOVA with repeated measures on both factors. Results revealed a significant effect of group on platelet activation parameters: P-selectin and GPIIb-IIIa expressions significantly decreased in the aronia group compared with the placebo group (F[1,9] = 10.282, p = 0.011 and F[1,9] = 7.860, p = 0.021, respectively). The effect of time was significant on both platelet aggregation markers: platelet-monocyte and platelet-neutrophil aggregates were significantly lower after the race (F[3,7] = 4.227, p = 0.014 and F[3,7] = 70.065, p = 0.000, respectively), with changes more pronounced in the later. All effects remained when platelets were exposed to an agonist. These results suggest that aronia consumption could counteract the half-marathon race-induced changes in platelet function. Novelty Aronia juice consumption significantly decreased the expression of platelet activation markers but did not affect platelet aggregation. The race itself did significantly reduce platelet-neutrophil aggregation. Aronia juice may serve as a supplement beverage for recreational runners to alleviate enhanced platelet reactivity caused by prolonged running.

Effects of anthocyanins and their gut metabolites on adenosine diphosphate-induced platelet activation and their aggregation with monocytes and neutrophils.

Accumulating evidence suggests that anthocyanins play an important role in the cardioprotective effects associated with consumption of anthocyanin-rich foods. These benefits may partly be attributed to their effects on platelets, significant contributors to cardiovascular disease development. This study aimed to investigate the impact of physiologically relevant concentrations of anthocyanins and their metabolites on platelet activation and platelet-leukocyte aggregation. Whole blood from seven healthy volunteers was treated with anthocyanins: cyanidin-3-arabinoside, cyanidin-3-glucoside, cyanidin-3-galactoside, delphinidin-3-glucoside and peonidin-3-glucoside at 0.1 µM concentration or gut metabolites: 4-hydroxybenzaldehyde, protocatechuic, vanillic, ferulic and hippuric acids at 0.5 µM, 0.2 µM, 2 µM, 1 µM, 2 µM concentration, respectively. Markers of adenosine diphosphate-induced platelet activation (P-selectin and GPIIb-IIIa expression) and platelet-monocyte and platelet-neutrophil aggregation were analyzed using flow cytometry. Cyanidin-3-arabinoside, delphinidin-3-glucoside, and peonidin-3-glucoside decreased agonist-induced P-selectin expression, while cyanidin-3-galactoside and cyanidin-3-arabinoside reduced platelet-neutrophil aggregation. Hippuric and protocatechuic acids inhibited P-selectin expression, ferulic acid reduced platelet-monocyte aggregation, while 4-hydroxybenzaldehyde affected P-selectin expression, platelet-neutrophil and monocyte aggregation. Only cyanidin-3-glucoside and protocatechuic acid decreased GPIIb-IIIa expression. These results demonstrate the bioactivity of anthocyanins and their gut metabolites at physiologically relevant concentrations on platelet function and interaction with leukocytes, presenting mechanisms by which they contribute to the beneficial effects of habitual consumption of anthocyanin-rich foods on cardiovascular health.

Anthocyanins and their gut metabolites reduce the adhesion of monocyte to TNFα-activated endothelial cells at physiologically relevant concentrations.

An increasing number of evidence suggests a protective role of dietary anthocyanins against cardiovascular diseases. Anthocyanins' extensive metabolism indicates that their metabolites could be responsible for the protective effects associated with consumption of anthocyanin-rich foods. The aim of this work was to investigate the effect of plasma anthocyanins and their metabolites on the adhesion of monocytes to TNFα-activated endothelial cells and on the expression of genes encoding cell adhesion molecules. Human umbilical vein endothelial cells (HUVECs) were exposed to circulating anthocyanins: cyanidin-3-arabinoside, cyanidin-3-galactoside, cyanidin-3-glucoside, delphinidin-3-glucoside, peonidin-3-glucoside, anthocyanin degradation product: 4-hydroxybenzaldehyde, or to their gut metabolites: protocatechuic, vanillic, ferulic and hippuric acid, at physiologically-relevant concentrations (0.1-2 µM) and time of exposure. Both anthocyanins and gut metabolites decreased the adhesion of monocytes to HUVECs, with a magnitude ranging from 18.1% to 47%. The mixture of anthocyanins and that of gut metabolites also reduced monocyte adhesion. However, no significant effect on the expression of genes encoding E-selectin, ICAM1 and VCAM1 was observed, suggesting that other molecular targets are involved in the observed effect. In conclusion, this study showed the potency of anthocyanins and their gut metabolites to modulate the adhesion of monocytes to endothelial cells, the initial step in atherosclerosis development, under physiologically-relevant conditions.