Depósito Académico
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- Urinary resveratrol metabolites output: Differential associations with cardiometabolic markers and liver enzymes in house-dwelling subjects featuring metabolic syndrome(MDPI AG, 2020) Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Rodriguez-Mateos, A. (Ana); Fito, M. (Montserrat); Sánchez, V.M. (Vicente Martín); Konieczna, J. (Jadwiga); Daimiel, L. (Lidia); Tinahones, F.J. (Francisco J.); Zulet, M.A. (María Ángeles); Tur, J.A. (Josep A.); Toledo, E. (Estefanía); Romaguera, D. (Dora); Xu, Y. (Yifan); Ruiz-Canela, M. (Miguel); Estruch, R. (Ramón); Diaz-Lopez, A. (Andres); Lamuela-Raventos, R.M. (Rosa Maria); Almanza-Aguilera, E. (Enrique); Abete, I. (Itziar); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Sayon-Orea, C. (Carmen); Bullón-Vela, M. V. (María Vanessa)Metabolic syndrome (MetS) components are strongly associated with increased risk of non-alcoholic fatty liver disease (NAFLD) development. Several studies have supported that resveratrol is associated with anti-inflammatory and antioxidant effects on health status. The main objective of this study was to assess the putative associations between some urinary resveratrol phase II metabolites, cardiometabolic, and liver markers in individuals diagnosed with MetS. In this cross-sectional study, 266 participants from PREDIMED Plus study (PREvención con DIeta MEDiterránea) were divided into tertiles of total urinary resveratrol phase II metabolites (sum of five resveratrol conjugation metabolites). Urinary resveratrol metabolites were analyzed by ultraperformance liquid chromatography coupled to triple quadrupole mass spectrometry (UPLC-Q-q-Q MS), followed by micro-solid phase extraction (µ-SPE) method. Liver function markers were assessed using serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT). Moreover, lipid profile was measured by triglycerides, very-low-density lipoprotein cholesterol (VLDL-c), and total cholesterol/high-density lipoprotein ratio (total cholesterol/HDL). Linear regression adjusted models showed that participants with higher total urine resveratrol concentrations exhibited improved lipid and liver markers compared to the lowest tertile. For lipid determinations: log triglycerides (βT3 = −0.15, 95% CI; −0.28, −0.02, p-trend = 0.030), VLDL-c, (βT3 = −4.21, 95% CI; −7.97, −0.46, p-trend = 0.039), total cholesterol/HDL ratio Moreover, (βT3 = −0.35, 95% CI; −0.66, −0.03, p-trend = 0.241). For liver enzymes: log AST (βT3 = −0.12, 95% CI; −0.22, −0.02, p-trend = 0.011, and log GGT (βT3 = −0.24, 95% CI; −0.42, −0.06, p-trend = 0.002). However, there is no difference found on glucose variables between groups. To investigate the risk of elevated serum liver markers, flexible regression models indicated that total urine resveratrol metabolites were associated with a lower risk of higher ALT (169.2 to 1314.3 nmol/g creatinine), AST (599.9 to 893.8 nmol/g creatinine), and GGT levels (169.2 to 893.8 nmol/g creatinine). These results suggested that higher urinary concentrations of some resveratrol metabolites might be associated with better lipid profile and hepatic serum enzymes. Moreover, urinary resveratrol excreted showed a reduced odds ratio for higher liver enzymes, which are linked to NAFLD.
- Inflammatory markers as diagnostic and precision nutrition tools for metabolic dysfunction-associated steatotic liver disease: Results from the Fatty Liver in Obesity trial(Elsevier, 2024) Martinez, J.A. (José Alfredo); Riezu-Boj, J.I. (José Ignacio); Tobaruela-Resola, A.L. (Ana Luz); Benito-Boíllos, A. (Alberto); Zulet, M.A. (María Ángeles); Tur, J.A. (Josep A.); Mogna-Peláez, P. (Paola); Milagro-Yoldi, F.I. (Fermín Ignacio); Herrero, J.I. (José Ignacio); Elorz, M. (Mariana); Abete, I. (Itziar)Background & aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern. The disease is silent, and its diagnosis is often delayed. Inflammatory markers constitute an interesting tool to act as subrogate, non-invasive markers. This study aimed to evaluate the changes of inflammatory markers throughout a two-year dietary intervention in subjects presenting MASLD, to determine which of the markers are suitable to predict the disease, and act as a customizing tool for MASLD's dietary treatment. Methods: Ninety-eight subjects with MASLD and forty-five controls from the Fatty Liver in Obesity (FLiO) Study were analyzed. MASLD was diagnosed and graded by ultrasound. The MASLD subjects were randomly assigned to two different dietary strategies, the American Heart Association (AHA diet) or a dietary strategy based on the Mediterranean pattern, which was specially designed for the study (FLiO diet), and then followed for two years. Hepatic status was additionally assessed through Magnetic Resonance Imaging (MRI), elastography, and determination of transaminases. Results & discussion: Inflammatory markers improved throughout the intervention in the MASLD sub- jects and managed to reach similar levels to controls, especially at 6 and 12 months. Additionally, leptin, adiponectin, M30, and LECT2 managed to significantly diagnose the disease at all time marks of the intervention, making them candidates for subrogate non-invasive markers of the disease. Moreover, baseline chemerin, leptin, LECT2, and M65 were used to build a predictive score to achieve greater weight loss, and therefore, which strategy could be more useful for MASLD ‘s treatment. The predictive score was significantly able assign a specific diet to 55% of the study participants, meaning that the remaining 45% could achieve the same amount of weight loss following either diet equally. Conclusion: Inflammatory markers constitute a potential non-invasive tool to be used in MASLD screening and could also constitute an interesting tool for MASLD's treatment customization, being able to predict the effectiveness of a dietary strategy based on the initial inflammatory state of each subject. Trial registration: www.clinicaltrials.gov (NCT03183193).
- Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target(2018) Martinez, J.A. (José Alfredo); Ramirez, M.J. (María Javier); Milagro-Yoldi, F.I. (Fermín Ignacio); Solas, M. (Maite); Janeiro-Arenas, M.H. (Manuel Humberto)Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.
- Dietary Inflammatory Index and liver status in subjects with different adiposity levels within the PREDIMED trial(2018) Babio, N. (Nancy); Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Fito, M. (Montserrat); Zulet, M.A. (María Ángeles); Shivappa, N. (Nitin); Tur, J.A. (Josep A.); Gomez-Gracia, E. (Enrique); Ruiz-Canela, M. (Miguel); Portillo, M.P. (María P.); Wärnberg, J. (Julia); Estruch, R. (Ramón); Corella, D. (Dolores); Abete, I. (Itziar); Pinto, X. (Xavier); Cantero-González, I. (Irene); Salas-Salvado, J. (Jordi); Hebert, J.R. (James R.); Aros, F. (Fernando)Background & aims: To assess the possible association between a validated Dietary Inflammatory Index (DII) and specific dietary components with suitable non-invasive markers of liver status in overweight and obese subjects within the PREDIMED study. Methods: A cross-sectional study encompassing 794 randomized overweight and obese participants (mean ± SD age: 67.0 ± 5.0 y, 55% females) from the PREDIMED (PREvencion con DIeta MEDiterr anea) trial was conducted. DII is a validated tool evaluating the effect of diet on six inflammatory biomarkers (IL-1b, IL-4, IL-6, IL-10, TNF-a and C-reactive protein). Furthermore, a validated 137-item food-frequencyquestionnaire was used to obtain the information about the food intake. In addition, anthropometric measurements and several non-invasive markers of liver status were assessed and the Fatty Liver Index (FLI) score was calculated. Results: A higher DII and lower adherence to Mediterranean diet (MeDiet) were associated with a higher degree of liver damage (FLI > 60) in obese as compared to overweight participants. Furthermore, the DII score was positively associated with relevant non-invasive liver markers (ALT, AST, GGT and FLI) and directly affected FLI values. Interestingly, a positive correlation was observed between liver damage (>50th percentile FLI) and nutrients and foods linked to a pro-inflammatory dietary pattern. Conclusions: This study reinforced the concept that obesity is associated with liver damage and revealed that the consumption of a pro-inflammatory dietary pattern might contribute to obesity and fatty liver disease features. These data suggest that a well-designed precision diet including putative antiinflammatory components could specifically prevent and ameliorate non-alcoholic fatty liver manifestations in addition to obesity.
- Oxidative stress and pro-inflammatory status in patients with non-alcoholic fatty liver disease(MDPI AG, 2020) Martinez, J.A. (José Alfredo); Abbate, M. (Manuela); Zulet, M.A. (María Ángeles); Tejada, S. (Silvia); Tur, J.A. (Josep A.); Quetglas-Llabrés, M. (Magdalena); Casares, M. (Miguel); Sureda, A. (Antoni); Montemayor, S. (Sofía); Monserrat-Mesquida, M. (Margalida); Abete, I. (Itziar); Mascaró, C.M. (Catalina M.)Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation, especially triglycerides, in hepatocytes. If the pathology is not properly treated, it can progress to nonalcoholic steatohepatitis (NASH) and continue to fibrosis, cirrhosis or hepatocarcinoma. Objective: The aim of the current research was to identify the plasma biomarkers of liver damage, oxidative stress and inflammation that facilitate the early diagnosis of the disease and control its progression. Methods: Antioxidant and inflammatory biomarkers were measured in the plasma of patients diagnosed with NAFLD (n = 100 adults; 40–60 years old) living in the Balearic Islands, Spain. Patients were classified according to the intrahepatic fat content (IFC) measured by magnetic resonance imaging (MRI). Results: Circulating glucose, glycosylated haemoglobin, triglycerides, low-density lipoprotein-cholesterol, aspartate aminotransferase and alanine aminotransferase were higher in patients with an IFC ≥ 2 of NAFLD in comparison to patients with an IFC of 0 and 1. The plasma levels of catalase, irisin, interleukin-6, malondialdehyde, and cytokeratin 18 were higher in stage ≥2 subjects, whereas the resolvin D1 levels were lower. No differences were observed in xanthine oxidase, myeloperoxidase, protein carbonyl and fibroblast growth factor 21 depending on liver status. Conclusion: The current available data show that the severity of NAFLD is associated with an increase in oxidative stress and proinflammatory status. It may be also useful as diagnostic purpose in clinical practice.
- Implication of Trimethylamine N-Oxide (TMAO) in disease: Potential biomarker or new therapeutic target(MDPI AG, 2018) Martinez, J.A. (José Alfredo); Ramirez, M.J. (María Javier); Milagro-Yoldi, F.I. (Fermín Ignacio); Solas, M. (Maite); Janeiro-Arenas, M.H. (Manuel Humberto)Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.
- Effect of TNF-Alpha on caveolin-1 expression and insulin signaling during adipocyte differentiation and in mature adipocytes(Karger, 2015) Martinez, J.A. (José Alfredo); Algarabel, M. (Miriam); Miguel-Vázquez, C. (Carlos) de; Milagro-Yoldi, F.I. (Fermín Ignacio); Palacios-Ortega, S. (Sara); Varela-Guruceaga, M. (Maider)Background/Aims: Tumor necrosis factor-α (TNF-α)-mediated chronic low-grade inflammation of adipose tissue is associated with obesity and insulin resistance. Caveolin-1 (Cav-1) is the central component of adipocyte caveolae and has an essential role in the regulation of insulin signaling. The effects of TNF-α on Cav-1 expression and insulin signaling during adipocyte differentiation and in mature adipocytes were studied. Methods: 3T3-L1 cells were differentiated (21 days) in the presence TNF-α (10 ng/mL) and mature adipocytes were also treated with TNF-α for 48 hours. Cav-1 and insulin receptor (IR) gene methylation were determined as well as Cav-1, IR, PKB/AKT-2 and Glut-4 expression and activation by real time RT-PCR and western blot. Baseline and insulin-induced glucose uptake was measured by the 2-[C14]-deoxyglucose uptake assay. Results: TNF-α slowed down the differentiation program, hindering the expression of some insulin signaling intermediates without fully eliminating insulin-mediated glucose uptake. In mature adipocytes, TNF-α did not compromise lipidstorage capacity, but downregulated the expression of the insulin signaling intermediates, totally blocking insulin-mediated glucose uptake. Insulin sensitivity correlated with the level of activated phospho-Cav-1 in both situations, strongly suggesting the direct contribution of Cav-1 to the maintenance of this physiological response. Conclusion: Cav-1 activation by phosphorylation seems to be essential for the maintenance of an active and insulin-sensitive glucose uptake.
- Dietary inflammatory index and incidence of cardiovascular disease in the PREDIMED study(MDPI, 2015) Babio, N. (Nancy); Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Fito, M. (Montserrat); Gonzalez, J.I. (José I.); Shivappa, N. (Nitin); Lapetra, J. (José); Schröder, H. (Helmut); Ramallal, R. (Raul); Ros, E. (Emilio); Ruiz-Canela, M. (Miguel); Estruch, R. (Ramón); PREDIMED; Serra-Majem, L. (Luis); Corella, D. (Dolores); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Hebert, J.R. (James R.); Aros, F. (Fernando); Gomez-Garcia, E. (Enrique); Garcia-Arellano, A. (Ana)Previous studies have reported an association between a more pro-inflammatory diet profile and various chronic metabolic diseases. The Dietary Inflammatory Index (DII) was used to assess the inflammatory potential of nutrients and foods in the context of a dietary pattern. We prospectively examined the association between the DII and the incidence of cardiovascular disease (CVD: myocardial infarction, stroke or cardiovascular death) in the PREDIMED (Prevención con Dieta Mediterránea) study including 7216 high-risk participants. The DII was computed based on a validated 137-item food frequency questionnaire. Multivariate-adjusted hazard ratios (HR) and 95% confidence intervals of CVD risk were computed across quartiles of the DII where the lowest (most anti-inflammatory) quartile is the referent. Risk increased across the quartiles (i.e., with increasing inflammatory potential): HRquartile2 = 1.42 (95%CI = 0.97–2.09); HRquartile3 = 1.85 (1.27–2.71); and HRquartile4 = 1.73 (1.15–2.60). When fit as continuous the multiple-adjusted hazard ratio for each additional standard deviation of the DII was 1.22 (1.06–1.40). Our results provide direct prospective evidence that a pro-inflammatory diet is associated with a higher risk of cardiovascular clinical events.
- Reshaping faecal gut microbiota composition by the intake of trans-resveratrol and quercetin in high-fat sucrose diet-fed rats(Elsevier, 2015) Martinez, J.A. (José Alfredo); Boque, N. (Noemi); Arias, N. (Noemi); Etxeberria, U. (Usune); Milagro-Yoldi, F.I. (Fermín Ignacio); Portillo, M.P. (María P.); Macarulla, M.T. (M. Teresa)Diet‐induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability and, when reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans‐resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high‐fat sucrose diet (HFS) and in turn, improve gut health. Wistar rats were randomized into four groups fed a HFS diet supplemented or not with trans‐resveratrol (15 mg/kg BW/day), quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body‐weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans‐resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet‐induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium 1 cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS diet‐induced gut microbiota dysbiosis. In contrast, trans‐resveratrol supplementation alone or in combination with quercetin, scarcely modified the profile of gut bacteria, but acted at intestinal level altering the mRNA expression of tight‐junction proteins (TJPs) and inflammation associated genes.
- Dietary inflammatory index and anthropometric measures of obesity in a population sample at high cardiovascular risk from the PREDIMED trial(Cambridge University Press, 2015) Martinez, J.A. (José Alfredo); Martinez-Gonzalez, M.A. (Miguel Ángel); Fiol, M. (Miquel); Fito, M. (Montserrat); Shivappa, N. (Nitin); Sanchez-Tainta, A. (Ana); Zazpe, I. (Itziar); Rekondo, J. (J.); Ros, E. (Emilio); Ruiz-Canela, M. (Miguel); Estruch, R. (Ramón); Santos-Lozano, J.M. (José M.); Lamuela-Raventos, R.M. (Rosa Maria); Serra-Majem, L. (Luis); Corella, D. (Dolores); Fernandez-Crehuet, J. (Joaquín); Pinto, X. (Xavier); Salas-Salvado, J. (Jordi); Hebert, J.R. (James R.)The dietary inflammatory index (DII) is a new tool to assess the inflammatory potential of diet. We aimed to determine the association between the DII and body mass index (BMI), waist circumference and waist to height ratio (WHtR). We conducted a cross-sectional study of 7,236 participants recruited into the PREDIMED trial (PREvención con DIeta MEDiterránea). Information from a validated 137-item food frequency questionnaire was used to calculate energy, foods and nutrients. A 14-item dietary screener was used to assess adherence to the Mediterranean diet (MeDiet). Sex-specific multivariable linear regression models were fitted to estimate differences (and 95% confidence intervals) in BMI, waist circumference and WHtR across quintiles of the DII. All nutrient intakes, healthy foods and adherence to the MeDiet were higher in the quintile with lowest DII score (more anti-inflammatory values) except for animal protein, saturated and monounsaturated fat. Though an inverse association between DII and total energy was apparent, the DII was associated with higher average BMI, waist circumference and WHtR after adjusting for known risk factors. The adjusted difference in WHtR for women and men between the highest and lowest quintile of DII was 1.60% (95% CI 0.87-2.33) and 1.04% (95% CI 0.35-1.74), respectively. Pro-inflammatory scores remained associated with obesity after controlling for the effect that adherence to a MeDiet had on inflammation. In conclusion, this study shows a direct association between the DII and indices of obesity and supports the hypothesis that diet may have a role in the development of obesity through inflammatory modulation mechanisms.