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The loss of β-cell mass is a common pathological process of type 1 and type 2 diabetes and α- to β-cell-like transdifferentiation has gained attention as a potential strategy to increase insulin production.This study used powerful integrative multi-omics bioinformatic tools to scrutinize and perform integrated analyses of publicly available diabetes-associated “omics” data to unveil novel molecular targets associated with α- to β-cell-like transdifferentiation. To achieve this goal, a comprehensive search on PubMed for human studies on gene expression alterations associated with diabetes was conducted Ninety-eight entries were retrieved from which 8 studies reporting microarray data, RNAseq and single-cell RNAseq (scRNAseq) were selected for the in-dept bioinformatic analysis. Each dataset was analyzed individually to identify differently expressed genes (DEG) (p < 0.05). DEGs were obtained using GEO2R tool available at Gene Expression Omnibus (GEO) repository or the supplementary data of the respective studies. Pathway enrichment analyses of DEGs were conducted using GeneTrail as a platform to access KEGG and WIKI pathways databases. Potential transcription factors were identified with Enrichr as a platform to TRRUST and TRANSFAC. For non-coding differentially expressed microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), targets were identified using the MIENTURNET27 and LncRRIsearch28 tools, respectively. Comparison of genes among studies reporting microarray data showed 808 common genes (3 studies in total). Pathways enrichment analysis pointed out cell signaling, endocrine system (insulin resistance and insulin secretion) and metabolism as common to at least two studies. A similar analysis was conducted for 5 studies reporting diabetes-related alterations of mRNA levels in RNAseq/scRNAseq analyses, further supporting these data. The extracted transcriptomic data was then used to search for potential transcription factors modulating specific diabetes-related regulons, which revealed the transcription factors RXRA, ELK1, CTCF, and AR in common to two or more studies.Regarding the non-coding RNAs, we identified 101 miRNAs in 5 studies from which 22 were common between 2 or more studies, together with 10 common lncRNAs among 3 or more studies. Bioinformatic analyses are ongoing to pinpoint the targets and pathways of these regulatory molecules in particular targeting α- to β-cell-like transdifferentiation. This research is funded by Fundação Ciência Tecnologia (FCT) by grant UIDB/04567/2020. R. Menezes is supported by the Science Employment Stimulus program from FCT. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mate is a traditional drink obtained from the leaves of yerba mate and rich in a diversity of plant bioactive compounds including polyphenols, particularly chlorogenic acids. Studies, even though limited, suggest that consumption of mate is associated with health effects, including prevention of cardiometabolic disorders. Molecular mechanisms underlying the potential health properties are still largely unknown, especially in humans. The aim of this study was to investigate nutrigenomic effects of mate consumption and identify regulatory networks potentially mediating cardiometabolic health benefits. Healthy middle-aged men at risk for CVD consumed a standardised mate extract or placebo for 4 weeks. Global gene expression, including protein coding and non-coding RNA profiles, was determined using microarrays. Biological function analyses were performed using integrated bioinformatic tools. Comparison of global gene expression profiles showed significant change following mate consumption with 2635 significantly differentially expressed genes, among which six are miRNA and 244 are lncRNA. Functional analyses showed that these genes are involved in regulation of cell interactions and motility, inflammation or cell signalling. Transcription factors, such as MEF2A, MYB or HNF1A, could have their activity modulated by mate consumption either by direct interaction with polyphenol metabolites or by interactions of metabolites with cell signalling proteins, like p38 or ERK1/2, that could modulate transcription factor activity and regulate expression of genes observed. Correlation analysis suggests that expression profile is inversely associated with gene expression profiles of patients with cardiometabolic disorders. Therefore, mate consumption may exert cardiometabolic protective effects by modulating gene expression towards a protective profile.

Passiflora setacea (PS), a fruit from the Brazilian biodiversity rich in polyphenols. PS juice reduced insulin, IL-6 levels and HOMA IR in humans. And its phenolic metabolites increased activity of PPAR-γ in BV-2 cells.

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.

Citrus flavanones may improve oxidative stress and insulin resistance induced by western diets. However, there is a paucity of studies investigating the change in protein expression levels. This study evaluated the protection and the mechanisms of action of citrus flavanone metabolites, hesperetin 7-glucuronide (H7G) and 3-(4'-hydroxyphenyl) propanoic acid (PA), on pancreatic β-cell function under oxidative stress induced by cholesterol using the global proteomics approach. Cholesterol induced changes in the global proteomic profile in the pancreatic β-cell line Min6. On the other hand, proteomics analysis identified 254 proteins differentially expressed with H7G and 352 with PA treatments, most of them were opposite to the changes induced by cholesterol. Bioinformatics analysis showed that these proteins are implicated in cell functions like cell signaling (insulin signaling, p30MAPK signaling, and others), metabolism (glucokinase and glutathione metabolisms), and inflammation pathways (TNF-α and NF-κB pathways). Also, the results of molecular docking suggest that H7G and PA could bind to putative transcription factors (PPAR-γ, STAT-3, CREB1, NF-κB, NFYA) and cell signaling proteins (IKK, RAS, Pi3K, ERK), which results in changes in protein expression observed. Altogether, these data suggest that the treatment with H7G and PA protects pancreatic β-cells against stress induced by cholesterol through multi-proteomic mechanisms of action.

Guideline recommendation for a plant bioactive such as flavan-3-ols is a departure from previous recommendations because it is not based on deficiencies but rather improvement in health outcomes. Nevertheless, there is a rapidly growing body of clinical data reflecting benefits of flavan-3-ol intake that outweigh potential harms. Thus, the objective of the Expert Panel was to develop an intake recommendation for flavan-3-ols and cardiometabolic outcomes to inform multiple stakeholders including clinicians, policymakers, public health entities, and consumers. Guideline development followed the process set forth by the Academy of Nutrition and Dietetics, which includes use of the Evidence to Decision Framework. Studies informing this guideline (157 randomized controlled trials and 15 cohort studies) were previously reviewed in a recently published systematic review and meta-analysis. Quality and strength-of-evidence along with risk-of-bias in reporting was reviewed. In drafting the guideline, data assessments and opinions by authoritative scientific bodies providing guidance on the safety of flavan-3-ols were considered. Moderate evidence supporting cardiometabolic protection resulting from flavan-3-ol intake in the range of 400-600mg/d was supported in the literature. Further, increasing consumption of dietary flavan-3-ols can help improve blood pressure, cholesterol concentrations, and blood sugar. Strength of evidence was strongest for some biomarkers (i.e., systolic blood pressure, total cholesterol, HDL cholesterol, and insulin/glucose dynamics). It should be noted that this is a food-based guideline and not a recommendation for flavan-3-ol supplements. This guideline was based on beneficial effects observed across a range of disease biomarkers and endpoints. Although a comprehensive assessment of available data has been reviewed, evidence gaps identified herein can inform scientists in guiding future randomized clinical trials.

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.

Obesity is associated with increased occurrence of cognitive and mood disorders. While consumption of high-fat diets (HFD) and associated obesity could have a detrimental impact on the brain, dietary bioactives may mitigate these harmful effects. We previously observed that (-)-epicatechin (EC) can mitigate HFD-induced anxiety-associated behaviors in mice. The aim of our study is to investigate the molecular mechanisms of EC actions in the hippocampus which underlies its anti-anxiety effects in HFD-fed mice using a multi-genomic approach. Healthy eight-week old male C57BL/6J mice were fed for 24 weeks either: (A) a control diet containing 10% total calories from fat; (B) a HFD containing 45% total calories from fat; or (C) the HFD supplemented with 20 mg EC per kg body weight. Hippocampi were isolated for genomic analysis using Affymetrix arrays, followed by in-depth bioinformatic analyses. Genomic analysis demonstrated that EC induced significant changes in mouse hippocampal global gene expression. We observed changes in the expression of 1001 protein-coding genes, 241 miRNAs, and 167 long non-coding RNAs. Opposite gene expression profiles were observed when the gene expression profile obtained upon EC supplementation was compared to the profile obtained after consumption of the HFD. Functionality analysis revealed that the differentially expressed genes regulate processes involved in neurofunction, inflammation, endothelial function, cell-cell adhesion, and cell signaling. In summary, the capacity of EC to mitigate anxiety-related behaviors in HFD-induced obese mice can be in part explained by its capacity to exert complex genomic modifications in the hippocampus, counteracting changes driven by consumption of the HFD and/or associated obesity.

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.

International audience; Impairment of gut function is one of the explanatory mechanisms of health status decline in elderly population. These impairments involve a decline in gut digestive physiology, metabolism and immune status, and associated to that, changes in composition and function of the microbiota it harbors. Continuous deteriorations are generally associated with the development of systemic dysregulations and ultimately pathologies that can worsen the initial health status of individuals. All these alterations observed at the gut level can then constitute a wide range of potential targets for development of nutritional strategies that can impact gut tissue or associated microbiota pattern. This can be key, in a preventive manner, to limit gut functionality decline, or in a curative way to help maintaining optimum nutrients bioavailability in a context on increased requirements, as frequently observed in pathological situations. The aim of this review is to give an overview on the alterations that can occur in the gut during aging and lead to the development of altered function in other tissues and organs, ultimately leading to the development of pathologies. Subsequently is discussed how nutritional strategies that target gut tissue and gut microbiota can help to avoid or delay the occurrence of aging-related pathologies.

Biological sex and a high glycemic diet (HGD) contribute to dementia, yet little is known about the operative molecular mechanisms. Our goal was to understand the differences between males and females in the multi-genomic response of the hippocampal microvasculature to the HGD, and whether there was vasculoprotection via the inhibition of soluble epoxide hydrolase (sEHI). Adult wild type mice fed high or low glycemic diets for 12 weeks, with or without an sEHI inhibitor (t-AUCB), had hippocampal microvessels isolated by laser-capture microdissection. Differential gene expression was determined by microarray and integrated multi-omic bioinformatic analyses. The HGD induced opposite effects in males and females: the HGD-upregulated genes were involved in neurodegeneration or neuroinflammation in males, whereas in females they downregulated the same pathways, favoring neuroprotection. In males, the HGD was associated with a greater number of clinical diseases than in females, the sEHI downregulated genes involved in neurodegenerative diseases to a greater extent with the HGD and compared to females. In females, the sEHI downregulated genes involved in endothelial cell functions to a greater extent with the LGD and compared to males. Our work has potentially important implications for sex-specific therapeutic targets for vascular dementia and cardiovascular diseases in males and females.

Dietary (poly)phenols have been extensively studied for their vasculoprotective effects and consequently their role in preventing or delaying onsets of cardiovascular and metabolic diseases. Even though early studies have ascribed the vasculoprotective properties of (poly)phenols primarily on their putative free radical scavenging properties, recent data indicate that in biological systems, (poly)phenols act primarily through genomic and epigenomic mechanisms. The molecular mechanisms underlying their health properties are still not well identified, mainly due to the use of physiologically non-relevant conditions (native molecules or extracts at high concentrations, rather than circulating metabolites), but also due to the use of targeted genomic approaches aiming to evaluate the effect only on few specific genes, thus preventing to decipher detailed molecular mechanisms involved. The use of state-of-the-art untargeted analytical methods represents a significant breakthrough in nutrigenomics, as these methods enable detailed insights into the effects at each specific omics level. Moreover, the implementation of multi-omics approaches allows integration of different levels of regulation of cellular functions, to obtain a comprehensive picture of the molecular mechanisms of action of (poly)phenols. In combination with bioinformatics and the methods of machine learning, multi-omics has potential to make a huge contribution to the nutrition science. The aim of this review is to provide an overview of the use of the omics, multi-omics, and integrative approaches in studying the vasculoprotective properties of dietary (poly)phenols and address the potentials for use of the machine learning in nutrigenomics.

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

Oxylipins are the oxidation products of polyunsaturated fatty acids and have been implicated in neurodegenerative disorders, including dementia. Soluble epoxide hydrolase (sEH) converts epoxy-fatty acids to their corresponding diols, is found in the brain, and its inhibition is a treatment target for dementia. In this study, male and female C57Bl/6J mice were treated with an sEH inhibitor (sEHI), trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks to comprehensively study the effect of sEH inhibition on the brain oxylipin profile, and modulation by sex. Ultra-high-performance liquid chromatography–tandem mass spectrometry was used to measure the profile of 53 free oxylipins in the brain. More oxylipins were modified by the inhibitor in males than in females (19 versus 3, respectively) and favored a more neuroprotective profile. Most were downstream of lipoxygenase and cytochrome p450 in males, and cyclooxygenase and lipoxygenase in females. The inhibitor-associated oxylipin changes were unrelated to serum insulin, glucose, cholesterol, or female estrous cycle. The inhibitor affected behavior and cognitive function as measured by open field and Y-maze tests in males, but not females. These findings are novel and important to our understanding of sexual dimorphism in the brain’s response to sEHI and may help inform sex-specific treatment targets.

Oxylipins have been implicated in many biological processes and diseases. Dysregulation of cerebral lipid homeostasis and altered lipid metabolites have been associated with the onset and progression of dementia. Although most dietary interventions have focused on modulation of dietary fats, the impact of a high sucrose diet on the brain oxylipin profile is unknown.Male and female C57BL/6J mice were fed a high sucrose diet (HSD, 34%) in comparison to a control low sucrose diet (LSD, 12%) for 12 weeks beginning at 20 weeks of age. The profile of 53 free oxylipins was then measured in brain by ultra-high performance liquid chromatography tandem mass spectrometry. Serum glucose and insulin were measured enzymatically. We first assessed whether there were any effects of the diet on the brain oxylipin profile, then assessed for sex differences.There were no differences in fasting serum glucose between the sexes for mice fed a HSD or in fasting serum insulin levels for mice on either diet. The HSD altered the brain oxylipin profile in both sexes in distinctly different patterns: there was a reduction in three oxylipins (by 47-61%) and an increase in one oxylipin (16%) all downstream of lipoxygenase enzymes in males and a reduction in eight oxylipins (by 14-94%) mostly downstream of cyclooxygenase activity in females. 9-oxo-ODE and 6-trans-LTB4 were most influential in the separation of the oxylipin profiles by diet in male mice, whereas 5-HEPE and 12-HEPE were most influential in the separation by diet in female mice. Oxylipins 9‑hydroxy-eicosatetraenoic acid (HETE), 11-HETE, and 15-HETE were higher in the brains of females, regardless of diet.A HSD substantially changes brain oxylipins in a distinctly sexually dimorphic manner. Results are discussed in terms of potential mechanisms and links to metabolic disease. Sex and diet effects on brain oxylipin composition may provide future targets for the management of neuroinflammatory diseases, such as dementia.

The effect of a high glycemic diet (HGD) on brain microvasculature is a crucial, yet understudied research topic, especially in females. This study aimed to determine the transcriptomic changes in female brain hippocampal microvasculature induced by a HGD and characterize the response to a soluble epoxide hydrolase inhibitor (sEHI) as a mechanism for increased epoxyeicosatrienoic acids (EETs) levels shown to be protective in prior models of brain injury. We fed mice a HGD or a low glycemic diet (LGD), with/without the sEHI (t-AUCB), for 12 weeks. Using microarray, we assessed differentially expressed protein-coding and noncoding genes, functional pathways, and transcription factors from laser-captured hippocampal microvessels. We demonstrated for the first time in females that the HGD had an opposite gene expression profile compared to the LGD and differentially expressed 506 genes, primarily downregulated, with functions related to cell signaling, cell adhesion, cellular metabolism, and neurodegenerative diseases. The sEHI modified the transcriptome of female mice consuming the LGD more than the HGD by modulating genes involved in metabolic pathways that synthesize neuroprotective EETs and associated with a higher EETs/dihydroxyeicosatrienoic acids (DHETs) ratio. Our findings have implications for sEHIs as promising therapeutic targets for the microvascular dysfunction that accompanies vascular dementia.

International audience; 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 multigenomic 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.

International audience; Dysfunction of blood-brain barrier formed by endothelial cells of cerebral blood vessels, plays a key role in development of neurodegenerative disorders. Epicatechin exerts vasculo-protective effects through genomic modifications, however molecular mechanisms of action, particularly on brain endothelial cells, are largely unknow. This study aimed to use a multi-omic approach (transcriptomics of mRNA, miRNAs and lncRNAs, and proteomics), to provide novel in-depth insights into molecular mechanisms of how metabolites affect brain endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological concentrations. We showed that metabolites can simultaneously modulate expression of protein-coding, non-coding genes and proteins. Integrative analysis revealed interactions between different types of RNAs and form functional groups of genes involved in regulation of processing like VEGF-related functions, cell signaling, cell adhesion and permeability. Molecular modeling of genomics data predicted that metabolites decrease endothelial cell permeability, increased by lipotoxic stress. Correlation analysis between genomic modifications observed and genomic signature of patients with vascular dementia and Alzheimer's diseases showed opposite gene expression changes. Taken together, this study describes for the first time a multi-omic mechanism of action by which (-)-epicatechin metabolites could preserve brain vascular endothelial cell integrity and reduce the risk of neurodegenerative diseases. Significance: Dysfunction of the blood-brain barrier (BBB), characterized by dysfunction of endothelial cells of cerebral blood vessels, result in an increase in permeability and neuroinflammation which constitute a key factor in the development neurodegenerative disorders. Even though it is suggested that polyphenols can prevent or delay the development of these disorders, their impact on brain endothelial cells and underlying mechanisms of actions are unknow. This study aimed to use a multi-omic approach including analysis of expression of mRNA, microRNA, long non-coding RNAs, and proteins to provide novel global in-depth insights into molecular mechanisms of how (-)-epicatechin metabolites affect brain microvascular endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological relevant conditions. The results provide basis of knowledge on the capacity of polyphenols to prevent brain endothelial dysfunction and consequently neurodegenerative disorders.