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Individuals with dementia and neurodegenerative diseases (NDDs) often suffer from cardiovascular diseases (CVDs). Neuroinflammation driven by conditions involved in CVDs is linked to disruptions in the central nervous system triggering immune reactions, perpetuating an "inflammatory-like" environment. The Mediterranean diet (MedDiet), known for its anti-inflammatory and antioxidant properties, has been proposed as a key factor to attenuate these risks. Blood nuclear cell samples were collected from 134 participants of the PREDIMED trial, which randomized participants to three diets: one supplemented with extra-virgin olive oil (MedDiet-EVOO), another with nuts (MedDiet-Nuts), and a low-fat control diet. These samples were analyzed at baseline and 12-month follow-up to assess the impact of these dietary interventions on gene expression markers. We first selected target genes by analyzing intersections between NDD and CVD associations. Significant gene expression changes from baseline to 12 months were observed in the participants allocated to the MedDiet-EVOO, particularly in CDKN2A, IFNG, NLRP3, PIK3CB, and TGFB2. Additionally, TGFB2 expression changed over time in the MedDiet-Nuts group. Comparative analyses showed significant differences in TGFB2 between MedDiet-EVOO and control, and in NAMPT between MedDiet-Nuts and control. Longitudinal models adjusted for different covariates also revealed significant effects for TGFB2 and NAMPT. In conclusion, our results suggest that one year of traditional MedDiet, especially MedDiet-EVOO, modulates gene expression associated with CVD risk and NDDs in older adults at high CV risk.

Background: Tree nuts and peanuts (henceforth, nuts) are nutrient-dense foods rich in neuroprotective components; thus, their consumption could benefit cognitive health. However, evidence to date is limited and inconsistent regarding the potential benefits of nuts for cognitive function., Objective: To prospectively evaluate the association between nut consumption and 2-y changes in cognitive performance in older adults at cognitive decline risk., Methods: A total of 6,630 participants aged 55 to 75 y (mean age 65.0±4.9 y, 48.4% women) with overweight/obesity and metabolic syndrome completed a validated semi-quantitative food frequency questionnaire and a comprehensive battery of neuropsychological tests at baseline and a 2-y follow-up. Composite cognitive scores were used to assess global, general, attention, and executive function domains. Nut consumption was categorized as <1, ≥1 to <3, ≥3 to <7, and ≥7 servings/wk (1 serving=30 g). Multivariable-adjusted linear regression models were fitted to assess associations between baseline nut consumption and 2-y cognitive changes., Results: Nut consumption was positively associated with 2-y changes in general cognitive function (P-trend <0.001). Compared with participants consuming <1 serving/wk of nuts, those categorized as consuming ≥3 to <7 and ≥7 servings/wk showed more favorable changes in general cognitive performance (β z-score [95% CI] = 0.06 [0.00,0.12] and 0.13 [0.06,0.20], respectively). No significant changes were observed in the multivariable-adjusted models for other cognitive domains assessed., Conclusion: Frequent nut consumption was associated with a smaller decline in general cognitive performance over 2 y in older adults at risk of cognitive decline. Randomized clinical trials to verify our findings are warranted., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the present review, we provide a comprehensive narrative overview of the current knowledge on the effects of total and specific types of nut consumption (excluding nut oil) on blood lipids and lipoproteins. We identified a total of 19 systematic reviews and meta-analyses of randomized controlled trials (RCTs) that were available in PubMed from the inception date to November 2022. A consistent beneficial effect of most nuts, namely total nuts and tree nuts, including walnuts, almonds, cashews, peanuts, and pistachios, has been reported across meta-analyses in decreasing total cholesterol (mean difference, MD, -0.09 to -0.28 mmol/L), LDL-cholesterol (MD, -0.09 to -0.26 mmol/L), and triglycerides (MD, -0.05 to -0.17 mmol/L). However, no effects on HDL-cholesterol have been uncovered. Preliminary evidence indicates that adding nuts into the regular diet reduces blood levels of apolipoprotein B and improves HDL function. There is also evidence that nuts dose-dependently improve lipids and lipoproteins. Sex, age, or nut processing are not effect modifiers, while a lower BMI and higher baseline lipid concentrations enhance blood lipid/lipoprotein responses. While research is still emerging, the evidence thus far indicates that nut-enriched diets are associated with a reduced number of total LDL particles and small, dense LDL particles. In conclusion, evidence from clinical trials has shown that the consumption of total and specific nuts improves blood lipid profiles by multiple mechanisms. Future directions in this field should include more lipoprotein particle, apolipoprotein B, and HDL function studies., Competing Interests: M.G.-F., A.-J.T. and P.A.S. have no conflicts of interest to declare. E.R. declares receiving grant support through his institution from the California Walnut Commission (Folsom, CA), in addition to personal funds for project supervision and advice and serving as non-paid member of its Scientific Advisory Committee; funds for travel and accommodation from the International Nut and Dried Fruit Council (INC); and personal funds from Alexion for serving in the advisory committee. K.S.P. has received research grants from the California Walnut Commission, The Peanut Institute, the American Pecan Council, and the American Pistachio Growers. P.M.K.-E. reports current and recent research funding from the American Pistachio Growers, the American Pecan Council, the Peanut Institute, and the California Walnut Commission. L.C.T. has received grant support and funds for travel and accommodation from the California Walnut Commission (CWC), The International Nut and Dried Fruit Council (INC) and Nuts for Life (Horticulture Australia), and served as a non-paid member of the Scientific Advisory Committee of the CWC. J.S.-S. reported receiving research support from the Instituto de Salud Carlos III, Ministerio de Educaci&oacute;n y Ciencia, the European Commission, the USA National Institutes of Health; receiving consulting fees or travel expenses from Instituto Danone and Abbott Laboratories, receiving nonfinancial support from Patrimonio Comunal Olivarero, the Almond Board of California, Pistachio Growers and Borges S.A; serving on the board of and receiving grant support through his institution from the International Nut and Dried Foundation; and personal fees from Instituto Danone; Serving in the Board of Danone Institute International.

Nuts are recommended for cardiovascular health, yet concerns remain that nuts may contribute to weight gain due to their high energy density. A systematic review and meta-analysis of prospective cohorts and randomized controlled trials (RCTs) was conducted to update the evidence, provide a dose-response analysis, and assess differences in nut type, comparator and more in subgroup analyses. MEDLINE, EMBASE, and Cochrane were searched, along with manual searches. Data from eligible studies were pooled using meta-analysis methods. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I 2 statistic). Certainty of the evidence was assessed by Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Six prospective cohort studies (7 unique cohorts, n = 569,910) and 86 RCTs (114 comparisons, n = 5873) met eligibility criteria. Nuts were associated with lower incidence of overweight/obesity (RR 0.93 [95% CI 0.88 to 0.98] P < 0.001, "moderate" certainty of evidence) in prospective cohorts. RCTs presented no adverse effect of nuts on body weight (MD 0.09 kg, [95% CI -0.09 to 0.27 kg] P < 0.001, "high" certainty of evidence). Meta-regression showed that higher nut intake was associated with reductions in body weight and body fat. Current evidence demonstrates the concern that nut consumption contributes to increased adiposity appears unwarranted., (© 2021 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Previous meta-analyses, with some methodological controversies, have assessed the relation between nut consumption and type 2 diabetes (T2D) risk and pointed to contradictory results, making desirable the performance of an updated meta-analysis., Objectives: We aimed to systematically review and meta-analyze all the published studies investigating the relations of total nuts and different types of nuts-i.e., walnuts, peanuts, peanut butter, and total tree nuts-with the prevalence and incidence of T2D., Methods: A systematic search was conducted in the PubMed and Cochrane databases through 12 August, 2020. The inverse variance method with fixed-effect models was used to pool data across studies, expressed as risk ratios (RRs) or ORs and 95% CIs for prospective cohort and cross-sectional studies, respectively. The Cochran Q test and I2 statistics were used to test and quantify heterogeneity, respectively. Dose-response meta-analysis was also conducted., Results: Eight studies (5 prospective and 3 cross-sectional) were included in the quantitative synthesis. Meta-analyses of cross-sectional studies and prospective cohort studies, comparing the highest with the lowest categories, revealed a nonsignificant association between total nut consumption and T2D. Meta-analyses of prospective cohort studies showed an inverse association between peanut butter consumption and T2D incidence (RR: 0.87; 95% CI: 0.77, 0.98; I2 = 50.6%; Pheterogeneity = 0.16), whereas no association was observed between peanuts or tree nuts and T2D. There was no evidence of a linear dose-response or nonlinear dose-response gradient for total nut and peanut consumption in prospective cohort studies. The certainty of the evidence using NutriGrade was very low for all the exposures., Conclusions: Current results do not demonstrate an association of total nut, peanut, or tree nut consumption with T2D. Peanut butter consumption may be inversely associated with this disease.This review protocol was registered at www.crd.york.ac.uk/prospero/ as CRD42020149756., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also associated with lower risk of cardiometabolic diseases., Objectives: The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD., Methods: The discovery population included 1833 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m2): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training-validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models., Results: A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P < 0.001)., Conclusions: A metabolite profile including 19 metabolites was associated with walnut consumption and with a lower risk of incident T2D and CVD in a Mediterranean population at high cardiovascular risk., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Many environmental and lifestyle factors have been implicated in the decline of sperm quality, with diet being one of the most plausible factors identified in recent years. Moreover, several studies have reported a close association between the alteration of specific sperm DNA methylation signatures and semen quality., Objectives: To evaluate the effect of tree nut consumption on sperm DNA methylation patterns in healthy individuals reporting eating a Western-style diet., Material and Methods: This is a post hoc analysis conducted in a subset of participants (healthy, non-smoking, and young) from the FERTINUTS 14-wk randomized-controlled, parallel trial, recruited between December 2015 and February 2017. The participants included in the current study (n = 72) were randomly selected in a proportion 2:1 from the original FERTINUTS trial between the 98 participants that completed the entire dietary intervention (nut group, n = 48; control group, n = 24). Sperm DNA methylation patterns were examined at baseline and after 14 weeks in 48 individuals consuming 60 g/d of mixed nuts (nut group) and in 24 individuals following the usual Western-style diet avoiding consumption of nuts (control group)., Results: Over the course of the trial, no significant changes in global methylation were observed between groups. However, in the nut group, we identified 36 genomic regions that were significantly differentially methylated between the baseline and the end of the trial and 97.2% of the regions displayed hypermethylation. We identified no such change in the control group over the same period of time. We also utilized the recently developed germ line age calculator to determine if nut consumption resulted in alterations to the epigenetic age of cells and no significant differences were found., Discussion and Conclusion: Adding nuts to a regular Western-style diet subtly impacts sperm DNA methylation in specific regions, demonstrating that there are some sperm epigenome regions that could respond to diet., (© 2020 American Society of Andrology and European Academy of Andrology.)

Background: High nut consumption has been previously associated with decreased prevalence of metabolic syndrome (MetS) regardless of race and dietary patterns., Objectives: The aim of this study was to assess whether changes in nut consumption over a 1-y follow-up are associated with changes in features of MetS in a middle-aged and older Spanish population at high cardiovascular disease risk., Methods: This prospective 1-y follow-up cohort study, conducted in the framework of the PREvención con DIeta MEDiterránea (PREDIMED)-Plus randomized trial, included 5800 men and women (55-75 y old) with overweight/obesity [BMI (in kg/m2) ≥27 and <40] and MetS. Nut consumption (almonds, pistachios, walnuts, and other nuts) was assessed using data from a validated FFQ. The primary outcome was the change from baseline to 1 y in features of MetS [waist circumference (WC), glycemia, HDL cholesterol, triglyceride (TG), and systolic and diastolic blood pressure] and excess weight (body weight and BMI) according to tertiles of change in nut consumption. Secondary outcomes included changes in dietary and lifestyle characteristics. A generalized linear model was used to compare 1-y changes in features of MetS, weight, dietary intakes, and lifestyle characteristics across tertiles of change in nut consumption., Results: As nut consumption increased, between each tertile there was a significant decrease in WC, TG, systolic blood pressure, weight, and BMI (P < 0.05), and a significant increase in HDL cholesterol (only in women, P = 0.044). The interaction effect between time and group was significant for total energy intake (P < 0.001), adherence to the Mediterranean diet (MedDiet) (P < 0.001), and nut consumption (P < 0.001). Across tertiles of increasing nut consumption there was a significant increase in extra virgin olive oil intake and adherence to the MedDiet; change in energy intake, on the other hand, was inversely related to consumption of nuts., Conclusions: Features of MetS and excess weight were inversely associated with nut consumption after a 1-y follow-up in the PREDIMED-Plus study cohort. This trial was registered at isrctn.com as ISRCTN89898870., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Context: Previous meta-analyses evaluating the association between nut consumption and the risk of cardiovascular disease (CVD) had substantial methodological limitations and lacked recently published large prospective studies; hence, making an updated meta-analysis highly desirable., Objective: To update the clinical guidelines for nutrition therapy in relation to the European Association for the Study of Diabetes (EASD), a systematic review and meta-analysis of prospective studies was conducted using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to summarize the evidence of the association between total nuts, specific types of nuts, and the incidence of, and mortality from, CVD outcomes., Data Sources: Relevant articles were identified by searching the PubMed and Cochrane databases., Data Extraction: Two independent researchers screened the articles to identify those that met the inclusion criteria., Data Analysis: The inverse variance method with fixed-effect or random-effects models was used to pool data across studies (expressed as risk ratio [RR] and 95% confidence interval [CI]). Heterogeneity was tested and quantified using the Cochrane Q test and I2-statistic, respectively. The GRADE system was used to assess the quality of the evidence., Results: Nineteen studies were included in the analyses. The results revealed an inverse association between total nut consumption (comparing highest vs lowest categories) and CVD incidence (RR, 0.85; 95%CI, 0.800.91; I2, 0%), CVD mortality (RR, 0.77; 95%CI, 0.72-0.82; I2, 3%), coronary heart disease (CHD) incidence (RR, 0.82; 95%CI, 0.69-0.96; I2, 74%), CHD mortality (RR, 0.76; 95%CI, 0.67-0.86; I2, 46%), stroke mortality (RR, 0.83; 95%CI, 0.75-0.93; I2, 0%), and atrial fibrillation (RR, 0.85; 95%CI, 0.73-0.99; I2, 0%). No association was observed with stroke incidence and heart failure. The certainty of the evidence ranged from moderate to very low., Conclusions: This systematic review and meta-analysis revealed a beneficial role of nut consumption in reducing the incidence of, and mortality from, different CVD outcomes., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lifestyle risk factors for erectile and sexual function include smoking, excessive alcohol consumption, lack of physical activity, psychological stress, and adherence to unhealthy diets. In the present study, we evaluated the effects of mixed nuts supplementation on erectile and sexual function. Eighty-three healthy male aged 18-35 with erectile function assessment were included in this FERTINUTS study sub-analysis; a 14-week randomized, controlled, parallel feeding trial. Participants were allocated to (1) the usual Western-style diet enriched with 60 g/day of a mixture of nuts (nut group; n = 43), or (2) the usual Western-style diet avoiding nuts (control group; n = 40). At baseline and the end of the intervention, participants answered 15 questions contained in the validated International Index of Erectile Function (IIEF), and peripheral levels of nitric oxide (NO) and E-selectin were measured, as surrogated markers of erectile endothelial function. Anthropometrical characteristics, and seminogram and blood biochemical parameters did not differ between intervention groups at baseline. Compared to the control group, a significant increase in the orgasmic function ( p -value = 0.037) and sexual desire ( p -value = 0.040) was observed during the nut intervention. No significant differences in changes between groups were shown in peripheral concentrations of NO and E-selectin. Including nuts in a regular diet significantly improved auto-reported orgasmic function and sexual desire.

Background: Nut consumption has been associated with improved nutrient adequacy and diet quality in healthy adult populations but this association has never been explored in individuals at high cardiovascular risk., Objective: to assess the associations between consumption of nuts and nutrient adequacy and diet quality in a Mediterranean population at high cardiovascular risk., Design: baseline assessment of nutritional adequacy in participants ( n = 6060, men and women, with ages 55⁻75 years old, with overweight/obesity and metabolic syndrome) in the PREDIMED-PLUS primary cardiovascular prevention randomized trial., Methods: nut intake was assessed using a validated food frequency questionnaire. Participants who reported consuming zero quantity of nuts were classified as 'non-nut consumers'. 'Nut consumers' were participants who reported consuming any quantity of nuts. Nineteen micronutrients were examined (vitamins B1, B2, B3, B6, B12, A, C, D, E and folic acid; Ca, K, P, Mg, Fe, Se, Cr, Zn, and iodine). The proportion of micronutrient inadequacy was estimated using the estimated average requirements (EAR) or adequate intake (AI) cut-points. Diet quality was also assessed using a 17-item Mediterranean dietary questionnaire (Mediterranean diet score, MDS), a carbohydrate quality index (CQI) and a fat quality index (FQI)., Results: eighty-two percent of participants were nut consumers (median of nut consumption 12.6 g/day; interquartile range: 6.0⁻25.2). Nut consumers were less likely to be below the EAR for vitamins A, B1, B2, B6, C, D, E, folic acid, and Ca, Mg, Se and Zn than non-nut consumers. Nut consumers were also more likely to be above the AI for K and Cr than non-nut consumers. Nut consumers had lower prevalence of inadequate micronutrient intakes, but also higher CQI, higher FQI, and better scores of adherence to the Mediterranean diet (Mediterranean diet score, MDS)., Conclusions: nut consumers had better nutrient adequacy, diet quality, and adherence to the MedDiet than those non-nut consumers.

Background: Human semen quality has declined in industrialized countries. Pollution, smoking, and the consumption of a Western-style diet are all hypothesized as potential causes., Objective: We evaluated the effect of chronic consumption of nuts on changes in conventional semen parameters and the potential mechanisms implicated., Design: The FERTINUTS study was a 14-wk randomized, controlled, parallel trial. A total of 119 healthy men, aged 18-35 y, were allocated to 1 of 2 intervention groups: one group was fed the usual Western-style diet enriched with 60 g of a mixture of nuts/d (nut group), and the other was fed the usual Western-style diet avoiding nuts (control group). Semen and blood samples were collected at baseline and at the end of the intervention. Dietary information was recorded throughout the trial. Changes in conventional semen parameters (pH, volume, sperm count and concentration, motility, and morphology) were determined as primary outcomes. The effect of nut consumption on sperm DNA fragmentation (SDF), reactive oxygen species (ROS) production, chromosome anomalies (X, Y, and 18), total DNA methylation, and microRNA expression were measured in sperm samples as potential causes of the changes in the seminogram., Results: Compared with the control group, improvements in total sperm count (P = 0.002) and vitality (P = 0.003), total motility (P = 0.006), progressive motility (P = 0.036), and morphology of sperm (P = 0.008) were observed in the nut group. Participants in the nut group showed an increase in the consumption of total fat, monounsaturated fatty acids, polyunsaturated fatty acids, magnesium, vitamin E, α-linolenic acid, total omega-3 (n-3) and ω-3:ω-6 ratio intake during the intervention. Participants in the nut group showed a significant reduction in SDF (P < 0.001) and in the expression of hsa-miR-34b-3p (P = 0.036). No significant changes in ROS, sperm chromosome anomalies, or DNA methylation were observed between groups., Conclusions: The inclusion of nuts in a Western-style diet significantly improves the total sperm count and the vitality, motility, and morphology of the sperm. These findings could be partly explained by a reduction in the sperm DNA fragmentation. This trial was registered at ISRCTN as ISRCTN12857940.

Background: Intervention studies suggest that incorporating walnuts into the diet may improve blood lipids without promoting weight gain., Objective: We conducted a systematic review and meta-analysis of controlled trials evaluating the effects of walnut consumption on blood lipids and other cardiovascular risk factors., Design: We conducted a comprehensive search of PubMed and EMBASE databases (from database inception to January 2018) of clinical trials comparing walnut-enriched diets with control diets. We performed random-effects meta-analyses comparing walnut-enriched and control diets for changes in pre-post intervention in blood lipids (mmol/L), apolipoproteins (mg/dL), body weight (kg), and blood pressure (mm Hg)., Results: Twenty-six clinical trials with a total of 1059 participants were included. The following weighted mean differences (WMDs) in reductions were obtained for walnut-enriched diets compared with control groups: -6.99 mg/dL (95% CI: -9.39, -4.58 mg/dL; P < 0.001) (3.25% greater reduction) for total blood cholesterol (TC) and -5.51 mg/dL (95% CI: -7.72, -3.29 mg/dL; P < 0.001) (3.73% greater reduction) for low-density lipoprotein (LDL) cholesterol. Triglyceride concentrations were also reduced in walnut-enriched diets compared with control [WMD = -4.69 (95% CI: -8.93, -0.45); P = 0.03; 5.52% greater reduction]. More pronounced reductions in blood lipids were observed when walnut interventions were compared with American and Western diets [WMD for TC = -12.30 (95% CI: -23.17, -1.43) and for LDL = -8.28 (95% CI: -13.04, -3.51); P < 0.001]. Apolipoprotein B (mg/dL) was also reduced significantly more on walnut-enriched diets compared with control groups [WMD = -3.74 (95% CI: -6.51, -0.97); P = 0.008] and a trend towards a reduction was observed for apolipoprotein A [WMD = -2.91 (95% CI: -5.98, 0.08); P = 0.057]. Walnut-enriched diets did not lead to significant differences in weight change (kg) compared with control diets [WMD = -0.12 (95% CI: -2.12, 1.88); P = 0.90], systolic blood pressure (mm Hg) [WMD = -0.72 (95% CI: -2.75, 1.30); P = 0.48], or diastolic blood pressure (mm Hg) [WMD = -0.10 (95% CI: -1.49, 1.30); P = 0.88]., Conclusions: Incorporating walnuts into the diet improved blood lipid profile without adversely affecting body weight or blood pressure.

Background: There is increasing evidence that nut consumption decreases the risk of cardiovascular disease. However, there are few data on the health effects of cashew nuts among adults with type 2 diabetes (T2DM)., Objective: The study aimed to investigate the effects of cashew nut supplementation on glycemia, body weight, blood pressure, and lipid profile in Asian Indians with T2DM., Methods: In a parallel-arm, randomized controlled trial, 300 adults with T2DM [mean ± SD age: 51 ± 9.3 y; body mass index (BMI; in kg/m2): 26.0 ± 3.4; 55% male] were randomly assigned to receive advice to follow a standard diabetic diet (control) or similar advice plus 30 g cashew nuts/d (intervention) for 12 wk. The macronutrient composition of the prescribed diabetic diet was 60-65% energy from carbohydrates, 15-25% from fat, and the rest from protein. Differences between groups in changes in anthropometric and biochemical variables were analyzed using linear models with robust variance estimation under an assumed independence working correlation., Results: Participants in the intervention group had a greater decrease in systolic blood pressure from baseline to 12 wk than did controls (-4.9 ± 13.7 compared with -1.7 ± 11.6 mm Hg; P = 0.04) and a greater increase in plasma HDL cholesterol compared with controls (+1.7 ± 5.6 compared with +0.1 ± 4.6 mg/dL; P = 0.01). There were no differences between the groups with respect to changes in body weight, BMI, blood lipid, and glycemic variables. Plasma oleic acid concentrations and self-reported dietary intake of nuts, oleic acid, and monounsaturated fatty acids suggested excellent compliance with the nut consumption., Conclusion: Cashew nut supplementation in Asian Indians with T2DM reduced systolic blood pressure and increased HDL cholesterol concentrations with no deleterious effects on body weight, glycemia, or other lipid variables. This study was registered at the clinical trial registry of India as CTRI/2017/07/009022., (© 2018 American Society for Nutrition. All rights reserved.)

DNA methylation could be reversible and mouldable by environmental factors, such as dietary exposures. The objective was to analyse whether an intervention with two Mediterranean diets, one rich in extra-virgin olive oil (MedDiet + EVOO) and the other one in nuts (MedDiet + nuts), was influencing the methylation status of peripheral white blood cells (PWBCs) genes. A subset of 36 representative individuals were selected within the PREvención con DIeta MEDiterránea (PREDIMED-Navarra) trial, with three intervention groups in high cardiovascular risk volunteers: MedDiet + EVOO, MedDiet + nuts, and a low-fat control group. Methylation was assessed at baseline and at five-year follow-up. Ingenuity pathway analysis showed routes with differentially methylated CpG sites (CpGs) related to intermediate metabolism, diabetes, inflammation, and signal transduction. Two CpGs were specifically selected: cg01081346- CPT1B / CHKB-CPT1B and cg17071192- GNAS/GNASAS , being associated with intermediate metabolism. Furthermore, cg01081346 was associated with PUFAs intake, showing a role for specific fatty acids on epigenetic modulation. Specific components of MedDiet, particularly nuts and EVOO, were able to induce methylation changes in several PWBCs genes. These changes may have potential benefits in health; especially those changes in genes related to intermediate metabolism, diabetes, inflammation and signal transduction, which may contribute to explain the role of MedDiet and fat quality on health outcomes., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Background: Lipid metabolites may partially explain the inverse association between the Mediterranean diet (MedDiet) and cardiovascular disease (CVD). Objective: We evaluated the associations between 1 ) lipid species and the risk of CVD (myocardial infarction, stroke, or cardiovascular death); 2 ) a MedDiet intervention [supplemented with extra virgin olive oil (EVOO) or nuts] and 1-y changes in these molecules; and 3 ) 1-y changes in lipid species and subsequent CVD. Design: With the use of a case-cohort design, we profiled 202 lipid species at baseline and after 1 y of intervention in the PREDIMED (PREvención con DIeta MEDiterránea) trial in 983 participants [230 cases and a random subcohort of 790 participants (37 overlapping cases)]. Results: Baseline concentrations of cholesterol esters (CEs) were inversely associated with CVD. A shorter chain length and higher saturation of some lipids were directly associated with CVD. After adjusting for multiple testing, direct associations remained significant for 20 lipids, and inverse associations remained significant for 6 lipids. When lipid species were weighted by the number of carbon atoms and double bonds, the strongest inverse association was found for CEs [HR: 0.39 (95% CI: 0.22, 0.68)] between extreme quintiles ( P -trend = 0.002). Participants in the MedDiet + EVOO and MedDiet + nut groups experienced significant ( P < 0.05) 1-y changes in 20 and 17 lipids, respectively, compared with the control group. Of these changes, only those in CE(20:3) in the MedDiet + nuts group remained significant after correcting for multiple testing. None of the 1-y changes was significantly associated with CVD risk after correcting for multiple comparisons. Conclusions: Although the MedDiet interventions induced some significant 1-y changes in the lipidome, they were not significantly associated with subsequent CVD risk. Lipid metabolites with a longer acyl chain and higher number of double bonds at baseline were significantly and inversely associated with the risk of CVD., (© 2017 American Society for Nutrition.)

Purpose: To assess the effects of a pistachio-enriched diet on the profile of circulating microRNAs (miRNAs) related to glucose metabolism and insulin resistance (IR)., Methods: Randomized crossover clinical trial in 49 subjects with prediabetes was performed. Subjects consumed a pistachio-supplemented diet (PD, 50 % carbohydrates, 33 % fat, including 57 g/day of pistachios) and an isocaloric control diet (CD, 55 % carbohydrates and 30 % fat) for 4 months each, separated by a 2-week washout period. The plasma profile of a set of seven predefined miRNAs related to glucose and insulin metabolism was analyzed by quantitative RT-PCR., Results: After the PD period, subjects have shown significant lower circulating levels of miR-192 and miR-375 compared to CD period, whereas miR-21 nonsignificantly increased after PD compared with CD (47 vs. 2 %, P = 0.092). Interestingly, changes in circulating miR-192 and miR-375 were positively correlated with plasma glucose, insulin and HOMA-IR., Conclusion: Chronic pistachio consumption positively modulates the expression of some miRNA previously implicated on insulin sensitivity.

Aims: The aim of this study was to evaluate the effect of the Mediterranean diet (MedDiet) on the incidence of heart failure (HF), a pre-specified secondary outcome in the PREDIMED (PREvención con DIeta MEDiterránea) primary nutrition-intervention prevention trial., Methods and Results: Participants at high risk of cardiovascular disease were randomly assigned to one of three diets: MedDiet supplemented with extra-virgin olive oil (EVOO), MedDiet supplemented with nuts, or a low-fat control diet. Incident HF was ascertained by a Committee for Adjudication of events blinded to group allocation. Among 7403 participants without prevalent HF followed for a median of 4.8 years, we observed 29 new HF cases in the MedDiet with EVOO group, 33 in the MedDiet with nuts group, and 32 in the control group. No significant association with HF incidence was found for the MedDiet with EVOO and MedDiet with nuts, compared with the control group [hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.41-1.13, and HR 0.92; 95% CI 0.56-1.49, respectively]., Conclusion: In this sample of adults at high cardiovascular risk, the MedDiet did not result in lower HF incidence. However, this pre-specified secondary analysis may have been underpowered to provide valid conclusions. Further randomized controlled trials with HF as a primary outcome are needed to better assess the effect of the MedDiet on HF risk., Trial Registration: ISRCTN35739639., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Nuts and dried fruit are essential foods in the Mediterranean diet. Their frequent consumption has been associated with the prevention and/or the management of such metabolic conditions as type 2 diabetes (T2D), metabolic syndrome and cardiovascular diseases. Several previous reviews of epidemiological studies and clinical trials have evaluated the associations of nuts and/or dried fruit with various metabolic disorders. However, no reviews have focused on the mechanisms underlying the role of nuts and/or dried fruit in insulin resistance and T2D. This review aims to report nut and dried-fruit nutritional interventions in animals and humans, and to focus on mechanisms that could play a significant role in the prevention and treatment of insulin resistance and T2D., Competing Interests: Pablo Hernández-Alonso, Lucía Camacho-Barcia and Mònica Bulló have nothing to declare. Jordi Salas-Salvadó is a nonpaid member of the Scientific Advisory Council of the International Nut Council.

Purpose: Serum nitric oxide (NO) reduction and increased endothelin-1 (ET-1) play a pivotal role in endothelial dysfunction and hypertension. Considering that traditional Mediterranean diet (TMD) reduces blood pressure (BP), the aim of this study was to analyze whether TMD induced changes on endothelial physiology elements such as NO, ET-1 and ET-1 receptors which are involved in BP control., Methods: Non-smoking women with moderate hypertension were submitted for 1 year to interventions promoting adherence to the TMD, one supplemented with extra virgin olive oil (EVOO) and the other with nuts versus a control low-fat diet (30 participants/group). BP, NO, ET-1 and related gene expression as well as oxidative stress biomarkers were measured., Results: Serum NO and systolic BP (SBP) or diastolic BP (DBP) were negatively associated at baseline, as well as between NO and ET-1. Our findings also showed a DBP reduction with both interventions. A negative correlation was observed between changes in NO metabolites concentration and SBP or DBP after the intervention with TMD + EVOO (p = 0.033 and p = 0.044, respectively). SBP reduction was related to an impairment of serum ET-1 concentrations after the intervention with TMD + nuts (p = 0.008). We also observed changes in eNOS, caveolin 2 and ET-1 receptors gene expression which are related to NO metabolites levels and BP., Conclusions: The changes in NO and ET-1 as well as ET-1 receptors gene expression explain, at least partially, the effect of EVOO or nuts on lowering BP among hypertensive women.

Circulating microparticles (cMPs) are small phospholipid-rich microvesicles shed by activated cells that play a pivotal role in cell signalling related to the pathogenesis of atherothrombosis. We aimed to investigate the prognostic value of cMPs released from different vascular cells for cardiovascular event (CVE) presentation in asymptomatic patients at high cardiovascular risk factors under nutritional and pharmacologic treatment. This is a nested case-control study of 50 patients from the five-year follow-up prospective PREDIMED trial enrolled in the nuts arm of the Mediterranean diet (MedDiet-nuts). We randomly selected 25 patients who had suffered a CVE during follow-up and pair-matched them for sex, age, and classical CV risk factors to 25 patients who remained asymptomatic (no-CVE). Total Annexin V-(AV)+ cMPs and cMPs from cells of the vascular compartment were quantified by flow cytometry at baseline and after one year follow-up. MedDiet-nuts and pharmacological treatment neither modified levels nor source of MP shedding in CVE patients. However, no-CVE patients showed 40-86 % decreased total AV+, PAC-1+/AV+, CD61+/AV+, CD142+/CD61+/AV+, CD62P+/AV+, CD146+/AV+, CD63+/AV+ and CD11a+/AV+ cMPs at one year follow-up (p≤0.046, all). CD142+/CD61+/AV+, CD146+/AV+ and CD45+/AV+ cMPs were decreased in no-CVE patients compared to CVE patients. A ROC-curve clustered model for CD142+/CD61+/AV+, CD45+/AV+ and CD146+/AV+ cMPs predicted a future CVE [p<0.0001, AUC=0.805 (0.672 to 0.938)]. In patients at high CV risk profile treated with a controlled MedDiet supplemented with nuts and receiving up-to-date CV drug treatment, reduced cMPs derived from activated platelets, leukocytes and endothelial cells are predictive of protection against CVE within the next four years.

Background: Epidemiological evidence suggests a cardioprotective role of α-linolenic acid (ALA), a plant-derived ω-3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine ω-3 fatty acids (long-chain n-3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all-cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long-chain n-3 polyunsaturated fatty acids (≥500 mg/day)., Methods and Results: We longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable-adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9-y follow-up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56-0.92) for all-cause mortality and 0.95 (95% CI 0.58-1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long-chain n-3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67-1.05) for all-cause mortality, 0.61 (95% CI 0.39-0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29-0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22-1.01) for sudden cardiac death. The highest reduction in all-cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45-0.87])., Conclusions: In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all-cause mortality, whereas protection from cardiac mortality is limited to fish-derived long-chain n-3 polyunsaturated fatty acids., Clinical Trial Registration: URL: http://www.Controlled-trials.com/. Unique identifier: ISRCTN35739639., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Importance: Breast cancer is the leading cause of female cancer burden, and its incidence has increased by more than 20% worldwide since 2008. Some observational studies have suggested that the Mediterranean diet may reduce the risk of breast cancer., Objective: To evaluate the effect of 2 interventions with Mediterranean diet vs the advice to follow a low-fat diet (control) on breast cancer incidence., Design, Setting, and Participants: The PREDIMED study is a 1:1:1 randomized, single-blind, controlled field trial conducted at primary health care centers in Spain. From 2003 to 2009, 4282 women aged 60 to 80 years and at high cardiovascular disease risk were recruited after invitation by their primary care physicians., Interventions: Participants were randomly allocated to a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat)., Main Outcomes and Measures: Breast cancer incidence was a prespecified secondary outcome of the trial for women without a prior history of breast cancer (n = 4152)., Results: After a median follow-up of 4.8 years, we identified 35 confirmed incident cases of breast cancer. Observed rates (per 1000 person-years) were 1.1 for the Mediterranean diet with extra-virgin olive oil group, 1.8 for the Mediterranean diet with nuts group, and 2.9 for the control group. The multivariable-adjusted hazard ratios vs the control group were 0.32 (95% CI, 0.13-0.79) for the Mediterranean diet with extra-virgin olive oil group and 0.59 (95% CI, 0.26-1.35) for the Mediterranean diet with nuts group. In analyses with yearly cumulative updated dietary exposures, the hazard ratio for each additional 5% of calories from extra-virgin olive oil was 0.72 (95% CI, 0.57-0.90)., Conclusions and Relevance: This is the first randomized trial finding an effect of a long-term dietary intervention on breast cancer incidence. Our results suggest a beneficial effect of a Mediterranean diet supplemented with extra-virgin olive oil in the primary prevention of breast cancer. These results come from a secondary analysis of a previous trial and are based on few incident cases and, therefore, need to be confirmed in longer-term and larger studies., Trial Registration: ISRCTN.org Identifier: ISRCTN35739639.

Background: Although several studies have assessed the effects of nut consumption (tree nuts, peanuts, and soy nuts) on blood pressure (BP), the results are conflicting., Objective: The aim was to conduct a systematic review and meta-analysis of published randomized controlled trials (RCTs) to estimate the effect of nut consumption on BP., Design: The databases MEDLINE, SCOPUS, ISI Web of Science, and Google Scholar were searched for RCTs carried out between 1958 and October 2013 that reported the effect of consuming single or mixed nuts (including walnuts, almonds, pistachios, cashews, hazelnuts, macadamia nuts, pecans, peanuts, and soy nuts) on systolic BP (SBP) or diastolic BP (DBP) as primary or secondary outcomes in adult populations aged ≥18 y. Relevant articles were identified by screening the abstracts and titles and the full text. Studies that evaluated the effects for <2 wk or in which the control group ingested different healthy oils were excluded. Mean ± SD changes in SBP and DBP in each treatment group were recorded for meta-analysis., Results: Twenty-one RCTs met the inclusion criteria. Our findings suggest that nut consumption leads to a significant reduction in SBP in participants without type 2 diabetes [mean difference (MD): -1.29; 95% CI: -2.35, -0.22; P = 0.02] but not in the total population. Subgroup analyses of different nut types suggest that pistachios, but not other nuts, significantly reduce SBP (MD: -1.82; 95% CI: -2.97, -0.67; P = 0.002). Our study suggests that pistachios (MD: -0.80; 95% CI: -1.43, -0.17; P = 0.01) and mixed nuts (MD: -1.19; 95% CI: -2.35, -0.03; P = 0.04) have a significant reducing effect on DBP. We found no significant changes in DBP after the consumption of other nuts., Conclusions: Total nut consumption lowered SBP in participants without type 2 diabetes. Pistachios seemed to have the strongest effect on reducing SBP and DBP. Mixed nuts also reduced DBP., (© 2015 American Society for Nutrition.)

Epidemiological and/or clinical trials have suggested that nut consumption has a beneficial impact on health outcomes such as hypertension, diabetes, CVD, cancer, other inflammatory conditions and total mortality. Nuts are nutrient-dense foods with a healthy fatty acid profile, as well as provide other bioactive compounds with recognised health benefits. Among nuts, pistachios have a lower fat and energy content and the highest levels of K, γ-tocopherol, vitamin K, phytosterols, xanthophyll carotenoids, certain minerals (Cu, Fe and Mg), vitamin B₆ and thiamin. Pistachios have a high antioxidant and anti-inflammatory potential. The aforementioned characteristics and nutrient mix probably contribute to the growing body of evidence that consumption of pistachios improves health. The present review examines the potential health effects of nutrients and phytochemicals in pistachios, as well as epidemiological and clinical evidence supporting these health benefits.

Background and Aims: Nuts have been demonstrated to improve several cardiovascular risk factors and the lipid profile in diabetic and pre-diabetic subjects. However, analysis of conventional serum lipid profiles does not completely explain the atherogenic risk associated with pre-diabetes. We therefore investigated whether chronic consumption of pistachio modifies the lipoprotein subclasses to a healthier profile in pre-diabetic subjects., Methods and Results: Randomized cross-over clinical trial in 54 subjects with pre-diabetes. Subjects consumed a pistachio-supplemented diet (PD, 50% carbohydrates, 33% fat, including 57 g/d of pistachios daily) and a control diet (CD, 55% carbohydrates, 30% fat) for 4 months each, separated by a 2-week wash-out. Diets were isocaloric and matched for protein, fiber and saturated fatty acids. Nuclear magnetic resonance (NMR) was performed to determine changes in plasma lipoprotein subclasses. Small low-density lipoprotein particles (sLDL-P) significantly decreased after pistachio consumption compared to the nut-free diet (P = 0.023). The non-high-density lipoprotein particles (non-HDL-P i.e. VLDL-P plus LDL-P) significantly decreased under the PD compared to CD (P = 0.041). The percentage of sHDL-P increased by 2.23% after the PD compared with a reduction of 0.08% after the CD (P = 0.014). Consequently, the overall size of HDL-P significantly decreased in the PD (P = 0.007)., Conclusion: Chronic pistachio consumption could modify the lipoprotein particle size and subclass concentrations independently of changes in total plasma lipid profile, which may help to explain the decreased risk of cardiovascular disease and mortality associated with those individuals who frequently consumed nuts., Registration Number: This study is registered at www.clinicaltrials.gov as NCT01441921., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The Mediterranean diet (MD) is considered a dietary pattern with beneficial effects on human health. The aim of this study was to assess the effect of an MD on urinary metabolome by comparing subjects at 1 and 3 years of follow-up, after an MD supplemented with either extra-virgin olive oil (MD + EVOO) or nuts (MD + Nuts), to those on advice to follow a control low-fat diet (LFD). Ninety-eight nondiabetic volunteers were evaluated, using metabolomic approaches, corresponding to MD + EVOO (n = 41), MD + Nuts (n = 27), or LFD (n = 30) groups. The (1)H NMR urinary profiles were examined at baseline and after 1 and 3 years of follow-up. Multivariate data analysis (OSC-PLS-DA and HCA) methods were used to identify the potential biomarker discriminating groups, exhibiting a urinary metabolome separation between MD groups against baseline and LFD. Results revealed that the most prominent hallmarks concerning MD groups were related to the metabolism of carbohydrates (3-hydroxybutyrate, citrate, and cis-aconitate), creatine, creatinine, amino acids (proline, N-acetylglutamine, glycine, branched-chain amino acids, and derived metabolites), lipids (oleic and suberic acids), and microbial cometabolites (phenylacetylglutamine and p-cresol). Otherwise, hippurate, trimethylamine-N-oxide, histidine and derivates (methylhistidines, carnosine, and anserine), and xanthosine were predominant after LFD. The application of NMR-based metabolomics enabled the classification of individuals regarding their dietary pattern and highlights the potential of this approach for evaluating changes in the urinary metabolome at different time points of follow-up in response to specific dietary interventions.

Background and Aim: Hypertension is one of the main cardiovascular risk factors in the elderly. The aims of this work were to evaluate if a one-year intervention with two Mediterranean diets (Med-diet) could decrease blood pressure (BP) due to a high polyphenol consumption, and if the decrease in BP was mediated by plasma nitric oxide (NO) production., Methods and Results: An intervention substudy of 200 participants at high cardiovascular risk was carried out within the PREDIMED trial. They were randomly assigned to a low-fat control diet or to two Med-diets, one supplemented with extra virgin olive oil (Med-EVOO) and the other with nuts (Med-nuts). Anthropometrics and clinical parameters were measured at baseline and after one year of intervention, as well as BP, plasma NO and total polyphenol excretion (TPE) in urine samples. Systolic and diastolic BP decreased significantly after a one-year dietary intervention with Med-EVOO and Med-nuts. These changes were associated with a significant increase in TPE and plasma NO. Additionally, a significant positive correlation was observed between changes in urinary TPE, a biomarker of TP intake, and in plasma NO (Beta = 4.84; 95% CI: 0.57-9.10)., Conclusions: TPE in spot urine sample was positively correlated with plasma NO in Med-diets supplemented with either EVOO or nuts. The statistically significant increases in plasma NO were associated with a reduction in systolic and diastolic BP levels, adding to the growing evidence that polyphenols might protect the cardiovascular system by improving the endothelial function and enhancing endothelial synthesis of NO., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to assess the association between nut consumption and all-cause mortality after 5-y follow-up in a Spanish cohort., Methods: The SUN (Seguimiento Universidad de Navarra, University of Navarra Follow-up) project is a prospective cohort study, formed by Spanish university graduates. Information is gathered by mailed questionnaires collected biennially. In all, 17 184 participants were followed for up to 5 y. Baseline nut consumption was collected by self-reported data, using a validated 136-item semi-quantitative food frequency questionnaire. Information on mortality was collected by permanent contact with the SUN participants and their families, postal authorities, and the National Death Index. The association between baseline nut consumption and all-cause mortality was assessed using Cox proportional hazards models to adjust for potential confounding. Baseline nut consumption was categorized in two ways. In a first analysis energy-adjusted quintiles of nut consumption (measured in g/d) were used. To adjust for total energy intake the residuals method was used. In a second analysis, participants were categorized into four groups according to pre-established categories of nut consumption (servings/d or servings/wk). Both analyses were adjusted for potential confounding factors., Results: Participants who consumed nuts ≥2/wk had a 56% lower risk for all-cause mortality than those who never or almost never consumed nuts (adjusted hazard ratio, 0.44; 95% confidence intervals, 0.23-0.86)., Conclusion: Nut consumption was significantly associated with a reduced risk for all-cause mortality after the first 5 y of follow-up in the SUN project., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Nuts are rich in many bioactive compounds that can exert beneficial effects on cardiovascular health. We reviewed the evidence relating nut consumption and the metabolic syndrome (MetS) and its components. Nuts reduce the postprandial glycemic response; however, long-term trials of nuts on insulin resistance and glycemic control in diabetic individuals are inconsistent. Epidemiologic studies have shown that nuts may lower the risk of diabetes incidence in women. Few studies have assessed the association between nuts and abdominal obesity, although an inverse association with body mass index and general obesity has been observed. Limited evidence suggests that nuts have a protective effect on blood pressure and endothelial function. Nuts have a cholesterol-lowering effect, but the relation between nuts and hypertriglyceridemia and high-density lipoprotein cholesterol is not well established. A recent pooled analysis of clinical trials showed that nuts are inversely related to triglyceride concentrations only in subjects with hypertriglyceridemia. An inverse association was found between the frequency of nut consumption and the prevalence and the incidence of MetS. Several trials evaluated the effect of nuts on subjects with MetS and found that they may have benefits in some components. Compared with a low-fat diet, a Mediterranean diet enriched with nuts could be beneficial for MetS management. The protective effects on metabolism could be explained by the modulation of inflammation and oxidation. Further trials are needed to clarify the role of nuts in MetS prevention and treatment., (© 2014 American Society for Nutrition.)

Background: It is unknown whether individuals at high cardiovascular risk sustain a benefit in cardiovascular disease from increased olive oil consumption. The aim was to assess the association between total olive oil intake, its varieties (extra virgin and common olive oil) and the risk of cardiovascular disease and mortality in a Mediterranean population at high cardiovascular risk., Methods: We included 7,216 men and women at high cardiovascular risk, aged 55 to 80 years, from the PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter, randomized, controlled, clinical trial. Participants were randomized to one of three interventions: Mediterranean Diets supplemented with nuts or extra-virgin olive oil, or a control low-fat diet. The present analysis was conducted as an observational prospective cohort study. The median follow-up was 4.8 years. Cardiovascular disease (stroke, myocardial infarction and cardiovascular death) and mortality were ascertained by medical records and National Death Index. Olive oil consumption was evaluated with validated food frequency questionnaires. Multivariate Cox proportional hazards and generalized estimating equations were used to assess the association between baseline and yearly repeated measurements of olive oil intake, cardiovascular disease and mortality., Results: During follow-up, 277 cardiovascular events and 323 deaths occurred. Participants in the highest energy-adjusted tertile of baseline total olive oil and extra-virgin olive oil consumption had 35% (HR: 0.65; 95% CI: 0.47 to 0.89) and 39% (HR: 0.61; 95% CI: 0.44 to 0.85) cardiovascular disease risk reduction, respectively, compared to the reference. Higher baseline total olive oil consumption was associated with 48% (HR: 0.52; 95% CI: 0.29 to 0.93) reduced risk of cardiovascular mortality. For each 10 g/d increase in extra-virgin olive oil consumption, cardiovascular disease and mortality risk decreased by 10% and 7%, respectively. No significant associations were found for cancer and all-cause mortality. The associations between cardiovascular events and extra virgin olive oil intake were significant in the Mediterranean diet intervention groups and not in the control group., Conclusions: Olive oil consumption, specifically the extra-virgin variety, is associated with reduced risks of cardiovascular disease and mortality in individuals at high cardiovascular risk., Trial Registration: This study was registered at controlled-trials.com (http://www.controlled-trials.com/ISRCTN35739639). International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.

Background: Prospective studies in non-Mediterranean populations have consistently related increasing nut consumption to lower coronary heart disease mortality. A small protective effect on all-cause and cancer mortality has also been suggested. To examine the association between frequency of nut consumption and mortality in individuals at high cardiovascular risk from Spain, a Mediterranean country with a relatively high average nut intake per person., Methods: We evaluated 7,216 men and women aged 55 to 80 years randomized to 1 of 3 interventions (Mediterranean diets supplemented with nuts or olive oil and control diet) in the PREDIMED ('PREvención con DIeta MEDiterránea') study. Nut consumption was assessed at baseline and mortality was ascertained by medical records and linkage to the National Death Index. Multivariable-adjusted Cox regression and multivariable analyses with generalized estimating equation models were used to assess the association between yearly repeated measurements of nut consumption and mortality., Results: During a median follow-up of 4.8 years, 323 total deaths, 81 cardiovascular deaths and 130 cancer deaths occurred. Nut consumption was associated with a significantly reduced risk of all-cause mortality (P for trend<0.05, all). Compared to non-consumers, subjects consuming nuts>3 servings/week (32% of the cohort) had a 39% lower mortality risk (hazard ratio (HR) 0.61; 95% CI 0.45 to 0.83). A similar protective effect against cardiovascular and cancer mortality was observed. Participants allocated to the Mediterranean diet with nuts group who consumed nuts>3 servings/week at baseline had the lowest total mortality risk (HR 0.37; 95% CI 0.22 to 0.66)., Conclusions: Increased frequency of nut consumption was associated with a significantly reduced risk of mortality in a Mediterranean population at high cardiovascular risk.Please see related commentary: http://www.biomedcentral.com/1741-7015/11/165., Trial Registration: Clinicaltrials.gov. International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.

Background: Epidemiologic studies have shown an inverse association between the frequency of nut consumption and body mass index (BMI) and risk of obesity. However, clinical trials that evaluated nut consumption on adiposity have been scarce and inconclusive., Objective: We performed a systematic review and meta-analysis of published, randomized nut-feeding trials to estimate the effect of nut consumption on adiposity measures., Design: MEDLINE and the Cochrane Central Register of Controlled Trials databases were searched for relevant clinical trials of nut intake that provided outcomes of body weight, BMI (in kg/m(2)), or waist-circumference measures and were published before December 2012. There were no language restrictions. Two investigators independently selected and reviewed eligible studies. The weighted mean difference (WMD) between nut or control diets was estimated by using a random-effects meta-analysis with 95% CIs., Results: Thirty-three clinical trials met our inclusion criteria. Pooled results indicated a nonsignificant effect on body weight (WMD: -0.47 kg; 95% CI: -1.17, 0.22 kg; I(2) = 7%), BMI (WMD: -0.40 kg/m(2); 95% CI: -0.97, 0.17 kg/m(2); I(2) = 49%), or waist circumference (WMD: -1.25 cm; 95% CI: -2.82, 0.31 cm; I(2) = 28%) of diets including nuts compared with control diets. These findings were remarkably robust in the sensitivity analysis. No publication bias was shown., Conclusion: Compared with control diets, diets enriched with nuts did not increase body weight, body mass index, or waist circumference in controlled clinical trials.

Background: Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events., Methods: In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years., Results: A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported., Conclusions: Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government's Instituto de Salud Carlos III and others; Controlled-Trials.com number, ISRCTN35739639.).

Introduction: Prospective studies have consistently suggested that nut consumption is inversely related to fatal and non-fatal coronary heart disease. Limited data are available on the epidemiological associations between nut intake and cardiometabolic risk factors., Objective: To evaluate associations between frequency of nut consumption and prevalence of cardiometabolic risk factors [obesity, metabolic syndrome (MetS), type-2 diabetes, hypertension, and dyslipidemia] in a Mediterranean population at high cardiovascular risk., Materials and Methods: Cross-sectional study of 7,210 men and women (mean age, 67 y) recruited into the PREDIMED study. MetS was defined by the harmonized ATPIII and IDF criteria. Diabetes and hypertension were assessed by clinical diagnosis and dyslipidemia (high triglycerides, low HDL-cholesterol, and hypercholesterolemia) by lipid analyses. Nut consumption was assessed using a validated food frequency questionnaire and categorized as <1, 1-3, and >3 servings/wk. Control of confounding was done with multivariate logistic regression., Results: Compared to participants consuming <1 serving/wk of nuts, those consuming >3 servings/wk had lower adjusted odds ratios (OR) for obesity (0.61, 95% confidence interval 0.54 to 0.68; P-trend <0.001), MetS (0.74, 0.65 to 0.85; P-trend<0.001), and diabetes (0.87, 0.78 to 0.99; P-trend = 0.043). Higher nut consumption was also associated with lower risk of the abdominal obesity MetS criterion (OR 0.68, 0.60 to 0.79; P-trend<0.001). No significant associations were observed for the MetS components high blood pressure, dyslipidemia, or elevated fasting glucose., Conclusions: Nut consumption was inversely associated with the prevalence of general obesity, central obesity, MetS, and diabetes in subjects at high cardiovascular risk.

Walnuts ( Juglans regia L.), hazelnuts ( Corylus avellana L.), and almonds ( Prunus dulcis Mill.) are rich sources of ellagitannins and proanthocyanidins. Gut microbiota plays a crucial role in modulating the bioavailability of these high molecular weight polyphenols. However, to date there are no studies evaluating the capacity to produce nut phenolic metabolites in subjects with metabolic syndrome (MetS), a pathology associated with an altered gut bacterial diversity. This study applied a LC-MS targeted approach to analyze the urinary excretion of nut phenolic metabolites in MetS subjects following 12 weeks of nut consumption, compared to sex- and age-matched individuals given a nut-free control diet. Metabolites were targeted in both hydrolyzed and nonhydrolyzed urine by LC-PDA-QqQ-MS/MS analysis, and identification of metabolites lacking available standards was confirmed by LC-ESI-ITD-FT-MS. Ellagitannin-derived urolithins A and B significantly increased after the nut-enriched-diet, urolithins C and D were also detected, and a complex combination of urolithin-conjugated forms was observed in nonhydrolyzed urine, confirming an extensive phase II metabolism after absorption. In contrast, no significant increases in proanthocyanidin microbial metabolites were observed in urine following nut consumption. Because the intestinal microbiota of the subjects in this study could catabolize ellagitannins into a wide range of urolithins, further research is strongly warranted on the in vivo potential of these microbial metabolites in reducing cardiometabolic risk.

Objective: To consider historical aspects of nuts in relation to origin and distribution, attributed medicinal benefits, symbolism, legends and superstitions., Design: Review of historical aspects of nuts., Setting: Mediterranean region., Subjects: The varieties reviewed include almonds, walnuts, hazelnuts, pine nuts and pistachios., Results and Conclusions: Like other foods, nuts have a wide variety of cultural connections to the areas where they grow and to the people who live there or eat them. History, symbolism and legends reveal the ancient tradition of nuts and how they are related to the lives of our ancestors. Archaeological excavations in eastern Turkey have uncovered the existence of a non-migratory society whose economy centred on harvesting nuts. This shows that nuts have been a staple in the human diet since the beginnings of history. Moreover, since ancient times nuts have been used for their medicinal properties. They also play a role in many old legends and traditions.

Through an HPLC-Q-TOF-MS-driven nontargeted metabolomics approach, we aimed to discriminate changes in the urinary metabolome of subjects with metabolic syndrome (MetS), following 12 weeks of mixed nuts consumption (30 g/day), compared to sex- and age-matched individuals given a control diet. The urinary metabolome corresponding to the nut-enriched diet clearly clustered in a distinct group, and the multivariate data analysis discriminated relevant mass features in this separation. Metabolites corresponding to the discriminating ions (MS features) were then subjected to multiple tandem mass spectrometry experiments using LC-ITD-FT-MS, to confirm their putative identification. The metabolomics approach revealed 20 potential markers of nut intake, including fatty acid conjugated metabolites, phase II and microbial-derived phenolic metabolites, and serotonin metabolites. An increased excretion of serotonin metabolites was associated for the first time with nut consumption. Additionally, the detection of urinary markers of gut microbial and phase II metabolism of nut polyphenols confirmed the understanding of their bioavailability and bioactivity as a priority area of research in the determination of the health effects derived from nut consumption. The results confirmed how a nontargeted metabolomics strategy may help to access unexplored metabolic pathways impacted by diet, thereby raising prospects for new intervention targets.

Background and Aims: Nut intake has been inversely related to body mass index (BMI) in prospective studies. We examined dietary determinants of adiposity in an elderly Mediterranean population with customarily high nut consumption., Methods and Results: A cross-sectional study was conducted in 847 subjects (56% women, mean age 67 years, BMI 29.7kg/m(2)) at high cardiovascular risk recruited into the PREDIMED study. Food consumption was evaluated by a validated semi-quantitative questionnaire, energy expenditure in physical activity by the Minnesota Leisure Time Activity questionnaire, and anthropometric variables by standard measurements. Nut intake decreased across quintiles of both BMI and waist circumference (P-trend <0.005; both). Alcohol ingestion was inversely related to BMI (P-trend=0.020) and directly to waist (P-trend=0.011), while meat intake was directly associated with waist circumference (P-trend=0.018). In fully adjusted multivariable models, independent dietary associations of BMI were the intake of nuts inversely (P=0.002) and that of meat and meat products directly (P=0.042). For waist circumference, independent dietary associations were intake of nuts (P=0.002) and vegetables (P=0.040), both inversely, and intake of meat and meat products directly (P=0.009). From the regression coefficients, it was predicted that BMI and waist circumference decreased by 0.78kg/m(2) and 2.1cm, respectively, for each serving of 30g of nuts. Results were similar in men and women., Conclusion: Nut consumption was inversely associated with adiposity independently of other lifestyle variables. It remains to be explored whether residual confounding related to a healthier lifestyle of nut eaters might in part explain these results., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Background and Aims: Virgin olive oil (VOO) and nuts are basic components of the Mediterranean diet, a heart-healthy dietary pattern. Nuts have well known cholesterol lowering effects, while evidence is unclear for VOO. We designed a study in hypercholesterolemic patients to assess the effects on serum lipids and other intermediate markers of cardiovascular risk of replacing 40% of the fat in the background diet with VOO, walnuts or almonds., Methods and Results: After a 4 week run-in period with a healthy diet, eligible candidates were randomized into three diet sequences in a crossover design, with a common background diet enriched with VOO, walnuts or almonds, lasting 4 weeks each. Outcomes were changes of serum lipids and oxidation and inflammation markers, measured by standard methods. Plasma fatty acids were determined by gas chromatography to assess compliance. In 18 participants completing the study (9 women, mean age 56 y, BMI 25.7 kg/m(2)), LDL-cholesterol was reduced from baseline by 7.3%, 10.8% and 13.4% after the VOO, walnut and almond diets, respectively (P = 0.001, Friedman test). Total cholesterol and LDL/HDL ratios decreased in parallel. LDL-cholesterol decreases were greater than predicted from dietary fatty acid and cholesterol exchanges among diets. No changes of other lipid fractions, oxidation analytes or inflammatory biomarkers were observed. Plasma fatty acid changes after each diet sequence supported good compliance., Conclusion: The results confirm the cholesterol lowering properties of nut-enriched diets. They also suggest that phenolic-rich VOO has a cholesterol lowering effect independently of its fatty acid content, which clearly deserves further study., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background and Aims: High blood pressure (BP) is considered a major risk factor for cardiovascular disease. Among lifestyle factors, diet plays a key role in the prevention and control of high BP. Therefore, it is important to elucidate which dietary components can exert beneficial effects on BP through modulation of endothelial function (EF) or by other mechanisms. In this paper we review the role of nutrients, foods, particularly nuts, and dietary patterns on BP control., Data Synthesis: Because nuts are low in sodium and contain significant amounts of mono- and polyunsaturated fatty acids, fiber, minerals such as magnesium, potassium and calcium, and antioxidants, they have been suggested as potentially protective foods against hypertension. Limited evidence from prospective studies and clinical trials suggests that nut consumption has a beneficial effect on both BP and EF. However, BP changes were a secondary outcome in nut feeding trials and no study used ambulatory BP monitoring as the standard for BP measurements., Conclusions: Further clinical trials, ideally using ambulatory BP monitoring, are needed to establish the potential protective effect of nut consumption on hypertension and vascular reactivity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background and Aims: Nuts have been part of the human diet since prehistoric times. The aim of the present article is to describe the most important historical and cultural aspects of nut consumption throughout history., Data Synthesis: We discuss the following historical aspects of nuts originating in the Mediterranean: prehistory, the Egyptian civilization, their spread through the Mediterranean region by the Greek, Phoenician and Roman civilizations, and their reintroduction into Europe by means of the Al-Andalus culture. Particular emphasis is placed on the healthy and nutritional attributes that nuts have had throughout history. We also consider the role of the first globalization of food--the exchange of nuts between continents--and discuss the symbolism that nuts have had for humans throughout history in the context of cultural aspects of the Mediterranean region., Conclusions: Nuts and fruits are probably the earliest foods consumed by humans and are considered to be important because of their nutritional properties. Nuts have also been used in the past by different civilizations as drugs to prevent or treat several diseases., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background and Aims: Knowledge of the effect of nut consumption on metabolic syndrome (MetS) components is limited. We assessed the effects of nut intake on adiposity, serum lipids, insulin resistance, and inflammatory biomarkers in patients with MetS., Methods and Results: In a randomized, parallel-group, 12-week feeding trial, 50 patients with MetS were given recommendations for a healthy diet with or without supplementation with 30 g/day of raw nuts (15 g walnuts, 7.5 g almonds and 7.5 g hazelnuts) (Nut and Control diet groups, respectively). Adiposity measures, serum lipids, insulin, Homeostasis Model Assessment (HOMA), interleukin-6 (IL-6) and other inflammatory biomarkers, and 48-h fecal fat were determined basally and at study's completion. Moderate weight loss, decreased adiposity, and lower blood pressure occurred similarly after both diets. The Control, but not the Nut diet, was associated with significant (P<0.05) reduction of LDL-cholesterol, with mean changes of -0.36 versus -0.13 mmol/L, respectively (between-group differences, P=0.154). The Nut diet reduced fasting insulin by 2.60 μU/mL (95% CI, -4.62 to -0.59) and HOMA-insulin resistance by 0.72 (-1.28 to -0.16) (P<0.05 versus Control diet; both). Among inflammatory markers, the Nut diet resulted in changes of median plasma IL-6 of -1.1 ng/L (-2.7 to -0.1; P=0.035 versus Control diet), but adjustment for weight loss attenuated the significance of the association. Stool fat decreased with the Control diet and slightly increased with the Nut diet (P<0.05 for between-group differences)., Conclusion: Patients with MetS show decreased lipid responsiveness but improved insulin sensitivity after daily intake of 30 g of mixed nuts., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Oxidative stress has been involved in the aetiology of hypertension, insulin resistance, the metabolic syndrome, cardiovascular disease and other chronic conditions. Several epidemiological studies suggest that a diet rich in natural antioxidants is associated with protective effects against major diseases, especially cardiovascular disease. The Mediterranean diet is rich in fat and foods with important antioxidant properties, such as fruits and vegetables, olive oil, and nuts. In this review we focus on epidemiological evidence and clinical trials that relate the Mediterranean diet with oxidative stress markers. We focus our review on two important Mediterranean vegetable sources of potentially oxidized fat-olive oil and nuts.

Objective: To evaluate the effect of the intake of whole walnuts and walnut fractions on the oxidant status in mice., Methods: Thirty-six C57BL/6J male mice were randomized to be fed one of three diets: 1) a standard diet (control group), 2) a standard diet with 10% of whole walnuts (walnut-diet group), or 3) a standard diet with 2% of walnut skins (walnut-skin-diet group) for 8 wk. The plasma antioxidant capacity was measured by oxygen radical-absorbance capacity and plasma ferric-reducing antioxidant potential. Conjugated diene formation and reduced glutathione levels were also analyzed., Results: We observed no changes in plasma oxidation capability between the walnut and walnut-skin groups with the exception of conjugated dienes. Plasma total antioxidant capacity and the ratio between reduced and oxidized forms of glutathione were lower in the walnut and walnut-skin groups than in the control group., Conclusion: The decrease in the antioxidant burden observed in enzymatic and non-enzymatic antioxidant systems after sustained consumption of a whole-walnut or a walnut-skin diet in mice may be related to the plasma oxidation capability being maintained in the groups consuming the walnut diets., (2010. Published by Elsevier Inc.)

Background & Aims: Oxidative stress has a key role in atherosclerosis, cancer and other chronic diseases. Some bioactive compounds in nuts have been implicated in antioxidant activities., Objective: We assessed how nut consumption affected several markers of oxidation and endothelial function (EF) in metabolic syndrome (MetS) patients., Patients and Methods: A randomized, controlled, parallel feeding trial was conducted on 50 MetS adults who were recommended a healthy diet supplemented or not with 30 g of mixed nuts (Nut and Control groups, respectively) every day for 12 weeks. The plasma antioxidant capacity (AC), oxidized LDL (oxLDL), conjugated diene (CD) formation, urine 8-isoprostanes, DNA damage assessed by yield of urine 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), and EF assessed by peripheral artery tonometry (PAT) and biochemical markers, were measured at baseline and the end of the intervention., Results: No significant differences in changes between groups were observed in AC, oxLDL, CD, 8-isoprostanes or EF during the intervention, whereas the reduction in DNA damage was significant in the Nut group compared to Control group (P < 0.001)., Conclusion: Nut consumption has no deleterious effect on lipid oxidation. The decrease in DNA damage observed in this study could contribute to explain the beneficial effects of regular nut consumption on some MetS features and several chronic diseases., (Copyright 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)