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Excessive intake of fructose is a significant contributor in the development of hypertension and pathogenesis of cardiometabolic diseases. We previously showed that dietary inulin can prevent fructose-induced hypertension in rats. Nevertheless, molecular mechanisms of both fructose and inulin in aorta remain unknown. The aim of this study was to identify global transcriptomic changes in aorta in rats on fructose-based diet or partial substitution of dietary fructose with inulin.At the end of study periods, aortas were isolated, RNA extracted, and transcriptomics performed using microarrays followed by in-dept bioinformatic analyses. We observed that fructose-based diet affected the expression of over 1700 genes involved in the regulation of vascular functions, cell signaling, and cellular metabolism. Partial substitution of dietary fructose with inulin affected the expression of over 1300 genes regulating endothelial and vascular functions, including relaxin signaling pathway, immune/inflammatory response, or cellular metabolism. Bioinformatic analyses revealed transcription factors, such as Junb or Nr4a2, and miRNAs, such as miR-206, miR-137 or miR-375, as potential transcriptional and post-transcriptional regulators of identified differentially expressed genes. Genes identified following both diets are associated with development of cardiovascular diseases, hypertension, immune system diseases and metabolic diseases. Moreover, a negative correlation between the expression profiles obtained by fructose-based diet and that by partial substitution of dietary fructose with inulin was observed.Our study showed that fructose can significantly impact global transcriptomic profile in aorta, changes that can be counteracted by inulin and which present relevant molecular mechanisms underlying its anti-hypertensive property.

International audience; Scope While cocoa flavanol (CF) consumption improves cardiovascular risk biomarkers, molecular mechanisms underlying their protective effects are not understood. Objective To investigate nutri(epi)genomic effects of CF and identify regulatory networks potential mediating vascular health benefits. Methods and Results Twenty healthy middle-aged men consume CF (bi-daily 450 mg) or control drinks for 1 month. Microarray analysis identifies 2235 differentially expressed genes (DEG) involved in processes regulating immune response, cell adhesion, or cytoskeleton organization. Distinct patterns of DEG correlate with CF-related changes in endothelial function, arterial stiffness, and blood pressure. DEG profile negatively correlates with expression profiles of cardiovascular disease patients. CF modulated DNA methylation profile of genes implicates in cell adhesion, actin cytoskeleton organization, or cell signaling. In silico docking analyses indicate that CF metabolites have the potential of binding to cell signaling proteins and transcription factors. Incubation of plasma obtained after CF consumption decrease monocyte to endothelial adhesion and dose-dependently increase nitric oxide-dependent chemotaxis of circulating angiogenic cells further validating the biological functions of CF metabolites. Conclusion In healthy humans, CF consumption may mediate vascular protective effects by modulating gene expression and DNA methylation towards a cardiovascular protective effect, in agreement with clinical results, by preserving integrity of immunological-endothelial barrier functions.

Citrus fruits and juices are a major source of dietary flavanones, and the regular consumption of these foods is inversely associated with the development of cardiometabolic diseases. However, the biological benefits depend on the bioavailability of these compounds, and previous studies have reported a large interindividual variability in the absorption and excretion of these compounds. Different factors, such as age, gender or genetic polymorphism of genes coding enzymes involved in the metabolism and transport of the flavanones, may explain this heterogeneity. This study aimed to assess the impact of single nucleotide polymorphism of sulfotransferases SULT1A1 and SULT1C4, and ABCC2 transporter genes on excretion of phase II flavanone metabolites in volunteers after 24 h of orange juice intake. Forty-six volunteers ingested a single dose of 500 mL of orange juice and 24-h urine was collected. The hesperetin and naringenin phase II metabolites were quantified in urine, and SNPs in SULT1A1, SULT1C4 and ABCC2 genes were genotyped. A significant (p < 0.05) relationship between the SNPs in these genes and the high excretion of phase II flavanone metabolites were observed. These results identified novel polymorphisms associated with higher absorption of flavanones, which may provide bases for future personalized nutritional guidelines for consuming flavanone-rich foods rich in these nutrients for better benefit from their health properties.

ScopeDiets rich in (poly)phenols have been associated with positive effects on neurodegenerative disorders, such as Parkinson's disease (PD). Several low-molecular weight (poly)phenol metabolites (LMWPM) are found in the plasma after consumption of (poly)phenol-rich food. It is expected that LMWPM, upon reaching the brain, may have beneficial effects against both oxidative stress and neuroinflammation, and possibly attenuate cell death mechanisms relate to the loss of dopaminergic neurons in PD.Methods and ResultsThis study investigates the neuroprotective potential of two blood-brain barrier permeant LMWPM, catechol-O-sulfate (cat-sulf), and pyrogallol-O-sulfate (pyr-sulf), in a human 3D cell model of PD. Neurospheroids were generated from LUHMES neuronal precursor cells and challenged by 1-methyl-4-phenylpyridinium (MPP+) to induce neuronal stress. LMWPM pretreatments were differently neuroprotective towards MPP+ insult, presenting distinct effects on the neuronal transcriptome. Particularly, cat-sulf pretreatment appeared to boost counter-regulatory defense mechanisms (preconditioning). When MPP+ is applied, both LMWPM positively modulated glutathione metabolism and heat-shock response, as also favorably shifting the balance of pro/anti-apoptotic proteins.ConclusionsOur findings point to the potential of LMWPM to trigger molecular mechanisms that help dopaminergic neurons to cope with a subsequent toxic insult. They are promising molecules to be further explored in the context of preventing and attenuating parkinsonian neurodegeneration. published

International audience; 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.

International audience; Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain’s microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12% sucrose/weight) or an HGD (34% sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of protein and non-protein-coding genes, gene networks, functional pathways, and transcription factors. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs. the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer’s dementia. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular inflammation through sEH.

Made available in DSpace on 2022-04-29T08:32:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Imbalances in gut microbiota composition occur in individuals with autism spectrum disorder (ASD). The administration of probiotics, prebiotics, and synbiotics is emerging as a potential and promising strategy for regulating the gut microbiota and improving ASD-related symptoms. We first investigated the survival of the probiotics Limosilactobacillus (L.) reuteri and Bifidobacterium (B.) longum alone, mixed and combined with a galacto-oligosaccharide (GOS) under simulated gastrointestinal conditions. Next, we evaluated the impact of probiotics (L. reuteri + B. longum), prebiotic (GOS), and synbiotic (L. reuteri + B. longum + GOS) on gut microbiota composition and metabolism of children with ASD using an in vitro fermentation model (SHIME®). The combination of L. reuteri, B. longum, and GOS showed elevated gastrointestinal resistance. The probiotic, prebiotic, and synbiotic treatments resulted in a positive modulation of the gut microbiota and metabolic activity of children with ASD. More specifically, the probiotic treatment increased the relative abundance of Lactobacillus, while the prebiotic treatment increased the relative abundance of Bifidobacterium and decreased the relative abundance of Lachnoclostridium. Changes in microbial metabolism were associated with increased short-chain fatty acid concentrations and reduced ammonium levels, particularly in the prebiotic and synbiotic treatments. Department of Food and Nutrition School of Pharmaceutical Sciences São Paulo State University (UNESP) Department of Biological Sciences School of Pharmaceutical Sciences São Paulo State University (UNESP) Department of Hydraulics and Sanitation School of Engineering of São Carlos University of São Paulo (USP) Department of Internal Medicine UC Davis School of Medicine University of California INRAE UNH Université Clermont Auvergne Faculty of Pharmacy Paris University Food and Human Nutrition Research Group University of Antioquia Department of Food and Nutrition School of Pharmaceutical Sciences São Paulo State University (UNESP) Department of Biological Sciences School of Pharmaceutical Sciences São Paulo State University (UNESP) FAPESP: 2017/01157-1 FAPESP: 2018/26645-1

International audience; Lipid oxidation is the major chemical phenomenon leading to the deterioration of edible oils by the diminution of their organoleptic and nutritional qualities. This study was aimed at profiling a phenolic extract from sweet Basil cultivated in Morocco and to investigate its possible protective effect against the oxidative process in sunflower edible oil as a natural alternative to synthetic antioxidants. The extract provides significant prevention of sunflower oil peroxidation after storage at 37 degrees C for 60 days. However, the effect was relatively less than that exerted by the BHA. Against, the phenolic extract significantly decreased the peroxidation value of oil after heating at 370 degrees C/5 h; the effect was comparable to that of BHA. Besides, the extract protects sunflower oil against oxidation induced by copper ion, but this activity remains statistically lower than that exerted by the BHA. Moreover, the DPPH radical scavenging activity of the phenolic extract is less than that recorded by the BHA. This extract inhibits also the oxidative bleaching of beta-carotene relatively less than BHA. The extract contains 153.19 +/- 1.05 mg/g total phenol. The HPLC analysis showed that the extract contains eight phenolic acids (caftaric acid, gallic acid, chlorogenic acid, caffeic acid, chicoric acid, rosmarinic acid, carnosic acid and p-hydroxybenzoic acid) and two flavonoids (rutin and luteolin-7 glucoside). In conclusion, we suggest that the phenolic Basil extract is a good source of natural antioxidants that might be exploited in edible oil preservation.

In a series of our previous works, we revealed the beneficial effects of applied soy isoflavones (genistein or daidzein) on the wide context of corticosteroidogenesis in vivo, in a rat model of the andropause. Soy isoflavones decreased the circulating levels of pituitary adrenocorticotropic hormone, inhibited aldosterone secretion, as well as corticosterone production and secretion, but stimulated dehydroepiandrosterone secretion, all in andropausal rats. In vitro studies indicate that the mechanism underlying these hormonal changes relies on inhibition of the pituitary tyrosine kinase and adrenocortical 3β-hydroxysteroid dehydrogenase enzymes by soy isoflavones. Although the clinical studies are in their infancy, the opinion is that genistein and daidzein have therapeutic potential for the safe treatment of ageing-caused androgen deprivation and glucocorticoid excess with related metabolic/hemodynamic issues in males. Our accumulated experience and knowledge in the field of biomedical effects of plant polyphenols have provided a platform for potential recommending the agenda to organize and accelerate experimental research aimed at producing the optimal supplementation. We hypothesize that an in vivo approach should first be exploited in the sequence of investigative steps, followed by in vitro studies and synchronously conducted molecular docking analyses. In vivo research, besides establishing the margin of exposure safety or adjustment of the correct polyphenol dose, enables identification and quantification of the metabolites of applied polyphenols in the blood. Subsequent in vitro exploitation of the metabolites and related docking analyses provide clarification of the molecular mechanisms of action of applied polyphenols. Chemical modification of the polyphenol structure or coupling it with nanoparticles might be the next step in optimizing the design of supplementation. Selected, intact or chemically-modified polyphenol molecules should be included in preclinical studies on a more closely-related species, while clinical studies would finally assess the safety and effectiveness of a polyphenol-based remedial strategy. The final supplement represents a product of an appropriate technological process, conducted in accordance with the recommendations derived from the preceding research.

Cardiovascular risk factors and biologic sex play a role in vascular dementia which is characterized by progressive reduction in cognitive function and memory. Yet, we lack understanding about the role sex plays in the molecular mechanisms whereby lipid stress contributes to cognitive decline. Five-week-old low-density lipoprotein deficient (LDL-R&minus, /&minus, ) male and female mice and C57BL/6J wild types (WT) were fed a control or Western Diet for 8 weeks. Differential expression of protein coding and non-protein coding genes (DEG) were determined in laser captured hippocampal microvessels using genome-wide microarray, followed by bioinformatic analysis of gene networks, pathways, transcription factors and sex/gender-based analysis (SGBA). Cognitive function was assessed by Y-maze. Bioinformatic analysis revealed more DEGs in females (2412) compared to males (1972). Hierarchical clusters revealed distinctly different sex-specific gene expression profiles irrespective of diet and genotype. There were also fewer and different biologic responses in males compared to females, as well as different cellular pathways and gene networks (favoring greater neuroprotection in females), together with sex-specific transcription factors and non-protein coding RNAs. Hyperlipidemic stress also resulted in less severe cognitive dysfunction in females. This sex-specific pattern of differential hippocampal microvascular RNA expression might provide therapeutic targets for dementia in males and females.

The Western diet (WD) and hyperlipidemia are risk factors for vascular disease, dementia, and cognitive impairment. However, the molecular mechanisms are poorly understood. This pilot study investigated the genomic pathways by which the WD and hyperlipidemia regulate gene expression in brain microvessels. Five-week-old C57BL/6J wild type (WT) control and low-density lipoprotein receptor deficient (LDL-R&minus, /&minus, ) male mice were fed the WD for eight weeks. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by a genome-wide microarray and bioinformatics analysis of laser-captured hippocampal microvessels. The WD resulted in the differential expression of 1972 genes. Much of the differentially expressed gene (DEG) was attributable to the differential regulation of cell signaling proteins and their transcription factors, approximately 4% was attributable to the differential expression of miRNAs, and 10% was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD. Lipotoxic injury resulted in complex and multilevel molecular regulation of the hippocampal microvasculature involving transcriptional and post-transcriptional regulation and may provide a molecular basis for a better understanding of hyperlipidemia-associated dementia risk.

Ingestion of (−)-epicatechin flavanols reverses endothelial dysfunction by increasing flow mediated dilation and by reducing vascular inflammation and oxidative stress, monocyte-endothelial cell adhesion and transendothelial monocyte migration in vitro and in vivo. This involves multiple changes in gene expression and epigenetic DNA methylation by poorly understood mechanisms. By in silico docking and molecular modeling we demonstrate favorable binding of different glucuronidated, sulfated or methylated (−)-epicatechin metabolites to different DNA methyltransferases (DNMT1/DNMT3A). In favor of this model, genome-wide DNA methylation profiling of endothelial cells treated with TNF and different (−)-epicatechin metabolites revealed specific DNA methylation changes in gene networks controlling cell adhesion-extravasation endothelial hyperpermeability as well as gamma-aminobutyric acid, renin-angiotensin and nitric oxide hypertension pathways. Remarkably, blood epigenetic profiles of an 8 weeks intervention with monomeric and oligomeric flavanols (MOF) including (−)-epicatechin in male smokers revealed individual epigenetic gene changes targeting similar pathways as the in vitro exposure experiments in endothelial cells. Furthermore, epigenetic changes following MOF diet intervention oppose atherosclerosis associated epigenetic changes. In line with biological data, the individual epigenetic response to a MOF diet is associated with different vascular health parameters (glutathione peroxidase 1 and endothelin-1 expression, acetylcholine-mediated microvascular response), in part involving systemic shifts in blood immune cell types which reduce the neutrophil–lymphocyte ratio (NLR). Altogether, our study suggests that different (−)-epicatechin metabolites promote vascular health in part via epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation.

Background: Passiflora setacea (PS) is a passionfruit variety of the Brazilian savannah and is a rich source of plant food bioactives with potential anti-inflammatory activity. This study aimed to investigate the effect of an acute intake of PS juice upon inflammation, metabolic parameters, and gene expression on circulating immune cells in humans. Methods: Overweight male volunteers (n = 12) were enrolled in two double-blind placebo-controlled studies. Blood samples were collected from fasting volunteers 3 h after the consumption of 250 mL of PS juice or placebo (PB). Metabolic parameters (insulin, glucose, total cholesterol, high-density lipoprotein (LDL), high-density lipoprotein (HDL), and total triglycerides) and circulating cytokines were evaluated (study 1). Peripheral blood mononuclear cell (PBMC) from the same subjects were isolated and RNA was extracted for transcriptomic analyses using microarrays (study 2). Results: Insulin and homeostatic model assessment for insulin resistance (HOMA-IR) levels decreased statistically after the PS juice intake, whereas HDL level increased significantly. Interleukin (IL)-17A level increased after placebo consumption, whereas its level remained unchanged after PS juice consumption. Nutrigenomic analyses revealed 1327 differentially expressed genes after PS consumption, with modulated genes involved in processes such as inflammation, cell adhesion, or cytokine&ndash, cytokine receptor. Conclusion: Taken together, these clinical results support the hypothesis that PS consumption may help the prevention of cardiometabolic diseases.

Made available in DSpace on 2020-12-12T01:16:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-02-01 The impact of habitual orange juice consumption on microbiota, lipid and sugar metabolism was investigated in a controlled clinical trial. The clinical procedure is as follows: ten women who had a regular diet without orange juice for 30 days (OJ-free diet), followed by a regular diet plus 300 ml d-1 orange juice for 60 days (OJ-Diet), and 30 days with a regular diet without orange juice (Washout). Biochemical and dietary parameters were monitored, and blood, urine and stool samples were collected every 30 days until the end of the study. Hesperidin and naringin metabolites in the urine were identified by UHPLC, and the microbiota composition of the feces was determined by 16S rRNA. At the end of the OJ-Diet, there was a reduction in glucose (-6.5%), insulin (-33%), insulin resistance (-44%), LDL-C (-16%) and triglycerides (-30%). After the washout, these parameters returned to their initial values. There were no changes in the body weight or fat during the experimental time. The intestinal bacteria, Lactobacillus spp., Akkermansia spp., and Ruminococcus spp., increased after the intervention with orange juice. In addition, an inverse correlation was detected between these bacteria and glycemia, insulin, HOMA-IR, triglycerides, total cholesterol and LDL-C, but a direct correlation with HDL-C. In conclusion, orange juice showed a prebiotic effect, modulating the intestinal microbiota while improving the glycemia and lipid profiles. Laboratory of Nutrition School of Pharmaceutical Science São Paulo State University-UNESP Department of Internal Medicine UC Davis School of Medicine University of California Université Clermont Auvergne INRA UNH CRNH Auvergne Laboratory of Nutrition School of Pharmaceutical Science São Paulo State University-UNESP

The growing interest in bioactive compounds, especially in polyphenols, is due to their abundance in the human diet and potentially positive effects on health. The consumption of polyphenols has been shown to possess anti-diabetic properties by preventing insulin resistance or insulin secretion through different signaling pathways, this effect is associated with their capacity to exert genomic modulations. Several studies have suggested that polyphenols could also bind to cellular proteins and modulate their activity, however, the mechanisms of action underlying their beneficial effects are complex and are not fully understood. The aim of this work was to characterize phenolic compounds present in blue corn and black bean extracts as well as identify their potential interactions with target proteins involved in diabetes pathogenesis using in silico approach. Total polyphenols content of both blue corn and black beans was identified using UPLC-ESI/qTOF/MS and quantified by colorimetric assays. In this work we identified twenty-eight phenolic compounds in the extracts, mainly anthocyanins, flavonols, hydroxycinamic acids, dihydroxybenzoic acids, flavones, isoflavones, and flavanols. Interactome of these compounds with thirteen target proteins involved in type 2 diabetes mellitus was performed in-silico. In total, 312 bioactive compounds/protein interaction analyses were acquired. Molecular docking results highlighted that nine of the top ten interactions correspond to anthocyanins, cyanidin 3-glucoside with 11β-HS, GFAT, PPARG; delphinidin 3-glucoside with 11β-HS, GFAT, PTP and RTKs; and petunidin 3-glucoside with 11β-HS and PTP. These proteins are involved in mechanisms regulating functions such as inflammation, insulin resistance, oxidative stress, glucose and lipid metabolism. In conclusion, this work provides a prediction of the potential molecular mechanism of black bean and blue corn polyphenols, specifically anthocyanins and could constitute new pathways by which compounds exert their antidiabetic benefits., Food science, Nutrition Natural product chemistry Diabetes Polyphenols Black bean Blue corn Molecular docking.

International audience; Cholesterol is one of the triggers of oxidative stress in the pancreatic-β cell, generating high levels of reactive oxygen species, which leads to impairment of insulin synthesis and secretion. Bioactive compounds, such as citrus flavanones, which possess anti-inflammatory and antioxidant activities, could reduce oxidative stress in β-cells and improve their function. We describe for the first time the protective effects of the phase-II flavanone metabolites [naringenin 7-O-glucuronide, hesperetin 3′-O-glucuronide, and hesperetin 7-O-glucuronide], and two flavanones-catabolites derived from gut microbiota metabolism [hippuric acid and 3-(4-hydroxyphenyl)propionic acid], on pancreatic β-cell line MIN6 under oxidative stress, at physiologically relevant concentration. Cholesterol reduced cell viability in a dose and time-dependent manner, with an improvement in the presence of the metabolites. Moreover, flavanone metabolites attenuated oxidative stress by reducing levels of lipid peroxides, superoxide anions, and hydrogen peroxide. In response to the reduction of reactive oxygen species, a decrease in superoxide dismutase and glutathione peroxidase activities was observed; these activities were elevated by cholesterol. Moreover, all the flavanone metabolites improved mitochondrial function and insulin secretion, and reduced apoptosis. Flavanone metabolites were found uptake by β-cells, and therefore could be responsible for the observed protective effects. These results demonstrated that circulating phase-II hesperetin and naringenin metabolites, and also phenolics derived from gut microbiota, protect pancreatic-β cells against oxidative stress, leading to an improvement in β-cell function and could be the bioactive molecules derived from the citrus consumption.

Flavanol intake positively influences several cardiometabolic risk factors in humans. However, the specific molecular mechanisms of action of flavanols, in terms of gene regulation, in the cell types relevant to cardiometabolic disease have never been systematically addressed. On this basis, we conducted a systematic literature review and a comprehensive bioinformatic analysis of genes whose expression is affected by flavanols in cells defining cardiometabolic health: hepatocytes, adipocytes, endothelial cells, smooth muscle cells and immune cells. A systematic literature search was performed using the following pre-defined criteria: treatment with pure compounds and metabolites (no extracts) at low concentrations that are close to their plasma concentrations. Differentially expressed genes were analyzed using bioinformatics tools to identify gene ontologies, networks, cellular pathways and interactions, as well as transcriptional and post-transcriptional regulators. The systematic literature search identified 54 differentially expressed genes at the mRNA level in in vitro models of cardiometabolic disease exposed to flavanols and their metabolites. Global bioinformatic analysis revealed that these genes are predominantly involved in inflammation, leukocyte adhesion and transendothelial migration, and lipid metabolism. We observed that, although the investigated cells responded differentially to flavanol exposure, the involvement of anti-inflammatory responses is a common mechanism of flavanol action. We also identified potential transcriptional regulators of gene expression: transcriptional factors, such as GATA2, NFKB1, FOXC1 or PPARG, and post-transcriptional regulators: miRNAs, such as mir-335-5p, let-7b-5p, mir-26b-5p or mir-16-5p. In parallel, we analyzed the nutrigenomic effects of flavanols in intestinal cells and demonstrated their predominant involvement in the metabolism of circulating lipoproteins. In conclusion, the results of this systematic analysis of the nutrigenomic effects of flavanols provide a more comprehensive picture of their molecular mechanisms of action and will support the future setup of genetic studies to pave the way for individualized dietary recommendations., COST (European Cooperation in Science and Technology) Action FA1403.

Part of: Nutrition Society Spring Meeting 2019 Conference on ‘Inter-individual differences in the nutrition response: from research to recommendations’; Food phytochemicals are increasingly considered to play a key role in the cardiometabolic health effects of plant foods. However, the heterogeneity in responsiveness to their intake frequently observed in clinical trials can hinder the beneficial effects of these compounds in specific subpopulations. A range of factors, including genetic background, gut microbiota, age, sex and health status, could be involved in these interindividual variations; however, the current knowledge is limited and fragmented. The European network, European Cooperation in Science and Technology (COST)-POSITIVe, has analysed, in a systematic way, existing knowledge with the aim to better understand the factors responsible for the interindividual variation in response to the consumption of the major families of plant food bioactives, regarding their bioavailability and bioefficacy. If differences in bioavailability, likely reflecting differences in human subjects’ genetics or in gut microbiota composition and functionality, are believed to underpin much of the interindividual variability, the key molecular determinants or microbial species remain to be identified. The systematic analysis of published studies conducted to assess the interindividual variation in biomarkers of cardiometabolic risk suggested some factors (such as adiposity and health status) as involved in between-subject variation. However, the contribution of these factors is not demonstrated consistently across the different compounds and biological outcomes and would deserve further investigations. The findings of the network clearly highlight that the human subjects’ intervention studies published so far are not adequate to investigate the relevant determinants of the absorption/metabolism and biological responsiveness. They also emphasise the need for a new generation of intervention studies designed to capture this interindividual variation.

Background and aim We previously showed that 12-month high-fat diet (HFD) in pigs led to fattening and increased artery intima-media-thickness, which were partly reversed after 3-month return to control diet (CD). The aim of this study was to decipher underlying mechanism of action by using transcriptomic analyses of intima and media of aorta. Methods and results Thirty-two pigs were divided into three groups: CD for 12 months; HFD for 12 months; switch diet group (regression diet; RD): HFD for 9 months followed by CD for 3 months. After 12 months, RNA was isolated from aorta intima and media for nutrigenomic analyses. HFD significantly affected gene expression in intima, while RD gene expression profile was distinct from the CD group. This suggests that switch to CD is not sufficient to correct gene expression alterations induced by HFD but counteracted expression of a group of genes. HFD also affected gene expression in media and as for intima, the expression profile of media of pigs on RD differed from that of these on CD. Conclusions This study revealed nutrigenomic modifications induced by long-term HFD consumption on arterial intima and media. The return to CD was not sufficient to counteract the genomic effect of HFD.

Oxidative damage of cells and tissues is broadly implicated in human pathophysiology, including cardiometabolic diseases. Polyphenols, as important constituents of the human diet and potentin vitrofree radical scavengers, have been extensively studied for their beneficial effects on cardiometabolic health. However, it has been demonstrated that thein vivoantioxidant activity of polyphenols is distinct from theirin vitrofree radical-scavenging capacity. Indeed, bioavailability of nutritional polyphenols is low and conditioned by complex mechanisms of absorption, distribution, metabolism and excretion. Nowadays, it is commonly accepted that the cellular antioxidant activity of polyphenols is mainly carried out via modification of transcription of genes involved in antioxidant defence. Importantly, polyphenols also contribute to cardiometabolic health by modulation of a plethora of cellular processes that are not directly associated with antioxidant enzymes, through nutri(epi)genomic mechanisms. Numerous human intervention studies have demonstrated beneficial effects of polyphenols on the key cardiometabolic risk factors. However, inconsistency of the results of some studies led to identification of the inter-individual variability in response to consumption of polyphenols. In perspective, a detailed investigation of the determinants of this inter-individual variability will potentially lead us towards personalised dietary recommendations. The phenomenon of inter-individual variability is also of relevance for supplementation with antioxidant (pro)vitamins.

Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive disorder characterized by the development of megaloblastic anemia, diabetes mellitus, and sensorineural deafness. We report on the first two Croatian patients with TRMA, compound heterozygotes for nonsense, c.373C > T; p.(Gln125Ter) and novel missense variant, c.1214C > G; p.(Thr405Arg) in SLC19A2 gene. The first was diagnosed at 4 months with diabetes mellitus and severe anemia requiring transfusions. As TRMA was suspected, thiamine therapy was immediately started to prevent further transfusions and insulin therapy. His brother developed extreme anemia at 3 weeks of age while waiting for the results of the genetic test. Severe anemia in this sibling may have been prevented if thiamine had been initiated earlier.

Microparticles play a role in cardiovascular disease pathology. The flavanol-like epicatechin is increasingly considered due to its cardioprotective effects. The aim of this study was to investigate the impact of epicatechin on microparticle generation, phenotype and procoagulant properties. Plasma samples from 15 healthy subjects were incubated with increasing concentrations of epicatechin (1 to 100 &mu, M). Then, the expression of glycoprotein IIb, phosphatidylserine (PS), glycoprotein Ib (GPIb) and P-selectin was assessed by flow cytometry analysis after (or not) platelet stimulation. Microparticle procoagulant activity was determined using ZymuphenTM MP and ZymuphenTM MP-TF for phospholipid and tissue factor content, and with thrombin generation (TG) assays for procoagulant function. Platelet microparticles that express GPIb (/&micro, L) decreased from 20,743 &plusmn, 24,985 (vehicle) to 14,939 &plusmn, 14,333 (p = 0.6), 21,366 &plusmn, 16,949 (p = 0.9) and 15,425 &plusmn, 9953 (p &lt, 0.05) in samples incubated with 1, 10 and 100 &micro, M epicatechin, respectively. Microparticle concentration (nM PS) decreased from 5.6 &plusmn, 2.0 (vehicle) to 5.1 &plusmn, 2.2 (p = 0.5), 4.5 &plusmn, 1.5 (p &lt, 0.05) and 4.7 &plusmn, 2.0 (p &lt, 0.05) in samples incubated with 1, 10 and 100&micro, M epicatechin, respectively. Epicatechin had no impact on tissue factor-positive microparticle concentration. Epicatechin decreased TG (endogenous thrombin potential, nM.min) from 586 &plusmn, 302 to 509 &plusmn, 226 (p = 0.3), 512 &plusmn, 270 (p = 0.3) and 445 &plusmn, 283 (p &lt, 0.05). These findings indicate that epicatechin affects microparticle release, phenotype and procoagulant properties.

Food matrix is known to interact with some dietary constituents and microconstituents during digestion. These interactions may potentially affect the metabolism and bioavailability of some compounds, and as a consequence modulate their biological effects. In this context, the aim of this study was to determine the effect of apple food matrix on the bioavailability of flavan-3-ols and on the ability of these compounds to modulate the nutrigenomic response to a high fat challenge in minipigs.Adult male Yucatan minipigs (n = 5) were assigned to a random treatment sequence of high-fat meals non supplemented or supplemented with 250 g of raw apple, 250 g of apple puree or 1.4 g of apple polyphenols extract, with a 7-days washout period between each treatment. Each supplementation provided 155 mg flavan-3-ol monomers. At each treatment period, fasting- and 1h-, 2h-, 3h-postprandial blood samples were collected, and the concentration in flavan-3-ol monomers was measured on hydrolyzed serum, using UPLC-Q-TOF MS. The ability of apple-derived products to modulate the postprandial gene expression profile was assessed and compared in circulating PBMCs collected at 3 h after consumption of the four tested meals using a microarray analysis.Results show that the apple matrix did not affect the kinetic of the postprandial absorption of flavan-3-ol monomers. The total flavan-3-ols concentrations measured at peak were significantly higher in the extract (x1.75), suggesting an impact of the apple matrix on flavan-3-ols absorption. However, no significant difference in total flavanols was observed between raw apple and apple puree.Principal Component Analysis of the microarray data from PBMCs identified three distinct clusters of gene expression patterns: one corresponding to gene expression profiles after the high-fat meal, one for meal supplemented with raw apples or apple puree, and a third cluster for meal supplemented with polyphenol extract. A set of 309 genes was identified as differentially expressed by apple-derived products compared to high-fat meal alone, including 93 modulated with the three apple products. The variations in gene expression were similar for only 75% of the 93 genes, suggesting that the apple matrix affects the nutrigenomic response to flavan-3-ols. A bioinformatics analysis revealed that genes affected by apple-derived products are involved in inflammation and leukocyte transendothelial migration, suggesting a beneficial impact of apple-derived products.In conclusion, these results raise awareness for considering the impact of food matrix on the biological responsiveness of polyphenols in future nutritional studies.

Proceedings Paper ; Book Series: Recent Advances in Polyphenol Research Conference: 28th International Conference on Polyphenols (ICP) Location: Tech Univ Wien, Vienna, AUSTRIA Date: JUL, 2016; A primary goal of nutrition research is to provide science‐based knowledge to optimize health, prevent diseases and, importantly nowadays, slow down dysfunction associated with ageing to ensure well‐being throughout life. Alterations in vascular function and integrity are closely associated with the onset of cardiovascular disease development and are also responsible for a large range of health problems. In this respect, it is important to identify scientific dietary strategies to prevent early vascular dysfunction. In recent decades, changes in lifestyles and diets have made unhealthy dietary patterns one of the major risk factors for chronic diseases. Population studies have shown that these diseases could be highly preventable by a high consumption of plant foods. Growing evidence also suggests that the health benefits associated with plant food consumption are related to their phytochemical content. (Poly)phenols constitute the most abundant phytochemicals in our diet and their biological properties may help to promote the beneficial effects of plant foods. This chapter highlights the relationship between vascular function and health and presents the current state of the art on the role of dietary (poly)phenols in the vascular protective effects of plant foods and related mechanisms, including findings from our lab related to citrus flavanones and vascular protection.

Epub ahead of print; The different stages of hemostasis (i.e., primary hemostasis, coagulation and fibrinolysis) are involved in the early atherothrombosis steps. The aim of this study was to investigate the effect of epicatechin, a major flavonoid compound, on the hemostasis phenotype using clinically relevant in vitro global assays that mimic the complexity of the in vivo hemostasis systems. Plasma samples from 10 healthy volunteers were spiked with increasing concentrations of epicatechin (1 to 100 μM). Epicatechin effect on primary hemostasis, coagulation and fibrinolysis was assessed by measuring platelet aggregation using light transmission aggregometry, thrombin generation and clot lysis time (CLT), respectively. Epicatechin (100 μM) significantly decreased the maximal platelet aggregation induced by adenosine diphosphate (-39%), thrombin receptor activating peptide (-48%), epinephrine (-30%), and collagen (-30%). The endogenous thrombin potential was significantly reduced starting from 1 μM epicatechin (1332 ± 230 versus 1548 ± 241 nM min for control) (p < 0.01). Fibrinolysis was promoted by epicatechin, as indicated by CLT decrease by 16 and 33% with 10 and 100 μM epicatechin respectively, compared with control (1271 ± 775 s). These findings show that epicatechin reduces platelet function and leads to an anticoagulant and pro-fibrinolytic profile, providing new evidence of its interest for cardiovascular disease prevention.

Background A healthy diet and optimal lifestyle choices are amongst the most important actions for the prevention of cardiometabolic diseases. Despite this, it appears difficult to convince consumers to select more nutritious foods. Furthermore, the development and production of healthier foods do not always lead to economic profits for the agro-food sector. Most dietary recommendations for the general population represent a “one-size-fits-all approach” which does not necessarily ensure that everyone has adequate exposure to health-promoting constituents of foods. Indeed, we now know that individuals show a high variability in responses when exposed to specific nutrients, foods, or diets. Purpose This review aims to highlight our current understanding of inter-individual variability in response to dietary bioactives, based on the integration of findings of the COST Action POSITIVe. We also evaluate opportunities for translation of scientific knowledge on inter-individual variability in response to dietary bioactives, once it becomes available, into practical applications for stakeholders, such as the agro-food industry. The potential impact from such applications will form an important impetus for the food industry to develop and market new high quality and healthy foods for specific groups of consumers in the future. This may contribute to a decrease in the burden of diet-related chronic diseases., Key messages Individual differences in ADME (Absorption, Digestion, Metabolism and Excretion) is believed to underpin much of the inter-individual variation in responses.Recent developments in the area of food metabolome databases and fast improvements in innovative metabotyping technologies hold great promise for improved profiling of dietary intake, exposure to individual ingredients, foods and dietary patterns, as well as our ability to identify individual responsiveness.The food industry needs well-defined population clusters or targets in order to be able to design “personalized products”.There are indeed excellent industrial opportunities for foods that modulate gut microbiota, and thereby enable the delivery of food bioactive metabolites.It is currently not clear whether knowledge on individual nutrient needs, based on genetic or metagenomic data, would affect long-term dietary and health behaviours.Data to support the development of dietary recommendations may need to be generated by new n-of-1-based study designs in the future.

Purpose Evidence exists regarding the beneficial effects of diets rich in plant-based foods regarding the prevention of cardiometabolic diseases. These plant-based foods are an exclusive and abundant source of a variety of biologically active phytochemicals, including polyphenols, carotenoids, glucosinolates and phytosterols, with known health-promoting effects through a wide range of biological activities, such as improvements in endothelial function, platelet function, blood pressure, blood lipid profile and insulin sensitivity. We know that an individual’s physical/genetic makeup may influence their response to a dietary intervention, and thereby may influence the benefit/risk associated with consumption of a particular dietary constituent. This inter-individual variation in responsiveness has also been described for dietary plant bioactives but has not been explored in depth. To address this issue, the European scientific experts involved in the COST Action POSITIVe systematically analyzed data from published studies to assess the inter-individual variation in selected clinical biomarkers associated with cardiometabolic risk, in response to the consumption of plant-based bioactives (poly)phenols and phytosterols. The present review summarizes the main findings resulting from the meta-analyses already completed. Results Meta-analyses of randomized controlled trials conducted within POSITIVe suggest that age, sex, ethnicity, pathophysiological status and medication may be responsible for the heterogeneity in the biological responsiveness to (poly)phenol and phytosterol consumption and could lead to inconclusive results in some clinical trials aiming to demonstrate the health effects of specific dietary bioactive compounds. However, the contribution of these factors is not yet demonstrated consistently across all polyphenolic groups and cardiometabolic outcomes, partly due to the heterogeneity in trial designs, low granularity of data reporting, variety of food vectors and target populations, suggesting the need to implement more stringent reporting practices in the future studies. Studies investigating the effects of genetic background or gut microbiome on variability were limited and should be considered in future studies. Conclusion Understanding why some bioactive plant compounds work effectively in some individuals but not, or less, in others is crucial for a full consideration of these compounds in future strategies of personalized nutrition for a better prevention of cardiometabolic disease. However, there is also still a need for the development of a substantial evidence-base to develop health strategies, food products or lifestyle solutions that embrace this variability., Key messages A balanced diet, rich in plant-based foods is known for the prevention of obesity, diabetes, and cardiovascular disease risk.(Poly)phenols and phytosterols displayed a range of biological effects of relevance to contribute to the cardiometabolic health benefits of plant foodsHowever, inter-individual variability in response to plant food bioactive consumption exists, and there is a need to understand the causes of this variation.Analysis of published RCTs examining impact of consumption of (poly)phenols and phytosterols on cardiometabolic risk factors demonstrated that a number of factors including age, sex, adiposity and health status could contribute to the effect demonstrated within these studies.Genome and microbiome studies will help identify what may be causing this variation.More studies, specifically designed to investigate individual variation are needed to fully understand the factors responsible for and the impact of this variationOnce fully understood, such variation should be used in directing personalised nutrition advice.

Hyperlipidemia is a risk factor for dementia, and chronic consumption of a Western Diet (WD) is associated with cognitive impairment. However, the molecular mechanisms underlying the development of microvascular disease in the memory centers of the brain are poorly understood. This pilot study investigated the nutrigenomic pathways by which the WD regulates gene expression in hippocampal brain microvessels of female mice. Five-week-old female low-density lipoprotein receptor deficient (LDL-R−/−) and C57BL/6J wild type (WT) mice were fed a chow or WD for 8 weeks. Metabolics for lipids, glucose and insulin were determined. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by genome-wide microarray and bioinformatics analysis of laser captured hippocampal microvessels. The WD resulted in differential expression of 2,412 genes. The majority of differential gene expression was attributable to differential regulation of cell signaling proteins and their transcription factors, approximately 7% was attributable to differential expression of miRNAs, and a lesser proportion was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD in females. Our findings revealed that chronic consumption of the WD resulted in integrated multilevel molecular regulation of the hippocampal microvasculature of female mice and may provide one of the mechanisms underlying vascular dementia.

Anthocyanins are phytochemicals widely found in plant foods, with berries and fruit-derived beverages as the main dietary sources. Accumulating evidence suggests the positive role of anthocyanins in preserving cardiovascular health. Epidemiological data show an association between anthocyanin intake and lower risk of myocardial infarction and cardiovascular-disease-related mortality. Clinical studies report the beneficial effects of the consumption of different anthocyanin-rich sources on surrogate markers of cardiovascular risk. Animal and in vitro evidence suggest the protective role of anthocyanins in dysfunctions related to the development of cardiovascular diseases. Still, the underlying molecular mechanisms of anthocyanin action seem complex and are not entirely clear. This review aims to give a comprehensive update on anthocyanins and their cardioprotective properties. It provides information on their sources; quantities consumed through diet; absorption; bioavailability; cardiovascular properties; and underlying mechanisms of action, including their effects on gene and protein expression and their interactions with cell-signaling pathways and miRNAs.

Potential health benefits of blueberries may be due to vascular effects of anthocyanins that predominantly circulate in blood as phenolic acid metabolites. We investigated which role blueberry anthocyanins and circulating metabolites play in mediating improvements in vascular function and explore potential mechanisms using metabolomics and nutrigenomics. Purified anthocyanins exerted a dose-dependent improvement of endothelial function in healthy humans, as measured by flow-mediated dilation. The effects were similar to those of wild blueberries containing similar amounts of anthocyanins, whereas control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month wild blueberry consumption increased flow-mediated dilation and lowered 24-hour ambulatory systolic blood pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 21 correlated with acute and chronic flow-mediated dilation improvements, respectively. Injection of these metabolites improved flow-mediated dilation in mice. Daily wild blueberry consumption led to differential expression (>1.2-fold) of 608 genes and 3 microRNAs, with Mir-181c showing a 13-fold increase in peripheral blood mononuclear cells. Patterns of 13 metabolites were independent predictors of gene expression changes and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response, and cell differentiation. Our results identify anthocyanin metabolites as major mediators of vascular bioactivities of blueberries and changes of cellular gene programs. Trial registration: NCT025208.

International audience; Background Ageing is a highly complex process marked by a temporal cascade of events, which promote alterations in the normal functioning of an individual organism. The triggers of normal brain ageing are not well understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin disorders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and preserve brain health are available, yet the molecular mechanisms underlying their biological action in both normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not been clearly elucidated. Objectives This review aims to summarise the current state of knowledge of vulnerabilities that predispose towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop ‘Nutrition for the Ageing Brain: Functional Aspects and Mechanisms’ in Copenhagen in June 2016. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). Conclusion Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation, and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be imposed in early-life to observe significant impact in older age.

In our previous work in mice, we have shown that chronic consumption of a Western diet (WD; 42% kcal fat, 0.2% total cholesterol and 34% sucrose) is correlated with impaired cognitive function. Cognitive decline has also been associated with alterations in DNA methylation. Additionally, although there have been many studies analyzing the effect of maternal consumption of a WD on DNA methylation in the offspring, few studies have analyzed how an individual's consumption of a WD can impact his/her DNA methylation. Since the frontal cortex is involved in the regulation of cognitive function and is often affected in cases of cognitive decline, this study aimed to examine how chronic consumption of a WD affects DNA methylation in the frontal cortex of mice. Eight-week-old male mice were fed either a control diet (CD) or a WD for 12 weeks, after which time alterations in DNA methylation were analyzed. Assessment of global DNA methylation in the frontal cortex using dot blot analysis revealed that there was a decrease in global DNA methylation in the WD-fed mice compared with the CD-fed mice. Bioinformatic analysis identified several networks and pathways containing genes displaying differential methylation, particularly those involved in metabolism, cell adhesion and cytoskeleton integrity, inflammation and neurological function. In conclusion, the results from this study suggest that consumption of a WD alters DNA methylation in the frontal cortex of mice and could provide one of the mechanisms by which consumption of a WD impairs cognitive function.

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.

Cardioprotective effects of dietary anthocyanins are partly attributed to their ability to maintain endothelial function. However, the underlying cellular and molecular mechanisms of action are not fully understood. This study aimed to evaluate the effect of anthocyanins and their gut metabolites, at physiologically-relevant conditions, on endothelial cell (EC) function and decipher the underlying molecular mechanisms of action using integrated omics approaches. Primary EC were treated with a mixture of 0.1 mu M cyanidin-3-arabinoside, 0.1 mu M cyanidin-3-galactoside, 0.1 mu M cyanidin-3-glucoside, 0.1 mu M delphinidin-3-glucoside, 0.1 mu M peonidin-3-glucoside and 0.5 mu M 4-hydroxybenzaldehyde for 3 h or a mixture of gut metabolites: 0.2 mu M protocatechuic, 2 mu M vanillic, 1 mu M ferulic and 2 mu M hippuric acids for 18 h. Also, successive exposure of EC to both mixtures was performed to mimic anthocyanin pharmacokinetics following their intake. Inflammatory stress was induced using TNF alpha and monocytes added to assess adhesion and transmigration. Effects of these mixtures on gene, miRNA expression and their potential interaction with cell signalling were investigated. Anthocyanins and their gut metabolites significantly reduced monocyte adhesion and transendothelial migration. Gene expression analysis, using macroarrays, showed that tested compounds modulated the expression of genes involved in cell-cell adhesion, cytoskeleton organisation or focal adhesion. Bioinformatics analyses of gene expression data identified potential transcription factors involved in the observed nutrigenomic effects and signalling proteins regulating their activity. Molecular docking revealed cell signalling proteins to which these bioactives may bind to and potentially affect their activity and the activation of downstream signalling, effects that were in agreement with the results of Western blot analyses. Microarray analysis showed that anthocyanins and their gut metabolites affected miRNA expression in EC, especially those involved in regulation of EC permeability, contributing to the observed changes in EC function. Integration of these results revealed endothelial-protective properties of anthocyanins and their gut metabolites and deciphered new underlying multi-target and multi-layered mode of action.

Molecular nutrition is relatively recent research discipline that aims to decipher molecular effects of nutrition at the cellular level and identify mechanisms underlying potential impact on health, protective or deleterious. The development and the use of holistic “omics” approach in the last decade or two have revealed the complexity of action of different nutrients at the molecular level. These nutrigenomic studies have shown that nutrients can impact transcriptional and post transcriptional regulation of gene expression, by impacting expression of mRNA, non-coding RNAs (both short and long) and proteins, but also modulate epigenetic profile of the cells. The capacity of nutrients to exert these nutrigenomic effects can be related to the their ability to bind to cell signaling proteins, modulate their activity and consequently that of transcription factors. The feature article gives a rapid overview of molecular mechanisms impacted by different nutrients.

Presented at 2. COST POSITIVe Scientific Workshop on « Omics breakthroughs in the Health effects of plant food bioactives ; Thessalonique (Grèce) - (2017-09-20 - 2017-09-21) / Workshop (Prodinra 408917); International audience; Although vasculo-protective effects of flavan-3-ols are widely accepted today, their impact on endothelial cell function and underlying molecular mechanisms of action remain unexplored. The aim of this study was to characterize the potential endothelium-protective effects of epicatechin metabolites and to define underlying mechanisms of action by an integrated systems biology approach. Upon dietary epicatechin supplementation in a mouse model of inflammation, reduced leukocyte rolling over vascular endothelium was observed. Pathway enrichment analysis of transcriptome, epigenome and miRNome profiles of endothelial cells exposed to plasma concentrations of epicatechin metabolites suggested significant changes in interactions with immune cell as well as permeability regarding immune cell transmigration. In line with our in-silico network analysis, in-vitro experiments confirmed that epicatechin metabolites reduce monocyte adhesion to endothelial cells and their transendothelial migration. Altogether, our in-vivo and in-vitro results support the outcome of a systems biology based network analysis of epigenome, transcriptome and miRNome profiles, which suggests that epicatechin metabolites mediate their vasculoprotective effects through dynamic regulation of endothelial cell monocyte adhesion and permeability. This study illustrates complex and multimodal mechanisms of action by which epicatechin modulate endothelial cell integrity.

cope Curcumin exerts biological activities of interest in cardiovascular prevention. However, its vascular protective effect is still poorly investigated in humans. The present study aims to assess vasculat effect of an acute intake of curcumin and its nutrigenomic impact in circulating immune cells. Methods and results In a randomised, double-blind, crossover design, eighteen healthy smokers consumed a placebo or a 5-gram of curcumin. Before and two hours after the intake, vascular function measurements were performed by using flow-mediated dilation (FMD). In addition, endothelial function in the microcirculation and blood pressure were evaluated. Plasma curcumin concentrations and changes in gene expression in peripheral blood mononuclear cells (PBMC) were analysed. No significant effect of curcumin on FMD was observed when considering the entire study population, mainly due to a high inter-individual variability. A subgroup analysis according to the gender or the cardiovascular-risk score revealed a significant effect of curcumin on FMD in women and in subjects presenting lower cardiovascular risk. No change in gene expression was observed when data were analysed for all volunteers but changes in expression were observed when analyzed according to gender. Conclusions This clinical trial highlights that a substantial variability in efficacy of curcumin exists across individuals. This article is protected by copyright. All rights reserved

Several epidemiological studies have linked flavonols with decreased risk of cardiovascular disease (CVD). However, some heterogeneity in the individual physiological responses to the consumption of these compounds has been identified. This meta‐analysis aimed to study the effect of flavonol supplementation on biomarkers of CVD risk such as, blood lipids, blood pressure and plasma glucose, as well as factors affecting their inter‐individual variability. Data from 18 human randomized controlled trials were pooled and the effect was estimated using fixed or random effects meta‐analysis model and reported as difference in means (DM). Variability in the response of blood lipids to supplementation with flavonols was assessed by stratifying various population subgroups: age, sex, country, and health status. Results showed significant reductions in total cholesterol (DM = −0.10 mmol/L; 95% CI: −0.20, −0.01), LDL cholesterol (DM = −0.14 mmol/L; Nutrients 2017, 9, 117 2 of 21 95% CI: −0.21, 0.07), and triacylglycerol (DM = −0.10 mmol/L; 95% CI: −0.18, 0.03), and a significant increase in HDL cholesterol (DM = 0.05 mmol/L; 95% CI: 0.02, 0.07). A significant reduction was also observed in fasting plasma glucose (DM = −0.18 mmol/L; 95%CI: −0.29, −0.08), and in blood pressure (SBP: DM = −4.84 mmHg; 95% CI: −5.64, −4.04; DBP: DM = −3.32 mmHg; 95% CI: -4.09, -2.55). Subgroup analysis showed a more pronounced effect of flavonol intake in participants from Asian countries and in participants with diagnosed disease or dyslipidemia, compared to healthy and normal baseline values. In conclusion, flavonol consumption improved biomarkers of CVD risk, however, country of origin and health status may influence the effect of flavonol intake on blood lipid levels