Tyrosol and its endogenous conversion into hydroxytyrosol in humans : Dietary sources, genetic modulation and clinical effects

Hydroxytyrosol is a health-promoting dietary phenol mainly present in extra virgin olive oil. Wine and beer are sources of tyrosol, a related phenolic compound. We have demonstrated that in humans tyrosol is endogenously converted into hydroxytyrosol following wine and beer consumption. Therefore, tyrosol rich foods could trigger equivalent health effects than those of hydroxytyrosol ones. The conversion of tyrosol into hydroxytyrosol is mediated by the polymorphic cytochrome P450 isoenzymes CYP2A6 and CYP2D6. In a randomized controlled clinical trial, we have shown that tyrosol and its conversion into hydroxytyrosol improved endothelial function in individuals at high cardiovascular risk following a 4-weeks of a dietary intervention enriched in tyrosol. A polygenic activity score to predict the metabolic fate of tyrosol to hydroxytyrosol based on CYP2A6 and CYP2D6 genotypes has also been developed. This score was capable of predicting the metabolism of tyrosol and the magnitude of the derived biological effects in a personalized manner.L’hidroxitirosol és un compost fenòlic amb propietats beneficioses per la salut present principalment en l’oli d’oliva verge extra. El vi i la cervesa són fonts de tirosol, un compost fenòlic relacionat. Hem demostrat que en humans el tirosol és convertit endògenament a hidroxitirosol després del consum d’aliments rics en tirosol com el vi o la cervesa. Conseqüentment, els aliments rics en tirosol, generarien efectes saludables equivalents als aliments rics en hidroxitirosol. La conversió és mediada per CYP2A6 i CYP2D6, dos isoenzims del citocrom P450 altament polimòrfics. Mitjançant un assaig clínic aleatori controlat s’ha evidenciat que el tirosol i la seva conversió a hidroxitirosol produeixen una millora en la funció endotelial en voluntaris amb risc cardiovascular després de 4 setmanes amb una dieta enriquida en tirosol. S’ha desenvolupat també un paràmetre de valoració numèric en base als genotips de CYP2A6 i CYP2D6 per predir el metabolisme del tirosol i la magnitud dels efectes biològics esperables de forma personalitzada

Tyrosol and its endogenous conversion into hydroxytyrosol in humans : Dietary sources, genetic modulation and clinical effects

Hydroxytyrosol is a health-promoting dietary phenol mainly present in extra virgin olive oil. Wine and beer are sources of tyrosol, a related phenolic compound. We have demonstrated that in humans tyrosol is endogenously converted into hydroxytyrosol following wine and beer consumption. Therefore, tyrosol rich foods could trigger equivalent health effects than those of hydroxytyrosol ones. The conversion of tyrosol into hydroxytyrosol is mediated by the polymorphic cytochrome P450 isoenzymes CYP2A6 and CYP2D6. In a randomized controlled clinical trial, we have shown that tyrosol and its conversion into hydroxytyrosol improved endothelial function in individuals at high cardiovascular risk following a 4-weeks of a dietary intervention enriched in tyrosol. A polygenic activity score to predict the metabolic fate of tyrosol to hydroxytyrosol based on CYP2A6 and CYP2D6 genotypes has also been developed. This score was capable of predicting the metabolism of tyrosol and the magnitude of the derived biological effects in a personalized manner.L’hidroxitirosol és un compost fenòlic amb propietats beneficioses per la salut present principalment en l’oli d’oliva verge extra. El vi i la cervesa són fonts de tirosol, un compost fenòlic relacionat. Hem demostrat que en humans el tirosol és convertit endògenament a hidroxitirosol després del consum d’aliments rics en tirosol com el vi o la cervesa. Conseqüentment, els aliments rics en tirosol, generarien efectes saludables equivalents als aliments rics en hidroxitirosol. La conversió és mediada per CYP2A6 i CYP2D6, dos isoenzims del citocrom P450 altament polimòrfics. Mitjançant un assaig clínic aleatori controlat s’ha evidenciat que el tirosol i la seva conversió a hidroxitirosol produeixen una millora en la funció endotelial en voluntaris amb risc cardiovascular després de 4 setmanes amb una dieta enriquida en tirosol. S’ha desenvolupat també un paràmetre de valoració numèric en base als genotips de CYP2A6 i CYP2D6 per predir el metabolisme del tirosol i la magnitud dels efectes biològics esperables de forma personalitzada

Wine and olive oil phenolic compounds interaction in humans

Extra virgin olive oil (EVOO) and red wine (RW) are two basic elements that form part of the so-called Mediterranean diet. Both stand out because of their high phenolic compound content and their potential related health benefits. The present study is focused on the metabolic disposition of resveratrol (RESV), tyrosol (TYR), and hydroxytyrosol (HT) following the consumption of EVOO, RW, and a combination of both. In this study, 12 healthy volunteers consumed a single dose of 25 mL of EVOO, 150 mL of RW, and a combination of both in a crossover randomized clinical trial. Urinary recovery of RESV, TYR, and HT was analysed in urine samples collected over a 6-h period following the intake of each treatment. Higher HT levels were observed following EVOO compared to RW (3788 1751 nmols and 2308 847 nmols respectively). After the combination of EVOO and RW, the recovery of TYR and HT metabolites increased statistically compared to their separate consumption (4925-1751 nmols of TYR and 6286 3198 nmols of HT). EVOO triggered an increase in glucuronide conjugates, while RW intake raised sulfate metabolites. Marginal effects were observed in RESV increased bioavailability after the combination of RW with the fat matrix provided by EVOO.This research was funded by the Instituto de Salud Carlos III (FI14/00072) and by grants from DIUE of Generalitat de Catalunya (2107 SGR 138). Miriam Martínez-Huélamo was supported by a Juan de la Cierva Formación postdoctoral fellowship from the Ministerio de Ciencia, Innovación y Universidades (FJCI-2015-25075) and Anna Boronat by a PFIS predoctoral fellowship from the Instituto de Salud Carlos III (PFIS-FI16/00106)

Olive oil phenolic compounds' activity against age-associated cognitive decline: clinical and experimental evidence

Epidemiological studies have shown that consuming olive oil rich in phenolic bioactive compounds is associated with a lower risk of neurodegenerative diseases and better cognitive performance in aged populations. Since oxidative stress is a common hallmark of age-related cognitive decline, incorporating exogenous antioxidants could have beneficial effects on brain aging. In this review, we firstly summarize and critically discuss the current preclinical evidence and the potential neuroprotective mechanisms. Existing studies indicate that olive oil phenolic compounds can modulate and counteract oxidative stress and neuroinflammation, two relevant pathways linked to the onset and progression of neurodegenerative processes. Secondly, we summarize the current clinical evidence. In contrast to preclinical studies, there is no direct evidence in humans of the bioactivity of olive oil phenolic compounds. Instead, we have summarized current findings regarding nutritional interventions supplemented with olive oil on cognition. A growing body of research indicates that high consumption of olive oil phenolic compounds is associated with better preservation of cognitive performance, conferring an additional benefit, independent of the dietary pattern. In conclusion, the consumption of olive oil rich in phenolic bioactive compounds has potential neuroprotective effects. Further research is needed to understand the underlying mechanisms and potential clinical applications

Ferulic acid metabolites attenuate LPS-induced inflammatory response in enterocyte-like cells

Ferulic acid (FA) is a polyphenol pertaining to the class of hydroxycinnamic acids present in numerous foods of a plant origin. Its dietary consumption leads to the formation of several phase I and II metabolites in vivo, which represent the largest amount of ferulates in the circulation and in the intestine in comparison with FA itself. In this work, we evaluated their efficacy against the proinflammatory effects induced by lipopolysaccharide (LPS) in intestinal Caco-2 cell monolayers, as well as the mechanisms underlying their protective action. LPS-induced overexpression of proinflammatory enzymes such as inducible nitric oxide synthase (iNOS) and the consequent hyperproduction of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) were limited by physiological relevant concentrations (1 µM) of FA, its derivatives isoferulic acid (IFA) and dihydroferulic acid (DHFA), and their glucuronidated and sulfated metabolites, which acted upstream by limiting the activation of MAPK p38 and ERK and of Akt kinase, thus decreasing the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) translocation into the nucleus. Furthermore, the compounds were found to promote the expression of Nrf2, which may have contributed to the downregulation of NF-ĸB activity. The overall data show that phase I/II metabolites retain the efficacy of their dietary free form in contrasting inflammatory response

Beer phenolic composition of simple phenols, prenylated flavonoids and alkylresorcinols

Beer is a fermented beverage with beneficial phenolic compounds and is widely consumed worldwide. The current study aimed to describe the content of three families of phenolic compounds with relevant biological activities: prenylated flavonoids (from hops), simple phenolic alcohols (from fermentation) and alkylresorcinols (from cereals) in a large sample of beers (n = 45). The prenylated flavonoids analyzed were xanthohumol, isoxanthohumol, 6- and 8-prenylnaringenin. The total prenylated flavonoids present in beer ranged from 0.0 to 9.5 mg/L. The simple phenolic alcohols analyzed were tyrosol and hydroxytyrosol, ranging from 0.2 to 44.4 and 0.0 to 0.1 mg/L, respectively. Our study describes, for the first time, the presence of low amounts of alkylresorcinols in beer, in concentrations ranging from 0.02 to 11.0 µg/L. The results in non-alcoholic beer and the differences observed in the phenolic composition among different beer types and styles highlight the importance of the starting materials and the brewing process (especially fermentation) on the final phenolic composition of beer. In conclusion, beer represents a source of phenolic compounds in the diet that could act synergistically, triggering beneficial health effects in the context of its moderate consumption.This research was funded by the Instituto de Salud Carlos III FEDER (PI14/00072) and by grants from DIUE of Generalitat de Catalunya (2017 SGR138). AB is recipient of a PFIS predoctoral fellowship from the Instituto Carlos III FEDER (PFIS-FI16/00106), NSD is recipient of predoctoral fellowship (2019-DI-47) from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) Generalitat de Catalunya. JMR is recipient of Marie Skłodowska-Curie grant agreement (No 712949) and from ACCIO. CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the ISCIII, Madrid, Spain

Effects of wine and tyrosol on the lipid metabolic profile of subjects at risk of cardiovascular disease: potential cardioprotective role of ceramides

Ceramides are a class of sphingolipids which have recently been shown to be better cardiovascular disease (CVD) risk predictors than traditional CVD risk biomarkers. Tyrosol (TYR) is a dietary phenolic compound known to possess cardioprotective effects per se or through its in vivo active metabolite hydroxytyrosol. The purpose of this study was to evaluate the effects of the co-administration of white wine (WW) and TYR on circulating levels of ceramides and other lipids in humans at high CVD risk. Volunteers underwent a randomized controlled crossover clinical trial (4-week duration per intervention) with three different interventions: control, WW, and WW enriched with a capsule of TYR (WW + TYR). Endothelial function cardiovascular biomarkers and plasma lipidomic profile were assessed before and after each intervention. It was found that the WW + TYR intervention resulted in lower levels of three ceramide ratios, associated with an improvement of endothelial function (Cer C16:0/Cer C24:0, Cer C18:0/Cer C24:0, and Cer C24:1/Cer C24:0), when compared to the control intervention. Moreover, WW + TYR was able to minimize the alterations in plasma diacylglycerols concentrations observed following WW. Overall, the results obtained show that the antioxidant TYR administered with WW exerts beneficial effects at the cardiovascular level, in part by modulating blood lipid profile

Prevention of cognitive decline in subjective cognitive decline APOE ε4 carriers after EGCG and a multimodal intervention (PENSA): Study design

Introduction: Subjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer's disease prevention trials. Methods: The PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention + EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color and Word Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium. Discussion: The use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions

Plasma concentrations of oleoylethanolamide in a primary care sample of depressed patients are increased in those treated with selective serotonin reuptake inhibitor-type antidepressants

Oleoylethanolamide (OEA) is a non-cannabinoid acylethanolamide with multiple physiological roles that has been proposed to have antidepressant-like activity in preclinical models. OEA shares biosynthetic pathways with anandamide (AEA) a transmitter involved in affective disorders and anxiety in humans. However, although the participation of OEA in depression has been proposed, both, the contribution of OEA to the depressive phenotype and the effect of antidepressant therapy on circulating levels of this and related non-cannabinoid acylethanolamides in humans are basically unknown. The main objective of this study is to compare the plasma concentrations of OEA and related acylethanolamides in a sample of primary care patients with depression (n = 69) with those of healthy non-depressed patients (n = 47). At the time of admission to the study, 22 patients were under selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and 47 patients were not receiving any type of intervention. In addition, plasma concentrations of the endocannabinoid 2-AG and two related monoacylglycerols were monitored. Plasma OEA concentrations were found to be elevated in depressed patients and to correlate with somatic symptoms of depression. Plasma concentrations of both, AEA and 2-AG, were found to be elevated also in depressed patients. Further analysis demonstrated that the elevation observed in the plasma concentrations of both, OEA and 2-AG, was associated to SSRI antidepressant therapy at the time of recruitment. Further clinical research is needed to understand whether SSRI-induced elevations in OEA levels contribute to the response to SSRI in depressed patients as described in preclinical models

Sex differences in endocannabinoids during 3 years of Mediterranean diet intervention: Association with insulin resistance and weight loss in a population with metabolic syndrome

Background: Excess circulating endocannabinoids (eCBs) and imbalanced N-acylethanolamines (NAEs) related eCBs abundance could influence dietary weight loss success. We aimed to examine sex differences in the impact of a 3-years Mediterranean diet (MedDiet) intervention on circulating eCBs, NAEs and their precursor fatty acids, and to analyze the interplay between changes in eCBs or NAEs ratios, insulin resistance and the achievement of clinically meaningful weight reductions. Methods: Prospective cohort study in a subsample of N = 105 participants (54.3% women; 65.6 ± 4.6 years) with overweight or obesity and metabolic syndrome that underwent a 3-years MedDiet intervention (PREDIMED-Plus study). Plasma eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), fatty acids, diet, glycemic homeostasis (including the assessment of insulin resistance-HOMA-IR), and cardiovascular risk markers were monitored (at 0-6-12-36 months). Results: Mediterranean diet adherence increased in both sexes and remained high during the 3 years of follow-up. Reductions in body weight, glycemic and cardiovascular parameters were larger in men than in women. Women presented higher concentrations of NAEs than men throughout the study. In both sexes, AEA and other NAEs (including OEA, and PEA) decreased after 6 months (for AEA: -4.9%), whereas the ratio OEA/AEA increased after 1 year (+5.8%). Changes in 2-AG (-3.9%) and the ratio OEA/PEA (+8.2%) persisted over the 3 years of follow-up. In women, 6-months changes in AEA (OR = 0.65) and the ratio OEA/AEA (OR = 3.28) were associated with the achievement of 8% weight reductions and correlated with HOMA-IR changes (r = 0.29 and r = -0.34). In men, OEA/PEA changes were associated with 8% weight reductions (OR = 2.62) and correlated with HOMA-IR changes (r = -0.32). Conclusion: A 3-years MedDiet intervention modulated plasma concentrations of eCBs and NAEs. Changes in AEA and in the relative abundance of NAEs were associated with clinically meaningful weight reductions. However, marked sex differences were identified in eCBs and NAEs, as well as in the efficacy of the intervention in terms of glycemic and cardiovascular parameters, which could be related to post-menopause alterations in glucose metabolism. These findings support a sex-balanced research strategy for a better understanding of the mechanisms underlying the regulation of body weight loss