Search

Abstract Background The Mediterranean diet (MedDiet) has demonstrated efficacy in preventing age-related cognitive decline and modulating plasma concentrations of endocannabinoids (eCBs) and N-acylethanolamines (NAEs, or eCB-like compounds), which are lipid mediators involved in multiple neurological disorders and metabolic processes. Hypothesizing that eCBs and NAEs will be biomarkers of a MedDiet intervention and will be related to the cognitive response, we investigated this relationship according to sex and apolipoprotein E (APOE) genotype, which may affect eCBs and cognitive performance. Methods This was a prospective cohort study of 102 participants (53.9% women, 18.8% APOE-ɛ4 carriers, aged 65.6 ± 4.5 years) from the PREDIMED-Plus-Cognition substudy, who were recruited at the Hospital del Mar Research Institute (Barcelona). All of them presented metabolic syndrome plus overweight/obesity (inclusion criteria of the PREDIMED-Plus) and normal cognitive performance at baseline (inclusion criteria of this substudy). A comprehensive battery of neuropsychological tests was administered at baseline and after 1 and 3 years. Plasma concentrations of eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and N-docosahexaenoylethanolamine (DHEA), were also monitored. Baseline cognition, cognitive changes, and the association between eCBs/NAEs and cognition were evaluated according to gender (crude models), sex (adjusted models), and APOE genotype. Results At baseline, men had better executive function and global cognition than women (the effect size of gender differences was − 0.49, p = 0.015; and − 0.42, p = 0.036); however, these differences became nonsignificant in models of sex differences. After 3 years of MedDiet intervention, participants exhibited modest improvements in memory and global cognition. However, greater memory changes were observed in men than in women (Cohen’s d of 0.40 vs. 0.25; p = 0.017). In men and APOE-ε4 carriers, 2-AG concentrations were inversely associated with baseline cognition and cognitive changes, while in women, cognitive changes were positively linked to changes in DHEA and the DHEA/AEA ratio. In men, changes in the OEA/AEA and OEA/PEA ratios were positively associated with cognitive changes. Conclusions The MedDiet improved participants’ cognitive performance but the effect size was small and negatively influenced by female sex. Changes in 2-AG, DHEA, the OEA/AEA, the OEA/PEA and the DHEA/AEA ratios were associated with cognitive changes in a sex- and APOE-dependent fashion. These results support the modulation of the endocannabinoid system as a potential therapeutic approach to prevent cognitive decline in at-risk populations. Trial registration ISRCTN89898870.

Abstract G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HT2AR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HT2AR coupling signature in response to different signaling probes, and its physiological consequences by combining computational modeling, in vitro and in vivo experiments with human postmortem brain studies. We show how chemical modification of the endogenous agonist serotonin dramatically impacts the G protein coupling profile of the 5-HT2AR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by Gαq protein activation, whereas psychosis-related behavior is modulated through Gαi1 stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.

Extra virgin olive oil (EVOO) represents a significant source of monounsaturated fatty acids (MUFA) and vitamin E, but it is also considered a functional food, due to the content of peculiar bioactive molecules, such as phenolic compounds, being able to modulate various processes related to aging and the most common metabolic and degenerative diseases. A lot of experimental research has focused on some of these components, but in most cases, the studies were performed in vitro testing compounds at non-physiological concentrations and achieving results that cannot easily be translated in vivo. Recent clinical studies demonstrated that in vivo these compounds are able to regulate physiological functions and prevent several pathological events including metabolic and cardiovascular diseases (CVDs), which represent the main causes of death worldwide. This review aims to sum up the major evidence on the beneficial effects of EVOO phenolic compounds in vivo on these pathologies, describing and evaluating the efficacy in relation to the mechanisms of diseases of the whole phenolic fraction and some of its specific components.

IntroductionThe maintenance of endothelial barrier function is essential for vasal homeostasis and prevention of cardiovascular diseases. Among the toxic stimuli involved in the initiation of atherosclerotic lesions, Gram negative lipopolysaccharide (LPS) has been reported to be able to trigger endothelial dysfunction, through the alteration of barrier permeability and inflammatory response. Hydroxytyrosol (HT) and tyrosol (Tyr), the major phenolic compounds of extra virgin olive oil (EVOO), as wells as their circulating sulphated and glucuronidated metabolites have been shown to exert anti-inflammatory effects at endothelial level.MethodsIn this study we investigated the protective effects of HT and Tyr metabolites on LPS-induced alteration of permeability in Human Umbilical Vein Endothelial Cells (HUVEC) monolayers and examined underlying signaling pathways, focusing on tight junction (TJ) proteins, mitogen-activated protein kinase (MAPK) and NOD-, LRR-and pyrin domain-containing protein 3 (NLRP3) inflammasome activation.ResultsIt was shown that LPS-increased permeability in HUVEC cells was due to the alteration of TJ protein level, following the activation of MAPK and NLRP3. HT and Tyr sulphated and glucuronidated metabolites were able to limit the effects exerted by LPS, acting as signaling molecules with an efficacy comparable to that of their precursors HT and Tyr.DiscussionThe obtained results add a further piece to the understanding of HT and Tyr metabolites mechanisms of action in vascular protection.

Almost all individuals with Down’s syndrome (DS) show the characteristic neuropathological features of Alzheimer’s disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-β1 (TGF-β1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-β1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19–35 years) and older DS subjects without AD (35–60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-β1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-β1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-β1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-β1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-β1 concentrations in DS subjects at higher risk to develop cognitive decline.

The impact of dietary intake on cognitive outcomes and dementia prevention is a topic of increasing interest. Meta-analyses of observational studies, mostly conducted within US and European populations, have reported benefits of healthy diet patterns on cognitive performance, but results from individual studies have been inconsistent. These inconsistencies are likely due to the diverse methodology used in studies, including different diet and cognitive function assessment instruments, follow-up periods, and analytical methods, which make drawing conclusions relevant to dietary guidance challenging. The objective of this project is to describe a protocol to conduct a retrospective harmonization study on dietary intake and cognitive health using data from European and US studies. The recommendations resulting from the project can be used to support evidence-based synthesis for future iterations of the Dietary Guidelines for Americans or other population-based dietary guidance. Additionally, this study will serve as a harmonization guide for future research on the relationship between diet patterns and cognition. The approach outlined ultimately aims to optimize resources and expedite research efforts for dementia prevention.

Summary: Traditional neuropsychological tests accurately describe the current cognitive state but fall short to characterize cognitive change over multiple short time periods. We present an innovative approach to remote monitoring of executive functions on a monthly basis, which leverages the performance indicators from self-administered computerized cognitive training games (NUP-EXE). We evaluated the measurement properties of NUP-EXE in N = 56 individuals (59% women, 60–80 years) at increased risk of Alzheimer’s disease (APOE-ϵ4 carriers with subjective cognitive decline) who completed a 12-month multimodal intervention for preventing cognitive decline. NUP-EXE presented good psychometric properties and greater sensitivity to change than traditional tests. Improvements in NUP-EXE correlated with improvements in functionality and were affected by participants’ age and gender. This novel data collection methodology is expected to allow a more accurate characterization of an individual’s response to a cognitive decline preventive intervention and to inform development of outcome measures for a new generation of intervention trials.

Abstract Background Few studies have analyzed the associations between impulsivity and dietary patterns. Some of them have shown a cross-sectional inverse relationship between impulsivity and healthy diet scores, whereas others reported a positive association with unhealthy dietary assessments. We aimed to examine longitudinal associations of impulsivity trait with adherence to healthy and unhealthy dietary patterns in older participants at high risk of cardiovascular disease over 3 years of follow-up. Methods A 3-year prospective cohort analysis within the PREDIMED-Plus-Cognition study conducted in 4 PREDIMED-Plus study centers was performed. The PREDIMED-Plus study aimed to test the beneficial effect of a lifestyle intervention on the primary prevention of cardiovascular disease. The participants with overweight or obesity and metabolic syndrome included in the present study (n = 462; mean age of 65.3 years; 51.5% female) completed both the UPPS-P Impulsive Behavior Scale (range: 0–236 points) and the 143-item Food Frequency Questionnaire at baseline, 1-year and 3-years of follow-up. Ten diet scores assessing healthy and unhealthy dietary patterns were evaluated. Linear mixed models were performed adjusting by several confounders to study the longitudinal associations between impulsivity trait and adherence to dietary pattern scores over 3 years of follow-up (also assessing interactions by sex, age, and intervention group). Results Impulsivity were negatively associated with adherence to the Healthy Plant-Based [β = -0.92 (95%CI -1.67, -0.16)], Mediterranean [β = -0.43 (95%CI -0.79, -0.07)], Energy-Restricted Mediterranean [β = -0.76 (95%CI -1.16, -0.37)], Alternative Healthy Eating Index [β = -0.88 (95%CI -1.52, -0.23)], Portfolio [β = -0.57 (95%CI -0.91, -0.22)], and DASH [β = -0.50 (95%CI -0.79, -0.22)] diet scores over 3 years of follow-up, whereas impulsivity was positively related with adherence to the unhealthy Western diet [β = 1.59 (95%CI 0.59, 2.58)] over time. An interaction by intervention group was found, with those participants in the intervention group with high impulsivity levels having lower adherence to several healthy dietary patterns. Conclusions Heightened impulsivity was longitudinally associated with lower adherence to healthy dietary patterns and higher adherence to the Western diet over 3 years of follow-up. Furthermore, nutritional intervention programs should consider impulsivity as a relevant factor for the intervention success. Trial registration Name of registry: Effect of an energy-restricted Mediterranean diet, physical activity and behavioral intervention on the primary prevention of cardiovascular disease. Trial registration number: ISRCTN 89,898,870. Date of registration: 05/28/2014.

Abstract Introduction Different components of the endocannabinoid (eCB) system such as their most well-known endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), have been implicated in brain reward pathways. While shared neurobiological substrates have been described among addiction-related disorders, information regarding the role of this system in behavioral addictions such as gambling disorder (GD) is scarce. Aims Fasting plasma concentrations of AEA and 2-AG were analyzed in individuals with GD at baseline, compared with healthy control subjects (HC). Through structural equation modeling, we evaluated associations between endocannabinoids and GD severity, exploring the potentially mediating role of clinical and neuropsychological variables. Methods The sample included 166 adult outpatients with GD (95.8% male, mean age 39 years old) and 41 HC. Peripheral blood samples were collected after overnight fasting to assess AEA and 2-AG concentrations (ng/ml). Clinical (i.e., general psychopathology, emotion regulation, impulsivity, personality) and neuropsychological variables were evaluated through a semi-structured clinical interview and psychometric assessments. Results Plasma AEA concentrations were higher in patients with GD compared with HC (p = .002), without differences in 2-AG. AEA and 2-AG concentrations were related to GD severity, with novelty-seeking mediating relationships. Conclusions This study points to differences in fasting plasma concentrations of endocannabinoids between individuals with GD and HC. In the clinical group, the pathway defined by the association between the concentrations of endocannabinoids and novelty-seeking predicted GD severity. Although exploratory, these results could contribute to the identification of potential endophenotypic features that help optimize personalized approaches to prevent and treat GD.

Abstract Background Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) play a pivotal role in stimulating motivational behavior toward food and energy metabolism. Aberrant functioning of the endocannabinoid system has been observed in extreme weight conditions (EWCs), suggesting it may influence pathophysiology. Then, we aimed to analyze fasting AEA and 2-AG plasma concentrations among individuals with EWC (i.e., anorexia nervosa [AN] and obesity with and without eating disorders [EDs]) compared with healthy controls (HCs), and its association with clinical variables and body mass index (BMI). Methods The sample included 113 adult women. Fifty-seven belonged to the obesity group, 37 without EDs (OB-ED) and 20 with ED (OB+ED classified within the binge spectrum disorders), 27 individuals from the AN group, and 29 from the HC group. Peripheral blood samples, several clinical variables, and BMI were evaluated. Results Unlike 2-AG, AEA concentrations showed significant differences between groups (p

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212–2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.

BackgroundExcess 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.MethodsProspective 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).ResultsMediterranean 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).ConclusionA 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.

Williams–Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

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.

En este trabajo se presenta al público un mapa inédito de Galicia, levantado en 1763 por el ingeniero militar gallego, Feliciano Míguez y que se consideraba en paradero desconocido. La única referencia a este mapa la hizo el cartógrafo Tomás López cuando lo relacionó entre las obras empleadas para formar el suyo, publicado en 1784. En este estudio se ofrece una pequeña biografía de su autor, se analizan los aspectos formales y técnicos del mapa, se traza un recorrido por las instituciones en las que estuvo depositado y en las que pasó desapercibida su trascendencia e importancia y, finalmente, se establece su posible relación con otros mapas que se formaron en Galicia en la misma década. [gl] Neste traballo preséntase ao público un mapa inédito de Galicia, levantado en 1763 polo enxeñeiro militar galego, Feliciano Míguez e que se consideraba en paradoiro descoñecido. A única referencia deste mapa fíxoa o cartógrafo Tomás López cando o relacionou entre as obras empregadas para formar o seu, publicado en 1784. Neste estudo ofrécese unha pequena biografía do seu autor, analízanse os aspectos formais e técnicos do mapa, faise un percorrido polas institucións nas que estivo depositado e nas que pasou desapercibida a súa transcendencia e importancia e, finalmente, inténtase establecer unha posible relación con outros mapas que se formaron en Galicia na mesma década.

Abstract This study examines if overweight/obesity are related to higher impulsivity, food addiction and depressive symptoms, and if these variables could be modified after 1 year of a multimodal intervention (diet, physical activity, psychosocial support). 342 adults (55–75 years) with overweight/obesity and metabolic syndrome (MetS) from the PREDIMED-Plus Cognition study were randomized to the intervention or to the control group (lifestyle recommendations). Cognitive and psychopathological assessments were performed at baseline and after 1-year follow-up. At baseline, higher impulsivity was linked to higher food addiction and depressive symptoms, but not to body mass index (BMI). Food addiction not only predicted higher BMI and depressive symptoms, but also achieved a mediational role between impulsivity and BMI/depressive symptoms. After 1 year, patients in both groups reported significant decreases in BMI, food addiction and impulsivity. BMI reduction and impulsivity improvements were higher in the intervention group. Higher BMI decrease was achieved in individuals with lower impulsivity. Higher scores in food addiction were also related to greater post-treatment impulsivity. To conclude, overweight/obesity are related to higher impulsivity, food addiction and depressive symptoms in mid/old age individuals with MetS. Our results also highlight the modifiable nature of the studied variables and the interest of promoting multimodal interventions within this population.

Abstract Trisomy of human chromosome 21 (Down syndrome, DS) alters development of multiple organ systems, including the face and underlying skeleton. Besides causing stigmata, these facial dysmorphologies can impair vital functions such as hearing, breathing, mastication, and health. To investigate the therapeutic potential of green tea extracts containing epigallocatechin-3-gallate (GTE-EGCG) for alleviating facial dysmorphologies associated with DS, we performed an experimental study with continued pre- and postnatal treatment with two doses of GTE-EGCG supplementation in a mouse model of DS, and an observational study of children with DS whose parents administered EGCG as a green tea supplement. We evaluated the effect of high (100 mg/kg/day) or low doses (30 mg/kg/day) of GTE-EGCG, administered from embryonic day 9 to post-natal day 29, on the facial skeletal development in the Ts65Dn mouse model. In a cross-sectional observational study, we assessed the facial shape in DS and evaluated the effects of self-medication with green tea extracts in children from 0 to 18 years old. The main outcomes are 3D quantitative morphometric measures of the face, acquired either with micro-computed tomography (animal study) or photogrammetry (human study). The lowest experimentally tested GTE-EGCG dose improved the facial skeleton morphology in a mouse model of DS. In humans, GTE-EGCG supplementation was associated with reduced facial dysmorphology in children with DS when treatment was administered during the first 3 years of life. However, higher GTE-EGCG dosing disrupted normal development and increased facial dysmorphology in both trisomic and euploid mice. We conclude that GTE-EGCG modulates facial development with dose-dependent effects. Considering the potentially detrimental effects observed in mice, the therapeutic relevance of controlled GTE-EGCG administration towards reducing facial dysmorphology in young children with Down syndrome has yet to be confirmed by clinical studies.

There has been a renewed interest in the potential use of psychedelics for the treatment of psychiatric conditions. Nevertheless, little is known about the mechanism of action and molecular pathways influenced by ayahuasca use in humans. Therefore, for the first time, our study aims to investigate the human metabolomics signature after consumption of a psychedelic, ayahuasca, and its connection with both the psychedelic-induced subjective effects and the plasma concentrations of ayahuasca alkaloids.Plasma samples of 23 individuals were collected both before and after ayahuasca consumption. Samples were analysed through targeted metabolomics and further integrated with subjective ratings of the ayahuasca experience (i.e., using the 5-Dimension Altered States of Consciousness Rating Scale [ASC]), and plasma ayahuasca-alkaloids using integrated network analysis. Metabolic pathways enrichment analysis using diffusion algorithms for specific KEGG modules was performed on the metabolic output.Compared to baseline, the consumption of ayahuasca increased N-acyl-ethanolamine endocannabinoids, decreased 2-acyl-glycerol endocannabinoids, and altered several large-neutral amino acids (LNAAs). Integrated network results indicated that most of the LNAAs were inversely associated with 9 out of the 11 subscales of the ASC, except for tryptophan which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with the ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in several pathways involved in neurotransmission such as serotonin and dopamine synthesis.In conclusion, a crosstalk between the circulating LNAAs and the subjective effects is suggested, which is independent of the alkaloid concentrations and provides insights into the specific metabolic fingerprint and mechanism of action underlying ayahuasca experiences.

Background and Aims: Plant-forward dietary patterns have been associated with cardiometabolic health benefits, which, in turn, have been related to cognitive performance with inconsistent findings. The objective of this study was to examine the relationship between baseline adherence to three a priori dietary patterns (Mediterranean, DASH, and MIND diets) with 2-year changes in cognitive performance in older adults with overweight or obesity and high cardiovascular disease risk.Methods: A prospective cohort analysis was conducted within the PREDIMED-Plus trial, involving 6,647 men and women aged 55–75 years with overweight or obesity and metabolic syndrome. Using a validated, semiquantitative 143-item food frequency questionnaire completed at baseline, the dietary pattern adherence scores were calculated. An extensive neuropsychological test battery was administered at baseline and 2-year follow-up. Multivariable-adjusted linear regression models were used to assess associations between 2-year changes in cognitive function z-scores across tertiles of baseline adherence to the a priori dietary patterns.Results: Adherence to the Mediterranean diet at baseline was associated with 2-year changes in the general cognitive screening Mini-Mental State Examination (MMSE, β: 0.070; 95% CI: 0.014, 0.175, P-trend = 0.011), and two executive function-related assessments: the Trail Making Tests Part A (TMT-A, β: −0.054; 95% CI: −0.110, − 0.002, P-trend = 0.047) and Part B (TMT-B, β: −0.079; 95% CI: −0.134, −0.024, P-trend = 0.004). Adherence to the MIND diet was associated with the backward recall Digit Span Test assessment of working memory (DST-B, β: 0.058; 95% CI: 0.002, 0.114, P-trend = 0.045). However, higher adherence to the DASH dietary pattern was not associated with better cognitive function over a period of 2 years.Conclusion: In older Spanish individuals with overweight or obesity and at high cardiovascular disease risk, higher baseline adherence to the Mediterranean dietary pattern may be associated with better cognitive performance than lower adherence over a period of 2 years.

Chronic alcohol intake has been shown to disrupt gut microbiota homeostasis, but whether microbiota modulation could prevent behavioral alterations associated with chronic alcohol intake remains unknown. We investigated the effects of synbiotic dietary supplementation on the development of alcohol-related addictive behavior in female and male mice and evaluated whether these effects were associated with changes in bacterial species abundance, short-chain fatty acids, tryptophan metabolism, and neurotransmitter levels in the prefrontal cortex and hippocampus. Chronic intermittent exposure to alcohol during 20 days induced escalation of intake in both female and male mice. Following alcohol deprivation, relapse-like behavior was observed in both sexes, but anxiogenic and cognitive deficits were present only in females. Synbiotic treatment reduced escalation and relapse to alcohol intake in females and males. In addition, the anxiogenic-like state and cognitive deficits observed in females following alcohol deprivation were abolished in mice exposed to synbiotic. Alcohol-induced differential alterations in microbial diversity and abundance in both sexes. In females, synbiotic exposure abrogated the alterations provoked by alcohol in Prevotellaceae UCG-001 and Ruminococcaceae UCG-014 abundance. In males, synbiotic exposure restored the changes induced by alcohol in Akkermansia and Muribaculum uncultured bacterium abundance. Following alcohol withdrawal, tryptophan metabolites, noradrenaline, dopamine, and γ-aminobutyric acid concentrations in the prefrontal cortex and the hippocampus were correlated with bacterial abundance and behavioral alterations in a sex-dependent manner. These results suggested that a dietary intervention with a synbiotic to reduce gut dysbiosis during chronic alcohol intake may impact differently the gut-brain-axis in females and males.

Background and Purpose: Both adherence to the Mediterranean diet (MedDiet) and the use of metformin could benefit the cognitive performance of individuals with type 2 diabetes, but evidence is still controversial. We examined the association between metformin use and cognition in older adults with type 2 diabetes following a MedDiet intervention.Methods: Prospective cohort study framed in the PREDIMED-Plus-Cognition sub-study. The PREDIMED-Plus clinical trial aims to compare the cardiovascular effect of two MedDiet interventions, with and without energy restriction, in individuals with overweight/obesity and metabolic syndrome. The present sub-study included 487 cognitively normal subjects (50.5% women, mean ± SD age of 65.2 ± 4.7 years), 30.4% of them (N = 148) with type 2 diabetes. A comprehensive battery of neurocognitive tests was administered at baseline and after 1 and 3 years. Individuals with type 2 diabetes that exhibited a good glycemic control trajectory, either using or not using metformin, were compared to one another and to individuals without diabetes using mixed-effects models with inverse probability of treatment weights.Results: Most subjects with type 2 diabetes (83.1%) presented a good and stable glycemic control trajectory. Before engaging in the MedDiet intervention, subjects using metformin scored higher in executive functions (Cohen's d = 0.51), memory (Cohen's d = 0.38) and global cognition (Cohen's d = 0.48) than those not using metformin. However, these differences were not sustained during the 3 years of follow-up, as individuals not using metformin experienced greater improvements in memory (β = 0.38 vs. β = 0.10, P = 0.036), executive functions (β = 0.36 vs. β = 0.02, P = 0.005) and global cognition (β = 0.29 vs. β = −0.02, P = 0.001) that combined with a higher MedDiet adherence (12.6 vs. 11.5 points, P = 0.031). Finally, subjects without diabetes presented greater improvements in memory than subjects with diabetes irrespective of their exposure to metformin (β = 0.55 vs. β = 0.10, P < 0.001). However, subjects with diabetes not using metformin, compared to subjects without diabetes, presented greater improvements in executive functions (β = 0.33 vs. β = 0.08, P = 0.032) and displayed a higher MedDiet adherence (12.6 points vs. 11.6 points, P = 0.046).Conclusions: Although both metformin and MedDiet interventions are good candidates for future cognitive decline preventive studies, a higher adherence to the MedDiet could even outweigh the potential neuroprotective effects of metformin in subjects with diabetes.

IntroductionType 2 diabetes has been linked to greater cognitive decline, but other glycemic parameters such as prediabetes, diabetes control and treatment, and HOMA-IR and HbA1c diabetes-related biomarkers have shown inconsistent results. Furthermore, there is limited research assessing these relationships in short-term studies. Thus, we aimed to examine 2-year associations between baseline diabetes/glycemic status and changes in cognitive function in older participants at high risk of cardiovascular disease.MethodsWe conducted a 2-year prospective cohort study (n=6,874) within the framework of the PREDIMED-Plus study. The participants (with overweight/obesity and metabolic syndrome; mean age 64.9 years; 48.5% women) completed a battery of 8 cognitive tests, and a global cognitive function Z-score (GCF) was estimated. At baseline, participants were categorized by diabetes status (no-diabetes, prediabetes, and

Scope. The postprandial effects of virgin olive oils (VOOs) enriched with phenolic compounds and triterpenes from the olive fruit on plasma glucose and insulin (primary outcomes), and gastrointestinal hormones responses were evaluated in healthy adults. Methods and results: Single doses (30 mL) of three oils were evaluated: optimized polyphenols-rich VOO (OVOO); functional olive oil (FOO): OVOO enriched with triterpene acids; and VOO with low content of polyphenols. Postprandial plasma insulin release was lower after the intake of the FOO compared to VOO, while plasma glucose levels were lower after the intake of the VOO compared to OVOO. Matsuda's index of insulin sensitivity improved after the intake of FOO and OVOO, while the insulinogenic index and gastric inhibitory polypeptide (GIP) tended to improve after the intake of OVOO. Conclusion: The enrichment of VOOs with bioactive compounds from the olive fruit increases its benefits, improving postprandial insulin release and peripheral tissue sensitivity.

Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.

Large-scale global reforestation goals have been proposed to help mitigate climate change and provide other ecosystem services. To explore reforestation potential in the United States, we used GIS analyses, surveys of nursery managers and foresters, and literature synthesis to assess the opportunities and challenges associated with meeting proposed reforestation goals. We considered a scenario where 26 million hectares (64 million acres) of natural and agricultural lands are reforested by 2040 with 30 billion trees at an estimated cost of $33 ($24–$53) billion USD. Cost per hectare will vary by region, site conditions, and other factors. This scenario would require increasing the number of tree seedlings produced each year by 1.7 billion, a 2.3-fold increase over current nursery production levels. Additional investment (not included in the reforestation cost estimate) will be needed to expand capacity for seed collection, seedling production, workforce development, and improvements in pre- and post-planting practices. Achieving this scenario will require public support for investing in these activities and incentives for landowners.

COVID-19 is described in a clinical case involving a patient who proposed the hypothesis that Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-interacting nutrients may help to prevent severe COVID-19 symptoms. Capsules of broccoli seeds containing glucoraphanin were being taken before the onset of SARS-CoV-2 infection and were continued daily for over a month after the first COVID-19 symptoms. They were found to reduce many of the symptoms rapidly and for a duration of 6–12 h by repeated dosing. When the patient was stable but still suffering from cough and nasal obstruction when not taking the broccoli capsules, a double-blind induced cough challenge confirmed the speed of onset of the capsules (less than 10 min). A second clinical case with lower broccoli doses carried out during the cytokine storm confirmed the clinical benefits already observed. A third clinical case showed similar effects at the onset of symptoms. In the first clinical trial, we used a dose of under 600 μmol per day of glucoraphanin. However, such a high dose may induce pharmacologic effects that require careful examination before the performance of any study. It is likely that the fast onset of action is mediated through the TRPA1 channel. These experimental clinical cases represent a proof-of-concept confirming the hypothesis that Nrf2-interacting nutrients are effective in COVID-19. However, this cannot be used in practice before the availability of further safety data, and confirmation is necessary through proper trials on efficacy and safety.

Abstract 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.

The effect of immunosuppressant treatments on the incidence of coronavirus disease (COVID-19) remains largely unknown. We studied the association between the pre-exposure to disease-modifying antirheumatic drugs (DMARDs) that decrease immunological responses and the incidence of COVID-19 to explore the possible effects of these treatments in early manifestations of the disease. For this purpose, we performed a cross-sectional study including 2,494 patients with immunomediated inflammatory diseases (IMIDs) recruited at the outpatient Rheumatology, Dermatology and Gastroenterology services of Hospital del Mar. The primary outcome was the clinical diagnosis of COVID-19 performed by a physician at the hospital or at the primary care center, from the March 1–29, 2020. Multivariable Poisson regression models were fitted to estimate COVID-19 relative risk (RR) adjusted by comorbidities. We revealed that biological (RR = 0.46, CI 95% = 0.31–0.67) and synthetic (RR = 0.62, CI 95% = 0.43–0.91) DMARDs used in IMIDs diminished the incidence of COVID-19. Striking sex differences were revealed with anti-TNFα compounds (RR = 0.50, CI 95% = 0.33–0.75) with higher effects in women (RR = 0.33, CI 95% = 0.17–0.647). Treatment with low glucocorticoid doses also revealed sex differences decreasing the incidence of COVID-19 predominantly in women (RR = 0.72, CI 95% = 0.42–1.22). Our results report a decreased incidence of COVID-19 in patients receiving specific DMARDs with different immunodepressor mechanisms with striking sex differences. These results underline the interest of repurposing specific DMARDs for the possibility of minimizing the severity of disease progression in the early stages of COVID-19.

Preclinical evidence suggests a main role of lysophosphatidic acid (LPA) signaling in drug addiction. Recently, we reported alterations in the plasma concentrations of LPA species in patients with alcohol use disorder (AUD). As there are sex differences in drug addiction, the main aim of the present study was to investigate whether relevant LPA species (16:0-LPA, 18:0-LPA, 18:1-LPA, 18:2-LPA and 20:4-LPA) were associated with sex and/or substance use disorder (SUD). This exploratory study was conducted in 214 abstinent patients with lifetime SUD, and 91 healthy control subjects. The SUD group was divided according to the diagnosis of AUD and/or cocaine use disorder (CUD). Participants were clinically assessed, and plasma samples were collected to determine LPA species and total LPA. We found that LPA concentrations were significantly affected by sex, and women showed higher concentrations than men. In addition, there were significantly lower 16:0-LPA, 18:2-LPA and total LPA concentrations in patients with SUD than in controls. Namely, patients with CUD and AUD + CUD showed lower LPA concentrations than controls or patients with AUD. In conclusion, our data suggest that LPA species could be potential biomarkers for SUD in women and men, which could contribute to a better stratification of these patients in treatment programs.

2,5-Dimethoxy-4-ethylphenethylamine (2C-E) is psychedelic phenylethylamine, with a chemical structure similar to mescaline, used as new psychoactive substance (NPS). It inhibits norepinephrine and serotonin uptake and, more relevant, acts as a partial agonist of the serotonin 2A (5-HT2A), 2B (5-HT2B), and (5-HT2C) receptors. Consumers have reported that 2C-E induces mild-moderate psychedelic effects, but its pharmacology in humans, including pharmacological effects and pharmacokinetics, have not yet studied. To assess the acute effects of 2C-E on physiological and subjective effects and evaluate its pharmacokinetics, an observational study was carried-out. Ten recreational users of psychedelics self-administered a single oral dose of 2C-E (6.5, 8, 10, 15, or 25 mg). Blood pressure and heart rate were evaluated at baseline, 2, 4, and 6 h post-administration. Three rating scales were administered to evaluate subjective effects: a set of Visual Analog Scales (VAS), the 49-item short form version of the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2, 4, and 6 h after self-administration. To assess 2C-E concentrations oral fluid (saliva) was collected during 6 h. 2C-E induced primarily alterations in perceptions, hallucinations, and euphoric-mood. Saliva maximal concentrations were achieved 2 h after self-administration. Administration of oral 2C-E at recreational doses produces a group of psychedelic-like effects such to 2C-B and other serotonin-acting drugs.

Mephedrone (4-MMC, mephedrone) is a synthetic cathinone derivative included in the class of new psychoactive substances. It is commonly used simultaneously with alcohol (ethanol). The aim of the present study was to evaluate the interactions on subjective, cardiovascular and hormone effects and pharmacokinetics between mephedrone and alcohol in humans. Eleven male volunteers participated as outpatients in four experimental sessions in a double-blind, randomized, cross-over, and placebo-controlled clinical trial. Participants received a single oral dose of 200 mg of mephedrone plus 0.8 g/kg of alcohol (combination condition); 200 mg of mephedrone plus placebo alcohol (mephedrone condition); placebo mephedrone plus 0.8 g/kg of ethanol (alcohol condition); and placebo mephedrone plus placebo alcohol (placebo condition). Outcome variables included physiological (blood pressure, heart rate, temperature, and pupil diameter), psychomotor (Maddox wing), subjective (visual analogue scales, Addiction Research Center Inventory 49 item short form, and Valoración de los Efectos Subjetivos de Sustancias con Potencial de Abuso questionnaire), and pharmacokinetic parameters (mephedrone and ethanol concentrations). The study was registered in ClinicalTrials.gov, number NCT02294266. The mephedrone and alcohol combination produced an increase in the cardiovascular effects of mephedrone and induced a more intense feeling of euphoria and well-being in comparison to the two drugs alone. Mephedrone reduced the sedative effects produced by alcohol. These results are similar to those obtained when other psychostimulants such as amphetamines and 3,4-methylenedioxymethamphetamine are combined simultaneously with alcohol. The abuse liability of mephedrone combined with alcohol is greater than that induced by mephedrone alone.

Abstract This study cross-sectionally examines in the elderly population: (a) the association of type 2 diabetes with executive function (EF); (b) the effect of BMI on both type 2 diabetes and EF; (c) the association between glycaemia control and EF in type 2 diabetes. 6823 older individuals with overweight/obesity and metabolic syndrome participating in the PREDIMED-PLUS study, were assessed with a battery of cognitive tests and a medical interview. ANOVA showed a significantly worse performance on EF in type 2 diabetes vs. non-diabetic individuals. Two complementary models were displayed: (1) in the whole sample, the presence of type 2 diabetes, depressive symptoms and BMI had a direct negative effect on EF, while apnoea had an indirect negative effect; (2) in the diabetes subsample, higher illness duration was associated with worse performance in EF. Participants with type 2 diabetes and HbA1c

Here we present new and original data on the endogenous conversion of tyrosol (Tyr) into hydroxytyrosol (OHTyr) in humans and its effects on the cardiovascular system. A randomized, crossover, controlled clinical trial was performed with individuals at cardiovascular risk (n = 33). They received white wine (WW) (females 1, males 2 standard drinks/day), WW plus Tyr capsules (WW + Tyr) (25mg Tyr capsule, one per WW drink), and water (control) ad libitum. Intervention periods were of 4 weeks preceded by three-week wash-out periods. We assessed the conversion of Tyr to OHTyr, its interaction with a polygenic activity score (PAS) from CYP2A6 and CYP2D6 genotypes, and the effects on cardiovascular risk markers. For further details and experimental findings please refer to the article “Cardiovascular benefits of tyrosol and its endogenous conversion into hydroxytyrosol in humans. A randomized, controlled trial” [1]. Keywords: Tyrosol, Hydroxytyrosol, Endogenous conversion, CYP2A6, CYP2D6, Cardiovascular risk

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.

Considered the β-keto analogue of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), 3,4-Methylenedioxymethcathinone (methylone) is a synthetic cathinone. Over the years, methylone has been used as a substitute for conventional psychostimulants, such as MDMA. To date, little is known about the human pharmacology of methylone; the only available information has been provided by surveys or published intoxication reports. In the present observational–naturalistic study, we evaluate the acute subjective and physiological effects of methylone after oral self-administration in comparison to MDMA in healthy poly-drug users. Fourteen participants (10 males, 4 females) selected their single oral doses of methylone from 100 to 300 mg (n = 8, mean dose 187.5 mg) or MDMA from 75 to 100 mg (n = 6, mean dose 87.5 mg) based on their experience. Study variables were assessed at 0, 1, 2, and 4 h (h) and included vital signs (non-invasive blood pressure, heart rate, cutaneous temperature) and subjective effects using visual analogue scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI) short form, and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) questionnaire. Additionally, oral fluid concentrations of methylone and MDMA were determined. Acute pharmacological effects produced by methylone followed the prototypical psychostimulant and empathogenic profile associated with MDMA, although they were less intense. Methylone concentrations in oral fluid can be considered a useful biomarker to detect acute exposure in oral fluid. Oral fluid concentrations of MDMA and methylone peaked at 2 h and concentrations of MDMA were in the range of those previously described in controlled studies. Our results demonstrate that the potential abuse liability of methylone is similar to that of MDMA in recreational subjects.

The aim of the present study was to assess whether different functional virgin olive oils (FVOOs) with varying phenolic compounds (PC) could protect the plasmatic fat-soluble vitamins, which in turn could improve the endothelial function. In order to select the optimal phenolic dose in the improvement of ischemic reactive hyperemia (IRH), a dose-response study (n = 12, healthy subjects) was performed and the enrichment of 500 mg PC/kg oil was selected. In a 3-week cross-over sustained study (n = 33 hypercholesterolemic subjects), the consumption of 25 mL/day of two phenol-enriched olive oils (one enriched with its own PC and another combined with thyme PC) increased IRH and plasma concentrations of retinol, β-cryptoxanthin and α-tocopherol, compared to a control virgin olive oil. A positive post-intervention correlation was observed for IRH values and HDL-c, β-cryptoxanthin, lutein and α-tocopherol. Results suggest that preservation of plasmatic fat-soluble vitamins by PC from FVOOS could partially explain the endothelial function benefits.

Longer life expectancy has led to an increase in the prevalence of age-related cognitive decline and dementia worldwide. Due to the current lack of effective treatment for these conditions, preventive strategies represent a research priority. A large body of evidence suggests that nutrition is involved in the pathogenesis of age-related cognitive decline, but also that it may play a critical role in slowing down its progression. At a population level, healthy dietary patterns interventions, such as the Mediterranean and the MIND diets, have been associated with improved cognitive performance and a decreased risk of neurodegenerative disease development. In the era of evidence-based medicine and patient-centered healthcare, personalized nutritional recommendations would offer a considerable opportunity in preventing cognitive decline progression. N-of-1 clinical trials have emerged as a fundamental design in evidence-based medicine. They consider each individual as the only unit of observation and intervention. The aggregation of series of N-of-1 clinical trials also enables population-level conclusions. This review provides a general view of the current scientific evidence regarding nutrition and cognitive decline, and critically states its limitations when translating results into the clinical practice. Furthermore, we suggest methodological strategies to develop N-of-1 clinical trials focused on nutrition and cognition in an older population. Finally, we evaluate the potential challenges that researchers may face when performing studies in precision nutrition and cognition.

Soy beans contain isoflavones, including daidzein and genistein, with biological activities related to therapeutic effects in reducing osteoporosis, decreasing adverse menopausal manifestations, providing protection from cardiovascular diseases, and reducing hormone-dependent cancers and age-related cognitive-decline. Daidzein has been described as inhibiting the aldehyde-dehydrogenase-2 enzyme (ALDH2), and reducing alcohol use in clinical pilot studies. Our aim was to evaluate the possible interactions between a soy extract product and alcohol in a crossover, single blind, randomized study. Ten healthy male volunteers participated in two experimental sessions: one with a single dose of alcohol (0.5 g/kg, Vodka Absolut, Sweden), and the other with four capsules of a soy extract product (Super-Absorbable Soy Isoflavones, Life-Extension, United States) and, 2 h later, the same dose of alcohol. Results showed no differences in vital signs except a slightly higher significative reduction in diastolic blood pressure at 2, 3, 4, and 8 h after administration with alcohol alone in comparison with soy extract+alcohol. Ethanol-induced subjective and adverse effects were similar for both conditions with the exception of headache (higher at 8 h after alcohol alone). Our results demonstrate that a single dose of a soy isoflavone extract did not influence alcohol pharmacokinetics and pharmacological effects and did not induce any disulfiram-reaction symptoms. Soy extract and alcohol did not interact and can be administered safely.

The data presented in this article are related to the paper âPrevalence of psychoactive substances, alcohol and illicit drugs, in Spanish drivers: A roadside study in 2015â. (https://doi.org/10.1016/j.forsciint.2017.07.005) Domingo-(Salvany et al., 2017) [1]. In that paper it was not possible to directly compare 2015 results with previous editions for various reasons, one of which was the lack of a similar weighting procedure. The present paper provides 2015 figures of roadside screening tests which are weighted for traffic flow intensity and therefore allow direct comparisons with the screening tests conducted among Spanish drivers in 2008 and 2013.

Mephedrone (4-methylmethcathinone) is a synthetic cathinone with psychostimulant properties which remains one of the most popular new psychoactive substances (NPS). It is frequently used orally and/or intranasally. To date, no studies have evaluated the acute effects and pharmacokinetics after self-administration of mephedrone orally (ingestion) and intranasally (insufflation) in naturalistic conditions. An observational study was conducted to assess and compare the acute pharmacological effects, as well as the oral fluid (saliva) concentrations of mephedrone self-administered orally and intranasally. Ten healthy experienced drug users (4 females and 6 males) self-administered a single dose of mephedrone, orally (n = 5, 100–200 mg; mean 150 mg) or intranasally (n = 5, 50–100 mg, mean 70 mg). Vital signs (blood pressure, heart rate, and cutaneous temperature) were measured at baseline (0), 1, 2, and 4 h after self-administration. Each participant completed subjective effects questionnaires: A set of Visual Analogue Scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI), and Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 1, 2, and 4 h after self-administration. Oral fluid and urine were collected during 4 h. Both routes of mephedrone self-administration enhanced ratings of euphoria and well-being effects and increased cardiovascular effects in humans. Although it was at times assessed that the oral route produced greater and larger effects than the intranasal one, concentrations of mephedrone in oral fluid and also the total amount of mephedrone and metabolites in urine showed that concentrations of mephedrone are considerably higher when self-administered intranasally in comparison to orally. Controlled clinical trials are needed to confirm our observational results.

Our aim was to assess the combination of olive tree-related extracts with the most favorable profile of in vitro bioactive properties. We tested the antioxidant (increment of low-density lipoprotein resistance against oxidation), vasoactive (promotion of nitric oxide release and decrease of endothelin-1 production in human umbilical vein endothelial cells), anti-inflammatory (decrease of the endothelial production of vascular cell adhesion molecule-1), and antithrombotic (reduction of the endothelial release of plasminogen activator inhibitor-1) capacities of six phenolic extracts and three triterpenic acid solutions (Ps and Ts, respectively). We tested extracts alone and in combination, at nutritional (Ps: 0.05–0.5 μmol/L; Ts: 0.001–0.1 μmol/L) and nutraceutical doses (Ps: 1–10 μmol/L; Ts: 0.25–10 μmol/L). The combination of Ps rich in 3,4-dihydroxyphenylglycol (76%, P2), hydroxytyrosol (95%, P3), and oleuropein (70%, P4) (final nutritional concentration: 0.15 μmol/L; final nutraceutical concentration: 3 μmol/L) was the best in order to prepare functional products and nutraceuticals with cardioprotective properties, despite the fact that the isolated extract with the greatest in vitro properties was P5 (75% oleocanthal), suggesting a potential synergistic effect among different olive components.

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.

The flavanol epigallocatechin gallate (EGCG) is being tested for the treatment of several diseases in humans. However, its bioavailability and pharmacokinetic profile needs a better understanding to enable its use in clinical trials. There is no consensus on the most appropriate concentration of EGCG in the body to obtain the maximum therapeutic effects. Therefore, the aim of this study is to analyze the bioavailability of EGCG orally administered alone or with different food supplements after overnight fasting in order to determine its optimal conditions (high concentrations in blood and the lowest interindividual variations) to be used as a pharmacological tool in human trials. Ten healthy volunteers (5 men and 5 women) aged 25 to 35 years were recruited prospectively. Three series of clinical experiments with a washout period of seven days among each were performed: (1) Teavigo® (EGCG extract) alone, (2) Teavigo® with a standard breakfast, and (3) FontUp® (Teavigo® commercially prepared with fats, carbohydrates, proteins, vitamins, and minerals). Blood samples were collected at 0, 30, 60, 90, 120, 180, 240, and 360 min after EGCG intake. Free EGCG in plasma was measured using a liquid chromatography and mass spectrometry UPLC-ESI-MS/MS analytical method. The pharmacokinetic variables analyzed statistically were area under the curve (AUC0–360), Cmax, Cav, Cmin, T1/2, and Tmax. EGCG (Teavigo®) alone was the group with higher AUC0–360, Cmax, and Cav both in men (3.86 ± 4.11 µg/mL/kg/6 h; 5.95 ng/mL/kg; 2.96 ng/mL/kg) and women (3.33 ± 1.08 µg/mL/kg/6 h; 6.66 ng/mL/kg; 3.66 ng/mL). Moreover, FontUp® was the group with the highest value of T1/2 both in men (192 ± 66 min) and women (133 ± 28 min). Teavigo® intake after fasting overnight revealed the highest concentration of EGCG in plasma according to its pharmacokinetic profile, indicating that this is an excellent alternative of administration if the experimental design requires good absorption in the gastrointestinal tract. Moreover, EGCG taken along with food supplements (FontUp®) improved the stability of the molecule in the body, being the best choice if the experimental design wants to reduce interindividual variation.

Schizophrenia (SCZ) is a neurodevelopmental disorder with a high genetic component, but the presence of environmental stressors can be important for its onset and progression. Cannabis use can be a major risk factor for developing SCZ. However, despite the available data on the neurobiological underpinnings of SCZ, there is an important lack of studies in human neuronal tissue and living cells addressing the effects of cannabis in SCZ patients. In this study, we analysed the most relevant bio-macromolecular constituents in olfactory neuroepithelium (ON) cells of healthy controls non-cannabis users, healthy cannabis users, SCZ patients non-cannabis users, and SCZ patients cannabis users using Synchrotron Radiation-Fourier Transform Infrared (SR-FTIR) spectrometry and microscopy. Our results revealed that SCZ patients non-cannabis users, and healthy cannabis users exhibit similar alterations in the macromolecular profile of ON cells, including disruption in lipid composition, increased lipid membrane renewal rate and lipid peroxidation, altered proteins containing more β-sheet structures, and showed an increase in DNA and histone methylation. Notably, these alterations were not observed in SCZ patients who use cannabis regularly. These data suggest a differential effect of cannabis in healthy controls and in SCZ patients in terms of the macromolecular constituents of ON cells.

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenylethylamine derivative, structurally similar to mescaline. It is a serotonin 5-hydroxytryptamine-2A (5-HT2A), 5-hydroxytryptamine-2B (5-HT2B), and 5-hydroxytryptamine-2C (5-HT2C) receptor partial agonist used recreationally as a new psychoactive substance. It has been reported that 2C-B induces mild psychedelic effects, although its acute pharmacological effects and pharmacokinetics have not yet been fully studied in humans. An observational study was conducted to assess the acute subjective and physiological effects, as well as pharmacokinetics of 2C-B. Sixteen healthy, experienced drug users self-administered an oral dose of 2C-B (10, 15, or 20 mg). Vital signs (blood pressure and heart rate) were measured at baseline 1, 2, 3, 4, and 6 hours (h). Each participant completed subjective effects using three rating scales: the visual analog scale (VAS), the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2–3 and 6 h after self-administration (maximum effects along 6 h), and the Hallucinogenic Rating Scale (maximum effects along 6 h). Oral fluid (saliva) was collected to assess 2C-B and cortisol concentrations during 24 h. Acute administration of 2C-B increased blood pressure and heart rate. Scores of scales related to euphoria increased (high, liking, and stimulated), and changes in perceptions (distances, colors, shapes, and lights) and different body feelings/surrounding were produced. Mild hallucinating effects were described in five subjects. Maximum concentrations of 2C-B and cortisol were reached at 1 and 3 h after self-administration, respectively. Oral 2C-B at recreational doses induces a constellation of psychedelic/psychostimulant-like effects similar to those associated with serotonin-acting drugs.

Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg−1) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatment for 15 days with OLHHA reduced the liver fat content and plasma triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally, OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the mRNA and protein expression of the cannabinoid type 1 receptor and a decrease in the expression of the lipogenic enzymes FAS and HMGCR primarily. However, changes in the mRNA expression of certain proteins were not associated with changes in the protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that OLHHA is a potential anti-steatotic drug that ameliorates the obesity-associated fatty liver and suggest the potential use of this new drug for the treatment of non-alcoholic fatty liver disease.

Adherence to the Mediterranean Diet (MD) has been associated with a reduced incidence of neurodegenerative diseases and better cognitive performance. Virgin olive oil, the main source of lipids in the MD, is rich in minor phenolic components, particularly hydroxytyrosol (HT). HT potent antioxidant and anti-inflammatory actions have attracted researchers’ attention and may contribute to neuroprotective effects credited to MD. In this review HT bioavailability and pharmacokinetics are presented prior to discussing health beneficial effects. In vitro and in vivo neuroprotective effects together with its multiple mechanisms of action are reviewed. Other microconstituents of olive oil are also considered due to their potential neuroprotective effects (oleocanthal, triterpenic acids). Finally, we discuss the potential role of HT as a therapeutic tool in the prevention of neurodegenerative diseases.

Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP), a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5–5–10–20 mM) and time-course (2–6–24 h) study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH), including the NAEs oleoyl ethanolamide (OEA) and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg). The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day) up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1)-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver toxicity after exposure to APAP overdose, and may contribute to its recovery through a long-term time-dependent response.

Previous research has shown that a single dose of MDMA induce a dissociative state, by elevating feelings of depersonalization and derealization. Typically, it is assumed that action on the 5-HT2A receptor is the mechanism underlying these psychedelic experiences. In addition, other studies have shown associations between dissociative states and biological parameters (heart rate, cortisol), which are elevated by MDMA. In order to investigate the role of the 5-HT2 receptor in the MDMA-induced dissociative state and the association with biological parameters, a placebo-controlled within-subject study was conducted including a single oral dose of MDMA (75 mg), combined with placebo or a single oral dose of the 5-HT2 receptor blocker ketanserin (40 mg). Twenty healthy recreational MDMA users filled out a dissociative states scale (CADSS) 90 min after treatments, which was preceded and followed by assessment of a number of biological parameters (cortisol levels, heart rate, MDMA blood concentrations). Findings showed that MDMA induced a dissociative state but this effect was not counteracted by pre-treatment with ketanserin. Heart rate was the only biological parameter that correlated with the MDMA-induced dissociative state, but an absence of correlation between these measures when participants were pretreated with ketanserin suggests an absence of directional effects of heart rate on dissociative state. It is suggested that the 5-HT2 receptor does not mediate the dissociative effects caused by a single dose of MDMA. Further research is needed to determine the exact neurobiology underlying this effect and whether these effects contribute to the therapeutic potential of MDMA.