Search

We have investigated whether the quality of dietary fat and supplementation with coenzyme Q(10) (CoQ) modifies expression of genes related with inflammatory response and endoplasmic reticulum stress in elderly persons. Twenty participants received three diets for 4 weeks each: Mediterranean diet + CoQ (Med + CoQ), Mediterranean diet (Med), and saturated fatty acid-rich diet (SFA). After 12-hour fast, volunteers consumed a breakfast with a fat composition similar to that consumed in each of the diets. Med and Med + CoQ diets produced a lower fasting calreticulin, IL-1b, and JNK-1 gene expression; a lower postprandial p65, IKK-b, MMP-9, IL-1b, JNK-1, sXBP-1, and BiP/Grp78 gene expression; and a higher postprandial IkB-a gene expression compared with the SFA diet. Med + CoQ diet produced a lower postprandial decrease p65 and IKK-b gene expression compared with the other diets. Our results support the anti-inflammatory effect of Med diet and that exogenous CoQ supplementation in synergy with a Med diet modulates the inflammatory response and endoplasmic reticulum stress. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence supports the role of advanced glycation end products (AGEs) in atherosclerosis in both diabetic and non-diabetic patients, suggesting that therapeutic strategies targeting AGEs may offer potential benefits in this population. The Mediterranean diet is associated with improved biomarkers and anthropometric measurements related with atherosclerosis in addition to its ability to modulate AGE metabolism. Our aim was to determine whether the reduction in atherosclerosis progression (measured by changes in intima-media thickness of both common carotid arteries (IMT-CC)), observed after consumption of a Mediterranean diet compared to a low-fat diet, is associated with a modulation of circulating AGE levels in patients with coronary heart disease (CHD)., Methods: 1002 CHD patients were divided in: (1) Non-increased IMT-CC patients, whose IMT-CC was reduced or not changed after dietary intervention and (2) Increased IMT-CC patients, whose IMT-CC was increased after dietary intervention. Serum AGE levels (methylglyoxal-MG and Nε-Carboxymethyllysine-CML) and parameters related to AGE metabolism (AGER1 and GloxI mRNA and sRAGE levels) and reduced glutathione (GSH) levels were measured before and after 5-years of dietary intervention., Results: The Mediterranean diet did not affect MG levels, whereas the low-fat diet significantly increased them compared to baseline (p = 0.029), leading to lower MG levels following the Mediterranean diet than the low-fat diet (p < 0.001). The Mediterranean diet, but not the low-fat diet, produced an upregulation of AGE metabolism, with increased AGER1 and GloxI gene expression as well as increased GSH and sRAGE levels in Non-increased IMT-CC patients (all p < 0.05). Although the Mediterranean diet increased MG levels in Increased IMT-CC patients, this increment was lower compared to the low-fat diet (all p < 0.05)., Conclusions: Our results suggest that an improvement in modulation of AGE metabolism, which facilitates better management of circulating AGE levels, may be one of the mechanisms through which the Mediterranean diet, compared to a low-fat diet, reduces the progression of atherosclerosis in patients with CHD. Trial registration https://clinicaltrials.gov/ct2/show/NCT00924937 , Clinicaltrials.gov number, NCT00924937., (© 2024. The Author(s).)

Background: Type 2 diabetes mellitus (T2DM) is recognized an independent risk factor for chronic kidney disease (CKD). The precise contribution and differential response to treatment strategies to reduce kidney dysfunction, depending on whether obesity is present alongside T2DM or not, remain to be fully clarified. Our objective was to improve our understanding of how obesity contributes to kidney function in patients with T2DM and coronary heart disease (CHD), who are highly predisposed to CKD, to assign the most effective dietary approach to preserve kidney function., Methods: 1002 patients with CHD and estimated glomerular filtration rate (eGFR)≥30 ml/min/1.73m 2 , were randomized to consume a Mediterranean diet (35% fat, 22% MUFA, < 50% carbohydrates) or a low-fat diet (28% fat, 12% MUFA, > 55% carbohydrates). Patients were classified into four groups according to the presence of T2DM and/or obesity at baseline: Non-Obesity/Non-T2DM, Obesity/Non-T2DM, Non-Obesity/T2DM and Obesity/T2DM. We evaluated kidney function using serum creatinine-based estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR) before and after 5-years of dietary intervention., Results: Patients with Obesity/T2DM had the lowest baseline eGFR and the highest baseline uACR compared to non-diabetics (p < 0.05). After dietary intervention, the Mediterranean diet induced a lower eGFR decline in patients with Obesity/T2DM, compared to a low-fat diet but not in the other groups (p = 0.014). The Mediterranean diet, but not the low-fat diet, also reduced uACR only in patients with Obesity/T2DM (p = 0.024)., Conclusions: Obesity provided an additive effect to T2DM resulting in a more pronounced decline in kidney function compared to T2DM alone when compared to non-diabetics. In patients with concomitant presence of T2DM and obesity, with more metabolic complications, consumption of a Mediterranean diet seemed more beneficial than a low-fat diet in terms of preserving kidney function. These findings provide valuable insights for tailoring personalized lifestyle modifications in secondary prevention of cardiovascular disease., Trial Registration: URL, http://www.cordioprev.es/index.php/en ., Clinicaltrials: gov number, NCT00924937., (© 2024. The Author(s).)

Background: Telomere Length (TL), a marker of cellular aging, holds promise as a biomarker to elucidate the molecular mechanism of diabetes. This study aimed to investigate whether shorter telomeres are associated with a higher risk of type 2 diabetes mellitus (T2DM) incidence in patients with coronary heart disease; and to determine whether the most suitable dietary patterns, particularly a Mediterranean diet or a low-fat diet, can mitigate the development of diabetes in these patients after a follow-up period of five years., Methods: The CORonary Diet Intervention with Olive oil and cardiovascular PREVention study (CORDIOPREV study) was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive two healthy diets. Clinical investigators were masked to treatment assignment; participants were not. Quantitative-PCR was used to assess TL measurements., Findings: 1002 patients (59.5 ± 8.7 years and 82.5% men) were enrolled into Mediterranean diet (n = 502) or a low-fat diet (n = 500) groups. In this analysis, we included all 462 patients who did not have T2DM at baseline. Among them, 107 patients developed T2DM after a median of 60 months. Cox regression analyses showed that patients at risk of short telomeres (TL < percentile 20th) are more likely to experience T2DM than those at no risk of short telomeres (HR 1.65, p-value 0.023). In terms of diet, patients at high risk of short telomeres had a higher risk of T2DM incidence after consuming a low-fat diet compared to patients at no risk of short telomeres (HR 2.43, 95CI% 1.26 to 4.69, p-value 0.008), while no differences were observed in the Mediterranean diet group., Conclusion: Patients with shorter TL presented a higher risk of developing T2DM. This association could be mitigated with a specific dietary pattern, in our case a Mediterranean diet, to prevent T2DM in patients with coronary heart disease., Trial Registration: Clinicaltrials.gov number NCT00924937., (© 2024. The Author(s).)

In order to evaluate whether telomere maintenance is associated with type 2 diabetes remission, newly diagnosed type 2 diabetes patients without glucose-lowering treatment (183 out of 1002) from the CORDIOPREV study (NCT00924937) were randomized to consume a Mediterranean or low-fat diet. Patients were classified as Responders, those who reverted from type 2 diabetes during the 5 years of dietary intervention ( n = 69), and Non-Responders, who did not achieve diabetes remission by the end of the follow-up period ( n = 104). We found no differences in diabetes remission between the two diets, and we determined telomere length (TL) by measuring qPCR, telomerase activity using the TRAP assay, and direct redox balance based on the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSH) via colorimetric assay. Responders exhibited higher baseline TL in comparison with Non-Responders ( p = 0.040), and a higher TL at baseline significantly predicted a higher probability of type 2 diabetes remission (OR 2.13; 95% CI, 1.03 to 4.41). After the dietary intervention, Non-Responders showed significant telomere shortening (-0.19, 95% CI -0.32 to 0.57; p = 0.005). Telomere shortening was significantly pronounced in type 2 diabetes patients with a worse profile of insulin resistance and/or beta-cell functionality: high hepatic insulin resistance fasting, a high disposition index (-0.35; 95% CI, -0.54 to -0.16; p < 0.001), and a low disposition index (-0.25; 95% CI, -0.47 to -0.01; p = 0.037). In addition, changes in TL were correlated to the GSH/GSSG ratio. Responders also showed increased telomerase activity compared with baseline ( p = 0.048), from 0.16 (95% CI, 0.08 to 0.23) to 0.28 (95% CI, 0.15 to 0.40), with a more marked increase after the dietary intervention compared with Non-Responders (+0.07; 95% CI, -0.06-0.20; p = 0.049). To conclude, telomere maintenance may play a key role in the molecular mechanisms underlying type 2 diabetes remission in newly diagnosed patients. However, further larger-scale prospective studies are necessary to corroborate our findings.

Aim: Advanced glycation end products (AGEs) play a role in kidney disease in type 2 diabetes mellitus (T2DM). However, there have been no prior controlled clinical trials examining the effects of specific diets on AGE metabolism and their impact on kidney function. Our aim was to assess whether modulating AGE metabolism resulting in reduced AGEs levels, after consumption of two healthy diets, could delay kidney function decline in patients with T2DM and coronary heart disease (CHD)., Methods: T2DM patients (540 out of 1002 patients from the CORDIOPREV study), with estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m 2 , were classified based on their baseline kidney function: normal eGFR (≥ 90 ml/min/1.73 m 2 ), mildly decreased eGFR (60- < 90 ml/min/1.73 m 2 ) and moderately decreased eGFR (<60 ml/min/1.73 m 2 ). Serum AGE levels, methylglyoxal (MG) and N-carboximethyllysine (CML), and gene expression related to AGE metabolism (AGER1, RAGE, and GloxI mRNA) were measured before and after 5-years of dietary intervention (a Mediterranean diet or a low-fat diet)., Results: Mediterranean diet produced a lower declined of eGFR compared to the low-fat diet only in patients with mildly decreased eGFR (P = 0.035). Moreover, Mediterranean diet was able to decrease MG levels and increase GloxI expression in normal and mildly decreased eGFR patients (all P < 0.05). One standard deviation increment of MG levels after dietary intervention resulted in a 6.8-fold (95 % CI 0.039;0.554) higher probability of eGFR decline., Conclusion: Our study showed that lowering circulating AGE levels, specifically MG, after following a Mediterranean diet, might be linked to the preservation of kidney function, evidenced by a decreased decline of eGFR in T2DM patients with CHD. Patients with mildly decreased eGFR could potentially benefit more from AGE reduction in maintaining kidney function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Atherosclerosis is the leading underlying cause of coronary heart disease (CHD). In patients with CHD, intima-media thickness of common carotid arteries (IMT-CC) is a reliable, validated, and non-invasive marker of the progression of atherosclerosis. Dietary intervention may affect IMT-CC evolution through different pathways. There is a lack of clinical trials evaluating the effect of total dietary antioxidant content of diets on IMT-CC, especially in patients with CHD., Objective: We evaluated the correlation between the diet's total antioxidant content and the changes in IMT-CC produced after 5 years of dietary intervention following two healthy diet models (Mediterranean diet and low-fat diet). We also evaluated whether the diet's total antioxidant content was related to the total redox capacity of the participants., Methods: From the total participants of the CORDIOPREV study (clinical trial register NCT00924937), 805 participants completed the IMT-CC measurement and the dietary antioxidant evaluation at baseline and after 5 years of dietary intervention. IMT-CC was carried out by ultrasound and the dietary antioxidant evaluation was performed by the Dietary Antioxidant Index (DAI). Additionally, direct redox balance was evaluated in a subset of population by the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSH) by colorimetric assay., Results: We observed an inverse correlation between evolution of DAI and IMT-CC after 5-years of dietary intervention. The mean of the DAI index augmented in the Mediterranean Diet group, whereas it decreased in the Low-fat group. DAI was correlated to the GSH/GSSG ratio, supporting DAI as an adequate estimator of diet's antioxidant content. When looking for individual components of the DAI that were associated to the changes in IMT-CC, an inverse correlation was found for carotenoids, vitamin E, vitamin C, and zinc and the IMT-CC., Conclusions: Our study indicates that, after five years of dietary intervention, changes in DAI inversely correlate with changes in IMT-CC in patients with CHD. Overall effect of Mediterranean diet resulted in an increase of DAI, conversely to low-fat. Specific elements included in the DAI index were inversely correlated with IMT-CC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pancreatic neuroendocrine tumors (PanNETs) comprise a heterogeneous group of tumors with growing incidence. Recent molecular analyses provided a precise picture of their genomic and epigenomic landscape. Splicing dysregulation is increasingly regarded as a novel cancer hallmark influencing key tumor features. We have previously demonstrated that splicing machinery is markedly dysregulated in PanNETs. Here, we aimed to elucidate the molecular and functional implications of CUGBP ELAV-like family member 4 ( CELF4 ), one of the most altered splicing factors in PanNETs. CELF4 expression was determined in 20 PanNETs, comparing tumor and non-tumoral adjacent tissue. An RNA sequencing (RNA-seq) dataset was analyzed to explore CELF4-linked interrelations among clinical features, gene expression, and splicing events. Two PanNET cell lines were employed to assess CELF4 function in vitro and in vivo . PanNETs display markedly upregulated CELF4 expression, which is closely associated with malignancy features, altered expression of key tumor players, and distinct splicing event profiles. Modulation of CELF4 influenced proliferation in vitro and reduced in vivo xenograft tumor growth. Interestingly, functional assays and RNA-seq analysis revealed that CELF4 silencing altered mTOR signaling pathway, enhancing the effect of everolimus. We demonstrate that CELF4 is dysregulated in PanNETs, where it influences tumor development and aggressiveness, likely by modulating the mTOR pathway, suggesting its potential as therapeutic target., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background and Aims: A critical telomere length (TL) is associated with cardiovascular mortality. Dietary habits have been demonstrated to affect cardiovascular risk. However, it remains unclear how exactly TL determines the response to specific dietary approaches in the reduction of arterial injury. We aimed to evaluate whether TL was associated with the progression of arterial injury (assessed by intima-media thickness of both common carotid arteries: IMT-CC), after long-term consumption of two healthy dietary models in patients with coronary heart disease (CHD)., Methods: From the 1002 CHD patients of the CORDIOPREV study, 903 completed IMT-CC and TL evaluation at baseline and were randomized to follow a Mediterranean diet or a low-fat diet for 5 years., Results: Patients at risk of short TL (TL < 20th percentile) presented an elevated IMT-CC, (0.79 ± 0.17 vs patients at non-risk 0.74 ± 0.17 p < 0.001). TL and IMT-CC showed an inverse association (β = -0.035, p = 0.002). Patients who consumed a Mediterranean diet, regardless of the risk of short TL, showed a significant decrease in IMT-CC, with a higher reduction in those patients with risk of short TL (-0.03 ± 0.11, p = 0.036). TL (β = 0.019, p = 0.024), age (β = -0.001, p = 0.031), energy intake (β = -0.000, p = 0.036), use of statins (β = -0.027, p = 0.028) and allocation into the Mediterranean diet (vs low-fat diet) (β = -0.024, p = 0.003) were significant contributors to changes in IMT-CC., Conclusions: Patients who had a reduced TL exhibited a greater decrease in IMT-CC after consuming a Mediterranean diet., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This work uses Compositional Data Analysis (CoDA) to examine the typical human faecal bacterial diversity in 39 healthy volunteers from the Andalusian region (Spain). Stool samples were subjected to high-throughput sequencing of the V3 and V4 regions of the 16S ribosomal RNA gene using Illumina MiSeq. The numbers of sequences per sample and their genus-level assignment were carried out using the Phyloseq R package. The alpha diversity indices of the faecal bacterial population were not influenced by the volunteer's sex (male or female), age (19-46 years), and weight (48.6-99.0 kg). To study the relationship between these variables and the faecal bacterial population, the ALDEx2 and coda4microbiome CoDA packages were used. Applying ALDEx2, a trend suggesting a connection between sex and the genera Senegalimassilia and Negatibacillus (slightly more abundant in females) and Desulfovibrio (more abundant in males) was found. Moreover, age was tentatively associated with Streptococcus , Tizzerella , and Ruminococaceae &#95;UCG-003, while weight was linked to Senegalimassilia. The exploratory tool of the coda4microbiome package revealed numerous bacterial log-ratios strongly related to sex and, to a lesser extent, age and weight. Moreover, the cross-sectional analysis identified bacterial signature balances able to assign sex to samples regardless of controlling for volunteers' age or weight. Desulfovibrio , Faecalitalea , and Romboutsia were relevant in the numerator, while Coprococcus , Streptococcus , and Negatibacillus were prominent in the denominator; the greater presence of these could characterise the female sex. Predictions for age included Caproiciproducens , Coprobacter , and Ruminoclostridium in the numerator and Odoribacter , Ezakiella , and Tyzzerella in the denominator. The predictions depend on the relationship between both groups, but the abundance of the first group and scarcity of the second could be related to older individuals. However, the association of the faecal bacterial population with weight did not yield a satisfactory model, indicating scarce influence. These results demonstrate the usefulness of the CoDA methodology for studying metagenomics data and, specifically, human microbiota.

Purpose: Diabetes remission is a phenomenon described in the context of drastic weight loss due to bariatric surgery or low-calorie diets. Evidence suggests that increasing the intake of plant protein could reduce the risk of type 2 diabetes. We sought for association between changes in plant protein intake in the context of 2 healthy diets without weight loss nor glucose-lowering medication, and diabetes remission in coronary heart disease patients from the CORDIOPREV study., Methods: Newly diagnosed type 2 diabetes participants without glucose-lowering treatment were randomized to consume a Mediterranean or a low-fat diet. Type 2 diabetes remission was assessed with a median follow-up of 60 months according to the ADA recommendation. Information on patient's dietary intake was collected using food-frequency questionnaires. At first year of intervention, 177 patients were classified according to changes in plant protein consumption into those who increased or decreased its intake, in order to perform an observational analysis on the association between protein intake and diabetes remission., Results: Cox regression showed that patients increasing plant protein intake were more likely to remit from diabetes than those who decreased its intake (HR = 1.71(1.05-2.77)). The remission occurred mainly at first and second year of follow-up with diminished number of patients achieving remission in the third year onwards. The increase in plant protein was associated with lower intake of animal protein, cholesterol, saturated fatty acids, and fat, and with higher intake of whole grains, fibre, carbohydrates, legumes, and tree nuts., Conclusion: These results support the need to increase protein intake of vegetal origin as dietary therapy to reverse type 2 diabetes in the context of healthy diets without weight loss., (© 2023. The Author(s).)

Background: Advanced glycation end products (AGEs) are pro-oxidant and cytotoxic compounds involved in the progression of chronic diseases as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The total body burden of AGEs also depend of those consume through the diet. Our aim was to analyze whether the reduction of AGE levels, after the consumption of two-healthy diets were associated with a greater decrease of intima-media thickness of both common carotid arteries (IMT-CC) in patients with T2DM and coronary heart disease (CHD)., Methods: 540 CHD patients with T2DM, at baseline, from the CORDIOPREV study, were divided into two groups: (1) Responders, patients whose IMT-CC was reduced or not changed after dietary intervention and (2) Non-responders, patients whose IMT-CC was increased after dietary intervention. A total of 423 completed baseline and the 5-year follow-up carotid ultrasounds were analyzed in this study., Results: Our data showed that Responders, despite had a higher baseline IMT-CC and serum methylglyoxal (MG) levels than Non-responders, showed a reduction of serum levels of this glycotoxin after dietary intervention. Conversely, in patients whose IMT-CC was increased after dietary intervention (Non-responders), serum MG levels were increased. Moreover, an increase of circulating level of AGEs (and in particular, MG), after dietary intervention, could be considered a risk factor for the progression of atherosclerosis in patients with T2DM and CHD., Conclusion: These results support the importance of identifying underlying mechanisms in the context of secondary prevention of CVD that would provide therapeutic targets to reduce the high risk of cardiovascular events of these patients., Clinical Trial Registration-Url: https://clinicaltrials.gov/ct2/show/NCT00924937. Unique Identifier: NCT00924937., (Copyright © 2022 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background and Objectives: A Mediterranean lifestyle may prevent and mitigate cardiometabolic disorders. We explored whether adherence to a Mediterranean lifestyle was prospectively associated with the risk of metabolic syndrome (MetS) among coronary heart disease (CHD) patients., Methods: The Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention (CORDIOPREV) study was an interventional diet study to compare a Mediterranean diet with a low-fat diet, in 1002 CHD patients. The Mediterranean lifestyle (MEDLIFE) index was used to assess adherence to a MEDLIFE at baseline, and after 5 years, in 851 participants from the CORDIOPREV study. Subjects were classified as having high (>13 points), moderate (12-13 points), and low (<12 points) adherence to the MEDLIFE. Multivariable logistic regression models were used to determine the association between MEDLIFE adherence and the risk of MetS development or reversal., Results: During the 5-year follow-up, CORDIOPREV participants with high adherence to MEDLIFE had a lower risk of MetS development (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.19-0.75, p < 0.01) and a higher likelihood of reversing preexisting MetS (OR 2.08 CI 95% 1.11-3.91, p = 0.02) compared with participants in the low MEDLIFE adherence group. Each additional one-point increment in the MEDLIFE index was associated with a 24% lower risk of MetS development (OR 0.76, 95% CI 0.64-0.90, p < 0.01) and a 21% higher likelihood of reversing preexisting MetS (OR 1.21 CI 95% 1.04-1.41, p = 0.01)., Conclusions: Our results showed that greater adherence to a MEDLIFE reduced the risk of subsequent MetS development and increased the likelihood of reversing preexisting MetS among patients with CHD at baseline., (© 2022 The Association for the Publication of the Journal of Internal Medicine.)

The search for vegetable-origin probiotic microorganisms is a recent area of interest. This study conducted a phase I clinical trial to assess the effects of oral administration of Lactiplantibacillus pentosus LPG1, a natural strain with probiotic potential isolated from table olive fermentations, on the gut microbiota. The trial was a randomised, placebo-controlled, single-blind study involving 39 healthy volunteers. Group A ( n = 20) ingested one capsule/day of L. pentosus LPG1 containing 1 × 10 10 UFC/capsule, while Group B ( n = 19) received one capsule/day containing only dextrose (placebo). The capsules were taken during breakfast for 30 consecutive days. Human stool samples were collected from all volunteers at the beginning (baseline) and at the end of the study (post-intervention) and were subjected to 16S rRNA metataxonomic analysis using Illumina MiSeq. Sequencing data at the genus level were statistically analysed using traditional methods and compositional data analysis (CoDA). After treatment, the alpha diversity in Group B (placebo) decreased according to an increase in the Berger and Parker dominance index ( p -value < 0.05); moreover, dominance D increased and Simpson 1-D index decreased ( p -value < 0.10). The Lactobacillus genus in the faeces was included in the CoDA signature balances ( selbal and coda4microbiome ) and played a notable role in distinguishing samples from baseline and post-intervention in Group A (LPG1). Additionally, ingesting L. pentosus LPG1 modified the gut microbiota post-intervention, increasing the presence of Parabacteroides and Agathobacter , but reducing Prevotella . These findings suggest that L. pentosus LPG1 is a potentially beneficial gut microbiota modulator in healthy persons.

Introduction: Mild cognitive impairment (MCI) can progress to Alzheimer's disease (AD). When MCI is not properly controlled, the speed of deterioration can dramatically increase. Reduction of oxidative stress/inflammation and the modulation of the gut-brain axis could be new potential therapeutic targets for the prevention and treatment of AD. Consumption of specific nutrients, diets and probiotic supplementation have been evaluated for neurodegenerative disorders. We focus on a detailed description of the study methods and baseline characteristics of a clinical trial aiming to evaluate the efficacy of a combined nutritional intervention, i.e., a Mediterranean diet with probiotics, on cognitive capacity in a population with MCI., Methods: In this randomized, latin-square crossover, double-blind, and controlled dietary intervention trial (clinicaltrials.gov NCT05029765), 47 MCI patients were randomized to consume three dietary interventions for 24-weeks each: (1) A Mediterranean diet supplemented with probiotics (10 9 colony-forming units of Lactobacillus rhamnosus and Bifidobacterium longum ); (2) A Mediterranean diet + placebo; and (3) A Healthy diet according to the World Health Organization (WHO) recommendations. Participants will be evaluated before and after each of the three intervention periods (each 24-weeks, with a total of 72-weeks) for adherence to the assigned diet, blood tests, cognitive performance, gut microbiota analysis and functional neuroimaging studies., Results: Fifty patients, ≥60 years-old and diagnosed with MCI, underwent randomization. A total of 47 patients completed follow-up dietary interventions (57.4% males), with a good glycemic control (HbA1c 5.8 ± 0.1%, fasting glucose and insulin 99.7 ± 3.3 mg/dL and 10.4 ± 0.9 mU/L, respectively), elevated systolic blood pressure (136.9 ± 2.1 mmHg) and increased degree of inflammation (high-sensitivity C-reactive protein, 8.8 ± 0.9 mg/dL). Baseline adherence to the Mediterranean diet was medium (7.5 ± 0.3 points on the score that ranged from 0 to 14 points)., Conclusion: The results of this clinical study would provide more evidence on the need for dietary therapeutic strategies, for clinical and individual practice, in the management of MCI patients to reduce the risk of AD development. Targeting lifestyle modifications in high-risk populations could prevent substantial cases of cognitive decline., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT05029765]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cardelo, Corina, Leon-Acuña, Quintana-Navarro, Alcala-Diaz, Rangel-Zuñiga, Camargo, Conde-Gavilan, Carmona-Medialdea, Vallejo-Casas, Carmona-Asenjo, Ochoa-Sepulveda, Aguera-Morales, Delgado-Lista, Katsiki, Lopez-Miranda, Perez-Jimenez, Yubero-Serrano and Perez-Martínez.)

Background: Men with obesity tend to be insulin resistant and often have low-normal testosterone concentrations. We conducted a clinical trial aimed to evaluate potential therapeutic strategies for low testosterone in men with obesity., Methods: We did a 1-year, parallel, randomized, double-blind, placebo-controlled trial, where we evaluated the independent and combined effects of metformin and testosterone in 106 men with obesity, aged 18-50 years, who had low levels of testosterone and no diabetes mellitus. The primary outcome was change in insulin resistance, measured as Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index. Secondary outcomes included changes in total and free serum testosterone, body composition, metabolic variables, erectile function, and health-related quality of life (HRQoL)., Results: In the intention-to-treat analysis, the HOMA-IR index decreased significantly in all active groups compared to placebo (metformin -2.4, 95 % CI -4.1 to -0.8, p = 0.004; testosterone -2.7, 95 % CI -4.3 to -1.1, p = 0.001; combination -3.4, 95 % CI -5.0 to -1.8, p < 0.001). Combination therapy was not superior to testosterone alone in decreasing insulin resistance (-0.7, 95 % CI -2.3 to 0.9, p = 0.383). Only the combination of metformin plus testosterone significantly increased total and free testosterone concentrations, compared to placebo. No significant changes in body composition (except for a higher decrease in fat mass in the metformin and combination group), metabolic variables, erectile function, or HRQoL were found with any treatment., Conclusions: Among men with obesity and low testosterone concentrations, the combination of metformin plus testosterone, metformin only, and testosterone only, compared to placebo, reduced insulin resistance with no evidence of additive benefit., Competing Interests: Declaration of competing interest None of the authors report a conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We investigated whether long-term consumption of two healthy diets (low-fat (LF) or Mediterranean (Med)) interacts with SIRT1 genotypes to modulate aging-related processes such as leucocyte telomere length (LTL), oxidative stress (OxS) and inflammation in patients with coronary heart disease (CHD). LTL, inflammation, OxS markers (at baseline and after 4 years of follow-up) and SIRT1-Single Nucleotide Polymorphisms (SNPs) (rs7069102 and rs1885472) were determined in patients from the CORDIOPREV study. We analyzed the genotype-marker interactions and the effect of diet on these interactions. Regardless of the diet, we observed LTL maintenance in GG-carriers for the rs7069102, in contrast to carriers of the minor C allele, where it decreased after follow-up (p = 0.001). The GG-carriers showed an increase in reduced/oxidized glutathione (GSH/GSSG) ratio (p = 0.003), lower lipid peroxidation products (LPO) levels (p < 0.001) and a greater decrease in tumor necrosis factor-alpha (TNF-α) levels (p < 0.001) after follow-up. After the LF diet intervention, the GG-carriers showed stabilization in LTL which was significant compared to the C allele subjects (p = 0.037), although the protective effects found for inflammation and OxS markers remained significant after follow-up with the two diets. Patients who are homozygous for the SIRT1-SNP rs7069102 (the most common genotype) may benefit from healthy diets, as suggested by improvements in OxS and inflammation in patients with CHD, which may indicate the slowing-down of the aging process and its related diseases.

Background: Cardiovascular disease (CVD) is the leading cause of disease burden in the world by non-communicable diseases. Nutritional interventions promoting high-quality dietary patterns with low caloric intake value and high nutrient density (ND) could be linked to a better control of CVD risk and recurrence of coronary disease. This study aims to assess the effects of a dietary intervention based on MedDiet or Low-Fat dietary intervention over changes in ND and food intake after 1 and 7 years of follow-up of the CORDIOPREV study., Methods: We prospectively analyzed the results of the 802 coronary patients randomized to two healthy dietary patterns (MedDiet = 425, Low-Fat Diet = 377) who completed the 7 years of follow-up and had all the dietary data need. Dietary intake information obtained from a validated 137-item Food Frequency Questionnaire was used to calculate 1- and 7-year changes in dietary intake and ND (measured as nutrient intake per 1000 kcal). T test was used to ascertain differences in food intake and ND between groups across follow-up time. Within-subject (dietary allocation group) differences were analyzed with ANOVA repeated measures., Results: From baseline to 7 years of follow-up, significant increases of vegetables, fruits, and whole cereals within groups (p < 0.001) was found. We found a higher increase in dietary intake of certain food groups with MedDiet in comparison with Low-Fat Diet for vegetables (46.1 g/day vs. 18.1 g/day, p < 00.1), fruits (121.3 g/day vs. 72.9 g/day), legumes (4.3 g/day vs. 0.16 g/day) and nuts (7.3 g/day vs. - 3.7 g/day). There was a decrease in energy intake over time in both groups, slightly higher in Low-Fat Diet compared to MedDiet group (- 427.6 kcal/day vs. - 279.8 kcal/day at 1st year, and - 544.6 kcal/day vs. - 215.3 kcal/day after 7 years of follow-up). ND of all the nutrients increased within group across follow-up time, except for Saturated Fatty Acids (SFA), cholesterol and sodium (p < 0.001)., Conclusions: A comprehensive dietary intervention improved quality of diet, reducing total energy intake and increasing the intake of healthy food groups and overall ND after 1 year and maintaining this trend after 7 years of follow-up. Our results reinforce the idea of the participation in trials, enhance nutrition literacy and produces better nutritional outcomes in adult patients with established CVD., Clinical Trial Registry: The trial was registered in 2009 at ClinicalTrials.gov (number NCT00924937)., (© 2022. The Author(s).)

Background and Aims: The extent of atherosclerotic coronary heart disease (CHD) is associated with its prognosis, thus discovering potential biomarkers related to worse outcomes could prove valuable. The present work aims to investigate whether lipoprotein subfractions are associated with angiographic CHD severity., Materials and Methods: Patients from the CORDIOPREV study exhibiting coronary lesions in angiography were classified into two groups (single-vessel coronary disease (SVD) or multivessel coronary disease (MVD)). High-throughput nuclear magnetic resonance (NMR) spectroscopy determined lipoprotein subfractions concentration and composition., Results: SVD patients showed a higher concentration of medium and small HDL particles compared with MVD patients. For medium HDL, total lipids, phospholipids, total cholesterol, cholesteryl esters and free cholesterol reflected HDL particle concentration, whereas, for small HDL, total lipids, phospholipids, and free cholesterol mirrored lipoprotein particle concentration. Among traditional cardiovascular risk factors, age, hypertension and T2D were independently associated with angiography severity. In multivariate logistic regression models, medium and small HDL particles remained inversely associated with angiography severity (OR 0.77 (95% CI: 0.64-0.91); OR 0.78 (95% CI: 0.67-0.91), respectively) after adjusting with covariates., Conclusion: In CHD patients mostly on statin treatment, angiography severity is inversely related to small and medium HDL subclasses concentration measured by NMR. These particles are also independent predictors of the presence of MVD, and its use increased the prediction of this entity over traditional risk factors., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: rs964184 variant in the ZPR1 gene has been associated with blood lipids levels both in fasting and postprandial state and with the risk of myocardial infarction in high-risk cardiovascular patients. However, whether this association is modulated by diet has not been studied., Objective: To investigate whether the type of diet (low-fat or Mediterranean diets) interacts with genetic variability at this loci to modulate fasting and postprandial lipids in coronary patients., Materials and Methods: The genotype of the rs964184 polymorphism was determined in the Cordioprev Study population (NCT00924937). Fasting and Postprandial triglycerides were assessed before and after 3 years of dietary intervention with either a Mediterranean or a low-fat diet. Postprandial lipid assessment was done by a 4-h oral fat tolerance test (OFTT). Differences in triglycerides levels were identified using repeated-measures ANCOVA., Results: From 523 patients (85% males, mean age 59 years) that completed the OFTT at baseline and after 3 years of intervention and had complete genotype information, 125 of them were carriers of the risk allele G. At the start of the study, these patients showed a higher fasting and postprandial triglycerides (TG) plasma levels. After 3 years of dietary intervention, G-carriers following a Mediterranean Diet maintained higher fasting and postprandial triglycerides, while those on the low-fat diet reduced their postprandial triglycerides to similar values to the population without the G-allele., Conclusion: After 3 years of dietary intervention, the altered postprandial triglyceride response induced by genetic variability in the rs964184 polymorphism of the ZPR1 gene can be modulated by a low-fat diet, better than by a Mediterranean diet, in patients with coronary artery disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alcala-Diaz, Arenas-de Larriva, Torres-Peña, Rodriguez-Cantalejo, Rangel-Zuñiga, Yubero-Serrano, Gutierrez-Mariscal, Cardelo, Luque, Ordovas, Perez-Martinez, Delgado-Lista and Lopez-Miranda.)

Individuals with evening chronotypes are prone to suffer chronodisruption and display worse lifestyle habits than morning-types, exhibiting higher cardiovascular diseases (CVD). However, it is unknown whether CVD patients, who are evening chronotypes, have higher cardiometabolic risk than morning-types. This study explored whether individual chronotypes were associated with cardiometabolic risk in patients from the CORDIOPREV study (n = 857). We also investigated whether potential associations were moderated by long-term consumption of two healthy diets (Mediterranean and Low-fat diets). This population was classified into chronotypes using the Morningness-Eveningness Questionnaire. Seven-day daily rhythms in wrist temperature (T), rest-activity (A) and position (P) were recorded in a subset of patients (n = 168), and an integrative variable TAP was determined. Metabolic Syndrome (MetS) was determined at baseline, and metabolic and inflammation markers were measured at baseline and yearly during the 4 years of follow-up. Differences in several lifestyle factors were analyzed according to chronotype. At all times, evening-types had higher triglycerides, C-reactive protein and homocysteine and lower high density lipoprotein cholesterol than morning-types (P < 0.05). Evening-types had a higher prevalence of MetS (OR 1.58 IC 95% [1.10 - 2.28], P = 0.01). Moreover, they were more sedentary, displayed less and delayed physical activity and ate and slept later. In addition, evening-types had lower amplitude, greater fragmentation, lower robustness and less stable circadian pattern at TAP (P < 0.01), all related to a less healthy circadian pattern. In conclusion, evening-types with CVD had higher cardiometabolic risk and less robust circadian-related rhythms than morning-types, regardless of the nutritional intervention., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Prostate-specific antigen (PSA) is the gold-standard marker to screen prostate cancer (PCa) nowadays. Unfortunately, its lack of specificity and sensitivity makes the identification of novel tools to diagnose PCa an urgent medical need. In this context, microRNAs (miRNAs) have emerged as potential sources of non-invasive diagnostic biomarkers in several pathologies. Therefore, this study was aimed at assessing for the first time the dysregulation of the whole plasma miRNome in PCa patients and its putative implication in PCa from a personalized perspective (i.e., obesity condition). Plasma miRNome from a discovery cohort (18 controls and 19 PCa patients) was determined using an Affymetrix-miRNA array, showing that the expression of 104 miRNAs was significantly altered, wherein six exhibited a significant receiver operating characteristic (ROC) curve to distinguish between control and PCa patients (area under the curve [AUC] = 1). Then, a systematic validation using an independent cohort (135 controls and 160 PCa patients) demonstrated that miR-107 was the most profoundly altered miRNA in PCa (AUC = 0.75). Moreover, miR-107 levels significantly outperformed the ability of PSA to distinguish between control and PCa patients and correlated with relevant clinical parameters (i.e., PSA). These differences were more pronounced when considering only obese patients (BMI > 30). Interestingly, miR-107 levels were reduced in PCa tissues versus non-tumor tissues (n = 84) and in PCa cell lines versus non-tumor cells. In vitro miR-107 overexpression altered key aggressiveness features in PCa cells (i.e., proliferation, migration, and tumorospheres formation) and modulated the expression of important genes involved in PCa pathophysiology (i.e., lipid metabolism [i.e., FASN] and splicing process). Altogether, miR-107 might represent a novel and useful personalized diagnostic and prognostic biomarker and a potential therapeutic tool in PCa, especially in obese patients., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Background & Aims: Lifestyle and dietary habits influence kidney function, playing an important role in the prevention and development of chronic kidney disease (CKD). The effectiveness of the Mediterranean diet in preserving kidney function has been seen in primary prevention. However, no scientific evidence is currently available to determine which dietary pattern is more effective in the management of CKD in secondary cardiovascular disease prevention. Thus, our aim was to evaluate the efficacy of the long-term consumption of two healthy dietary patterns (a Mediterranean diet rich in extra-virgin olive oil (EVOO) compared to a low-fat diet rich in complex carbohydrates) in preserving kidney function in coronary heart disease (CHD) patients., Methods: CHD patients (n = 1002) from the CORDIOPREV study were randomized to follow a Mediterranean diet (35% fat, 22% MUFA, <50% carbohydrates) or a low-fat diet (28% fat, 12% MUFA, >55% carbohydrates). Kidney function was assessed by the determination of serum creatinine-based estimated glomerular filtration rate (eGFR) at baseline and after 5-years of dietary intervention. Patients were classified according to their type 2 diabetes (T2DM) status, using baseline eGFR (normal eGFR: ≥ 90 mL/min/1.73 m 2 ; mildly-impaired eGFR: 60 to <90 mL/min/1.73 m 2 , severely-impaired eGFR: <60 mL/min/1.73 m 2 ) to evaluate its influence on the progression of kidney function. Multiple linear regression analysis were performed to determine the contribution of different clinical and anthropometric parameters to changes in eGFR., Results: Although eGFR declined after both dietary interventions compared to baseline (all p < 0.001), the Mediterranean diet produced a lower decline of eGFR compared to the low-fat diet in patients with T2DM (p = 0.040). This effect was also observed when the overall population was considered (p = 0.033). No significant differences were observed in eGFR between the two diets in non-T2DM patients. In addition, this differential effect of the Mediterranean diet was mainly observed in patients with mildly-impaired eGFR in which this diet slowed eGFR progression (p = 0.002)., Conclusions: The long-term consumption of a Mediterranean diet rich in EVOO, when compared to a low-fat diet, may preserve kidney function, as shown by a reduced decline in eGFR in CHD patients with T2DM. Patients with mildly-impaired eGFR may benefit more from the beneficial effect of the consumption of the Mediterranean diet in preserving kidney function. These findings reinforce the clinical benefits of the Mediterranean diet in the context of secondary cardiovascular disease prevention., Clinical Trial Registration: URL, http://www.cordioprev.es/index.php/en. Clinicaltrials.gov number, NCT00924937., Competing Interests: Conflict of interest The authors declare that they have no current or potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Obesity is a metabolic chronic disease with important associated morbidities and mortality. Bariatric surgery is the most effective treatment for maintaining long-term weight loss in severe obesity and, consequently, for decreasing obesity-related complications, including chronic inflammation., Aim: To explore changes in components of the inflammasome machinery after bariatric surgery and their relation with clinical/biochemical parameters at baseline and 6 months after bariatric surgery., Patients and Methods: Twenty-two patients with morbid-obesity that underwent bariatric surgery (sleeve gastrectomy and Roux-en-Y gastric bypass) were included. Epidemiological/clinical/anthropometric/biochemical evaluation was performed at baseline and 6 months after bariatric surgery. Inflammasome components and inflammatory-associated factors [nucleotide-binding oligomerization domain-like receptors (NLRs), inflammasome activation components, cytokines and inflammation/apoptosis-related components, and cell-cycle and DNA-damage regulators) were evaluated in peripheral blood mononuclear cells (PBMCs) at baseline and 6 months after bariatric surgery. Clinical molecular correlations/associations were analyzed. Functional parameters (lipid accumulation/viability/apoptosis) were analyzed in response to specific inflammasome components silencing in liver HepG2 cells)., Results: A profound dysregulation of inflammasome components after bariatric surgery was found, especially in NLRs and cell-cycle and DNA damage regulators. Several components were associated with baseline metabolic comorbidities including type 2 diabetes (C-C motif chemokine ligand 2/C-X-C motif chemokine receptor 1/sirtuin 1), hypertension (absent in melanoma 2/ASC/purinergic receptor P2X 7), and dyslipidemia [C-X-C motif chemokine ligand 3 (CXCL3)/NLR family pyrin domain containing (NLRP) 7) and displayed changes in their molecular profile 6 months after bariatric surgery. The gene expression fingerprint of certain factors NLR family CARD domain containing 4 (NLRC4)/NLRP12/CXCL3)/C-C motif chemokine ligand 8/toll-like receptor 4) accurately differentiated pre- and postoperative PBMCs. Most changes were independent of the performed surgical technique. Silencing of NLRC4/NLRP12 resulted in altered lipid accumulation, apoptosis rate, and cell viability in HepG2 cells., Conclusion: Bariatric surgery induces a profound alteration in the gene expression pattern of components of the inflammasome machinery in PBMCs. Expression and changes of certain inflammasome components are associated to baseline metabolic comorbidities, including type 2 diabetes, and may be related to the improvement and reversion of some obesity-related comorbidities after bariatric surgery., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Lifestyle and diet affect cardiovascular risk, although there is currently no consensus about the best dietary model for the secondary prevention of cardiovascular disease. The CORDIOPREV study (Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention) is an ongoing prospective, randomized, single-blind, controlled trial in 1002 coronary heart disease patients, whose primary objective is to compare the effect of 2 healthy dietary patterns (low-fat rich in complex carbohydrates versus Mediterranean diet rich in extra virgin olive oil) on the incidence of cardiovascular events. Here, we report the results of one secondary outcome of the CORDIOPREV study. Thus, to evaluate the efficacy of these diets in reducing cardiovascular disease risk. Intima-media thickness of both common carotid arteries (IMT-CC) was ultrasonically assessed bilaterally. IMT-CC is a validated surrogate for the status and future cardiovascular disease risk., Methods: From the total participants, 939 completed IMT-CC evaluation at baseline and were randomized to follow a Mediterranean diet (35% fat, 22% monounsaturated fatty acids, <50% carbohydrates) or a low-fat diet (28% fat, 12% monounsaturated fatty acids, >55% carbohydrates) with IMT-CC measurements at 5 and 7 years. We also analyzed the carotid plaque number and height., Results: The Mediterranean diet decreased IMT-CC at 5 years (−0.027±0.008 mm; P<0.001), maintained at 7 years (−0.031±0.008 mm; P<0.001), compared to baseline. The low-fat diet did not modify IMT-CC. IMT-CC and carotid plaquemax height were higher decreased after the Mediterranean diet, compared to the low-fat diet, throughout follow-up. Baseline IMT-CC had the strongest association with the changes in IMT-CC after the dietary intervention., Conclusions: Long-term consumption of a Mediterranean diet rich in extravirgin olive oil, if compared to a low-fat diet, was associated with decreased atherosclerosis progression, as shown by reduced IMT-CC and carotid plaque height. These findings reinforce the clinical benefits of the Mediterranean diet in the context of secondary cardiovascular prevention., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00924937.

Coenzyme Q 10 (CoQ 10 ), which plays a key role in the electron transport chain by providing an adequate, efficient supply of energy, has another relevant function as an antioxidant, acting in mitochondria, other cell compartments, and plasma lipoproteins. CoQ 10 deficiency is present in chronic and age-related diseases. In particular, in cardiovascular diseases (CVDs), there is a reduced bioavailability of CoQ 10 since statins, one of the most common lipid-lowering drugs, inhibit the common pathway shared by CoQ 10 endogenous biosynthesis and cholesterol biosynthesis. Different clinical trials have analyzed the effect of CoQ 10 supplementation as a treatment to ameliorate these deficiencies in the context of CVDs. In this review, we focus on recent advances in CoQ 10 supplementation and the clinical implications in the reduction of cardiovascular risk factors (such as lipid and lipoprotein levels, blood pressure, or endothelial function) as well as in a therapeutic approach for the reduction of the clinical complications of CVD.

Evidence suggests that enriching a diet with plant-based proteins could reduce the risk of developing type 2 diabetes mellitus. In the present work, we evaluated the association between the change in plant protein intake (adjusted by energy) and incidence of type 2 diabetes mellitus in patients with coronary heart disease from the CORDIOPREV (coronary diet intervention with olive oil and cardiovascular prevention) study. At baseline and during the follow-up, patients underwent medical examination and blood and oral glucose tolerance tests. Information on patient's dietary intake was gathered by registered dietitians using a validated food frequency questionnaire. A total of 106 out of 436 nondiabetic patients at baseline developed type 2 diabetes mellitus after a median follow-up of 60 months. Cox regression analyses showed that patients who belonged to the group that increased plant protein intake exhibited a lower risk of developing the disease (HR = 0.64, (0.43-0.96)). Changes in plant protein intake were positively correlated with changes in carbohydrates, fibre, and legumes intake and negatively correlated with changes in saturated fatty acids intake. Results of the present study support the need of improving diet with plant-based proteins to prevent the onset of type 2 diabetes mellitus.

Background: Peripheral artery disease (PAD) is recognized as a significant predictor of mortality and adverse cardiovascular outcomes in patients with coronary heart disease (CHD). In fact, coexisting PAD and CHD is strongly associated with a greater coronary event recurrence compared with either one of them alone. High-density lipoprotein (HDL)-mediated cholesterol efflux capacity (CEC) is found to be inversely associated with an increased risk of incident CHD. However, this association is not established in patients with PAD in the context of secondary prevention. In this sense, our main aim was to evaluate the association between CEC and PAD in patients with CHD and whether the concurrent presence of PAD and T2DM influences this association., Methods: CHD patients (n = 1002) from the CORDIOPREV study were classified according to the presence or absence of PAD (ankle-brachial index, ABI ≤ 0.9 and ABI > 0.9 and < 1.4, respectively) and T2DM status. CEC was quantified by incubation of cholesterol-loaded THP-1 cells with the participants' apoB-depleted plasma was performed., Results: The presence of PAD determined low CEC in non-T2DM and newly-diagnosed T2DM patients. Coexisting PAD and newly-diagnosed T2DM provided and additive effect providing an impaired CEC compared to non-T2DM patients with PAD. In established T2DM patients, the presence of PAD did not determine differences in CEC, compared to those without PAD, which may be restored by glucose-lowering treatment., Conclusions: Our findings suggest an inverse relationship between CEC and PAD in CHD patients. These results support the importance of identifying underlying mechanisms of PAD, in the context of secondary prevention, that provide potential therapeutic targets, that is the case of CEC, and establishing strategies to prevent or reduce the high risk of cardiovascular events of these patients. Trial registration https://clinicaltrials.gov/ct2/show/NCT00924937 . Unique Identifier: NCT00924937.

Evidence from observational and in vitro studies suggests that insulin growth-factor-binding protein type 2 (IGFBP2) is a promising protein in non-communicable diseases, such as obesity, insulin resistance, metabolic syndrome, or type 2 diabetes. Accordingly, great efforts have been carried out to explore the role of IGFBP2 in obesity state and insulin-related diseases, which it is typically found decreased. However, the physiological pathways have not been explored yet, and the relevance of IGFBP2 as an important pathway integrator of metabolic disorders is still unknown. Here, we review and discuss the molecular structure of IGFBP2 as the first element of regulating the expression of IGFBP2 . We highlight an update of the association between low serum IGFBP2 and an increased risk of obesity, type 2 diabetes, metabolic syndrome, and low insulin sensitivity. We hypothesize mechanisms of IGFBP2 on the development of obesity and insulin resistance in an insulin-independent manner, which meant that could be evaluated as a therapeutic target. Finally, we cover the most interesting lifestyle modifications that regulate IGFBP2, since lifestyle factors (diet and/or physical activity) are associated with important variations in serum IGFBP2.

Context: Prostate cancer (PCa) is one of the leading causes of cancer-related death among the male population worldwide. Unfortunately, current medical treatments fail to prevent PCa progression in a high percentage of cases; therefore, new therapeutic tools to tackle PCa are urgently needed. Biguanides and statins have emerged as antitumor agents for several endocrine-related cancers., Objective: To evaluate: (1) the putative in vivo association between metformin and/or statins treatment and key tumor and clinical parameters and (2) the direct effects of different biguanides (metformin/buformin/phenformin), statins (atorvastatin/simvastatin/lovastatin), and their combination, on key functional endpoints and associated signalling mechanisms., Methods: An exploratory/observational retrospective cohort of patients with PCa (n = 75) was analyzed. Moreover, normal and tumor prostate cells (normal [RWPE-cells/primary prostate cell cultures]; tumor [LNCaP/22RV1/PC3/DU145 cell lines]) were used to measure proliferation/migration/tumorsphere-formation/signalling pathways., Results: The combination of metformin+statins in vivo was associated to lower Gleason score and longer biochemical recurrence-free survival. Moreover, biguanides and statins exerted strong antitumor actions (ie, inhibition of proliferation/migration/tumorsphere formation) on PCa cells, and that their combination further decreased; in addition, these functional parameters compared with the individual treatments. These actions were mediated through modulation of key oncogenic and metabolic signalling pathways (ie, AR/mTOR/AMPK/AKT/ERK) and molecular mediators (MKI67/cMYC/androgen receptor/cell-cycle inhibitors)., Conclusions: Biguanides and statins significantly reduced tumor aggressiveness in PCa, with this effect being more potent (in vitro and in vivo) when both compounds are combined. Therefore, given the demonstrated clinical safety of biguanides and statins, our results suggest a potential therapeutic role of these compounds, especially their combination, for the treatment of PCa., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Scope: It is hypothesized that decreased advanced glycation end products (AGEs) levels could affect type 2 diabetes mellitus (T2DM) remission in newly diagnosed patients through the consumption of two healthy diets., Methods and Results: Patients from CORDIOPREV study, all with previous cardiovascular events, with T2DM at the beginning of the study are included. Patients are randomized to a Mediterranean or a low-fat diet for five years. No different diabetes remission rates are found among diets. Serum methylglioxal (MG) and carboximethyllysine (CML), levels dietary AGE, as well as gene expression of AGER1 and RAGE are measured. Serum MG decreases only after the consumption of the Mediterranean diet. Moreover, a COX regression analysis shows that each SD decrease in the MG, occurring after the Mediterranean diet, increases the probability of T2DM remission with HR:2.56(1.02-6.25) and p = 0.046 and each SD increase in disposition index at baseline increases the probability of remission with HR:1.94(1.32-2.87) and p = 0.001., Conclusions: It is demonstrated that the reduction of serum AGEs levels and the modulation of its metabolism, occurring after the consumption of a Mediterranean diet, might be involved in the molecular mechanism underlying the T2DM remission of newly diagnosed patients with coronary heart disease., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Apart from its main function in the mitochondria as a key element in electron transport, Coenzyme Q 10 (CoQ 10 ) has been described as having multiple functions, such as oxidant action in the generation of signals and the control of membrane structure and phospholipid and cellular redox status. Among these, the most relevant and most frequently studied function is the potent antioxidant capability of its coexistent redox forms. Different clinical trials have investigated the effect of CoQ 10 supplementation and its ability to reduce oxidative stress. In this review, we focused on recent advances in CoQ 10 supplementation, its role as an antioxidant, and the clinical implications that this entails in the treatment of chronic diseases, in particular cardiovascular diseases, kidney disease, chronic obstructive pulmonary disease, non-alcoholic fatty liver disease, and neurodegenerative diseases. As an antioxidant, CoQ 10 has proved to be of potential use as a treatment in diseases in which oxidative stress is a hallmark, and beneficial effects of CoQ 10 have been reported in the treatment of chronic diseases. However, it is crucial to reach a consensus on the optimal dose and the use of different formulations, which vary from ubiquinol or ubiquinone Ubisol-Q 10 or Qter ® , to new analogues such as MitoQ, before we can draw a clear conclusion about its clinical use. In addition, a major effort must be made to demonstrate its beneficial effects in clinical trials, with a view to making the implementation of CoQ 10 possible in clinical practice.

Background: Endothelial dysfunction is a crucial step in atherosclerosis development, and its severity is determinant for the risk of cardiovascular recurrence. Diet may be an effective strategy to protect the endothelium, although there is no consensus about the best dietary model. The CORonary Diet Intervention with Olive oil and cardiovascular PREVention (CORDIOPREV) study is an ongoing prospective, randomized, single-blind, controlled trial in 1,002 coronary heart disease (CHD) patients, whose primary objective is to compare the effect of 2 healthy dietary patterns (low-fat versus Mediterranean diet) on the incidence of cardiovascular events. Here, we report the results of one secondary outcome of the CORDIOPREV study: to evaluate the effect of these diets on endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery., Methods and Findings: From the total participants taking part in the CORDIOPREV study, 805 completed endothelial function study at baseline and were randomized to follow a Mediterranean diet (35% fat, 22% monounsaturated fatty acids [MUFAs], and <50% carbohydrates) or a low-fat diet (28% fat, 12% MUFAs, and >55% carbohydrates), with endothelial function measurement repeated after 1 year. As secondary objectives and to explore different underlying mechanisms in the modulation of endothelial function, we quantified endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) and evaluated, in 24 preselected patients, in vitro cellular processes related to endothelial damage (reactive oxygen species, apoptosis, and senescence) and endothelial repair (cell proliferation and angiogenesis), as well as other modulators (micro-RNAs [miRNAs] and proteins). Patients who followed the Mediterranean diet had higher FMD (3.83%; 95% confidence interval [CI]: 2.91-4.23) compared with those in the low-fat diet (1.16%; 95% CI: 0.80 to 1.98) with a difference between diets of 2.63% (95% CI: 1.89-3.40, p = 0.011), even in those patients with severe endothelial dysfunction. We observed higher EPC levels (group difference: 1.64%; 95% CI: 0.79-2.13, p = 0.028) and lower EMPs (group difference: -755 EMPs/μl; 95% CI: -1,010 to -567, p = 0.015) after the Mediterranean diet compared with the low-fat diet in all patients. We also observed lower intracellular reactive oxygen species (ROS) production (group difference: 11.1; 95% CI: 2.5 to 19.6, p = 0.010), cellular apoptosis (group difference: -20.2; 95% CI: -26.7 to -5.11, p = 0.013) and senescence (18.0; 95% CI: 3.57 to 25.1, p = 0.031), and higher cellular proliferation (group difference: 11.3; 95% CI: 4.51 to 13.5, p = 0.011) and angiogenesis (total master segments length, group difference: 549; 95% CI: 110 to 670, p = 0.022) after the Mediterranean diet than the low-fat diet. Each dietary intervention was associated with distinct changes in the epigenetic and proteomic factors that modulate biological process associated with endothelial dysfunction. The evaluation of endothelial function is a substudy of the CORDIOPREV study. As in any substudy, these results should be treated with caution, such as the potential for false positives because of the exploratory nature of the analyses., Conclusions: Our results suggest that the Mediterranean diet better modulates endothelial function compared with a low-fat diet and is associated with a better balance of vascular homeostasis in CHD patients, even in those with severe endothelial dysfunction., Clinical Trial Registration: URL, http://www.cordioprev.es/index.php/en. clinicaltrials.gov number NCT00924937., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Adherence to a healthy dietary pattern positively influences clinical outcomes in cardiovascular prevention, but long-term adherence is difficult to maintain. We evaluated 5-year changes in dietary habits, adherence achieved, and its maintenance in a cohort of coronary patients from the CORDIOPREV study., Methods: 1002 coronary patients were randomized to a Mediterranean diet (n = 502) or a low-fat diet (n = 500) and received individual-group-telephone visits and personalized dietary advice. A validated food-frequency questionnaire, a 14-point Mediterranean diet adherence screener, and a 9-point low-fat diet adherence score were used. Dietary adherence was categorized into Low, Medium, and High Adherence. Changes in nutrient intake, food consumption, and adherence were analyzed on a yearly basis. The maintenance of long-term dietary adherence was evaluated using data after the first year and fifth year., Results: From baseline to 5 years, significant increases were observed in overall dietary adherence (Mediterranean diet from 8.9 to 11.4; low-fat diet from 3.9 to 7.1) and in the percentage of patients considered High Adherence (Mediterranean diet from 41 to 89%; low-fat diet from 4 to 67%). When we evaluated the maintenance of adherence, patients considered Low and Medium Adherence at 1 year increased their adherence at the 5 years with both diets and patients considered High Adherence maintained their adherence with a Mediterranean diet, but decreased their adherence with a low-fat diet., Conclusions: A comprehensive dietary intervention results in an overall long-term improvement and maintenance of adherence to the Mediterranean and low-fat diets. In our population, the Mediterranean diet group achieved a high level of adherence in the short term which was maintained in the long term.

Background: Aging is associated with a high risk for cardiovascular disease. The relation of obesity and risk of cardiovascular events appears to be more closely linked to certain clinical or metabolic phenotypes than to obesity itself. Our aim was to establish whether aging influenced the metabolic phenotypes regarding to cardiovascular risk, evaluated by changes in the intima media thickness-common carotid (IMT-CC), in coronary heart disease (CHD) patients., Methods: In this cross-sectional study, 1002 CHD patients were studied at entry from the CORDIOPREV study. We performed carotid ultrasound assessment to obtain their IMT-CC values. Carotid atherosclerosis was considered to exist if IMT-CC > 0.7 mm., Results: Age determined a higher IMT-CC, regardless metabolic phenotype (all p < 0.05). Metabolically healthy non-obese (MHNO) aged< 60 showed a lesser prevalence for carotid atherosclerotic disease than metabolically sick non-obese (MSNO) and obese (MSO), while MHNO aged≥60 only showed less prevalence for the disease than the MSO. Carotid atherosclerosis associated with age, sex, impaired fasting glucose (IFG), hypertension and high sensitivity C-reactive protein (hsCRP). However, in patients aged< 60, it associated with sex and IFG and in the age ≥ 60 group, with hypertension and hsCRP., Conclusions: Our results suggest that CHD patients aged≥60 are less metabolic flexible compared to patients aged< 60. Thus, MHO patients aged≥60 show the same risk of suffering carotid atherosclerosis as those with metabolic disease, while MHO patients aged< 60 show lower risk than MSO. This fact indicates the need to focus on therapeutic strategies in order to modify those parameters related to obesity and metabolic inflexibility in patients with CHD before entering old age.

Diabetes (T2DM) is a major global health issue, and developing new approaches to its prevention is of paramount importance. We hypothesized that abnormalities in lipid metabolism are involved in alpha-cell deregulation. We therefore studied the metabolic factors underlying alpha-cell dysfunction in T2DM progression after a dietary intervention (Mediterranean and low-fat). Additionally, we evaluated whether postprandial glucagon levels may be considered as a predictive factor of T2DM in cardiovascular patients. Non-T2DM participants from the CORDIOPREV study were categorized by tertiles of the area under the curve (AUC) for triacylglycerols and also by tertiles of AUC for glucagon. Our results showed that patients with higher triacylglycerols levels presented elevated postprandial glucagon ( P = 0.009). Moreover, we observed higher risk of T2DM (hazard ratio: 2.65; 95% confidence interval: 1.56-4.53) in subjects with elevated glucagon. In conclusion, high postprandial lipemia may induce alpha-cell dysfunction in cardiovascular patients. Our results also showed that postprandial glucagon levels could be used to predict T2DM development.

Endothelial dysfunction and intima-media thickness of common carotid arteries (IMT-CC) are considered subclinical markers of atherosclerotic cardiovascular disease (ASCVD). Advanced glycation end products (AGEs) are increased in type 2 diabetes mellitus (T2DM) patients, compared with non-diabetics, being implicated in micro- and macrovascular complications. Our aim was to compare serum AGEs levels and subclinical atherosclerotic markers between patients with established and newly diagnosed T2DM. Among 540 patients with T2DM and coronary heart disease from the CORDIOPREV study, 350 patients had established T2DM and 190 patients had newly diagnosed T2DM. Serum levels of AGEs (methylglyoxal (MG) and N-carboxymethyl lysine (CML)) and subclinical atherosclerotic markers (brachial flow-mediated vasodilation (FMD) and IMT-CC) were measured. AGEs levels (all p < 0.001) and IMT-CC ( p = 0.025) were higher in patients with established vs. newly diagnosed T2DM, whereas FMD did not differ between the two groups. Patients with established T2DM and severe endothelial dysfunction (i.e., FMD < 2%) had higher serum MG levels, IMT-CC, HOMA-IR and fasting insulin levels than those with newly diagnosed T2DM and non-severe endothelial dysfunction (i.e., FMD ≥ 2%) (all p < 0.05). Serum CML levels were greater in patients with established vs. newly diagnosed T2DM, regardless of endothelial dysfunction severity. Serum AGEs levels and IMT-CC were significantly higher in patients with established vs. newly diagnosed T2DM, highlighting the progressively increased risk of ASCVD in the course of T2DM. Establishing therapeutic strategies to reduce AGEs production and delay the onset of cardiovascular complications in newly diagnosed T2DM patients or minimize ASCVD risk in established T2DM patients is needed., Competing Interests: N.K. has given talks, attended conferences and participated in trials sponsored by Astra Zeneca, Bausch Health, Boehringer Ingelheim, Elpen, Mylan, NovoNordisk, Sanofi, Servier and Vianex. The other authors declare that they have no current or potential conflicts of interest.

Background: Dysregulation of splicing variants (SVs) expression has recently emerged as a novel cancer hallmark. Although the generation of aberrant SVs (e.g. AR-v7/sst5TMD4/etc.) is associated to prostate-cancer (PCa) aggressiveness and/or castration-resistant PCa (CRPC) development, whether the molecular reason behind such phenomena might be linked to a dysregulation of the cellular machinery responsible for the splicing process [spliceosome-components (SCs) and splicing-factors (SFs)] has not been yet explored., Methods: Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinically-localized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42)., Findings: A profound dysregulation in the expression of multiple components of the splicing machinery (i.e. 7 SCs/19 SFs) were found in PCa compared to their non-tumor adjacent-regions. Notably, overexpression of SNRNP200, SRSF3 and SRRM1 (mRNA and/or protein) were associated with relevant clinical (e.g. Gleason score, T-Stage, metastasis, biochemical recurrence, etc.) and molecular (e.g. AR-v7 expression) parameters of aggressiveness in PCa-samples. Functional (cell-proliferation/migration) and mechanistic [gene-expression (qPCR) and protein-levels (western-blot)] assays were performed in normal prostate cells (PNT2) and PCa-cells (LNCaP/22Rv1/PC-3/DU145 cell-lines) in response to SNRNP200, SRSF3 and/or SRRM1 silencing (using specific siRNAs) revealed an overall decrease in proliferation/migration-rate in PCa-cells through the modulation of key oncogenic SVs expression levels (e.g. AR-v7/PKM2/XBP1s) and alteration of oncogenic signaling pathways (e.g. p-AKT/p-JNK)., Interpretation: These results demonstrate that the spliceosome is drastically altered in PCa wherein SNRNP200, SRSF3 and SRRM1 could represent attractive novel diagnostic/prognostic and therapeutic targets for PCa and CRPC., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We try to explore whether long-term consumption of two healthy dietary patterns (low-fat [LF] diet or Mediterranean diet [MedDiet]) interacts with the apolipoprotein E (APOE) single-nucleotide polymorphisms (SNPs: rs439401, rs440446 and rs7412) modulating postprandial hypertriglyceridemia (ppHTG) in coronary heart disease (CHD) patients., Methods and Results: We selected patients from the CORDIOPREV study with genotyping and who underwent an oral fat load test (FLT) at baseline and after 3 years follow-up (n = 506). After 3 years of follow-up, we found a gene-diet interaction between the APOE rs439401 SNP and MedDiet. Specifically, T-allele carriers in the MedDiet group showed a more significant decrease in postprandial triglycerides (TG: P = 0.03) and large triacylglycerol-rich lipoproteins (TRLs) TG (large TRLs TG; P = 0.01) compared with CC subjects. Consistently, the area under the curve of TG (AUC-TG; P-interaction = 0.03) and AUC-large TRLs TG (P-interaction = 0.02) were significantly lower in T-allele carriers compared with CC subjects., Conclusions: The long-term consumption of a MedDiet modulates ppHTG through APOE genetic variants in CHD patients. This gene-diet interaction may contribute to a more precise dietary advice in CHD patients., (© 2019 Stichting European Society for Clinical Investigation Journal Foundation.)

The beneficial effects of a Mediterranean diet on human health and, in particular, on lowering risk of cardiovascular disease, has been mainly attributed to its high content to extra virgin olive oil (EVOO). While its main fatty acid, oleic acid, is considered important to these effects, EVOO has other biological properties that depend on, or are potentiated by other minor components of this oil. Initially, the mechanisms considered as possible causes of this cardioprotective effect of EVOO were based on the incidence on the so-called traditional risk factors (especially lipids and blood pressure). However, the high relative reduction in the prevalence of cardiovascular morbidity and mortality were not proportional to the limited findings about regulation of those traditional risk factors. In addition to several studies confirming the above effects, current research on beneficial effect of EVOO, and in particular in conjunction with Mediterranean style diets, is being focused on defining its effects on newer cardiovascular risk factors, such as inflammation, oxidative stress, coagulation, platelet aggregation, fibrinolysis, endothelial function or lipids or on the modulation of the conditions which predispose people to cardiovascular events, such as obesity, metabolic syndrome or type 2 diabetes mellitus. In the current review, we will mainly focus on reviewing the current evidence about the effects that EVOO exerts on alternative factors, including postprandial lipemia or coagulation, among others, discussing the underlying mechanism by which it exerts its effect, as well as providing a short review on future directions.

Leukocyte telomere length (LTL) shortening is a biomarker of cellular aging that can be decelerated by diet. We aimed to investigate the effect of dietary intake of vitamin E on biomarkers of cellular senescence in patients with established cardiovascular disease. To this end, DNA from 1,002 participants of the CORDIOPREV study (NCT00924937) was isolated and LTL was measured by real-time PCR. Dietary information was collected using a 146-item food frequency questionnaire, and several oxidative stress and damage biomarkers were determined. We found that patients with an inadequate intake of vitamin E according to the European Food Safety Authority, U.S. Food and Nutrition Board, and Spanish dietary recommendation had shorter LTL than those with an adequate intake (p = .004, p = .015, and p = .005, respectively). Moreover, we observed a positive correlation between olive oil, fish consumption and LTL (r2 = .083, p = .010; r2 = .090, p = .006, respectively). Subjects who consumed more than 30 mL olive oil/day had longer LTL than subjects with lower consumption (p = .013). Furthermore, we observed higher glutathione peroxidase activity in subjects consuming less vitamin E (p = .031). Our findings support the importance of an adequate consumption of the antioxidant vitamin E, and the value of the diet as a modulating tool of the senescence process., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Coenzyme Q 10 (CoQ 10 ) is a ubiquitous molecule present in all eukaryotic organisms whose principal role in the cell is related to its participation in the electron transport chain in the inner mitochondrial membrane. CoQ 10 plays a major role in the control of cell redox status, and both the amount and functionality of this molecule have been related to the regulation of reactive oxygen species generation. Numerous reports can be found discussing the implications of CoQ 10 supplementation in human studies and clinical trials related to aging. However, few reviews have made an updating through the translational point of view to integrate both basic and clinical aspects. The aim of this paper is to review our current knowledge from CoQ 10 implications at biochemical and physiological level, in order to unravel the molecular mechanisms involved in its application in clinical practice. Although the importance of CoQ 10 has been mainly attributed to its role as an agent for energy transduction in mitochondria, new functions for CoQ 10 have been described in the recent past years, including anti-inflammatory effects, gene expression regulation and lipid bilayer membranes stabilization, which explain its involvement in aging and age-related diseases such as cardiovascular diseases, renal failure and neurodegenerative diseases.

Background: Patients with type 2 diabetes (T2D) have an elevated postprandial lipemia (PPL) that has been associated with increased cardiovascular risk., Objective: We aimed to analyze whether the long-term consumption of 2 healthy dietary patterns is associated with an improvement in PPL and remnant cholesterol (RC) concentrations in patients with T2D., Design: We selected patients from the Cordioprev study who underwent oral fat load tests (FLTs) at baseline and the 3-y follow-up (241 patients with and 316 patients without T2D). Subjects were randomly assigned to receive either a Mediterranean diet rich in olive oil (MedDiet; 35% of calories from fat [22% monounsaturated fatty acids (MUFAs)] and 50% from carbohydrates) or a low-fat (LF) diet [<30% fat (12-14% MUFAs) and 55% of calories from carbohydrates]. Lipids were measured in serial bloods drawn at 0, 1, 2, 3, and 4 h after the FLT., Results: After 3 y of dietary intervention, patients with T2D showed an improvement in their PPL measured as postprandial triglycerides (TGs) (P < 0.0001), TG area under the curve (AUC) (P = 0.001), and TG-rich lipoproteins (TRLs-TG; P = 0.001) compared with baseline. Subgroup analysis, based on the type of dietary intervention, showed that those T2D patients randomly assigned to the MedDiet presented a reduction in the TG AUC of 17.3% compared with baseline (P = 0.003). However, there were no differences for T2D patients randomly assigned to the LF diet (P > 0.05) or in patients without T2D (P > 0.05) regardless of the dietary intervention. In addition, the MedDiet induced a significant improvement in the RC AUC in patients with T2D (P = 0.04). However, there was no significant improvement in those following the LF diet., Conclusions: Our findings show that the long-term consumption of a MedDiet rich in olive oil improves PPL and RC concentrations mainly in patients with T2D. This trial was registered at clinicaltrials.gov as NCT00924937.

Diabetic kidney disease (DKD) is characterized by progressive glomerulosclerosis (GS). ROP mice have a sclerosis-prone phenotype. However, they develop severe, rapidly progressive GS when rendered diabetic. Since GS also develops in aged C57Bl6 mice, and can be reversed using bone marrow from young mice which have lower oxidative stress and inflammation (OS/Infl), we postulated that this might also apply to DKD. Therefore, this pilot study asked whether reducing OS/Infl in young adult sclerosis-prone (ROP) diabetic mice leads to resolution of existing GS in early DKD using safe, FDA-approved drugs.After 4 weeks of stable streptozotocin-induced hyperglycemia 8-12 week-old female mice were randomized and treated for 22 weeks as follows: 1) enalapril (EN) (n = 8); 2) pyridoxamine (PYR)+EN (n = 8); 3) pentosan polysulfate (PPS)+EN (n = 7) and 4) PPS+PYR+EN (n = 7). Controls were untreated (non-DB, n = 7) and hyperglycemic (DB, n = 8) littermates. PPS+PYR+EN reduced albuminuria and reversed GS in DB. Treatment effects: 1) Anti-OS/Infl defenses: a) PPS+PYR+EN increased the levels of SIRT1, Nrf2, estrogen receptor α (ERα) and advanced glycation endproduct-receptor1 (AGER1) levels; and b) PYR+EN increased ERα and AGER1 levels. 2) Pro-OS/Infl factors: a) PPS+PYR+EN reduced sTNFR1, b) all except EN reduced MCP1, c) RAGE was reduced by all treatments. In summary, PYR+PPS+EN modulated GS in sclerosis-prone hyperglycemic mice. PYR+PPS+EN also decreased albuminuria, OS/Infl and the sclerosis-prone phenotype. Thus, reducing OS/Infl may reverse GS in early diabetes in patients, and albuminuria may allow early detection of the sclerosis-prone phenotype., Competing Interests: The authors have declared that no competing interests exist.