Gold Nanoparticles Supported on Ceria Nanoparticles Modulate Leukocyte–Endothelium Cell Interactions and Inflammation in Type 2 Diabetes

Diabetes; Gold-ceria nanoparticle; InflammationDiabetes; Nanopartícula de oro-ceria; InflamaciónDiabetis; Nanopartícula d'or-cèria; InflamacióGold-ceria nanoparticles (Au/CeO2) are known to have antioxidant properties. However, whether these nanoparticles can provide benefits in type 2 diabetes mellitus (T2D) remains unknown. This work aimed to study the effects of Au/CeO2 nanoparticles at different rates of gold purity (10, 4.4, 1.79 and 0.82) on leukocyte–endothelium interactions and inflammation in T2D patients. Anthropometric and metabolic parameters, leukocyte–endothelium interactions, ROS production and NF-κB expression were assessed in 57 T2D patients and 51 healthy subjects. T2D patients displayed higher Body Mass Index (BMI) and characteristic alterations in carbohydrate and lipid metabolism. ROS production was increased in leukocytes of T2D patients and decreased by Au/CeO2 at 0.82% gold. Interestingly, Au/CeO2 0.82% modulated leukocyte–endothelium interactions (the first step in the atherosclerotic process) by increasing leukocyte rolling velocity and decreasing rolling flux and adhesion in T2D. A static adhesion assay also revealed diminished leukocyte–endothelium interactions by Au/CeO2 0.82% treatment. NF-κB (p65) levels increased in T2D patients and were reduced by Au/CeO2 treatment. Cell proliferation, viability, and apoptosis assays demonstrated no toxicity produced by Au/CeO2 nanoparticles. These results demonstrate that Au/CeO2 nanoparticles at 0.82% exert antioxidant and anti-inflammatory actions in the leukocyte–endothelium interaction of T2D patients, suggesting a protective role against the appearance of atherosclerosis and cardiovascular diseases when this condition exists.This study was financed by grants PI22/00424, PI19/00838, PI19/0437 and CIBERehd CB06/04/0071 by Carlos III Health Institute and by the European Regional Development Fund (ERDF “A way to build Europe”); ACIF/2020/370 (P.D.-P.), GRISOLIAP/2019/091 (F.C.) and APOSTD/2020/145 (S.L.-D); S.R.-L is recipient of a Maria Zambrano fellowship ZA21-049, from the requalification of the Spanish university system from the Ministry of Universities of the Government of Spain, financed by the European Union, Next Generation EU, PROMETEO/2019/027 by the Ministry of Health of the Valencian Regional Government. C.L.-M. was supported by Erasmus+ internship grant through Uppsala University, Sweden

Metabolic footprint of aging and obesity in red blood cells

Aging; Metabolomics; ObesityEnvelliment; Metabolòmica; ObesitatEnvejecimiento; Metabolómica; ObesidadAging is a physiological process whose underlying mechanisms are still largely unknown. The study of the biochemical transformations associated with aging is crucial for understanding this process and could translate into an improvement of the quality of life of the aging population. Red blood cells (RBCs) are the most abundant cells in humans and are involved in essential functions that could undergo different alterations with age. The present study analyzed the metabolic alterations experienced by RBCs during aging, as well as the influence of obesity and gender in this process. To this end, the metabolic profile of 83 samples from healthy and obese patients was obtained by Nuclear Magnetic Resonance spectroscopy. Multivariate statistical analysis revealed differences between Age-1 (≤45) and Age-2 (>45) subgroups, as well as between BMI-1 (<30) and BMI-2 (≥30) subgroups, while no differences were associated with gender. A general decrease in the levels of amino acids was detected with age, in addition to metabolic alterations of glycolysis, the pentose phosphate pathway, nucleotide metabolism, glutathione metabolism and the Luebering-Rapoport shunt. Obesity also had an impact on the metabolomics profile of RBCs; sometimes mimicking the alterations induced by aging, while, in other cases, its influence was the opposite, suggesting these changes could counteract the adaptation of the organism to senescence.This work was supported by the Carlos III Health Institute and the European Regional Development Fund (PI16/02064 and PI20/01588), the Agency for Management of University and Research Grants (AGAUR) of Catalonia (2017SGR1303) and the Ministry of Economy and Competitiveness (SAF2017-89229-R). Equipment employed in this work was partially funded by Generalitat Valenciana and ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020)

Metabolic fingerprint of acromegaly and its potential usefulness in clinical practice

Acromegaly; Metabolomics; Amino acidsAcromegalia; Metabolómica; AminoácidosAcromegàlia; Metabolòmica; AminoàcidsInsulin-like growth factor-1 (IGF-1) and growth hormone (GH) levels are the main targets for monitoring acromegaly activity, but they are not in close relationship with the clinical course of the disease and the associated comorbidities. The present study was aimed at identifying metabolites that could be used as biomarkers for a better disease phenotyping. For this purpose, metabolic fingerprint using an untargeted metabolomic approach was examined in serum from 30 patients with acromegaly and 30 age-matched controls. Patients with acromegaly presented fewer branched-chain amino acids (BCAAs) compared to the control group (valine: 4.75 ± 0.87 vs. 5.20 ± 1.06 arbitrary units (AUs), p < 0.05; isoleucine: 2.54 ± 0.41 vs. 2.80 ± 0.51 AUs; p < 0.05). BCAAs were also lower in patients with active disease compared to patients with normal levels of IGF-1 with or without medical treatment. GH, but not IGF-1, serum levels were inversely correlated with both valine and isoleucine. These findings indicate that low levels of BCAAs represent the main metabolic fingerprint of acromegaly and that GH, rather than IGF-1, might be the primary mediator. In addition, our results suggest that the assessment of BCAAs could help to identify active disease and to monitor the response to therapeutic strategies.This research was funded by Pfizer Global Investigator Initiated Research. J.P.C. and R.M.L. are funded by Junta de Andalucía (CTS-1406, BIO-0139), Ministerio de Ciencia, Innovación y Universidades (BFU2016-80360-R), and Instituto de Salud Carlos III, co-funded by European Union (ERDF/ESF, “Investing in your future”: PI16/00264, CP15/00156 and CIBERobn). CIBER is an initiative of Instituto de Salud Carlos III

Diabetic Retinopathy and Skin Tissue Advanced Glycation End Products Are Biomarkers of Cardiovascular Events in Type 2 Diabetic Patients

Cardiovascular disease biomarkers; Diabetic complications; Type 2 diabetesBiomarcadores de enfermedades cardiovasculares; Complicaciones de la diabetes; Diabetes tipo 2Biomarcadors de malalties cardiovasculars; Complicacions de la diabetis; Diabetis tipus 2Risk of cardiovascular events is not homogeneous in subjects with type 2 diabetes; therefore, its early identification remains a challenge to be met. The aim of this study is to evaluate whether the presence of diabetic retinopathy and accumulation of advanced glycation end-products in subcutaneous tissue can help identify patients at high risk of cardiovascular events. For this purpose, we conducted a prospective study (mean follow-up: 4.35 years) comprising 200 subjects with type 2 diabetes with no history of clinical cardiovascular disease and 60 non-diabetic controls matched by age and sex. The primary outcome was defined as the composite of myocardial infarction, coronary revascularization, stroke, lower limb amputation or cardiovascular death. The Cox proportional hazard multiple regression analysis was used to determine the independent predictors of cardiovascular events. The patients with type 2 diabetes had significantly more cardiovascular events than the non-diabetic subjects. Apart from the classic factors such as age, sex and coronary artery calcium score, we observed that the diabetic retinopathy and advanced glycation end-products in subcutaneous tissue were independent predictors of cardiovascular events. We conclude that the diabetic retinopathy and advanced glycation end-products in subcutaneous tissue could be useful biomarkers for selecting type 2 diabetic patients in whom the screening for cardiovascular disease should be prioritized, thereby creating more personalized and cost-effective medicine.This research was funded by grants from the Spanish Institute of Health (ISCIII) in the setting of Integrative Excellence Projects (PIE 2013/27) and the European Foundation for the Study of Diabetes (EFSD Pilot Research Grant Programme for Innovative Measurement of Diabetes Outcomes 2017). The study funders were not involved in the design of the study

Phenotyping Type 2 Diabetes in Terms of Myocardial Insulin Resistance and Its Potential Cardiovascular Consequences: A New Strategy Based on 18F-FDG PET/CT

Cardiovascular risk; Myocardial insulin resistance; Type 2 diabetesRisc cardiovascular; Resistència miocàrdica a la insulina; Diabetis tipus 2Riesgo cardiovascular; Resistencia miocárdica a la insulina; Diabetes tipo 2Background: Systemic insulin resistance is generally postulated as an independent risk factor of cardiovascular events in type 2 diabetes (T2D). However, the role of myocardial insulin resistance (mIR) remains to be clarified. Methods: Two 18F-FDG PET/CT scans were performed on forty-three T2D patients at baseline and after hyperinsulinemic–euglycemic clamp (HEC). Myocardial insulin sensitivity (mIS) was determined by measuring the increment in myocardial 18F-FDG uptake after HEC. Coronary artery calcium scoring (CACs) and myocardial radiodensity (mRD) were assessed by CT. Results: After HEC, seventeen patients exhibited a strikingly enhancement of myocardial 18F-FDG uptake and twenty-six a marginal increase, thus revealing mIS and mIR, respectively. Patients with mIR showed higher mRD (HU: 38.95 [33.81–44.06] vs. 30.82 [21.48–38.02]; p = 0.03) and CACs > 400 (AU: 52% vs. 29%; p = 0.002) than patients with mIS. In addition, HOMA-IR and mIS only showed a correlation in those patients with mIR. Conclusions: 18F-FDG PET combined with HEC is a reliable method for identifying patients with mIR. This subgroup of patients was found to be specifically at high risk of developing cardiovascular events and showed myocardial structural changes. Moreover, the gold-standard HOMA-IR index was only associated with mIR in this subgroup of patients. Our results open up a new avenue for stratifying patients with cardiovascular risk in T2D.This research was funded by the Carlos III Health Institute and the European Regional Development Fund (PI16/02064 and PI20/01588) and AGAUR (2017SGR1303 and 2017SGR1144)

Identification of Myocardial Insulin Resistance by Using Liver Tests: A Simple Approach for Clinical Practice

Cardiovascular risk; Myocardial insulin resistance; Non-alcoholic fatty liver diseaseRiesgo cardiovascular; Resistencia a la insulina del miocardio; Enfermedad del higado graso no alcoholicoRisc cardiovascular; Resistència a la insulina del miocardi; Malaltia del fetge gras no alcohòlicBackground: We report that myocardial insulin resistance (mIR) occurs in around 60% of patients with type 2 diabetes (T2D) and was associated with higher cardiovascular risk in comparison with patients with insulin-sensitive myocardium (mIS). These two phenotypes (mIR vs. mIS) can only be assessed using time-consuming and expensive methods. The aim of the present study is to search a simple and reliable surrogate to identify both phenotypes. Methods: Forty-seven patients with T2D underwent myocardial [18F]FDG PET/CT at baseline and after a hyperinsulinemic–euglycemic clamp (HEC) to determine mIR were prospectively recruited. Biochemical assessments were performed before and after the HEC. Baseline hepatic steatosis index and index of hepatic fibrosis (FIB-4) were calculated. Furthermore, liver stiffness measurement was performed using transient elastography. Results: The best model to predict the presence of mIR was the combination of transaminases, protein levels, FIB-4 score and HOMA (AUC = 0.95; sensibility: 0.81; specificity: 0.95). We observed significantly higher levels of fibrosis in patients with mIR than in those with mIS (p = 0.034). In addition, we found that patients with mIR presented a reduced glucose uptake by the liver in comparison with patients with mIS. Conclusions: The combination of HOMA, protein, transaminases and FIB-4 is a simple and reliable tool for identifying mIR in patients with T2D. This information will be useful to improve the stratification of cardiovascular risk in T2D.This work was supported by the Carlos III Health Institute and the European Regional Development Fund (PI16/02064, PI20/01588) and the Agency for Management of University and Research Grants (AGAUR) of Catalonia (2017SGR1303)

Reactivos ocluidos en aluminosilicatos: Reactividad y comportamiento en óptica no lineal

En la presente tesis doctoral está dividida en dos partes, una dedicada a la óptica no lineal y en concreto a la generación de segundo armónico (GSA) donde un compuesto se irradia con luz de longitud de onda &#61548; y éste es capaz de devolver al medio luz de longitud de onda &#61548;/2. La otra parte está dedicada al estudio de los complejos de Meisenheimer, que son los intermedios que surgen de la reacción de Substitución Nucleófila Aromática. El nexo de unión de ambas partes son los aluminosilicatos porosos, utilizados en el caso de la óptica no lineal como soportes de procesos porosos y en el caso de los complejos de Meisenheimer como estabilizadores de este tipo de intermedios.En la parte dedicada a la óptica no lineal se realizan tres tipos de estudió de GSA: i) homólogos del verde de Malaquita, ii) p-nitroanilina incorporada en zeolitas y iii) C60. Para el primer estudio se llevó a cabo la síntesis de los homólogos del verde de malaquita y posteriormente se les realizaron los ensayos de GSA en forma de film y sólido microcristalino. En el segundo se estudió la influencia de los canales de la zeolita, con p-nitroanilina incorporada, en la obtención de GSA. En último lugar se realizó el estudió de GSA del C60 incorporado en aluminosilicatos y polímeros.En la segunda parte se llevaron a cabo tres tipos de estudio: i) Estudio del mecanismo de descomposición de un complejo de Meisenheimer activado mediante irradiación y/o O2, ii) Estabilización de un complejo de Meisenheiemer en zeolitas e hidrotalcitas y iii) Estudio del mecanismo de transferencia de hidruro entre un complejo de Meisenheimer y agentes oxidantes aceptores de hidruro.The present thesis is divided into two different parts. The first part is devoted to non-linear optics and, specifically, to second harmonic generation (SHG). SHG consists in doubling the frequency of light by irradiation of an active medium. The second part of the thesis is dedicated to the study of Meisenheimer complexes, which are the intermediates of the Nucleophylic Aromatic Substitution reaction. The link between both parts is the use of porous aluminosilicates. They were used as matrices for the optical active species in the first part of thesis, and as stabilizers of the Meisenheimer complexes in the second part.The SHG efficiency of three different types of systems were investigated in the first part of the work: i) homologues of malachite green, ii) p-nitroaniline embedded in zeolites, and iii) C60. In the first case, new derivatives of the malachite green dye were synthesized and their SHG properties were investigated in thin films and as a microcristalline solid. Second, the influence of the ordering of p-nitroaniline within zeolites with different degrees of directionality on the SHG efficiencies was studied. Finally, the SHG behavior of C60 embedded in aluminosilicates and linked to polymers was probed.In the second part of thesis devoted to Meisenheimer complexes, the attention was focused on the following points: i) the decomposition mechanism of the complexes induced by light and/or oxygen, ii) the incorporation and stabilization of these species within zeolites and hidrotalcites, and iii) the mechanism of hydride transfer between the Meisenheimer complexes and oxidizing, hydride-acceptor agents