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Promoting a healthy diet is a relevant strategy for preventing non-communicable diseases. This study aims to evaluate the impact of an innovative tool, the SAlBi educa nutrition app, in primary healthcare dietary counseling to improve dietary profiles as well as adherence to the Mediterranean diet. A multi-center randomized control trial comprising 104 participants was performed. Both control (n = 49) and intervention (n = 55) groups attended four once-weekly sessions focusing on healthy eating habits and physical activity, over one month. As well as attending the meetings, the intervention group used the app, which provides self-monitoring and tailored dietary advice based on the Mediterranean diet model. In a second intervention (one arm trial), the potential of SAlBi educa was evaluated for three months during the COVID-19 pandemic. At 4 weeks, the intervention group had significantly increased their carbohydrate intake (7.7% (95% CI: 0.16 to 15.2)) and decreased their total fat intake (−5.7% (95% CI: −10.4 to −1.15)) compared to the control group. Significant differences were also found for carbohydrates (3.5% (95% CI: −1.0 to 5.8)), total fats (−5.9% (95% CI: −8.9 to −3.0)), fruits and vegetables (266.3 g/day (95% CI: 130.0 to 402.6)), legumes (7.7g/day (95% CI: 0.2 to 15.1)), starchy foods (36.4 g/day (95% CI: 1.1 to 71.7)), red meat (−17.5 g/day (95% CI: −34.0 to −1.1)), and processed meat (−6.6 g/day (95% CI: −13.1 to −0.1)) intakes during the COVID-19 pandemic. SAlBi educa is a useful tool to support nutrition counseling in primary healthcare, including in special situations such as the COVID-19 pandemic. Trial registration: ISRCTN57186362. Consejería de Salud y Familia, Junta de Andalucía (Innovative Project in Health) grant number PIN-0050-2018.

The objectives of this chapter are to summarize and discuss (i) the anthocyanins structure and content in foodstuffs and their dietary intake (ii) the anthocyanins bioavailability and human metabolic pathways and (iii) the in vitro and in vivo potent anti-neuroinflammatory effects of anthocyanins and their metabolites. Indeed, anthocyanins are polyphenolic compounds belonging to the group of flavonoids, and are one of the most commonly consumed polyphenols in a normal diet. They are responsible of red, blue and purple color of several fruits and vegetables and their intake has been related with several human health benefits. The anthocyanins structures diversities as well as their content in various fruits, vegetables and cereals is addressed. Moreover, despite the growing evidence for the protective effects of anthocyanins, it is important to highlight that the in vivo bioavailability of these compounds is relatively low in comparison to their more stable metabolites. Indeed, after consumption, these bioactives are subjected to substantial transformations in human body. Phase I and II metabolites generated by intestinal and hepatic enzymatic reactions, and phenolic acids produced by gut microbiota and their metabolized forms, are the most important metabolic anthocyanins forms. For this reason, the study of the biological properties of these circulating metabolites represents a more in vivo realistic situation. Although the anthocyanin bioavailability researches in humans are limited, they will be discussed together with a global metabolic pathway for the main anthocyanins. Moreover, several works have demonstrated that anthocyanins can cross the blood brain barrier, and accumulate in brain endothelial cells, brain parenchymal tissue, striatum, hippocampus, cerebellum and cortex. Consequently, the study of anthocyanins as potent therapeutic agents in neurodegenerative diseases has gained relevance and the principal and the most recent studies are also discussed in the book chapter.

Angiogenesis is a key process involved in both cancer and cardiovascular diseases, the vascular endothelial growth factor (VEGF) and its VEGF receptor-2 (VEGFR-2) being the main triggers. The aim of this study was to determine the molecular mechanism underlying the potent inhibition of VEGF signaling by hydroxytyrosol (HT) metabolites and indolic compounds and establish a relation between their structure and bioactivity. Experiments involved the evaluation of their potential to inhibit VEGF on human umbilical vein endothelial cells (HUVECs) by ELISA assay and their subsequent effect on the downstream signaling pathway (PLCγ1, Akt, and endothelial nitric oxide synthetase (eNOS)) by Western blot. Respectively, 3,4-dihydroxyphenylacetaldehyde (DOPAL) (100 µM) and indole pyruvic acid (IPy) (1 mM) were capable of inhibiting VEGFR-2 activation with an IC50 value of 119 µM and 1.037 mM. The anti-angiogenic effect of DOPAL and IPy is mediated via PLCγ1. Additionally, DOPAL significantly increases eNOS phosphorylation, while IPy maintained it. These data provide for the first time evidence of the anti-angiogenic effect of DOPAL and IPy for future use as potential bioactive food ingredients. Ministerio de Ciencia e Innovación PID2019-108722RB-C32 Junta de Andalucía (P18-RT-3098)

In recent years, the use of applications to improve dietary habits has increased. Although numerous nutrition apps are available on the market, only few have been developed by health and nutrition professionals based on scientific evidence and subsequently tested to prove their usability. The main objective of this study was to design, develop, and evaluate the usability of a tailored nutrition application to be used to promote healthy eating habits. In order to decide app design and content, three focus groups took place with fifteen professionals from primary healthcare, nutrition, and food science and computer science, as well as expert users. For the general and feedback message design, a reference model based on the scientific literature was developed. To address the multi-perspective approach of users' and external healthcare professionals' feedback, a one-day pilot testing with potential users and healthcare professionals was conducted with four focus groups. To evaluate the relevance and potential usability of the app a 1-month pilot test was conducted in a real-life environment. A total of 42 volunteers participated in the one-day pilot testing, and 39 potential users participated in the 1-month pilot test. The SAlBi educa app developed includes an online dietary record, a self-monitoring tool to evaluate dietary patterns, general and feedback messages, and examples of traditional Mediterranean recipes. The usability study showed that volunteers think that SAlBi educa is pleasant (59%) and easy to learn to use (94%). Over 84% of the volunteers declared that the nutritional messages were clear and useful. Volunteers stated that general and tailored recommendations, as well as self-monitoring, were SAlBi educa's most motivating and useful features. SAlBi educa is an innovative, user-friendly nutritional education tool with the potential to engage and help individuals to follow dietary habits based on the Mediterranean model. Junta de Andalucía PIN-0050-2018

BACKGROUND Mobile applications are one of the fastest growing technology fields in recent years. The rise of smartphones and the special concern about food in the population, as well as the increase in overweight and obesity and their association with non-communicable diseases, makes it necessary to combine both technology and nutrition disciplines to promote healthy eating patterns. OBJECTIVE The main objective of this study was to design and develop a tailored nutrition application to promote healthy eating habits as a tool to support the primary care Dietetic Counselling Program. Additionally, usability study was also performed. METHODS Three focus groups were conducted with 15 primary health care professionals (Family Doctors, Nurses and Public Health and Health Promotion Technicians), Professors and Lectures of Nutrition and Food, expert users (students of the Pharmacy Degree) and Telecommunications Engineers to decide the app design and content. Additionally, for the general and feedback message design a reference model was developed bases in the scientific literature. To evaluate the relevance potential usability, acceptability, credibility, and comprehensibility of the information and interface of the app a pilot testing in a real-life environment with potential users and Health Care Professionals was carried out in four focus groups organized in four different primary health care centers. Participants included forty-two Health Professionals and users. RESULTS The SAlBi educa app developed includes an online dietary record, a self-monitoring tool to evaluate dietary patterns, general and feedback messages and traditional Mediterranean recipe examples. The reference message model included the following characteristics: length of approximately 160 characters, frequency of 1-4 messages/week, simple tone y language, personalized with the user's name and empathic to allow user empowering. More than 60 general and 65 feedback messages were designed following this model. Usability study showed that 91.7% of the participants find SAlBi educa stimulating and easy to use (87.1% of volunteers). It is worth noting that 92.3% of volunteers stated that both general and tailored nutrition messages are clear, useful (100%), relevant (97.4%) and the 86.1% agree that they have the potential to persuade people to improve their diet and physical activity. A total of 95.0% of participants would use SAlBi educa in the future and recommend. CONCLUSIONS SAlBi educa is an innovative nutritional education tool developed based on scientific evidence that has the potential to become an effective solution for supporting Nutrition Counseling in primary health care.

International audience; Stilbenes are phenolic compounds present in different higher plant families that have shown different biological activities, such as antioxidant properties and antitumoral and anti-atherosclerotic effects, among others. Angiogenesis is a key process involved in both cancer and cardiovascular diseases, the vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 being the main triggers. Certain polyphenol compounds, such as flavonoids, have shown a potent capacity to inhibit VEGF and, consequently, angiogenesis. The present work, therefore, aims to evaluate the potential effect of stilbenes on inhibiting VEGF and their subsequent effect on the downstream signaling pathway (PLCγ1, Akt, and eNOS). VEGFR-2 activation was studied through an ELISA assay in the HUVEC line, while the phosphorylation of intracellular downstream proteins PLCγ1, Akt, and eNOS was tested by Western blot. Student's t test was used to determine significant differences between samples. On the one hand, astringin, pallidol, and ω-viniferin showed the lowest IC values (2.90 ± 0.27, 4.42 ± 0.67, and 6.10 ± 1.29 μM, respectively) against VEGFR-2 activation. Additionally, VEGF-induced PLCγ1 phosphorylation was significantly inhibited by ε-viniferin, astringin, and ω-viniferin. However, ε-viniferin and pallidol simultaneously enhanced eNOS activation, proving to be via Akt activation in the case of ε-viniferin. For the first time, these data suggest that stilbenes such as astringin, pallidol, ω-viniferin, and ε-viniferin have a potential anti-angiogenic effect and they could be further considered as anti-VEGF ingredients in food and beverages. In addition, ε-viniferin and pallidol significantly allowed eNOS activation and could likely prevent the side effects caused by anti-VEGF hypertension drugs.

Background and Aims Tryptophan is involved in the formation of bioactive compounds, such as melatonin (MEL) and 3‐indoleacetic acid (3‐IAA), by yeast. Melatonin is a neurohormone whose occurrence in wine has been widely reported in recent years. The occurrence, however, of MEL and other indolic compounds related to tryptophan metabolism by wine yeast strains has been scarcely reported in grape musts. This work examined the occurrence of these compounds during the alcoholic fermentation (AF) of musts from seven grape cultivars, Corredera, Chardonnay, Moscatel, Palomino Fino, Sauvignon Blanc, Tempranillo and Vijiriega. Methods and Results Must was fermented with three Saccharomyces cerevisiae strains and then in two cases an additional sequential inoculation with the non‐Saccharomyces yeast Torulaspora delbrueckii was carried out. Fermented must samples were analysed by UHPLC/HRMS to determine the concentration of: l‐tryptophan, 5‐hydroxytryptophan, 5‐hydroxytryptamine, N‐acetyl‐5‐hydroxytryptamine, MEL, 3‐IAA, tryptamine, tryptophol and l‐tryptophan ethyl ester. The profile of indolic compounds during AF with the Aroma White strain depended on the cultivar. The yeast strain did not influence the profile of indolic compounds; instead, fermentation time was found to be a more influential factor. Conclusions The production of indolic compounds during the AF depends largely on the cultivar used and the day of fermentation on natural grape musts. Significance of the Study This is the first study that quantifies 5‐hydroxytryptophan and N‐acetyl‐5‐hydroxytryptamine during the AF of grape must. The occurrence of compounds with bioactive potential, for example 3‐IAA and ML, during fermentation with commercial yeast strains is also described.

Increasing evidence supports that the traditional Mediterranean dietary pattern is related to the reduction of cognitive decline and neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. A considerable intake of plant foods, fish and extra-virgin olive oil, and a moderate consumption of red wine, all of them characteristic of the Mediterranean diet are behind these effects. These foods are especially rich in polyphenols (secoiridoids, stilbenes, and flavonoids) and mono- and polyunsaturated fatty acids. Neuroinflammation is a common feature shared by neurodegenerative disorders and seems to play a key role in the development and progression of these pathologies. Microglial cells, the principal orchestrators of neuroinflammation, can be polarized in different phenotypes that can change or coexist during the inflammation process. The release of proinflammatory cytokines and mediators is produced by the classically named M1-activated microglia, whereas the M2/resolution phenotype promotes neuroregeneration and the release of antiinflammatory cytokines. Thereby, this chapter summarizes the current evidence of MD diet components in mitigating microglia-mediated neuroinflammation.

Melatonin and serotonin are bioactive compounds present in foods and beverages and related to neuroprotection and anti-angiogenesis, among other activities. They have been described in wines and the role of yeast in their formation is clear. Thus, this study evaluates the content of these bioactives and other related indolic compounds in beer. For this purpose, commercial beers were analyzed by a validated UHPLC-HRMS method and sample treatment optimized due to the low concentrations expected. Moreover, a wort was fermented with different commercial beer yeast (Abbaye, Diamond, SafAle, SafLager) in order to monitor the formation of these bioactives during the elaboration process. Results show that indolic compounds such as N-acetylserotonin and 3-indoleacetic acid are produced during the alcoholic fermentation of wort. Moreover, the occurrence of four indolic compounds (5-hydroxytryptophan, N-acetylserotonin, 3-indoleacetic acid, l-tryptophan ethyl ester) in commercial beers is reported for the first time.

Anthocyanins are the major polyphenolic compounds in strawberry fruit responsible for its color. Due to their sensitivity, they are affected by food processing techniques such as fermentation that alters both their chemical composition and organoleptic properties. This work aims to evaluate the impact of different fermentation processes on individual anthocyanins compounds in strawberry wine and vinegar by UHPLC-MS/MS Q Exactive analysis. Nineteen, 18, and 14 anthocyanin compounds were identified in the strawberry initial substrate, strawberry wine, and strawberry vinegar, respectively. Four and 8 anthocyanin compounds were tentatively identified with high accuracy for the 1st time to be present in the beverages obtained by alcoholic fermentation and acetic fermentation of strawberry, respectively. Both, the total and the individual anthocyanin concentrations were decreased by both fermentation processes, affecting the alcoholic fermentation to a lesser extent (19%) than the acetic fermentation (91%). Indeed, several changes in color parameters have been assessed. The color of the wine and the vinegar made from strawberry changed during the fermentation process, varying from red to orange color, this fact is directly correlated with the decrease of anthocyanins compounds.

Hydroxytyrosol is well known for its potent antioxidant activity and anticarcinogenic, antimicrobial, cardioprotective and neuroprotective properties. Main food sources are olive oil (formed from the hydrolysis of oleuropein) and wine. One possible explanation to its origin in wines is the synthesis from tyrosol, which in turn is produced from the Ehrlich pathway by yeasts. This work aims to explore the factors that could increase the content as the strain of yeast, the initial tyrosine concentrations as precursor and the effect of synthetic and sterilized natural grape musts. Alcoholic fermentations in synthetic must showed that hydroxytyrosol is produced by all the yeast strains under study. Commercial Saccharomyces cerevisiae yeasts were those which produced higher concentrations, being the Red Fruit strain the biggest producer (6.12 ng/mL). Once the strain was selected, alcoholic fermentations were performed in synthetic must, with different tyrosine concentrations. The amount of hydroxytyrosol did not increase in a proportional way as tyrosine does. On the other hand, higher concentrations of hydroxytyrosol were obtained in natural grape musts (10.46 ng/mL) than in synthetic must (4.03 ng/mL). This work confirms the capacity of winemaking yeasts to produce the bioactive hydroxytyrosol.

Angiogenesis drives evolution and destabilisation of atherosclerotic plaques and the growth and expansion of tumour cells. Vascular endothelial growth factor (VEGF) is the main endogenous pro-angiogenic factor in humans. The aim was to provide insight into the anti-VEGF activity of bioactive compounds derived from aromatic amino acids (serotonin, melatonin, 3-indoleacetic acid, 5-hydroxytryptophol and hydroxytyrosol). Experiments involved endothelial cell migration (wound-healing assay), the molecular mechanisms (ELISA assay) and the downstream effects (phospholipase C gamma 1 (PLC&gamma, 1), protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) by Western blot) on human umbilical vein endothelial cells (HUVECs). The data suggest for the first time that hydroxytyrosol interacts with surface components of the endothelial cell membrane (, preventing VEGF from activating its receptor. Serotonin and 5-hydroxytryptophol significantly inhibited HUVEC migration (98% and 50%, respectively) following the same mechanism. Conversely to other bioactive compounds, the anti-angiogenic effect of melatonin, serotonin, 3-indoleacetic acid and 5-hydroxytryptophol is not mediated via PLC&gamma, 1. However, hydroxytyrosol inhibits PLC&gamma, 1 phosphorylation. Additionally, melatonin and serotonin maintained eNOS phosphorylation and hydroxytyrosol significantly activated eNOS&mdash, all via Akt. These data provide new evidence supporting the interest in melatonin, serotonin, 3-indoleacetic acid, 5-hydroxytryptophol and hydroxytyrosol for their further exploitation as anti-VEGF ingredients in food.

The abnormal assembly of α-synuclein (α-Syn) is an initial step in the formation of Lewy bodies in the brain, which finally causes the neuronal death, being considered as a pathological hallmark in Parkinson’s disease (PD). Certain food bioactives or their metabolites at very low concentrations can trespass the blood brain barrier (BBB) that might, thereafter, act simultaneously. The aim of this work was to evaluate the inhibitory and destabilising capacities on α-Syn kinetics and the neuroprotective effects of three well-known bioactive compounds able to cross the BBB and present in foods; melatonin (MEL), protocatechuic acid (PCA) and hydroxytyrosol (HT), and their combinations. For this purpose, different in vitro techniques (Thioflavin T (ThT), Transmission Electronic Microscopy (TEM), electrophoresis and MTT assay) were used. All tested compounds and their combinations were able to abolish the toxicity induced by α-Syn. In addition, the combination of PCA (100 µM) +HT (100 µM) showed the highest inhibitory effect against α-Syn fibril formation and destabilises α-Syn fibrils (88 and 62%, respectively). This is the first time that MEL, PCA and HT prove a joint effect against α-Syn aggregation and toxicity when they are tested together.

Melatonin supplements are used widely in Europe and the United States (US) to alleviate jet-lag and other sleep-delay disorders. Recently, the European Commission authorized two health claims for food containing melatonin, with a minimum dose per quantified portion. This study aimed to determine the dose of melatonin in food supplements marketed in Europe (Spain) and the US by validating a liquid chromatography method with diode array detection (LC-DAD). Additionally, contaminants present in melatonin supplements were analyzed using ultra-high-performance liquid chromatography coupled to an orbitrap mass spectrometer. We tentatively identified 8 tryptophan-related contaminants in melatonin supplements, suggesting tighter impurity control in melatonin supplements is necessary. The LC-DAD validated method achieved reliable results regarding recovery, precision, repeatability, limit of detection, limit of quantitation and linearity. Label melatonin dose varied from 1–1.95 mg/unit and 0.3–5 mg/unit for supplements marketed in Europe (Spain) and the US, respectively. Four out of seventeen supplements showed significant deviations from melatonin content declared on the label (from −60% to −20%). Regarding health claims, three out of the ten supplements purchased in Spain should not include the claim “reduction of time taken to fall asleep”, as their melatonin content is lower than 1 mg.

Orange juice is a rich source of bioactive compounds. Fermentation processes have been carried out in fruits, resulting in products with higher bioactive compound contents than the substrates. The aim of this study was to evaluate changes in phenolic acids, flavones and flavanone derivatives during the alcoholic fermentation process (15 days) in orange juice and to optimize the fermentation time. A total of 45 (poly)phenolic compounds were detected by UHPLC coupled with a linear trap quadrupole (LTQ) and Orbitrap Elite series mass analyser (UHPLC-Orbitrap-MS/MS). We tentatively identified 21 hydroxycinnamic acids, including ferulic acid, caffeic acid, and sinapic acid, in addition to 18 hydroxycinnamic acid derivatives (7 ferulic acid derivatives, 8 caffeic acid derivatives, 2 sinapic acid derivatives, a p-coumaric acid derivative) as well as 2 hydroxybenzoic acid derivatives, a hydroxypropionic acid derivative and other compounds (citric acid, quinic acid, 3 quinic acid derivatives) for the first time in fermented orange juice. In addition, 16 flavonoids, 7 flavanones (didymin, hesperidin, narirutin and 4 narirutin derivatives), 7 flavonols (kaempferol derivatives) and 2 flavones (diosmetin, vicenin-2) were putatively identified in fermented orange juice for the first time. Total hydroxycinnamic acid, benzoic acid, flavones and flavonol derivative contents showed significant increases (7.9, 4.7, 18.3 and 24.5%, respectively) on day 11 of fermentation relative to the original juice. The optimum time for the procedure was 11 days, after which the highest content of (poly)phenolic compounds was reached. The potential beverage produced by alcoholic fermentation of orange juice would exert greater health effects in humans than the substrate, derived from both the (poly)phenolic content and the low level of alcoholic content.

1 Scope We recently reported potent inhibition of VEGF signalling by two flavanols at sub‐micromolar concentrations, mediated by direct binding of the flavanols to VEGF. The aim of this study was to quantify the inhibitory potency and binding affinity of a wide range of dietary polyphenols and determine the structural requirements for VEGF inhibition. 2 Methods and results The concentration of polyphenol required to cause 50% inhibition (IC50) of VEGF‐dependent VEGFR‐2 activation in HUVECS was determined after pretreating VEGF with polyphenols at various concentations. Binding affinities and binding sites on VEGF were predicted using in‐silico modelling. Ellagic acid and 15 flavonoids had IC50 values ≤10 μM while 28 other polyhenols were weak/non‐inhibitors. Structural features associated with potent inhibition included 3‐galloylation, C‐ring C2=C3, total OH, B‐ring catechol, C‐ring 3‐OH of flavonoids. Potency was not associated with polyphenol hydrophobicity. There was a strong correlation between potency of inhibition and binding affinities, and all polyphenols were predicted to bind to a region on VEGF involved in VEGFR‐2 binding. 3 Conclusion Specific polyphenols bind directly to a discrete region of VEGF and inhibit VEGF signalling, and this potentially explains the associations between consumption of these polyphenols and CVD risk.

There is a considerable consensus that the increased production and/or aggregation of α-synuclein (αsyn) plays a central role in the pathogenesis of Parkinson's disease (PD). Therefore, a method of identifying molecules that block αsyn aggregation and prevent the loss of dopaminergic neurons is urgently needed in order to treat or slow the progression of PD. Hydroxytyrosol (HT), a well-known bioactive food compound present in olive oil, olives and wine, possesses demonstrated antioxidant and anti-inflammatory properties that can cross the Blood Brain Barrier (BBB). In the present work, the role of HT, tyrosol (TYR) and other tyrosine metabolites (hydroxyphenyl acetic acid (HPAA)) against αsyn aggregation, destabilisation and toxicity was evaluated through the use of different in vitro tests (Thioflavin T (ThT), Transmission Electronic Microscopy (TEM), electrophoresis and MTT assay). Results show that HT presents a strong inhibitory effect preventing αsyn aggregation and exercising a destabilising effect by disaggregating αsyn fibrils. Moreover, HT is able to counteract αsyn-induced toxicity. This is the first time that the effect of HT against αsyn toxicity and aggregation is evaluated. Thus, HT can be considered a promising compound for further approaches to tackling PD.

International audience; Scope: Amyloid-beta peptide is the main component of senile plaques in Alzheimer's disease. The inhibition of amyloid-beta peptide assembly, the destabilization of amyloid-beta peptide aggregates, and the decrease of its cytotoxicity for the prevention of neuronal death are considered neuroprotective effects. In this work, the protective effects against amyloid-beta peptide aggregation and cytotoxicity of eight indolic compounds are evaluated: tryptophan, tryptamine, serotonin, tryptophol, N-acetylserotonin, 3-indoleacetic acid, tryptophan ethyl ester, and melatonin. Methods and results: Thioflavin T spectroscopic assay, transmission electron microscopy, western blotting, circular dichroism, NMR, cell viability (thiazolyl blue tetrazolium bromide assay), quantitative PCR, and heme oxygenase activity are used. Serotonin is the most effective compound for inhibiting amyloid-beta peptide aggregation. Almost all the indolic compounds tested prevent amyloid-beta peptide-induced and increase cell viability, being between 9 and 25%. Melatonin and serotonin are the most active. Moreover, serotonin increased the expression of SIRT-1 and 2, heat shock protein 70, and heme oxygenase activity, this being a possible mechanism underlying the observed neuroprotective effect. Conclusion: Melatonin and other related indolic compounds, mainly serotonin, show an inhibitory and destabilizing effect on amyloid-beta peptide fibril formation and they possess neuroprotective properties related to the vitagenes system.

Neuroinflammation is a pathological feature of quite a number of Central Nervous System diseases such as Alzheimer and Parkinson’s disease among others. The hallmark of brain neuroinflammation is the activation of microglia, which are the immune resident cells in the brain and represents the first line of defense when injury or disease occur. Microglial activated cells can adopt different phenotypes to carry out its diverse functions. Thus, the shift into pro-inflammatory/neurotoxic or anti-inflammatory/neuroprotective phenotypes, depending of the brain environment, has totally changed the understanding of microglia in neurodegenerative disease. For this reason, novel therapeutic strategies which aim to modify the microglia polarization are being developed. Additionally, the understanding of how nutrition may influence the prevention and/or treatment of neurodegenerative diseases has grown greatly in recent years. The protective role of Mediterranean diet (MD) in preventing neurodegenerative diseases has been reported in a number of studies. The Mediterranean dietary pattern includes as distinctive features the moderate intake of red wine and extra virgin olive oil, both of them rich in polyphenolic compounds, such as resveratrol, oleuropein and hydroxytyrosol and their derivatives, which have demonstrated anti-inflammatory effects on microglia on in vitro studies. This review summarizes our understanding of the role of dietary phenolic compounds characteristic of the MD in mitigating microglia-mediated neuroinflammation, including explanation regarding their bioavailability, metabolism and blood–brain barrier. Ministerio de Economía y Competitividad (España) MICINN AGL2013-47300-C3-2-R, MICINN AGL2016-77505- C3-2-R

In this study, the nonanthocyanin (poly)phenolic profile of an alcoholic-fermented strawberry beverage was characterized. High-performance liquid chromatography coupled with a triple-quadropole mass spectrometer and ultra-high-performance liquid chromatography coupled with a linear trap quadropole and an Orbitrap mass analyzer was used to identify nonanthocyanin phenolic compounds. Sixty-six compounds were identified, and 13 of these were identified for the first time in strawberry or its derived alcoholic fermented beverage: protocatechuic acid-4-O-β-hexoside, brevifolin carboxylic acid, ferulic acid glucuronide, dimer caffeic acid-O-hexoside, luteolin-3'-O-xyloside, isorhamnetin 3-O-glucoside, taxifolin-O-glucoside, (+)-aromadendrin rhamnoside, eriodictyol-7-O-glucoside, (+)-taxifolin, (+)-aromadendrin, eriodictyol, and homovanillic acid. The alcoholic fermentation process produced significant increases in certain compounds, such as homovanillic acid and p-hydroxybenzoic acid, while a significant decrease in galloyl bis-HHDP-glucose was observed. Linear discriminant analysis correctly classified samples initial, final, and pasteurized, which led to the conclusion that alcoholic fermentation induces significant changes in composition, mainly in relation to the 19 compounds represented in the tables of this work.

cope Excessive concentrations of vascular endothelial growth factor (VEGF) drive angiogenesis and cause complications such as increased growth of tumours and atherosclerotic plaques. The aim of this study was to determine the molecular mechanism underlying the potent inhibition of VEGF signalling by polyphenols. Methods and results We show that the polyphenols epigallocatechin gallate from green tea and procyanidin oligomers from apples potently inhibit VEGF-induced VEGF receptor-2 (VEGFR-2) signalling in human umbilical vein endothelial cells by directly interacting with VEGF. The polyphenol-induced inhibition of VEGF-induced VEGFR-2 activation occurred at nanomolar polyphenol concentrations and followed bi-phasic inhibition kinetics. VEGF activity could not be recovered by dialysing VEGF-polyphenol complexes. Exposure of VEGF to epigallocatechin gallate or procyanidin oligomers strongly inhibited subsequent binding of VEGF to human umbilical vein endothelial cells expressing VEGFR-2. Remarkably, even though VEGFR-2 signalling was completely inhibited at 1 μM concentrations of polyphenols, endothelial nitric oxide synthase was shown to still be activated via the PI3K/Akt signalling pathway which is downstream of VEGFR-2. Conclusion These data demonstrate for the first time that VEGF is a key molecular target for specific polyphenols found in tea, apples and cocoa which potently inhibit VEGF signalling and angiogenesis at physiological concentrations. These data provide a plausible mechanism which links bioactive compounds in food with their beneficial effects.

Strawberries are harvested in a short period of time frequently involving fruit surplus. This paper studies the impact of the strawberry purée elaboration process on the chemical composition of the final products. Thirty-two phenolic compounds were studied by Liquid Chromatography with Diode Array Detector (LC-DAD) and Mass Spectrometry (LC-MS). An LC-DAD method was set up and validated and the non-anthocyanin phenolic profile was quantified at the different steps of production, for three elaboration processes and two harvests (2011 and 2012). We have tentatively identified apigenin-7-O-glucoside, luteolin-3-O-glucuronide, malonyl caffeoylquinic acid, trans-resveratrol glucoside and caffeoylglucaric isomer. (+)-Catechin and HHDP-galloylglucose were the most abundant phenolic compounds. The most abundant flavonol was kaempferol-3-glucoside. The purée maintains the fruit's non-anthocyanin phenolic composition and in vitro antioxidant activity as determined by ORAC and DPPH methods. This fact suggests that strawberry purée could be considered a valuable ingredient for producing food derivatives.

Strawberry is widely harvested in Spain. It is a highly perishable fruit and surplus production may be used to produce innovative foods. This paper studies the influence of gluconic fermentation by Gluconobacter japonicus on the non-anthocyanin content and antioxidant activity of strawberry. A total of 43 non-anthocyanin phenolic compounds were identified. To the best of our knowledge, this paper reports five compounds for the first time in strawberry and its derivatives, tentatively identified as: monogalloyl diglucose, 5-hydroxy feruloyl hexose, dihydrokaempferol hexoside, kaempferol neohesperidoside and (−)chicoric acid. It was further observed that gluconic fermentation leaves in vitro antioxidant activity practically unchanged. Gluconic fermentation by Gluconobacter japonicus can be considered a potential tool for producing fermented beverages. It transforms glucose into gluconic acid, which allows diabetics to consume the drink, while maintaining bioactive compound concentration and antioxidant activity. Industrial relevance As strawberry is a highly perishable product, fruits spoil quickly, leading to substantial economic losses. Therefore, the transformation of strawberry surplus into new, longer-lasting products is a financially worthwhile solution for the industry and producers. Our gluconic beverages were elaborated by traditional process using exclusively strawberry as raw material easily transferable to industrial scale. The main innovation aspect relies on developing an innovative product, aiming to fulfill consumers demand who are permanently seeking for different taste and flavors. At the same time its composition in sugars (non-glucose, original fructose content) makes these products very suitable for dietetic purposes.

International audience; Preventing the abnormal assembly of α-synuclein (α-Syn) and the correct modulation of vitagenes system exercise strong neuroprotective effects. It has been reported that melatonin (MEL), protocatechuic acid (PCA) and hydroxytyrosol (HT) reduce α-Syn toxicity. Their effect on the vitagenes system of PC12 cells have not been explored yet. These bioactive can cross the blood brain barrier (BBB). Therefore, this work aims to evaluate the inhibitory and destabilising capacities of MEL, PCA, HT, and their combinations on α-Syn kinetics and effects on vitagenes system (sirtuin-1 (SIRT-1), sirtuin-2 (SIRT-2), heme oxygenase (HO-1) and heat shock protein 70 (Hsp-70)). In vitro techniques (Thioflavin T (ThT), Transmission Electronic Microscopy (TEM), electrophoresis, MTT assay and qPCR) were used. Compounds, both individually and simultaneously were able to decrease the toxicity induced by α-Syn. Concurrently, occurrence of PCA (100 μM) +HT (100 μM) showed the highest inhibitory effect against α-Syn fibril formation and destabilisation of α-Syn fibrils (88 and 62%, respectively). Moreover, these compounds increased the expression of SIRT-2, HO-1 and Hsp70, contributing to a neuroprotective effect. In addition, the most important result is the increase on the expression of SIRT-2 caused by the combination of MEL + HT + PCA in the absence of α-Syn fibrils.

Excessive concentrations of vascular endothelial growth factor (VEGF) trigger angiogenesis, which causes complications such as the destabilization of atherosclerotic plaques and increased growth of tumors. This work focuses on the determination of the inhibitory activity of melatonin and other indolic related compounds on VEGF-induced VEGF receptor-2 (VEGFR-2) activation and an approximation to the molecular mechanism underlying the inhibition. Quantification of phosphorylated VEGFR-2 was measured by ELISA. Migration wound-healing assay was used to determine cell migration of human umbilical vein endothelial cells (HUVECs). This is the first time that melatonin, 3-indolacetic acid, 5-hydroxytryptophol, and serotonin are proved to significantly inhibit VEGF-induced VEGFR-2 activation in human umbilical vein endothelial cells and subsequent angiogenesis. 3-Indolacetic acid showed the highest inhibitory effect (IC50 value of 0.9704 mM), followed by 5-hydroxytryptophol (35% of inhibition at 0.1 mM), melatonin (30% of inhibition at 1 mM), and serotonin (24% of inhibition at 1 mM). An approximation to the molecular mechanism of the inhibition has been proposed, suggesting that indolic compounds might interact with the cell surface components of the endothelial membrane in a way that prevents VEGF from activating the receptor. Additionally, wound-healing assay revealed that exposure of HUVECs to melatonin and 3-indolacetic acid in the presence of VEGF significantly inhibited cell migration by 87% and 99%, respectively, after 24 h. These data demonstrate that melatonin, 3-indolacetic acid, 5-hydroxytryptophol, and serotonin would be good molecules for future exploitation as anti-VEGF signaling agents. España, Ministerio de Ciencia e Innovación AGL2013-47300-C3-2-R

Vinegar is the result of a double fermentation process (alcoholic fermentation followed by acetification) starting from any edible carbohydrate-rich source. It is widely consumed as a condiment and ingredient in different food formulations and recipes (sauces, marinades, dressings). The variety of vinegars in the market is relevant and new products are being introduced. Due to its acidic condition, vinegar exerts a preserving role in any food to which it is added, being an active killing agent for the main foodborne bacteria pathogens. Its health properties are related to its acetic acid content that exhibits antiglycemic and antidiabetic effects and to polyphenols present in it that act as antioxidants. More research involving human intervention trials is needed in order to properly substantiate the antiobesity, antihypercholesterolemic, and antiglycemic effects.

Protocatechuic acid (PCA) is the major metabolite of the anthocyanin known as cyanidin 3-glucoside. It is found in plasma and tissues, such as the brain, heart, liver, and kidneys, following consumption of a rich source of this flavonoid. The abnormal pathological assembly of amyloid-β (Aβ) and α-synuclein (αS) is an underlying mechanism involved in the formation of amyloid plaques and Lewy bodies in the brain, which are responsible for neuropathology symptoms in Alzheimer's (AD) and Parkinson's diseases (PD), respectively. This research was performed to evaluate the protective effects of PCA, by establishing its potential role in inhibiting aggregation and fibril destabilization of Aβ and αS proteins. It has been found that PCA inhibits the aggregation of Aβ and αS and destabilizes their preformed fibrils. These results were confirmed by TEM images, electrophoresis, and immunoblotting experiments. Furthermore, PCA prevents the death of PC12 cells triggered by Aβ- and αS-induced toxicity.

Wine intake affects the antioxidant enzyme activities that contribute to the overall antioxidant properties of wine. The purpose of this study is to evaluate whether alcohol-free wine has any effect on antioxidant enzymes. The study was a randomized cross-over human intervention. A low phenolic diet (LPD) was designed to prevent interference from polyphenols in other food sources. In the first period, the volunteers ate only this low phenolic diet; in the second, they ate this diet and also drank 300 mL of alcohol-free wine. The enzymes under study were: superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. The activities of glutathione reductase, superoxide dismutase and catalase decreased during the LPD period and increased in the LPD+dealcoholized wine period. On the third day of intervention, significant changes were observed in glutathione reductase and superoxide dismutase activity for both intervention periods under study. Catalase activity changed significantly on the seventh day of intervention. Antioxidant enzymes modulated their activity more easily than the endogenous antioxidants, which did not undergo any changes. Our results show for the first time that the increase in the activity of the antioxidant enzymes is not due to the alcohol content in wine but to the polyphenolic composition. Therefore, alcohol-free wine could be an excellent source of antioxidants to protect people suffering from oxidative stress (cancer, diabetes, alzheimer, etc.) who should not consume alcohol.

The purpose of this work is to evaluate the phenolic profile and the antioxidant activity of commercial dealcoholised wines and monitor the stability of their composition over time. This work also aims to test the influence of reverse osmosis (RO) process on phenolic compounds and on the antioxidant activity (AA) of dealcoholised wine. AA was measured by ORAC, DPPH and FRAP assays. Phenolic compounds were determined by LC-DAD. In the commercial dealcoholised wines, AA fell by between 33% and 54% and the concentration of phenolic compounds decreased significantly after 30 days of storage. However, RO process did not significantly affect any phenolic acids, regardless of their chemical structure (benzoic acids, cinnamic acids) and alcoholic degree. The AA and phenolic compounds of these products were monitored for seven months. No significant changes were observed. RO process therefore makes it possible to obtain a healthy, low-alcohol (

This paper explores the bioactive composition of strawberry (Camarosa variety) [Fragaria × ananassa (Rosaceae Family)] describing its anthocyanin composition and measuring the antioxidant activity (AA) of isolated pigments. Pelargonidin-3-glucoside was the major compound followed by pelargonidin-3-rutinoside and 11 pelargonidin and cyanidin derivatives, determined by LC–DAD–MS. Additionally, delphinidin-3-glucoside, peonidin-3-glucoside, and cyanidin-3-galactoside were tentatively identified for the first time in strawberry. Another original contribution was the identification of 5-carboxypyranopelargonidin-3-glucoside in the Camarosa strawberry variety. We isolated two different fractions with pelargonidin-3-glucoside and pelargonidin-3-rutinoside at 90% and 92% purity, respectively, using CCC. ORAC and FRAP assays showed that pelargonidin-3-glucoside is more active than 3-rutinoside. Thus, the sugar substituent determines AA. Pelargonidin-3-glucoside contributed to 32.61% (ORAC) and 17.58% (FRAP) of the overall AA of the extract. We submitted both the strawberry and the purified anthocyanin fractions to a simulated digestion process. The pelargonidin-3-rutinoside fraction and polymeric compounds maintained their AA.

Vinegars elaborated from white wine can be characterized by their phenolic composition. Indeed, for authenticity purpose, phenolic composition can be used to identify Sherry and Balsamic vinegars. However, the phenolic composition of red wine vinegars has scarcely been studied. Anthocyanin compounds in particular remain largely unknown. This study focuses on the analysis of anthocyanin compounds in red wine vinegar and the effect of acetification with submerged culture on such vinegars. The vinegar used in this study was produced from a young Cabernet Sauvignon wine in a laboratory-scale fermenter. Subsequent analyses of both wine and vinegar included their anthocyanin profile (by LC/MS), and their non-anthocyanin phenolic profile (by LC/DAD). In addition, wine and vinegar anthocyanin extracts were fractionated by CCC to determine the contribution of the fractions to overall antioxidant activity (AA), using ORAC, FRAP and DPPH assays. A total of 20 anthocyanin compounds were identified in the vinegar. As far as we know, this is the first time that anthocyanin-derived pigments (pyranoanthocyanins and ethyl-linked compounds) have been identified in red vinegar in such detail. Moreover, an original contribution of this study is the identification for the first time of catechyl-pyranocyanidin-3-glucoside in vinegar and wine, as well as two anthocyanin compounds not previously reported in vinegar or Cabernet Sauvignon wine: acetyl vitisin B and coumaroyl vitisin B. After the acetification process, vitisin-type and ethyl-linked compounds increased and monomeric anthocyanins, phenolic acids (ferulic acid, caffeic acid and caftaric acid) and flavan-3-ol ((+)-catechin) decreased. Although the proportion by weight of the polymeric compound fraction is similar in wine and vinegar, the AA of these polymers in vinegar is significantly greater (p

The traditional production of wine vinegar is a lengthy process with little or no microbiological control. The aim of this study was to shorten the acetification process via three different strategies: changes in wood type; barrel shape; and the inoculation of an Acetobacter pasteurianus pure culture. The barrel shape was modified by constructing two prototypes with higher liquid-air interface. We compared the changes in acetic acid bacteria (AAB) population dynamics in these barrels with those of a submerged method. The wood type had no effect on the acetification length, whereas the shape of the barrel resulted in a significant shortening of the acetification length. Although the selected AAB strain did not always take over, it reduced the biodiversity of the AAB. The inoculated strain was predominant in oak barrels, whereas in the highly aerated prototypes Gluconacetobacter species (Ga. intermedius and/or Ga. europaeus) displaced A. pasteurianus, as what occurs in the submerged method.

A procedure for the sensory analysis of vinegar, which provides reproducible results and minimizes the standard deviation of attributes, was developed. A new tasting protocol was proposed that leads to low dispersions of panelists' answers. The list of attributes that describe vinegars was extended to a total of 13, the importance (or discriminant utility) of which was analyzed by using Partial Least Squares Regression related techniques. The attributes selected showed a good between-run reproducibility as was shown by the Discriminant Partial Least Squares Regression analysis on replications. The proposed methodology proved to be useful for tasting very different types of wine vinegars (i.e., sherry and red and white wine vinegars). PRACTICAL APPLICATIONS As the vinegar market is now making products from different raw materials, we believed that it would be interesting to improve sensory analysis. The European Union (EU) regulates the sensory analysis of oil but not of vinegar. Our manuscript describes a tasting protocol that aims to provide more reproducible results, proposes a broader vocabulary for describing vinegars and uses statistical tools to verify the reliability of new attributes.

A crucial step in the production of high-quality wine vinegars is ageing in wood. This study aims to determine how wood barrels affect vinegar quality. For this purpose, vinegars were aged in barrels made from acacia, cherry, chestnut and oak wood. Two kinds of vinegars were studied: balsamic and red-wine vinegars. Analysis of samples included total phenol index (TPI), total monomeric anthocyanins (TA), dry extract, and phenolic and furanic compounds by liquid chromatography with photodiode array detection (LC–DAD) in a total of 98 samples. The concentration of HMF, 2-furfuraldehyde, protocatechualdehyde and vanillin significantly increased during ageing. Taxifolin is present in vinegars aged in cherry wood, confirmed by liquid chromatography–mass spectrometry/mass (LC–MS/MS). Hence, it can be a marker of vinegars aged in cherry wood. This is the first time that this compound has been identified in wine vinegars. On the other hand, ellagic acid is a characteristic compound for samples aged in chestnut and oak barrels. An unknown peak was found in all vinegar samples (groups F, T and M) which were aged in acacia wood. Linear discriminant analysis was used to classify samples as a function of the type of wood and ageing time, with phenolic compounds as variables. The linear functions obtained correctly classified – at 100% – red vinegars according to the type of wood. If ageing time (0–365 days) is considered, 62.5% and 100% of the red and balsamic vinegar samples, respectively, were well classified. The effect of wood on vinegar quality is obvious enough to be perceived by the senses in triangle tests. Woody, sweet and vanilla descriptors presented the highest scores for vinegars aged in oak wood. On the other hand, ageing in cherry wood increased markers for red-fruit attributes. These results prove that wood used in vinegar ageing determines both the chemical composition and sensorial properties.

The presence of phenolic compounds has been extensively studied in Sherry and Balsamic vinegars due to their impact on quality but little work has been done on red wine vinegars. Phenolic compounds were monitored during the acetification of red wine vinegars produced by surface culture in different wood barrels (oak, chestnut, acacia and cherry). A total of 166 samples were analysed for phenolic compounds using LC-DAD, the total phenol index (TPI) and the total monomeric anthocyanins (TA). Twelve phenolic compounds were identified corresponding to phenolic acids, flavanols and stilbens. Most phenolic acids did not significantly change their concentrations in the different acetifications. (+)-Catechin and resveratrol glycoside underwent significant decreases during acetification while gallic acid and gallic ethyl ester increased substantially for those vinegars produced in chestnut wood. The concentrations of phenolic compounds were used to build the functions for discriminant analysis. Samples belonging to two wine substrates (groups F and T) were correctly classified with 98.6% (group F) and 100% (group T) for the four types of wood barrels. During acetification a decrease (∼50%) in the content of total monomeric anthocyanins was observed. According to the results of triangle difference test the panel was able to distinguish most of the vinegars according to the different woods they were made in. The results of descriptive sensory analysis show that oak and cherry gave the maximum scores for most of the descriptors.

Overproduction of strawberry leads to food waste, as it is very perishable. Therefore, strategies to transform it into new products are appreciated. This research focuses on characterization of the nonanthocyanin phenolic content of a beverage obtained from strawberry by gluconic and acetic fermentation and subsequently monitored for 90 days of storage, at two temperatures. Sixty-four nonanthocyanin (poly)phenols were identified by high-resolution mass spectrometry (UHPLC coupled with linear trap quadrupole and Orbitrap mass analyzer) and, for the first time, four compounds were reported in beverages fermented from strawberry: aromadendrin hexoside, phloretin 2'-O-xylosyl glucoside, dihydroferulic acid 4-O-glucuronide, and kaempferol hexosyl hexoside. During the storage time the increase in protocatechuic acid content was 13 times and condensed tannins diminished, especially procyanidin trimer. Statistical analysis showed that the composition remains unchanged until day 15 of storage at room temperature (27-30 °C) and until day 30 under refrigerated conditions (4 °C).

Yeast metabolism produces compounds derived from tryptophan, which are found in fermented beverages, such as wine and beer. Melatonin and serotonin, in particular, may play a significant role due to their bioactivity in humans. Indeed, the former is a neurohormone related to circadiam rhythms, which also has a putative protective effect against degenerative diseases. Serotonin, on the other hand, is a neurotransmitter itself, in addition to being a precursor of melatonin synthesis. This paper summarizes data reported on fermented beverages, to evaluate dietary intake. Additionally, the article reviews observed effects of yeast amino acid metabolites on the prevention of neurodegenerative diseases (Alzheimer’s and Parkinson’s) and angiogenesis, focusing on evidence of the molecular mechanism involved and identification of molecular targets

Wood shavings are widely employed in vinegar making to reduce aging time. Accordingly, this study aims to evaluate the effects of using shavings from different wood species (acacia, cherry, chestnut, and oak) and of toasting on the release of phenolic compounds into vinegar during the aging process. The study involved aging vinegars using previously toasted shavings and untoasted ones, at 0.5% and 1% (w/v), and collecting samples at 15 and 30 days. The phenolic compounds were analyzed by LC-DAD during the aging process. As a result, wood markers naringenin and kaempferol (cherry), robinetin and fustin (acacia), and isovanillin (oak) were identified for the first time in vinegars. The results also showed that toasting wood shavings decreases the concentration of most flavonoid wood markers (e.g., (+)-taxifolin, naringenin, and fustin) in vinegar, but that it is essential for the highest releases of aldehyde compounds (syringaldehyde, protocatechualdehyde, and vanillin). Remarkably, 15 days was sufficient to obtain the highest increases of most polyphenol compounds in the vinegar. Statistical analysis (linear discriminant analysis) proved that the phenolic compounds identified in vinegars are useful for discriminating vinegars regarding the wood species of the shavings used to accelerate aging.