Camacho-Barcia L, García-Gavilán J, Martínez-González MÁ, Fernández-Aranda F, Galié S, Corella D, Cuenca-Royo A, Romaguera D, Vioque J, Alonso-Gómez ÁM, Wärnberg J, Martínez JA, Serra-Majem L, Estruch R, Bernal-López MR, Lapetra J, Pintó X, Tur JA, Garcia-Rios A, Bueno-Cavanillas A, Delgado-Rodríguez M, Matía-Martín P, Daimiel L, Martín-Sánchez V, Vidal J, Vázquez C, Ros E, Canela MR, Sorlí JV, de la Torre R, Konieczna J, Oncina-Cánovas A, Tojal-Sierra L, Pérez-López J, Abete I, Sánchez-Villegas A, Casas R, Muñoz-Garach A, Santos-Lozano JM, Bouzas C, Razquin C, Martínez-Lacruz R, Castañer O, Yañez AM, Valls-Enguix R, Belló-Mora MC, Basterra-Gortari J, Basora J, Salas-Salvadó J, Bulló M.
Vitamin K dietary intake is associated with cognitive function in an older adult Mediterranean population.
Age Ageing. 2022 Feb 2;51(2):afab246.
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.Keywords: Vitamin K; cognitive impairment; cognitive-neuropsychological tests; older people; phylloquinone.
Olloquequi J, Cano A, Sanchez-López E, Carrasco M, Verdaguer E, Fortuna A, Folch J, Bulló M, Auladell C, Camins A, Ettcheto M.
Protein tyrosine phosphatase 1B (PTP1B) as a potential therapeutic target for neurological disorders.
Biomed Pharmacother. 2022 Nov;155:113709.
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. Keywords: Alzheimer’s disease; Insulin receptor; Neurodegenerative diseases; Neuroinflammation; Neurological disorders; PTP1B; Type 2 diabetes.
Bulló M, Papandreou C, García-Gavilán J, Ruiz-Canela M, Li J, Guasch-Ferré M, Toledo E, Clish C, Corella D, Estruch R, Ros E, Fitó M, Lee CH, Pierce K,
Razquin C, Arós F, Serra-Majem L, Liang L, Martínez-González MA, Hu FB, Salas-Salvadó J.
Tricarboxylic acid cycle related-metabolites and risk of atrial fibrillation and heart failure.
Metabolism. 2021 Dec;125:154915.
Background: Tricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF.Methods: We used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d/l-2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use.Results: Comparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d/l-2-hydroxyglutarate were associated with a higher risk of AF [ORQ4 vs. Q1 (95% CI): 1.80 (1.21-2.67), 2.13 (1.45-3.13), 1.87 (1.25-2.81) and 1.95 (1.31-2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01-1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d/l-2-hydroxyglutarate were 2.15 (1.29-3.56), 2.16 (1.25-3.72), 2.63 (1.56-4.44) and 1.82 (1.10-3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF.Conclusion: These findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes. Keywords: Atrial fibrillation; Heart failure; Hydroxyglutarate; PREDIMED; Tricarboxylic acid cycle metabolites.
Papandreou C, Bulló M, Hernández-Alonso P, Ruiz-Canela M, Li J, Guasch-Ferré M, Toledo E, Clish C, Corella D, Estruch R, Ros E, Fitó M, Alonso-Gómez A, Fiol
M, Santos-Lozano JM, Serra-Majem L, Liang L, Martínez-González MA, Hu FB, Salas-Salvadó J.
Choline Metabolism and Risk of Atrial Fibrillation and Heart Failure in the PREDIMED Study.
Clin Chem. 2021 Jan 8;67(1):288-297.
Background: Few studies have examined the associations of trimethylamine-N-oxide (TMAO) and its precursors (choline, betaine, dimethylglycine, and L-carnitine) with the risk of atrial fibrillation (AF) and heart failure (HF). This study sought to investigate these associations. Methods: Prospective associations of these metabolites with incident AF and HF were examined among participants at high cardiovascular risk in the PREDIMED study (PREvención con DIeta MEDiterránea) after follow-up for about 10 years. Two nested case-control studies were conducted, including 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma levels of TMAO and its precursors were semi-quantitatively profiled with liquid chromatography tandem mass spectrometry. Odds ratios were estimated with multivariable conditional logistic regression models. Results: After adjustment for classical risk factors and accounting for multiple testing, participants in the highest quartile vs. the lowest quartile of baseline choline and betaine levels had a higher risk of AF [OR (95% CI): 1.85 (1.30-2.63) and 1.57 (1.09-2.24), respectively]. The corresponding OR for AF for extreme quartiles of dimethylglycine was 1.39 (0.99-1.96). One SD increase in log-transformed dimethylglycine was positively associated with AF risk (OR, 1.17; 1.03-1.33). The corresponding ORs for HF for extreme quartiles of choline, betaine, and dimethylglycine were 2.51 (1.57-4.03), 1.65 (1.00-2.71) and 1.65 (1.04-2.61), respectively. TMAO and L-carnitine levels were not associated with AF or HF. Conclusions: Our findings support the role of the choline metabolic pathway in the pathogenesis of AF and HF. Keywords: PREDIMED; Trimethylamine-N-oxide; atrial fibrillation; choline metabolism; heart failure.
Galié S, García-Gavilán J, Papandreou C, Camacho-Barcía L, Arcelin P, Palau-Galindo A, Rabassa A, Bulló M.
Effects of Mediterranean Diet on plasma metabolites and their relationship with insulin resistance and gut microbiota composition in a crossover randomized clinical trial.
Clin Nutr. 2021 Jun;40(6):3798-3806.
Background & aims: The Mediterranean Diet (MedDiet) may decrease the cardiometabolic risk through modulation of metabolic pathways. Furthermore, the interplay between MedDiet, metabolites and microbial metabolism may improve our understanding on the metabolic effects of this diet. We aimed to evaluate the effect of the MedDiet compared to nuts supplementation on circulating metabolites and their relationship with cardiometabolic health. We further examined whether changes in the metabolomic profiles were associated with changes in gut microbiota composition in a multi-omics integrative approach. Methods: Forty-four adults with Metabolic Syndrome (MetS), (aged 37-65) participated in a randomized controlled, crossover 2-months dietary-intervention trial with a 1-month wash-out period, consuming a MedDiet or a non MedDiet plus nuts (50 g/day). Nutritional data were collected at the beginning and the end of each intervention period using 3-day dietary records, as well as fasting blood and fecal samples. Plasma metabolites (m = 378) were profiled using targeted metabolomics. Associations of these metabolites with the interventions were assessed with elastic net regression analyses. Gut microbiota composition was assessed by 16S rRNA sequencing. A sparse least regression analysis combined with a canonical correlation analysis was conducted between the plasma selected metabolites and genera in order to identify the relevant dual-omics signatures discriminating the dietary interventions. Results: Changes in 65 circulating metabolites were significantly associated with the MedDiet (mainly lipids, acylcarnitines, amino acids, steroids and TCA intermediates). Importantly, these changes were associated with decreases in glucose, insulin and HOMA-IR. The network analysis identified two main clusters of genera with an opposite behaviour towards selected metabolites, mainly PC species, ChoE(20:5), TGs and medium/long-chain acylcarnitines. Conclusion: Following a MedDiet, rather than consuming nuts in the context of a non-MedDiet was associated with a specific plasma metabolomic profile, which was also related to metabolic improvements in adults with MetS. The identified correlated network between specific bacteria and metabolites suggests interplay between diet, circulating metabolites and gut microbiota. The trial was registered in the ISRCTN with identifier ISRCTN88780852, https://doi.org/10.1186/ISRCTN88780852.Keywords: Gut microbiota; Insulin resistance; Mediterranean diet; Nuts; Plasma metabolome.