Transcriptional response to a Mediterranean diet intervention exerts a modulatory effect on neuroinflammation signaling pathway.

Background: The Traditional Mediterranean Diet (TMD) is known to have beneficial effects on several chronic diseases. However, data concerning the whole transcriptome modulation of the TMD are scarce.Objective: We aimed to explore the effects of the TMD on the whole transcriptome of individuals at high cardiovascular risk.Methods: Thirty-four participants at high cardiovascular risk were randomly assigned to a TMD enriched with extra-virgin olive oil (TMD + VOO), mixed nuts (TMD + Nuts), or a control diet based on low-fat diet recommendations. A microarray analysis in circulating peripheral blood mononuclear cells of the participants was conducted before and after 3 months of the intervention. The association of changes in gene expression was modeled into canonical pathways by conducting an untargeted functional analysis with the Ingenuity Pathway Analysis® (IPA). Effects were considered significant when the absolute z-score values were ≥2.0 and the logarithm P (adjusted by the Benjamini-Hochberg procedure [BH]) values were ≥1.30.Results: According to IPA, interventions with TMD + Nuts, TMD + VOO, and control diet downregulated neuroinflammation, triggering receptor expressed on myeloid cells 1 , and cholecystokinin/gastrin-mediated signaling pathways, respectively. The gene expression among these pathways included cytokines, T-cell activation receptors, nuclear factor kappa ß/inflammasome components, pro-inflammatory enzymes and cell cycle regulators.Conclusion: The current findings suggest that the TMD enriched with mixed nuts or VOO downregulate transcriptomic pathways, including those related to neuroinflammation, which could influence development of neurodegenerative diseases. Our data should be corroborated in other tissue cells, such as neurons and glial cells. The PREDIMED trial was registered at https://www.controlled-trials.com (ISRCTN35739639).

Association of Calcitriol Supplementation with Reduced COVID-19 Mortality in Patients with Chronic Kidney Disease: A Population-Based Study.

Treatment with calcitriol, the hormonal form of vitamin D, has shown beneficial effects in experimental models of acute lung injury. In this study, we aimed to analyze the associations between calcitriol supplementation and the risk of SARS-CoV2 infection or COVID-19 mortality. Individuals ≥18 years old living in Catalonia and supplemented with calcitriol from April 2019 to February 2020 were compared with propensity score matched controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality. Associations between calcitriol supplementation and outcome variables were analyzed using multivariable Cox proportional regression. A total of 8076 patients were identified as being on calcitriol treatment. Advanced chronic kidney disease and hypoparathyroidism were the most frequent reasons for calcitriol supplementation in our population. Calcitriol use was associated with reduced risk of SARS-CoV2 infection (HR 0.78 [CI 95% 0.64-0.94], p = 0.010), reduced risk of severe COVID-19 and reduced COVID-19 mortality (HR 0.57 (CI 95% 0.41-0.80), p = 0.001) in patients with advanced chronic kidney disease. In addition, an inverse association between mean daily calcitriol dose and COVID-19 severity or mortality was observed in treated patients, independently of renal function. Our findings point out that patients with advanced chronic kidney disease could benefit from calcitriol supplementation during the COVID-19 pandemic.

A Functional Virgin Olive Oil Enriched with Olive Oil and Thyme Phenolic Compounds Improves the Expression of Cholesterol Efflux-Related Genes: A Randomized, Crossover, Controlled Trial.

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

Phenol-enriched olive oils improve HDL antioxidant content in hypercholesterolemic subjects. A randomized, double-blind, cross-over, controlled trial.

At present, high-density lipoprotein (HDL) function is thought to be more relevant than HDL cholesterol quantity. Consumption of olive oil phenolic compounds (PCs) has beneficial effects on HDL-related markers. Enriched food with complementary antioxidants could be a suitable option to obtain additional protective effects. Our aim was to ascertain whether virgin olive oils (VOOs) enriched with (a) their own PC (FVOO) and (b) their own PC plus complementary ones from thyme (FVOOT) could improve HDL status and function. Thirty-three hypercholesterolemic individuals ingested (25 ml/day, 3 weeks) (a) VOO (80 ppm), (b) FVOO (500 ppm) and (c) FVOOT (500 ppm) in a randomized, double-blind, controlled, crossover trial. A rise in HDL antioxidant compounds was observed after both functional olive oil interventions. Nevertheless, α-tocopherol, the main HDL antioxidant, was only augmented after FVOOT versus its baseline. In conclusion, long-term consumption of phenol-enriched olive oils induced a better HDL antioxidant content, the complementary phenol-enriched olive oil being the one which increased the main HDL antioxidant, α-tocopherol. Complementary phenol-enriched olive oil could be a useful dietary tool for improving HDL richness in antioxidants.

Clinical Utility of Multimarker Genetic Risk Scores for Prediction of Incident Coronary Heart Disease: A Cohort Study Among Over 51 000 Individuals of European Ancestry.

BACKGROUND: We evaluated whether including multilocus genetic risk scores (GRSs) into the Framingham Risk Equation improves the predictive capacity, discrimination, and reclassification of asymptomatic individuals with respect to coronary heart disease (CHD) risk. METHODS AND RESULTS: We performed a cohort study among 51 954 European-ancestry members of a Northern California integrated healthcare system (67% female; mean age 59) free of CHD at baseline (2007-2008). Four GRSs were constructed using between 8 and 51 previously identified genetic variants. After a mean (±SD) follow-up of 5.9 (±1.5) years, 1864 incident CHD events were documented. All GRSs were linearly associated with CHD in a model adjusted by individual risk factors: hazard ratio (95% confidence interval) per SD unit: 1.21 (1.15-1.26) for GRS_8, 1.20 (1.15-1.26) for GRS_12, 1.23 (1.17-1.28) for GRS_36, and 1.23 (1.17-1.28) for GRS_51. Inclusion of the GRSs improved the C statistic (ΔC statistic =0.008 for GRS_8 and GRS_36; 0.007 for GRS_12; and 0.009 for GRS_51; all P<0.001). The net reclassification improvement was 5% for GRS_8, GRS_12, and GRS_36 and 4% for GRS_51 in the entire cohort and was (after correcting for bias) 9% for GRS_8 and GRS_12 and 7% for GRS_36 and GRS_51 when analyzing those classified as intermediate Framingham risk (10%-20%). The number required to treat to prevent 1 CHD after selectively treating with statins up-reclassified subjects on the basis of genetic information was 36 for GRS_8 and GRS_12, 41 for GRS_36, and 43 for GRS_51. CONCLUSIONS: Our results demonstrate significant and clinically relevant incremental discriminative/predictive capability of 4 multilocus GRSs for incident CHD among subjects of European ancestry.

Olive Oil Polyphenols Decrease LDL Concentrations and LDL Atherogenicity in Men in a Randomized Controlled Trial.

BACKGROUND: Olive oil polyphenols have shown protective effects on cardiovascular risk factors. Their consumption decreased oxidative stress biomarkers and improved some features of the lipid profile. However, their effects on LDL concentrations in plasma and LDL atherogenicity have not yet been elucidated. OBJECTIVE: Our objective was to assess whether the consumption of olive oil polyphenols could decrease LDL concentrations [measured as apolipoprotein B-100 (apo B-100) concentrations and the total number of LDL particles] and atherogenicity (the number of small LDL particles and LDL oxidizability) in humans. METHODS: The study was a randomized, cross-over controlled trial in 25 healthy European men, aged 20-59 y, in the context of the EUROLIVE (Effect of Olive Oil Consumption on Oxidative Damage in European Populations) study. Volunteers ingested 25 mL/d raw low-polyphenol-content olive oil (LPCOO; 366 mg/kg) or high-polyphenol-content olive oil (HPCOO; 2.7 mg/kg) for 3 wk. Interventions were preceded by 2-wk washout periods. Effects of olive oil polyphenols on plasma LDL concentrations and atherogenicity were determined in the sample of 25 men. Effects on lipoprotein lipase (LPL) gene expression were assessed in another sample of 18 men from the EUROLIVE study. RESULTS: Plasma apo B-100 concentrations and the number of total and small LDL particles decreased (mean ± SD: by 5.94% ± 16.6%, 11.9% ± 12.0%, and 15.3% ± 35.1%, respectively) from baseline after the HPCOO intervention. These changes differed significantly from those after the LPCOO intervention, which resulted in significant increases of 6.39% ± 16.6%, 4.73% ± 22.0%, and 13.6% ± 36.4% from baseline (P < 0.03). LDL oxidation lag time increased by 5.0% ± 10.3% from baseline after the HPCOO intervention, which was significantly different only relative to preintervention values (P = 0.038). LPL gene expression tended to increase by 26% from baseline after the HPCOO intervention (P = 0.08) and did not change after the LPCOO intervention. CONCLUSION: The consumption of olive oil polyphenols decreased plasma LDL concentrations and LDL atherogenicity in healthy young men. This trial was registered at www.controlled-trials.com as ISRCTN09220811.

Complementary phenol-enriched olive oil improves HDL characteristics in hypercholesterolemic subjects. A randomized, double-blind, crossover, controlled trial. The VOHF study.

SCOPE: Consumption of olive oil (OO) phenolic compounds (PCs) has beneficial effects on lipid profile. HDL functionality is currently considered to be a more important issue than its circulating quantity. Our aim was to assess whether functional virgin olive oils (FVOOs), one enriched with its own PC (500 ppm; FVOO) and another with OOPC (250 ppm) plus additional complementary PCs from thyme (250 ppm) (total: 500 ppm; FVOOT (functional virgin olive oil with thyme)), could improve HDL functionality related properties versus a virgin OO control (80 ppm; VOO). METHODS AND RESULTS: In a randomized, double-blind, crossover, controlled trial, 33 hypercholesterolemic volunteers received 25 mL/day of VOO, FVOO, and FVOOT during 3 wk. HDL cholesterol increased 5.74% (p < 0.05) versus its baseline after the FVOOT consumption in the participants without hypolipidemic medication. We detected, after FVOOT consumption, an increase in HDL2 -subclass (34.45, SD = 6.38) versus VOO intake (32.73, SD = 6.71). An increment in esterified cholesterol/free cholesterol and phospholipids/free cholesterol in HDL was observed after FVOOT consumption (1.73, SD = 0.56; 5.44, SD = 1.39) compared with VOO intervention (1.53, SD = 0.35; 4.97, SD = 0.81) and FVOO intervention (1.50, SD = 0.33; 4.97, SD = 0.81). Accordingly, lecithin-cholesterol acyltransferase mass increased after FVOOT consumption (1228 µg/mL, SD = 130), compared with VOO consumption (1160 µg/mL, SD = 144). An improvement in HDL oxidative-status was reflected after FVOOT consumption versus its baseline, given an increment in the paraoxonase activity (118 × 10(3) U/L, SD = 24). CONCLUSION: FVOOT improves HDL-subclass distribution and composition, and metabolism/antioxidant enzyme activities. FVOOT could be a useful dietary tool in the management of high cardiovascular risk patients.

Olive oil polyphenols enhance high-density lipoprotein function in humans: a randomized controlled trial.

OBJECTIVE: Olive oil polyphenols have shown beneficial properties against cardiovascular risk factors. Their consumption has been associated with higher cholesterol content in high-density lipoproteins (HDL). However, data on polyphenol effects on HDL quality are scarce. We, therefore, assessed whether polyphenol-rich olive oil consumption could enhance the HDL main function, its cholesterol efflux capacity, and some of its quality-related properties, such HDL polyphenol content, size, and composition. APPROACH AND RESULTS: A randomized, crossover, controlled trial with 47 healthy European male volunteers was performed. Participants ingested 25 mL/d of polyphenol-poor (2.7 mg/kg) or polyphenol-rich (366 mg/kg) raw olive oil in 3-week intervention periods, preceded by 2-week washout periods. HDL cholesterol efflux capacity significantly improved after polyphenol-rich intervention versus the polyphenol-poor one (+3.05% and -2.34%, respectively; P=0.042). Incorporation of olive oil polyphenol biological metabolites to HDL, as well as large HDL (HDL2) levels, was higher after the polyphenol-rich olive oil intervention, compared with the polyphenol-poor one. Small HDL (HDL3) levels decreased, the HDL core became triglyceride-poor, and HDL fluidity increased after the polyphenol-rich intervention. CONCLUSIONS: Olive oil polyphenols promote the main HDL antiatherogenic function, its cholesterol efflux capacity. These polyphenols increased HDL size, promoted a greater HDL stability reflected as a triglyceride-poor core, and enhanced the HDL oxidative status, through an increase in the olive oil polyphenol metabolites content in the lipoprotein. Our results provide for the first time a first-level evidence of an enhancement in HDL function by polyphenol-rich olive oil.

In vivo transcriptomic profile after a Mediterranean diet in high-cardiovascular risk patients: a randomized controlled trial.

BACKGROUND: Nutrients can exert healthy effects through nutrigenomic modulation. Data are scarce concerning the in vivo effect of a sustained traditional Mediterranean diet (TMD) pattern on the whole transcriptomic response. OBJECTIVE: We explored the overall nutrigenomic effect associated with a TMD. DESIGN: We focused on biological pathways related to cardiovascular disease (CVD) in a subsample (n = 34) of the Prevención Con Dieta Mediterránea (PREDIMED) study, which was a large, parallel-group, multicenter, randomized controlled trial that aimed to assess the effects of TMD on the primary prevention of CVD in individuals with high cardiovascular risk. Participants were randomly assigned to a low-fat diet control group or TMD intervention groups [traditional Mediterranean diet supplemented with virgin olive oil (TMD+VOO) or traditional Mediterranean diet supplemented with nuts (TMD+Nuts)] in equal proportions. Three-month changes in whole genome peripheral blood mononuclear cells were assessed by using whole transcriptome microarray analyses. RESULTS: A functional annotation analysis was performed on 241 selected responder genes after the TMD+VOO (139 upregulated and 102 downregulated genes), 312 selected responder genes after the TMD+Nuts (165 upregulated and 147 downregulated genes), and 145 selected responder genes after the low-fat (100 upregulated and 45 downregulated genes) diets. Of 18 cardiovascular canonical pathway analyses, 12 pathways were differentially expressed, and 43% of pathways were modulated by both TMDs; the most prevalent pathways were related to atherosclerosis and hypertension. After simultaneous testing adjustment, 9 pathways were modulated by the TMD+VOO diet, and 4 pathways were modulated by the TMD+Nuts diet. CONCLUSION: One of the mechanisms by which TMD, particularly if supplemented with virgin olive oil, can exert health benefits is through changes in the transcriptomic response of genes related to cardiovascular risk. This trial was registered at the London-based Current Controlled Trials register as ISRCTN35739639.

Olive oil polyphenols enhance the expression of cholesterol efflux related genes in vivo in humans. A randomized controlled trial.

Both oleic acid and polyphenols have been shown to increase high-density lipoprotein (HDL) cholesterol and to protect HDL from oxidation, a phenomenon associated with a low cholesterol efflux from cells. Our goal was to determine whether polyphenols from olive oil could exert an in vivo nutrigenomic effect on genes related to cholesterol efflux in humans. In a randomized, controlled, cross-over trial, 13 pre/hypertensive patients were assigned 30 ml of two similar olive oils with high (961 mg/kg) and moderate (289 mg/kg) polyphenol content. We found an increase in ATP binding cassette transporter-A1, scavenger receptor class B type 1, peroxisome proliferator-activated receptor (PPAR)BP, PPARα, PPARγ, PPARδ and CD36 gene expression in white blood cells at postprandial after high polyphenol olive oil when compared with moderate polyphenol olive oil intervention (P<.017), with COX-1 reaching borderline significance (P=.024). Linear regression analyses showed that changes in gene expression were related to a decrease in oxidized low-density lipoproteins and with an increase in oxygen radical absorbance capacity and olive oil polyphenols (P<.05). Our results indicate a significant role of olive oil polyphenols in the up-regulation of genes involved in the cholesterol efflux from cells to HDL in vivo in humans. These results are in agreement with previous ones concerning the fact that benefits associated with polyphenol-rich olive oil consumption on cardiovascular risk could be mediated through an in vivo nutrigenomic effect in humans.