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Anthocyanins (ACNs) are phenolic compounds present in foods and have undefined health benefits. The present umbrella review aimed to analyze the effects of ACNs on multiple aspects of human health (from systematic reviews and meta-analyses [SRMs] of randomized controlled trials [RCTs]), and the associations of ACNs with the risk of various diseases (from SRMs of observational studies [OSs]). Following the PRISMA methodology, the PubMed, SCOPUS, and Cochrane databases were searched up to November 1, 2020 for OS-SRMs and RCT-SRMs that examined the effects of ACNs on health. The risk of bias of RCT-SRMs was assessed using the AMSTAR 2, and that of OS-SRMs was assessed using the Joanna Briggs Institute methodology. Based on 5 OS-SRMs (57 studies and 2 134 336 participants), ACNs of various sources were significantly associated with a reduction in the risks of hypertension and type 2 diabetes mellitus. According to 8 RCT-SRMs (139 interventions and >4984 participants), ACNs improved plasmatic lipids, glucose metabolism, and endothelial function, without affecting blood pressure. No associations between ACNs and breast or gastric cancer risks were found. ACN intake opens new pathways for the management of glucose metabolism, the plasmatic lipid profile, and the improvement of endothelial function in humans.

Purpose To assess the sustained and acute effects, as well as the influence of sustained consumption on the acute effects, of orange juice (OJ) with a natural hesperidin content and hesperidin-enriched OJ (EOJ) on blood (BP) and pulse (PP) pressures in pre- and stage-1 hypertensive individuals. Methods In a randomized, parallel, double-blind, placebo-controlled trial, participants (n = 159) received 500 mL/day of control drink, OJ, or EOJ for 12 weeks. Two dose–response studies were performed at baseline and after 12 weeks. Results A single EOJ dose (500 mL) reduced systolic BP (SBP) and PP, with greater changes after sustained treatment where a decrease in diastolic BP (DBP) also occurred (P P P P Conclusion Hesperidin in OJ reduces SBP and PP after sustained consumption, and after a single dose, the chronic consumption of EOJ enhances its postprandial effect. Decreases in systemic and transcriptomic biomarkers were concomitant with BP and PP changes. EOJ could be a useful co-adjuvant tool for BP and PP management in pre- and stage-1 hypertensive individuals.

The present study evaluated the impact of different thermal (infrared-drying, hot air-drying and purée pasteurization) and non-thermal (freeze-drying) processing technologies on red-fleshed apple (poly)phenolic compounds. We further investigated the processing effect on the (poly)phenol bioavailability in a crossover postprandial study where three subjects consumed three apple products (freeze-dried snack, hot air-dried snack and pasteurized purée). (Poly)phenolic compounds present in the apple products and their biological metabolites in urine were analyzed using liquid chromatography coupled to mass spectrometry (UPLC-MS/MS). When comparing different processes, infrared-drying caused important losses in most of the apple (poly)phenolics, while hot air-drying and purée pasteurization maintained approximately 83% and 65% of total (poly)phenols compared with the freeze-dried snack, respectively. Anthocyanins in particular were degraded to a higher extent, and hot air-dried apple and pasteurized purée maintained respectively 26% and 9% compared with freeze-dried apple snack. The acute intake showed that pasteurized purée exhibited the highest (poly)phenol bioavailability, followed by hot air-drying and freeze-dried snack, highlighting the impact of processing on (poly)phenols absorption. In conclusion, for obtaining affordable new red-fleshed apple products with enhanced (poly)phenol bioavailability, purée pasteurization and hot air-drying represent viable techniques. However, to obtain a red-fleshed apple snack with high anthocyanin content, freeze-drying is the technique that best preserves them., This study was supported by the Spanish Ministry of Industry, Economy and Competitiveness (MINECO) through the AGL2016-76943-C2-1-R and AGL2016-76943-C2-2-R projects (co-funded by the Agencia Estatal de Investigación (AEI) and the European Regional Development Fund (ERDF)); Iziar A. Ludwig was supported by the Spanish Ministry of Industry, Economy and Competitiveness (Juan de la Cierva, FJCI-2014-20689) and 2017PMF-POST2-19 The Martí I Franqués Research Grants Programme Universitat Rovira i Virgili (Reus, Tarragona, Spain); and Silvia Yuste through a grant by the University of Lleida. In addition, the authors are grateful to NUFRI SAT (Mollerussa, Lleida, Catalonia, Spain) for providing the red-fleshed apples.

Background & aims: Whether bioactive lysophospholipids (lyso-PLs) and trimethylamine-N-oxide (TMAO) serve as non-invasive biomarkers in early human hypercholesterolemia (HC) is unknown. This study aimed to assess whether serum lyso-PLs and plasma TMAO may be suitable susceptibility/risk biomarkers of HC in humans. Secondarily, we aimed to evaluate the relationships between targeted metabolites, diet composition and circulating liver transaminases, and verify these results in hamsters. Methods: A targeted metabolomics and lipidomics approach determined plasma TMAO and serum lysophosphatidylcholines (lyso-PCs) and lysophosphatidylethanolamines (lyso-PEs) in low (L-LDL-c) and moderate to high (MH-LDL-c) LDL-cholesterol subjects. Additionally, the relationships between targeted metabolites, liver transaminases and diet, particularly fatty acid intake, were tested. In parallel, plasma and liver lyso-PL profiles were studied in 16 hamsters fed a moderate high-fat (HFD) or low-fat (LFD) diet for 30 days. Results: Predictive models identified lyso-PC15:0 and lyso-PE18:2 as the most discriminant lyso-PLs among groups. In MH-LDL-c (n ¼ 48), LDL-cholesterol and saturated FAs were positively associated with lyso-PC15:0, whereas in L-LDL-c (n ¼ 70), LDL-cholesterol and polyunsaturated fatty acids (PUFAs) were negatively and positively related to lyso-PE18:2, respectively. Interestingly, in MH-LDL-c, the lower lyso-PE 18:2 concentrations were indicative of higher LDL-cholesterol levels. Intrahepatic accumulation of lyso-PLs-containing essential n-6 PUFAs, including lyso-PE18:2, were higher in HFD-fed hamsters than LFD-fed hamsters. The research leading to these results was supported by the Eu-ropean Commission through its Seventh Framework Programme "BIOmarkers of Robustness of Metabolic Homeostasis for Nutrigenomics-derived Health CLAIMS Made on Food" Project (FP7-KBBE-20 09-3 BIOCLAIMS) under grant agreement number 244995. Additionally, it was financially supported by the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under grant agreement: TEC-NOMIFOOD project (CER-20191010)

Food plays a key role in people’s health and quality of life. Inadequate eating habits or a deficient diet can lead to the development of non-communicable diseases (NCDs). The present review aims to describe the health and social factors related to food insecurity (FI) in adults in high-income countries and evaluate their impact on cardiometabolic risk (CMR). Following the PRISMA procedures, a systematic review was conducted by searching in biomedical databases. Full articles were screened (nf = 228) and critically appraised, and 12 studies met the inclusion criteria. Based on the selected studies, the results grouped information based on (i) the characteristics of the population in FI, (ii) the impact of FI on NCDs, and (iii) the cardiovascular and all-cause mortality risk of the FI population. Considering the minimum and maximum percentage data, people of the categories female sex (46.2–57.6%), education level lower than high school (11–67.46%), non-Hispanic white ethnicity (37.4–58%), single or separated or widowed (45–64.8%), and current smoker (35.5–61.1%) make up the population with FI in high-income countries. All of these factors presented a significant association (p < 0.001) with cardiovascular risk factors. The highest odds ratios (OR) for the FI population are described for obesity (OR = 2.49, 95% CI; 1.16–5.33) and myocardial infarction (OR = 2.19, 95% CI). Interventions that integrate FI screening and the measurement of CMR factors into routine clinical care may be an important step to identify vulnerable populations and subsequently improve and prevent NCDs. Thus, food-diet policies and public-health-based interventions are needed to be included in the measurement of CMR in the assessment of FI.

The present study aimed to evaluate the metabolism and bioavailability of anthocyanins (ACN) and other phenolics from red-fleshed apple (RFA) and to define the intake biomarkers compared to common white-fleshed apple (WFA). Acute and sustained (6-week) interventions were combined in a randomized, controlled and parallel study with 121 hypercholesterolemic subjects. Another arm consuming ACN-rich infusion from aronia fruit (ARO) provided matched content and profile of ACN. Plasma, urine and faeces samples were analyzed using UPLC-MS/MS. Results showed higher bioavailability of ACN after ARO compared to RFA, showing a clear apple matrix effect. The dihydrochalcone phloretin-2¿ -O-glucuronide was the most discriminant intake biomarker of both apples. The urinary peonidin-3-O-galactoside was a good biomarker after both ARO and RFA intakes, whereas peonidin-O-arabinoside was reported to be specific from ARO. The elucidation of the phenolic metabolism and the selection of intake biomarkers is a promising approach to relate phenolic compounds and human health., This study was supported by the Spanish Ministry of Industry, Economy and Competitiveness through the AGL2016-76943-C2-1-R and AGL2016-76943-C2-2-R projects (co-funded by the European Social Fund, European Union); M.J. Motilva thanks to Consejo Superior de Investigaciones Científicas-CSIC for partial funding throught the “Ayudas incorporacion ´ a escalas científicas CSIC, 2018” (Reference 201870I129). L.R. was Sara Borrell postdoctoral contract and she is a Serra Húnter Fellow. I.A.L. enjoys a post-doctoral contract (2017PMFPOST2-19) from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement and from the Universitat Rovira i Virgili (URV). S.Y. was supported by a pre-doctoral grant from the University of Lleida. The authors are grateful to CALIDAD PASCUAL (Aranda de Duero, Burgos, Spain) for generously providing the Bezoya mineral water to prepare daily Aronia infusion.

The aim of this study was to investigate comprehensively the metabolic pathways and human bioavailability of anthocyanins and other (poly)phenols in an apple matrix, and to elucidate potential intake biomarkers. After the acute intake of a red-fleshed apple freeze-dried snack, plasma and urine were collected and analyzed by UPLC-MS/MS. A total of 37 phase-II and microbial phenolic metabolites were detected in plasma and urine. Among these, phloretin glucuronide, cyanidin-3-O-galactoside (plasma and urine) and peonidin-3-O-galactoside (urine) were the only metabolites detected in all the volunteers and not detected at basal conditions. The maximum urine excretion was detected at 2–4 h, and the main increase in plasma of phloretin glucuronide and cyanidin-3-O-galactoside was observed at 2 h post-intake (61.0 ± 6.82 and 10.3 ± 1.50 nM, respectively). These metabolites could be selected as the best intake biomarkers of red-fleshed apple and might be useful in human intervention studies when studying its health effects., This study was supported by the Spanish Ministry of Industry, Economy and Competitiveness through the AGL2016-76943-C2-1-R and AGL2016-76943-C2-2-R projects (co-funded by the European Social Fund, European Union); I.A.L. enjoys a post-doctoral contract (2017PMF-POST2-19) from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement and from the Universitat Rovira i Virgili (URV). S.Y. was supported by a grant from the University of Lleida. In addition, the authors are grateful to NUFRI SAT (Mollerussa, Lleida, Catalonia, Spain) for providing the red-fleshed apples. A.P. has Torres Quevedo contract (Subprograma Estatal de Incorporación, Plan Estatal de Investigación Científica y Técnica y de Innovación).

Protein functional interactions could explain the biological response of secoiridoids (SECs), main phenolic compounds in virgin olive oil (VOO). The aim was to assess protein¿protein interactions (PPIs) of the aorta gap junction alpha-1 (GJA1) and the heart peptidyl-prolyl cis-trans isomerase (FKBP1A), plus the phosphorylated heart proteome, to describe new molecular pathways in the cardiovascular system in rats using nanoliquid chromatography coupled with mass spectrometry. PPIs modified by SECs and associated with GJA1 in aorta rat tissue were calpain, TUBA1A, and HSPB1. Those associated with FKBP1A in rat heart tissue included SUCLG1, HSPE1, and TNNI3. In the heart, SECs modulated the phosphoproteome through the main canonical pathways PI3K/mTOR signaling (AKT1S1 and GAB2) and gap junction signaling (GAB2 and GJA1). PPIs associated with GJA1 and with FKBP1A, the phosphorylation of GAB2, and the dephosphorylation of GJA1 and AKT1S1 in rat tissues are promising protein targets promoting cardiovascular protection to explain the health benefits of VOO., The work summarized in this paper was supported in part by grants (grant nos. MEFOPC Project, AGL2012-40144-C03-02 and AGL2012-40144-C03-03, and AppleCOR Project, AGL2016-76943-C2-2-R) from the Ministerio de Economía, Industria y Competitividad, the Agencia Estatal de Investigación (AEI), and the European Regional Development Fund (ERDF). L.R. is supported by a Sara Borrell postdoctoral grant (CD14/00275; Spain), A.P. is supported by a postdoctoral grant (PTQ-15-08068; Spain), and Ú.C. is supported by a Pla Estratègic de Recerca i Innovació en Salut (PERIS) postdoctoral grant (SLT002/16/00239; Catalunya, Spain).

We aimed to differentiate gut microbiota composition of overweight/obese and lean subjects and to determine its association with clinical variables and dietary intake. A cross-sectional study was performed with 96 overweight/obese subjects and 32 lean subjects. Anthropometric parameters were positively associated with Collinsella aerofaciens, Dorea formicigenerans and Dorea longicatena, which had higher abundance the overweight/obese subjects. Moreover, different genera of Lachnospiraceae were negatively associated with body fat, LDL and total cholesterol. Saturated fatty acids (SFAs) were negatively associated with the genus Intestinimonas, a biomarker of the overweight/obese group, whereas SFAs were positively associated with Roseburia, a biomarker for the lean group. In conclusion, Dorea formicigenerans, Dorea longicatena and Collinsella aerofaciens could be considered obesity biomarkers, Lachnospiraceae is associated with lipid cardiovascular risk factors. SFAs exhibited opposite association profiles with butyrate-producing bacteria depending on the BMI. Thus, the relationship between diet and microbiota opens new tools for the management of obesity. This research was funded by the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation, grant number CER-20191010.

In the present study, potential associations between dietary phenolic compounds (PCs), gut microbiota composition and targeted faecal metabolites were identified in a cross-sectional study including grade 1 hypertensive (HT) and normotensive (NT) subjects. We performed comprehensive quantification of PC intake, together with 16S rRNA gene sequencing of the gut microbiota, and faecal and plasma short-chain fatty acids (SCFAs) determination. The results showed multiple-way relationships between PCs from several plant-based foods and 25 bacterial taxa previously defined as discriminant biomarkers among groups. Remarkably, coffee PCs were positively associated with systolic and diastolic blood pressure, faecal SCFAs, Bacteroides plebeius and Bacteroides coprocola in HT and negatively associated with Faecalibacterium prausnitzii and Christensenellaceae R-7 in NT. Olive fruit PCs were positively associated with Ruminococcaceae UCG-010, Christensenellaceae R-7 and plasma SCFAs in NT. These interplays with discriminant bacterial taxa in HT and NT subjects highlight the potential role of specific PCs as gut microbiome modulators in either the pathogenesis or prevention of hypertension.

The intake of olive oil (OO) enriched with phenolic compounds (PCs) promotes ex vivo HDL-mediated macrophage cholesterol efflux in humans. We aimed to determine the effects of PC-enriched virgin OO on reverse cholesterol transport (RevCT) from macrophages to feces in vivo. Female C57BL/6 mice were given intragastric doses of refined OO (ROO) and a functional unrefined virgin OO enriched with its own PC (FVOO) for 14 days. Our experiments included two independent groups of mice that received intragastric doses of the phenolic extract (PE) used to prepare the FVOO and the vehicle solution (saline), as control, for 14 days. FVOO intake led to a significant increase in serum HDL cholesterol and its ability to induce macrophage cholesterol efflux in vitro when compared with ROO group. This was concomitant with the enhanced macrophage-derived [3H]cholesterol transport to feces in vivo. PE intake per se also increased HDL cholesterol levels and significantly promoted in vivo macrophage-to-feces RevCT rate when compared with saline group. PE upregulated the expression of the main macrophage transporter involved in macrophage cholesterol efflux, the ATP binding cassettea1. Our data provide direct evidence of the crucial role of OO PCs in the induction of macrophage-specific RevCT in vivo., This work was partly funded by the Instituto de Salud Carlos III and FEDER “Una manera de hacer Europa” grants PI14-01648 and PI18-00164 (to F.B.-V.), PI16-00139 and PI19-00136 (to J.C.E-G), and CB06/03/0028 (to M.F. (Montserrat Fitó)); by the Ministerio de Economía, Indústria y Competitividad and FEDER AppleCOR Project (subproject AGL2016-76943-C2-2-R and subproject AGL2016- 76943-C2-1-R) (to R.S.), AGL2009-13517-C03-01 and AGL2012-40144-C03-01 (to M.F. (Montserrat Fitó)); by the Agència de Gestió d’Ajuts Universitaris i de Recerca 2014-SGR-240, 2017-SGR-522, 2017-SGR-222, and 2017-BP-00021; by the Jane and Aatos Erkko Foundation (to M.J. and J.M.); and the Finnish Foundation for Cardiovascular Research (to M.J.). M.F. (Marta Farràs) has a Sara Borrell contract (CD17/00233). CIBERDEM and CIBEROBN are initiatives of the Instituto de Salud Carlos III.

Hypertension is an independent and preventable risk factor for the development of cardiovascular diseases, however, little is known about the impact of gut microbiota composition in its development. We carried out comprehensive gut microbiota analysis and targeted metabolomics in a cross-sectional study of 29 non-treated hypertensive (HT) and 32 normotensive (NT) subjects. We determined fecal microbiota composition by 16S rRNA gene sequencing and bacterial functions by metagenomic analysis. The microbial metabolites analysed were short chain fatty acids (SCFA) both in plasma and feces, and trimethylamine N-oxide (TMAO) in plasma. The overall bacterial composition and diversity of bacterial community in the two groups were not significantly different. However, Ruminococcaceae NK4A214, Ruminococcaceae_UCG-010, Christensenellaceae_R-7, Faecalibacterium prausnitzii and Roseburia hominis were found to be significantly enriched in NT group, whereas, Bacteroides coprocola, Bacteroides plebeius and genera of Lachnospiraceae were increased in HT patients. We found a positive correlation between the HT-associated species and systolic and diastolic blood pressure after adjusted for measured confounders. SCFA showed antagonistic results in plasma and feces, detecting in HT subjects significant higher levels in feces and lower levels in plasma, which could indicate a less efficient SCFA absorption. Overall, our results present a disease classifier based on microbiota and bacterial metabolites to discriminate HT individuals from NT controls in a first disease grade prior to drug treatment. We wish to acknowledge the support of the Institut d’Investigació Sanitària Pere Virgili (IISPV) and the EURECAT-Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut (Reus, Spain), the University of Lleida through the SY grant, the LR Sara Borrell postdoctoral grant (CD14/00275), and AP Torres Quevedo contract (Subprograma Estatal de Incorporación, Plan Estatal de Investigación Científica y Técnica y de Innovación). LC was granted by Ayudas Para La Promoción De Empleo Joven E Implantación De La Garantía Juvenil En I + D + I (PEJ-2014-A-67028). NFOC-Salut group is a consolidated research group of Generalitat de Catalunya, Spain (2017 SGR522).

The analysis of the fat-soluble vitamins A and E and lipid micronutrients in blood, such as carotenoids, is an important parameter to monitor the micronutrient status in humans. Although the potential of dried blood spot (DBS) cards, the use of this technique for blood sampling and subsequent analysis of these fat-soluble micronutrients has been poorly or not studied. An analytical method based on DBS cards (FTA® DMPK-A) combined with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has been developed and validated for the determination of carotenoids (lutein, zeaxanthin, β-cryptoxanthin and β-carotene), tocopherols (α-tocopherol, γ-tocopherol and δ-tocopherol) and all-trans-retinol in human blood. Under optimum DBS card extraction conditions, the extraction recoveries of the studied compounds were higher than 72%, the sample matrix effect lower than 17%, and the detection limits at hundred nM concentration levels. The developed method was applied to the analysis of human blood, and the concentration ranges obtained fell within the expected ranges previously reported in healthy adults. Moreover, the influence of hematocrit effect was investigated in a range of 25–55% in order to compare the obtained results to those reported in the literature for the analysis of plasma samples. This method represents an improvement over current techniques reported in the literature due to the use of a non-invasive blood collection method, and moreover, this methodology was for the first time 1) validated for the analysis of all-trans-retinol, tocopherols and carotenoids, and 2) applied for the determination of tocopherols in human blood samples., This study was supported by the Spanish Ministry of Industry, Economy and Competitiveness through the AGL2016-76943-C2-1-R and AGL2016-76943-C2-2-R projects (co-funded by the European Social Fund, European Union); M.J. Motilva thanks to Consejo Superior de Investigaciones Científicas-CSIC for partial funding throught the “Ayudas incorporación a escalas científicas CSIC, 2018” (Reference 201870I129). I.A.L. enjoys a post-doctoral contract (2017PMF-POST2-19) from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement and from the Universitat Rovira i Virgili (URV). S.Y. was supported by a pre-doctoral grant from the University of Lleida.

The main aim of this work is to gain insight into the potential mechanisms of hydroxytyrosol (HT) and its mainplasmatic metabolites (HTmet) that improve the endothelial function. Feeding ApoE−/−mice with 10 mg/kg/day of HT derivatives for 12 weeks significantly reduced E-selectin, VCAM-1, MCP-1, ICAM-1, and F4/80 ex-pression compared with the control group in the isolated aorta. Furtherin-vitromechanistic assays revealed thatboth HT and HTmet could reduce the adhesion of Jurkat-T-lymphocytes to human aortic endothelial cells at1–5 μM, significantly greater reductions being observed with HTmet. This process appeared to be regulated bythe MAPK pathway through the inactivation of p38δ, JNK1-3, CREB, AKT3, p53 and P70 S6 Kinase. We con-cluded that supplementation with HT precursors from olive oil might attenuate the initial steps of atherosclerosisat a molecular level. The reduction of lymphocyte adhesion and the modulation of MAPK pathway by HTmetcould explain this phenomenon. This work was partly supported by state grant: The MEFOPC Project (Subprojects AGL2012-40144-C03-02 and AGL2012-40144-C03-03) from the Spanish Ministry of Education and Science (Ministerio de Educación y Ciencia). We wish to acknowledge the support of the Institut d’Investigació Sanitària Pere Virgili (IISPV) and the EURECAT-Centre Tecnològic de Nutrició i Salut (CTNS), Reus, Spain and the University of Lleida through the M-C. López de las Hazas grant and the L. Rubió Sara Borrell postdoctoral grant (CD14/00275). And the Ú. Catalán Pla estratègic de recerca i innovació en salut (PERIS) post-doctoral grant (SLT002/16/00239; Catalunya, Spain). NFOC-Salut group is a consolidated research group of Generalitat de Catalunya, Spain (2014 SGR 873).

The consumption of antioxidant-rich foods such as virgin olive oil (VOO) promotes high-density lipoprotein (HDL) anti-atherogenic capacities. Intake of functional VOOs (enriched with olive/thyme phenolic compounds (PCs)) also improves HDL functions, but the gene expression changes behind these benefits are not fully understood. Our aim was to determine whether these functional VOOs could enhance the expression of cholesterol efflux-related genes. In a randomized, double-blind, crossover, controlled trial, 22 hypercholesterolemic subjects ingested for three weeks 25 mL/day of: (1) a functional VOO enriched with olive oil PCs (500 mg/kg), (2) a functional VOO enriched with olive oil (250 mg/kg) and thyme PCs (250 mg/kg, FVOOT), and, (3) a natural VOO (olive oil PCs: 80 mg/kg, control intervention). We assessed whether these interventions improved the expression of cholesterol efflux-related genes in peripheral blood mononuclear cells by quantitative reverse-transcription polymerase chain reactions. The FVOOT intervention upregulated the expression of CYP27A1 (P = 0.041 and P = 0.053, versus baseline and the control intervention, respectively), CAV1 (P = 0.070, versus the control intervention), and LXR&beta, RXR&alpha, and PPAR&beta, /&delta, (P = 0.005, P = 0.005, and P = 0.038, respectively, relative to the baseline). The consumption of a functional VOO enriched with olive oil and thyme PCs enhanced the expression of key cholesterol efflux regulators, such as CYP27A1 and nuclear receptor-related genes.

Hydroxytyrosol (HT) is involved in healthful activities and is beneficial to lipid metabolism. Many investigations focused on finding tissue-specific targets of HT through the use of different omics approaches such as transcriptomics and proteomics. However, it is not clear which (if any) of the potential molecular targets of HT reported in different studies are concurrently affected in various tissues. Following the bioinformatic analyses of publicly available data from a selection of in vivo studies involving HT-supplementation, we selected differentially expressed lipid metabolism-related genes and proteins common to more than one study, for validation in rodent liver samples from the entire selection. Four miRNAs (miR-802-5p, miR-423-3p, miR-30a-5p, and miR-146b-5p) responded to HT supplementation. Of note, miR-802-5p was commonly regulated in the liver and intestine. Our premise was that, in an organ crucial for lipid metabolism such as the liver, consistent modulation should be found for a specific target of HT even if different doses and duration of HT supplementation were used in vivo. Even though our results show inconsistency regarding differentially expressed lipid metabolism-related genes and proteins across studies, we found Fgf21 and Rora as potential novel targets of HT. Omics approaches should be fine-tuned to better exploit the available databases., This research was funded by grants from the Spanish “Agencia Estatal de Investigación” and the European FEDER Funds to AD and RMH (AGL2016-78922-R); the Ministerio de Economía y Competitividad–Fondo Europeo de Desarrollo Regional (SAF2016-75441-R) and the Fondo Social Europeo–Gobierno de Aragón (B16_17R) to MAN and JO; the Fundación Ramón Areces (CIVP18A3888) to AD, JG-Z, JTC, MCC, FV and RMH; the CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERObn) to JAM, MPP, JO and MAN; and POR FESR 3S4H to FV. CIBERObn. is an initiative of the ISCIII, Spain. MCLH, LdP and MB R-R were recipients of contracts from the Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid, Fondo Social Europeo, and the Iniciativa de Empleo Juvenil YEI (PEJD-2016/BIO-2781, PEJD-2017-PRE/BIO-5100, and PEJD-2018-POST/BIO 8933), respectively.

Gut microbiota has been suggested to affect lipid metabolism. The objective of this study was to characterize the faecal microbiota signature and both short chain fatty acids (SCFAs) and bile acids (BA) profile of hypercholesterolemic subjects. Microbiota composition, SCFAs, BA and blood lipid profile from male volunteers with hypercholesterolemia (HC) and normocholesterolemia (NC) were determined by 16S rDNA sequencing, HPLC, GC and NMR, respectively. HC subjects were characterized by having lower relative abundance of Anaeroplasma (0.002% vs 0.219%, p-value = 0.026) and Haemophilus (0.041% vs 0.078%, p-value = 0.049), and higher of Odoribacter (0.51% vs 0.16%; p-value = 0.044). Correlation analysis revealed that Anaeroplasma and Haemophilus were associated to an unfavourable lipid profile: they correlated negatively to cholesterol and triglycerides related biomarkers and the ratio total to high density lipoprotein (HDL) cholesterol, and positively to HDL size. Odoribacter displayed an opposite behaviour. Faecal SCFAs profile revealed higher abundance of isobutyric (2.76% vs 0.82%, p-value = 0.049) and isovaleric acid (1.32% vs 0.06%, p-value = 0.016) in HC. Isobutyric acid correlated positively with Odoribacter and lipid parameters indicative of an unfavourable profile. BA profile did not show differences between groups. It was concluded that HC subjects showed a particular faecal bacterial signature and SCFAs profile associated with their lipid profile. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the Seventh Framework Programme of the European Union (FP7/2007-2013) under REA grant agreement No. 600388 (TECNIOspring Progamme) and from the Agency for Business Competitiveness of the Government of Catalonia ACCIÓ that support the fellowship given to Ana Belén Granado-Serrano (TECSPR14-0-0023). I.A.L enjoys a post-doctoral contract (2017PMF-POST2-19) from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement and from the Universitat Rovira i Virgili (URV).

Anthocyanins (ACNs) are promising health-enhancing phenolic compounds. We focus on ACN animal tissue bioavailability to provide an evidentiary link between tissue ACNs and their associated health properties. We performed a systematic review of electronic libraries; 279 results were retrieved, and 13 publications met inclusion criteria. Extracted information included animal model employed, administration route, doses, analysis method, and ACN concentration values in tissues. Total ACN concentrations were detected in mice kidney (2.17 × 105 pmol/g), liver (1.73 × 105 pmol/g), heart (3.6 × 103 pmol/g), and lung (1.16 × 105 pmol/g); and in pig brain (6.08 × 103 pmol/g). ACNs showed a predominance of parent ACNs in long-term experiments versus an ACN metabolite predominance in short-term experiments. ACNs detected in animal tissues, such as cyanidin-3-glucoside, suggest it may have an important role in human health. This information could be useful to determine proper ACN-intake biomarkers in biological samples in futures studies. The AppleCOR Project (Subproject AGL2016-76943-C2-2-R and Suproject AGL2016-76943-C2-1-R) has been possible with the support of Ministerio de Economia , Indústria y Competitividad, the Agencia Estatal de Investigación (AEI) and the European Regional Development Fund (ERDF). B.A.S.-R. enjoys a 2017MFP-COFUND-30 predoctoral fellowship contract. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 713679 and from the Universitat Rovira i Virgili (URV). Ú.C. has a Pla estratègic de recerca i innovació en salut (PERIS) postdoctoral grant (SLT002/16/00239; Catalunya, Spain) from Generalitat de Catalunya; NFOC-Salut group is a consolidated research group of Generalitat de Catalunya, Spain (2017 SGR 522).

[Scope] The main findings of the “Virgin Olive Oil and HDL Functionality” (VOHF) study and other related studies on the effect of phenol‐enriched virgin olive oil (VOO) supplementation on cardiovascular disease are integrated in the present work., [Methods and results] VOHF assessed whether VOOs, enriched with their own phenolic compounds (FVOO) or with those from thyme (FVOOT), improve quantity and functionality of HDL. In this randomized, double‐blind, crossover, and controlled trial, 33 hypercholesterolemic subjects received a control VOO (80 mg kg−1), FVOO (500 mg kg−1), and FVOOT (500 mg kg−1; 1:1) for 3 weeks. Both functional VOOs promoted cardioprotective changes, modulating HDL proteome, increasing fat‐soluble antioxidants, improving HDL subclasses distribution, reducing the lipoprotein insulin resistance index, increasing endogenous antioxidant enzymes, protecting DNA from oxidation, ameliorating endothelial function, and increasing fecal microbial metabolic activity. Additional cardioprotective benefits were observed according to phenol source and content in the phenol‐enriched VOOs. These insights support the beneficial effects of OO and PC from different sources., [Conclusion] Novel therapeutic strategies should increase HDL‐cholesterol levels and enhance HDL functionality. The tailoring of phenol‐enriched VOOs is an interesting and useful strategy for enhancing the functional quality of HDL, and thus, it can be used as a complementary tool for the management of hypercholesterolemic individuals., This work was supported by grants: the VOHF Study (AGL2009-13517- C03) and the MEFOPC Project (AGL2012-40144-C03) from the Spanish Ministry of Education and Science. The authors wish to acknowledge the support of the IISPV, the EURECAT-CTNS, and the COS; Reus, Spain. M.C.L.H has predoctoral student grant from the Universitat de Lleida. A.P. has Torres Quevedo contract (Subprograma Estatal de Incorporaci´on, Plan Estatal de Investigaci´on Cient´ıfica y T´ecnica y de Innovaci´on). L.R. and M.F. have Sara Borrell postdoctoral grants (CD14/00275, 2015–2017;CD17/00233, 2018–2021). M.F. was also supported by a joint contract of the ISCIII and Health Department of the Catalan Government (CES12/025; CB06/03/0028). U.C. has a PERIS post-doctoral grant ´ (SLT002/16/00239; Catalunya, Spain). NFOC-Salut group is a consolidated research group of Generalitat de Catalunya, Spain (2017 SGR 522).CIBERDEM and CIBEROBN are initiatives of ISCIII of Spain which is supported by FEDER funds (CB06/03).

[Scope] The application of dried blood spot (DBS) cards for the study in human blood of dietary polyphenol bioavailability has been poorly studied. [Methods and results] An analytical method based on blood sampling with DBS cards combined with LC–MS/MS has been developed and validated. To test the method validation, the phenolic metabolites are determined in human blood and plasma obtained after an acute intake of a red‐fleshed apple snack in ten volunteers. Capillary blood by finger prick is compared to venous blood by venipuncture and whole blood is also compared to their corresponding venous plasma samples. Moreover, the venous plasma results using DBS cards are compared to those obtained by microElution solid phase extraction (µSPE). The main phenolic metabolites detected in blood and plasma samples are phloretin glucuronide, dihydroxyphenylpropionic acid sulphate, (methyl) catechol sulphate, catechol glucuronide, and hydroxyphenyl‐γ‐valerolactone glucuronide. No significant differences are observed between capillary blood, venous blood, and plasma samples using DBS, and neither between plasma samples analyzed by DBS or µSPE. [Conclusions] Finger‐prick blood sampling based on DBS appears to be a suitable alternative to the classic invasive venipuncture for the determination of circulating phenolic metabolites in nutritional postprandial studies, This study was supported by the Spanish Ministry of Industry, Economy and Competitiveness through the AGL2016‐76943‐C2‐1‐R and AGL2016‐76943‐C2‐2‐R projects (co‐funded by the European Social Fund, European Union); by the Spanish Ministry of Industry, Economy and Competitiveness through the I. A. Ludwig postdoctoral research contract (Juan de la Cierva, FJCI‐2014‐20689); and by the University of Lleida through the Silvia Yuste doctoral grant. In addition, the authors are grateful to NUFRI (Mollerussa, Lleida, Catalonia, Spain) for providing the apples. Ú.C. has a PERIS post‐doctoral grant (SLT002/16/00239; Catalunya, Spain). NFOC‐Salut group is a consolidated research group of Generalitat de Catalunya, Spain (2017 SGR 522).

Hydroxytyrosol (HT) and its derivatives represent the minor components of Virgin Olive Oil (VOO) that are of great interest for their pharmacological properties and among the most widely researched natural antioxidant compounds. In this review, the occurrence and metabolic fate of HT and its precursors are presented prior to discussing its beneficial effects on health. Bioavailability studies show that the metabolites detected in plasma depend on the model used (animal or human), the HT source (simple molecule or complex precursors) and the dose administered. However, in all cases HT sulphate appears to be the most ubiquitous metabolite in biofluids and it seems probable that it is responsible to a great extent for HT biological effects. Epidemiological evidence of HT and its derivatives against such lifestyle-associated pathologies as cancer, cardiovascular and neurodegenerative diseases is reviewed together with the newest perspectives on the mechanisms of action based on in-vitro and animal studies. According to the reviewed data, HT and its precursors could have the potential clinical use in cardiovascular diseases; more epidemiological data is needed to demonstrate their neurodegenerative diseases and cancer prevention.

Gene expression mediated by the transcription factor cAMP-responsive element-binding protein (CREB) is essential for a wide range of brain processes. The transcriptional coactivartor CREB-regulated transcription coactivator-1 (CRTC1) is required for efficient induction of CREB target genes during neuronal activity. However, the mechanisms regulating induction of specific CREB/CRTC1-dependent genes during neuronal activity remain largely unclear. Here, we investigated the molecular mechanisms regulating activity-dependent gene transcription upon activation of the CREB/CRTC1 signaling pathway in neurons. Depolarization and cAMP signals induce preferential transcription of activity-dependent genes containing promoters with proximal CRE/TATA sequences, such as c-fos, Dusp1, Nr4a1, Nr4a2 and Ptgs2, but not genes with proximal CRE/TATA-less promoters (e.g. Nr4a3, Presenilin-1 and Presenilin-2). Notably, biochemical and chromatin immunoprecipitation analyses reveal constitutive binding of CREB to target gene promoters in the absence of neuronal activity, whereas recruitment of CRTC1 to proximal CRE/TATA promoters depends on neuronal activity. Neuronal activity induces rapid CRTC1 dephosphorylation, nuclear translocation and binding to endogenous CREB. These results indicate that neuronal activity induces a preferential binding of CRTC1 to the transcriptional complex in CRE/TATA-containing promoters to engage activity-dependent transcription in neurons.