Effects of a High-Fat Diet on Insulin-Related miRNAs in Plasma and Brain Tissue in APPSwe/PS1dE9 and Wild-Type C57BL/6J Mice.

Insulin resistance (IR)-related miRNAs have been associated with the development and progression of Alzheimer's disease (AD). The dietary modulation of these miRNAs could become a potential strategy to manage AD. The aim of this study was to evaluate the effect of a high-fat diet (HFD), which aggravates AD-related pathogenic processes, on serum, cortex and hippocampus IR-related miRNA expression. C57BL/6J WT and APPSwe/PS1dE9 mice were fed either an HFD or a conventional diet till 6 months of age. The mice fed with the HFD showed a significant increase in body weight and worsening glucose and insulin metabolism. miR-19a-3p was found to be up-regulated in the cortex, hippocampus and serum of APP/PS1 mice and in the serum and hippocampus of WT mice fed with the HFD. miR-34a-5p and miR-146a-5p were up-regulated in the serum of both groups of mice after consuming the HFD. Serum miR-29c-3p was overexpressed after consuming the HFD, along with hippocampal miR-338-3p and miR-125b-5p, only in WT mice. The HFD modulated the expression of peripheral and brain miRNAs related to glucose and insulin metabolism, suggesting the potential role of these miRNAs not only as therapeutic targets of AD but also as peripheral biomarkers for monitoring AD.

Bile Acids and Risk of Adverse Cardiovascular Events and All-Cause Mortality in Patients with Acute Coronary Syndrome.

The relationship between bile acids (BAs) and adverse cardiovascular events following acute coronary syndrome (ACS) have been little investigated. We aimed to examine the associations of BAs with the risk of cardiovascular events and all-cause mortality in ACS. We conducted a prospective study on 309 ACS patients who were followed for 10 years. Plasma BAs were quantified by liquid chromatography coupled to tandem mass spectrometry. Cox regression analyses with elastic net penalties were performed to associate BAs with MACE and all-cause mortality. Weighted scores were computed using the 100 iterated coefficients corresponding to each selected BA, and the associations of these scores with these adverse outcomes were assessed using multivariable Cox regression models. A panel of 10 BAs was significantly associated with the increased risk of MACE. The hazard ratio of MACE per SD increase in the estimated BA score was 1.35 (95% CI 1.12-1.63). Furthermore, four BAs were selected from the elastic net model for all-cause mortality, although their weighted score was not independently associated with mortality. Our findings indicate that primary and secondary BAs may play a significant role in the development of MACE. This insight holds potential for developing strategies to manage ACS and prevent adverse outcomes.

The association of glucose metabolism measures and diabetes status with Alzheimer's disease biomarkers of amyloid and tau: A systematic review and meta-analysis.

Conflicting evidence exists on the relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) biomarkers. Therefore, we conducted a random-effects meta-analysis to evaluate the correlation of glucose metabolism measures (glycated hemoglobin, fasting blood glucose, insulin resistance indices) and DM status with AD biomarkers of amyloid-ß and tau measured by positron emission tomography or cerebrospinal fluid. We selected 37 studies from PubMed and Embase, including 11,694 individuals. More impaired glucose metabolism and DM status were associated with higher tau biomarkers (r=0.11[0.03-0.18], p=0.008; I2=68%), but were not associated with amyloid-ß biomarkers (r=-0.06[-0.13-0.01], p=0.08; I2=81%). Meta-regression revealed that glucose metabolism and DM were specifically associated with tau biomarkers in population settings (p=0.001). Furthermore, more impaired glucose metabolism and DM status were associated with lower amyloid-ß biomarkers in memory clinic settings (p=0.004), and in studies with a higher prevalence of dementia (p<0.001) or lower cognitive scores (p=0.04). These findings indicate that DM is associated with biomarkers of tau but not with amyloid-ß. This knowledge is valuable for improving dementia and DM diagnostics and treatment.

Exploring small non-coding RNAs as blood-based biomarkers to predict Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) diagnosis relies on clinical symptoms complemented with biological biomarkers, the Amyloid Tau Neurodegeneration (ATN) framework. Small non-coding RNA (sncRNA) in the blood have emerged as potential predictors of AD. We identified sncRNA signatures specific to ATN and AD, and evaluated both their contribution to improving AD conversion prediction beyond ATN alone. METHODS: This nested case-control study was conducted within the ACE cohort and included MCI patients matched by sex. Patients free of type 2 diabetes underwent cerebrospinal fluid (CSF) and plasma collection and were followed-up for a median of 2.45-years. Plasma sncRNAs were profiled using small RNA-sequencing. Conditional logistic and Cox regression analyses with elastic net penalties were performed to identify sncRNA signatures for A+(T|N)+ and AD. Weighted scores were computed using cross-validation, and the association of these scores with AD risk was assessed using multivariable Cox regression models. Gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) enrichment analysis of the identified signatures were performed. RESULTS: The study sample consisted of 192 patients, including 96 A+(T|N)+ and 96 A-T-N- patients. We constructed a classification model based on a 6-miRNAs signature for ATN. The model could classify MCI patients into A-T-N- and A+(T|N)+ groups with an area under the curve of 0.7335 (95% CI, 0.7327 to 0.7342). However, the addition of the model to conventional risk factors did not improve the prediction of AD beyond the conventional model plus ATN status (C-statistic: 0.805 [95% CI, 0.758 to 0.852] compared to 0.829 [95% CI, 0.786, 0.872]). The AD-related 15-sncRNAs signature exhibited better predictive performance than the conventional model plus ATN status (C-statistic: 0.849 [95% CI, 0.808 to 0.890]). When ATN was included in this model, the prediction further improved to 0.875 (95% CI, 0.840 to 0.910). The miRNA-target interaction network and functional analysis, including GO and KEGG pathway enrichment analysis, suggested that the miRNAs in both signatures are involved in neuronal pathways associated with AD. CONCLUSIONS: The AD-related sncRNA signature holds promise in predicting AD conversion, providing insights into early AD development and potential targets for prevention.

Dietary fat, telomere length and cognitive function: unravelling the complex relations.

PURPOSE OF REVIEW: The review aims to explore the recent evidence on the associations between different dietary fat intake and cognitive function, and to understand the role of telomere length in this relationship. RECENT FINDINGS: Clinical and preclinical studies included in this review suggest that dietary fat intake is associated with cognitive function and telomere length. High intake of saturated fats and trans fats, commonly found in ultra-processed foods, appears to have negative effects on cognitive function and telomere length, while other dietary fats, such as omega-3 polyunsaturated fatty acids and monounsaturated fatty acids are associated with improved cognitive performance and reduced telomere attrition. Controversial results related to omega-6 polyunsaturated fatty acids intake and its impact on cognitive function were found. Dietary fats may affect telomere length and cognition through oxidative stress, inflammation, and insulin resistance. SUMMARY: The current review illustrated the relationship between dietary fat and cognitive function by focusing on the role of telomere length as a potential intermediator. More future studies are required, however, in order to develop targeted interventions aimed at preserving cognitive well-being throughout life.

Dietary intake of metals, metalloids, and persistent organic pollutants in Spanish pregnant women. ECLIPSES study.

OBJECTIVE: This study aimed to describe dietary intake and important dietary sources to pollutants as well as to identify maternal socio-economic and lifestyle factors associated with high intake during pregnancy in women residing in a Mediterranean city with heavy industrial activity. METHODS: Dietary intake during pregnancy of As, InAs, Cd, MeHg, Pb, PCDD/Fs, DL-PCBs, and NDL-PCBs in 701 pregnant women participating in the longitudinal ECLIPSES study was calculated based on a 45-item food-frequency questionnaire and a database of pollutants in food of the Catalan Food Safety Agency. Details on socio-economic, lifestyle, and anthropometric variables were also collected. RESULTS: The mean dietary intake of pollutants per day and the food group that contributed the most (%) was: 286.51 µg of As (71.27% from white fish), 4.14 µg of InAs (70.16% from cereals-tubers), 6.27 µg of Cd (47.51% from seafood), 5.00 µg of MeHg (52.88% from blue fish), 3.32 µg of Pb (30.15% from cereals-tubers), 9.93 pg of PCDD/Fs (from many food categories), 18.39 pg of DL-PCBs (59.74% from blue fish) and 181.00 ng of NDL-PCBs (44.58% from blue fish). Adjusted multivariate analysis revealed that older age was associated with high As intake, higher educational level was related to low InAs, Cd, and DL-PCBs intake, and alcohol use and smoking were linked with high Pb intake. CONCLUSION: The dietary intake of pollutants including As and DL-PCBs among pregnant women exceeds or almost reaches the EFSA safety threshold. These findings support the urgent need for local governments to pay special attention to this situation and develop specific prevention strategies for this vulnerable group.

TCA cycle metabolites associated with adverse outcomes after acute coronary syndrome: mediating effect of renal function.

Aims: To examine relationships of tricarboxylic acid (TCA) cycle metabolites with risk of cardiovascular events and mortality after acute coronary syndrome (ACS), and evaluate the mediating role of renal function in these associations. Methods: This is a prospective study performed among 309 ACS patients who were followed for a mean of 6.7 years. During this period 131 patients developed major adverse cardiovascular events (MACE), defined as the composite of myocardial infarction, hospitalization for heart failure, and all-cause mortality, and 90 deaths were recorded. Plasma concentrations of citrate, aconitate, isocitrate, succinate, malate, fumarate, α-ketoglutarate and d/l-2-hydroxyglutarate were quantified using LC-tandem MS. Multivariable Cox regression models were used to estimate hazard ratios, and a counterfactual-based mediation analysis was performed to test the mediating role of estimated glomerular filtration rate (eGFR). Results: After adjustment for traditional cardiovascular risk factors and medications, positive associations were found between isocitrate and MACE (HR per 1 SD, 1.25; 95% CI: 1.03, 1.50), and between aconitate, isocitrate, d/l-2-hydroxyglutarate and all-cause mortality (HR per 1 SD, 1.41; 95% CI: 1.07, 1.84; 1.58; 95% CI: 1.23, 2.02; 1.38; 95% CI: 1.14, 1.68). However, these associations were no longer significant after additional adjustment for eGFR. Mediation analyses demonstrated that eGFR is a strong mediator of these associations. Conclusion: These findings underscore the importance of TCA metabolites and renal function as conjunctive targets in the prevention of ACS complications.

Lipoprotein Particle Profiles Associated with Telomere Length and Telomerase Complex Components.

Telomere length (TL) is a well-known marker of age-related diseases. Oxidative stress and inflammation increase the rate of telomere shortening, triggering cellular senescence. Although lipoproteins could have anti-inflammatory and proinflammatory functional properties, the relationship between lipoprotein particles with TL and telomerase activity-related genes has not been investigated much. In this study, we assessed the associations of lipoprotein subfractions with telomere length, TERT, and WRAP53 expression in a total of 54 pre-diabetic subjects from the EPIRDEM study. We regressed TL, TERT, and WRAP53 on 12 lipoprotein subclasses, employing a Gaussian linear regression method with Lasso penalty to determine a lipoprotein profile associated with telomere-related parameters. The covariates included age, sex, body mass index (BMI), dyslipidemia, statin consumption, and physical activity leisure time. We identified a lipoprotein profile composed of four lipoprotein subfractions associated with TL (Pearson r = 0.347, p-value = 0.010), two lipoprotein subfractions associated with TERT expression (Pearson r = 0.316, p-value = 0.020), and five lipoprotein subfractions associated with WRAP53 expression (Pearson r = 0.379, p-value =0.005). After adjusting for known confounding factors, most lipoprotein profiles maintained the association with TL, TERT, and WRAP53. Overall, medium and small-sized HDL particles were associated with shorter telomeres and lower expression of TERT and WRAP53. Large HDL particles were associated with longer telomere and lower expression of WRAP53, but not with TERT. Our results suggest that the lipoprotein profiles are associated with telomere length, TERT, and WRAP53 expression and should be considered when assessing the risk of chronic diseases.

A novel rhein-huprine hybrid ameliorates disease-modifying properties in preclinical mice model of Alzheimer's disease exacerbated with high fat diet.

BACKGROUND: Alzheimer's disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features. In fact, ß-secretase (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, have been considered promising targets for both pathologies. In this regard, due to the multifactorial origin of these diseases, current research efforts are focusing on the development of multi-target drugs as a very promising option to derive effective treatments for both conditions. In the present study, we evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and AChE inhibitor, both considered key factors not only in AD but also in metabolic pathologies. Thus, the aim of this study is to evaluate the effects of this compound in APP/PS1 female mice, a well-established familial AD mouse model, challenged by high-fat diet (HFD) consumption to concomitantly simulate a T2DM-like condition. RESULTS: Intraperitoneal treatment with RHE-HUP in APP/PS1 mice for 4 weeks reduced the main hallmarks of AD, including Tau hyperphosphorylation, Aß42 peptide levels and plaque formation. Moreover, we found a decreased inflammatory response together with an increase in different synaptic proteins, such as drebrin 1 (DBN1) or synaptophysin, and in neurotrophic factors, especially in BDNF levels, correlated with a recovery in the number of dendritic spines, which resulted in memory improvement. Notably, the improvement observed in this model can be attributed directly to a protein regulation at central level, since no peripheral modification of those alterations induced by HFD consumption was observed. CONCLUSIONS: Our results suggest that RHE-HUP could be a new candidate for the treatment of AD, even for individuals with high risk due to peripheral metabolic disturbances, given its multi-target profile which allows for the improvement of some of the most important hallmarks of the disease.

The link between cognition and somatic conditions related to insulin resistance in the UK Biobank study cohort: a systematic review.

Clinical and genomic studies have shown an overlap between neuropsychiatric disorders and insulin resistance (IR)-related somatic conditions, including obesity, type 2 diabetes, and cardiovascular diseases. Impaired cognition is often observed among neuropsychiatric disorders, where multiple cognitive domains may be affected. In this review, we aimed to summarise previous evidence on the relationship between IR-related diseases/traits and cognitive performance in the large UK Biobank study cohort. Electronic searches were conducted on PubMed, Scopus, and Web of Science until April 2022. Eighteen articles met the inclusion criteria and were qualitatively reviewed. Overall, there is substantial evidence for an association between IR-related cardio-metabolic diseases/traits and worse performance on various cognitive domains, which is largely independent of possible confoundings. The most consistent findings referred to IR-related associations with poorer verbal and numerical reasoning ability, as well as slower processing speed. The observed associations might be mediated by alterations in immune-inflammation, brain integrity/connectivity, and/or comorbid somatic or psychiatric diseases/traits. Our findings provide impetus for further research into the underlying neurobiology and possible new therapeutic targets.

Plasma trimethylamine-N-oxide, its precursors and risk of cardiovascular events in patients with acute coronary syndrome: Mediating effects of renal function.

Aims: To examine associations of the gut microbial metabolite trimethylamine-N-oxide (TMAO) and its precursors with risk of cardiovascular events in acute coronary syndrome (ACS), and determine whether these associations were mediated by renal function. Methods: In this prospective cohort study, we included 309 patients with ACS. During a mean follow-up of 6.7 years, 131 patients developed major adverse cardiovascular events (MACE) (myocardial infarction, hospitalization for heart failure, and all-cause mortality). Plasma concentrations of TMAO, trimethylamine (TMA), choline, betaine, dimethylglycine and L-carnitine were profiled by liquid chromatography tandem mass spectrometry. Hazard ratios were estimated with multivariable Cox regression models. The mediating role of estimated glomerular filtration rate (eGFR) was tested under a counterfactual framework. Results: After adjustment for traditional cardiovascular risk factors and medications, participants in the highest tertile vs. the lowest tertile of baseline TMAO and dimethylglycine concentrations had a higher risk of MACE [(HR: 1.83; 95% CI: 1.08, 3.09) and (HR: 2.26; 95% CI: 1.17, 3.99), respectively]. However, with regards to TMAO these associations were no longer significant, whereas for dimethylglycine, the associations were attenuated after additional adjustment for eGFR. eGFR mediated the associations of TMAO (58%) and dimethylglycine (32%) with MACE incidence. The associations between dimethylglycine and incident MACE were confirmed in an internal validation. No significant associations were found for TMA, choline, betaine and L-carnitine. Conclusion: These findings suggest that renal function may be a key mediator in the association of plasma TMAO with the development of cardiovascular events after ACS. The present findings also support a role of dimethylglycine in the pathogenesis of MACE, which may be mediated, at least partially, by renal function.

Protein tyrosine phosphatase 1B (PTP1B) as a potential therapeutic target for neurological disorders.

Protein tyrosine phosphatase 1B (PTP1B) is a typical member of the PTP family, considered a direct negative regulator of several receptor and receptor-associated tyrosine kinases. This widely localized enzyme has been involved in the pathophysiology of several diseases. More recently, PTP1B has attracted attention in the field of neuroscience, since its activation in brain cells can lead to schizophrenia-like behaviour deficits, anxiety-like effects, neurodegeneration, neuroinflammation and depression. Conversely, PTP1B inhibition has been shown to prevent microglial activation, thus exerting a potent anti-inflammatory effect and has also shown potential to increase the cognitive process through the stimulation of hippocampal insulin, leptin and BDNF/TrkB receptors. Notwithstanding, most research on the clinical efficacy of targeting PTP1B has been developed in the field of obesity and type 2 diabetes mellitus (TD2M). However, despite the link existing between these metabolic alterations and neurodegeneration, no clinical trials assessing the neurological advantages of PTP1B inhibition have been performed yet. Preclinical studies, though, have provided strong evidence that targeting PTP1B could allow to reach different pathophysiological mechanisms at once. herefore, specific interventions or trials should be designed to modulate PTP1B activity in brain, since it is a promising strategy to decelerate or prevent neurodegeneration in aged individuals, among other neurological diseases. The present paper fails to include all neurological conditions in which PTP1B could have a role; instead, it focuses on those which have been related to metabolic alterations and neurodegenerative processes. Moreover, only preclinical data is discussed, since clinical studies on the potential of PTP1B inhibition for treating neurological diseases are still required.

Gut Microbiota-Derived Metabolites and Cardiovascular Disease Risk: A Systematic Review of Prospective Cohort Studies.

Gut microbiota-derived metabolites have recently attracted considerable attention due to their role in host-microbial crosstalk and their link with cardiovascular health. The MEDLINE-PubMed and Elsevier's Scopus databases were searched up to June 2022 for studies evaluating the association of baseline circulating levels of trimethylamine N-oxide (TMAO), secondary bile acids, short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), tryptophan and indole derivatives, with risk of cardiovascular disease (CVD). A total of twenty-one studies were included in the systematic review after evaluating 1210 non-duplicate records. There were nineteen of the twenty-one studies that were cohort studies and two studies had a nested case-control design. All of the included studies were of high quality according to the "Newcastle-Ottawa Scale". TMAO was positively associated with adverse cardiovascular events and CVD/all-cause mortality in some, but not all of the included studies. Bile acids were associated with atrial fibrillation and CVD/all-cause mortality, but not with CVD. Positive associations were found between BCAAs and CVD, and between indole derivatives and major adverse cardiovascular events, while a negative association was reported between tryptophan and all-cause mortality. No studies examining the relationship between SCFAs and CVD risk were identified. Evidence from prospective studies included in the systematic review supports a role of microbial metabolites in CVD.

JNK1 and JNK3: divergent functions in hippocampal metabolic-cognitive function.

BACKGROUND AND AIM: The appearance of alterations in normal metabolic activity has been increasingly considered a risk factor for the development of sporadic and late-onset neurodegenerative diseases. In this report, we induced chronic metabolic stress by feeding of a high-fat diet (HFD) in order to study its consequences in cognition. We also studied the effects of a loss of function of isoforms 1 and 3 of the c-Jun N-terminal Kinases (JNK), stress and cell death response elements. METHODS: Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice at 9 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-GTT and IP­ITT) were performed to evaluate peripheral biometrics. Additionally, cognitive behavioral tests and analysis of spine density were performed to assess cognitive function. Molecular studies were carried out to confirm the effects of metabolic stressors in the hippocampus relative to cognitive loss. RESULTS: Our studies demonstrated that HFD in Jnk3-/- lead to synergetic responses. Loss of function of JNK3 led to increased body weight, especially when exposed to an HFD and they had significantly decreased response to insulin. These mice also showed increased stress in the endoplasmic reticulum and diminished cognitive capacity. However, loss of function of JNK1 promoted normal or heightened energetic metabolism and preserved cognitive function even when chronically metabolically stressed. CONCLUSIONS: Downregulation of JNK3 does not seem to be a suitable target for the modulation of energetic-cognitive dysregulations while loss of function of JNK1 seems to promote a good metabolic-cognitive profile, just like resistance to the negative effects of chronic feeding with HFD.

Taxonomic and Functional Fecal Microbiota Signatures Associated With Insulin Resistance in Non-Diabetic Subjects With Overweight/Obesity Within the Frame of the PREDIMED-Plus Study.

Objective: An altered gut microbiota has been associated with insulin resistance, a metabolic dysfunction consisting of cellular insulin signaling impairment. The aim of the present study is to determine the taxonomic and functional fecal microbiota signatures associated with HOMA-IR index in a population with high cardiovascular risk. Methods: A total of 279 non-diabetic individuals (55-75 years aged) with overweight/obesity and metabolic syndrome were stratified according to tertiles of HOMA-IR index. Blood biochemical parameters, anthropometric measurements and fecal samples were collected at baseline. Fecal microbial DNA extraction, 16S amplicon sequencing and bioinformatics analysis were performed. Results: Desulfovibrio, Odoribacter and Oscillospiraceae UCG-002 were negatively associated with HOMA-IR index, whereas predicted total functional abundances revealed gut metabolic modules mainly linked to amino acid degradation. Butyricicoccus, Erysipelotrichaceae UCG-003, Faecalibacterium were positively associated with HOMA-IR index, whereas predicted total functional abundances revealed gut metabolic modules mainly linked to saccharide degradation. These bacteria contribute differentially to the gut metabolic modules, being the degree of contribution dependent on insulin resistance. Both taxa and gut metabolic modules negatively associated to HOMA-IR index were linked to mechanisms involving sulfate reducing bacteria, improvement of intestinal gluconeogenesis and production of acetate. Furthermore, both taxa and gut metabolic modules positively associated to HOMA-IR index were linked to production and mechanisms of action of butyrate. Conclusions: Specific taxonomic and functional fecal microbiota signatures associated with insulin resistance were identified in a non-diabetic population with overweight/obesity at high cardiovascular risk. These findings suggest that tailoring therapies based on specific fecal microbiota profiles could be a potential strategy to improve insulin sensitivity.

Application of Machine Learning Solutions to Optimize Parameter Prediction to Enhance Automatic NMR Metabolite Profiling.

The quality of automatic metabolite profiling in NMR datasets from complex matrices can be affected by the numerous sources of variability. These sources, as well as the presence of multiple low-intensity signals, cause uncertainty in the metabolite signal parameters. Lineshape fitting approaches often produce suboptimal resolutions to adapt them in a complex spectrum lineshape. As a result, the use of software tools for automatic profiling tends to be restricted to specific biological matrices and/or sample preparation protocols to obtain reliable results. However, the analysis and modelling of the signal parameters collected during initial iteration can be further optimized to reduce uncertainty by generating narrow and accurate predictions of the expected signal parameters. In this study, we show that, thanks to the predictions generated, better profiling quality indicators can be outputted, and the performance of automatic profiling can be maximized. Our proposed workflow can learn and model the sample properties; therefore, restrictions in the biological matrix, or sample preparation protocol, and limitations of lineshape fitting approaches can be overcome.

Vitamin K dietary intake is associated with cognitive function in an older adult Mediterranean population.

BACKGROUND: In the last years, evidence that dietary vitamin K could have a role in the cognitive domain has increased. However, data from large trials are limited. The objective of this study was to assess the association of 2 year changes in the dietary intake of vitamin K with cognitive function measured through neuropsychological performance tests. METHODS: In 5,533 participants of the multicentre PREDIMED-Plus study (48.1% women, age 65.1 ± 4.9 years with overweight/obesity and metabolic syndrome), we assessed the adjusted odds ratios of cognitive function decline according to 2 year changes in vitamin K intake. Participants answered a battery of cognitive function tests and Food Frequency Questionnaires (FFQs) in order to estimate the vitamin K dietary intake. RESULTS: After adjusting for potential cofounders, the highest tertile of change of dietary vitamin K intake (median [IQR]; 194.4 µg/d [120.9, 373.1]) was inversely associated with a Mini-Mental State Examination (MMSE) score ≤24 (OR [95% CI]; 0.53 [0.35, 0.79] P for trend = 0.002) compared with a decrease in the intake of vitamin K (median [IQR]; -97.8 µg/d [-292.8, -51.5]). A significant positive association between changes in dietary vitamin K intake and the semantic verbal fluency test scores (OR [95% CI]; 0.69 [0.51, 0.94] P for trend = 0.019) was found. CONCLUSIONS: An increase of the intake of dietary vitamin K was associated with better cognitive function scores, independently of recognised risk factors for cognitive decline, in an older adult Mediterranean population with high cardiovascular risk.

GSPE pre-treatment protects against long-term cafeteria diet-induced mitochondrial and inflammatory affectations in the hippocampus of rats.

Deregulations like the loss of sensitivity to insulin (insulin resistance) and chronic inflammation are alterations very commonly found in sporadic forms of neurodegenerative pathologies. Thus, finding strategies to protect against them, may lead to a reduction in the incidence and/or affectation of these pathologies. The grape seed-derived proanthocyanidins extract (GSPE) is a mixture of compounds highly enriched in polyphenols and flavonoids that have shown to have a wide range of therapeutic benefits due to their antioxidant and anti-inflammatory properties. OBJECTIVES: This study aimed to assess the protective effects of a short pre-treatment of GSPE in the hippocampus against a prolonged feeding with cafeteria diet. METHODS: GSPE was administered for 10 days followed by 12 weeks of cafeteria diet. We analyzed transcriptional activity of genes and protein expression of key mediators of neurodegeneration in brain samples. RESULTS: Results indicated that GSPE was able to protect against cellular damage through the activation of AKT, as well as promote the maintenance of mitochondrial function by conserving the OXPHOS complexes and upregulating the antioxidant SOD. DISCUSSION: We observed that GSPE decreased inflammatory activation as observed through the downregulation of JNK, IL6 and TNFα, just like the reduction in reactive profile of astrocytes. Overall, the data presented here offers an interesting and hopeful initial step for future long-term studies on the beneficial effects of a supplementation of common diets with polyphenol and flavonoid substances for the amelioration of typical early hallmarks of neurodegeneration.

Inflammatory potential of diet and bone mineral density in a senior Mediterranean population: a cross-sectional analysis of PREDIMED-Plus study.

PURPOSE: Inflammation could play a key role in tissue damage and bone metabolism. The modified dietary inflammatory score (M-DIS) is a validated tool to estimate the inflammatory potential of the diet. In the present study, we evaluate the associations between the M-DIS and bone mineral density (BMD) in a senior Mediterranean population with overweight/obesity and metabolic syndrome. METHODS: Baseline cross-sectional association between the M-DIS and bone mineral density was assessed in 1134 participants of the multicenter PREDIMED-Plus trial (aged 55-75 with overweight/obesity and metabolic syndrome). BMD was measured using Dual-energy X-ray Absorptiometry scans and participants answered a food frequency questionnaire to determine the M-DIS. BMD was categorized as low BMD when T score was equal or lower than -1 and normal BMD in another case. Associations between BMD and M-DIS were evaluated by using linear and logistic regressions adjusted by other co-variates. RESULTS: Participants in the top tertile of the M-DIS had a lower BMD at total femur [ß (95% CI) - 0.02 (- 0.04, - 0.01)], trochanter areas [ß (95% CI) - 0.03 (- 0.05, - 0.01)] and lumbar spine area [ß (95% CI) - 0.03 (- 0.07, 0.01)] (but in the last case, measures were less precise and hence not statistically significant) compared to those in the lower M-DIS tertile. Multiple logistic regression analyses showed that the odds of the total femur and femoral trochanter osteopenia/osteoporosis were higher in participants in the top tertile compared to those in the lowest tertile of M-DIS [OR (95% CI) 1.71 (1.12, 2.64), P for trend 0.015; 2.02 (1.29, 3.21), P for trend 0.002, respectively]. CONCLUSION: A high pro-inflammatory diet, measured by the M-DIS, is associated with lower BMD in a senior Mediterranean population with metabolic syndrome.

Cross-Sectional Associations between HDL Structure or Function, Cell Membrane Fatty Acid Composition, and Inflammation in Elderly Adults.

BACKGROUND: Cell membrane fatty acid composition has been related to inflammation and cardiovascular disease (CVD) risk. Dysregulation of HDL function is also considered a CVD risk factor. OBJECTIVES: We aimed to investigate whether the content of cell membrane fatty acids and HDL functionality are linked to each other as well as to inflammation. METHODS: This cross-sectional analysis involved 259 participants (mean age: 67.9 y) with overweight/obesity (mean BMI: 29.5 kg/m2) from a coronary artery disease case-control study nested within the PREDIMED (PREvención con DIeta MEDiterránea) trial for which HDL functional parameters [apoA-I, apoA-IV, and apoC-III; cholesterol efflux capacity (CEC); HDL oxidative inflammatory index (HOII); sphingosine-1-phosphate (S1P); serum amyloid A (SAA); and complement-3 (C3) protein] were quantified. We also assessed 22 fatty acids in blood cell membranes using GC and inflammatory markers (IFN-γ and IL-1b, IL-6, IL-8, and IL-10) in serum. Associations of HDL-related variables with cell membrane fatty acids and with inflammatory markers were assessed using multivariable linear regression analyses with elastic net penalty. RESULTS: ApoA-I, apoC-III, CEC, HOII, S1P, and SAA, but not apoA-IV and C3 protein, were associated with membrane fatty acids. S1P and SAA were directly associated with IL-6, whereas apoA-I and C3 protein showed inverse associations with IL-6. Specific fatty acids including myristic acid (14:0) and long-chain n-6 fatty acids being negatively and positively associated with IL-8, respectively, were also found to be positively associated with SAA. CONCLUSIONS: This study suggests interrelations between indicators of inflammation and both blood cell membrane fatty acid composition and HDL structure/functional parameters in a Mediterranean population at high CVD risk.This trial was registered at www.isrctn.com as ISRCTN35739639.