Reactivos ocluidos en aluminosilicatos : reactividad y comportamiento en óptica no lineal /

Consultable des del TDXTítol obtingut de la portada digitalitzadaEn 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 y éste es capaz de devolver al medio luz de longitud de onda /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

General aspects in the use of graphenes in catalysis

[EN] This perspective is aimed at presenting some issues that, in our opinion, have still to be better addressed in the field of graphenes as catalysts. After an introductory section, the article comments on how the number of layers present on the catalyst, termed frequently as graphene, could be in some cases in contradiction with good practices about what should be or not considered as graphene. It will also be commented that some of the characterization tools that are employed in some cases for graphenes as catalysts, like specific surface area measurements based on isothermal gas adsorption on powders or XRD patterns are not well suited to characterizing graphenes. The potential role of impurities and structural defects in graphene catalysis has been highlighted showing the importance of providing exhaustive analysis of the materials. This perspective includes a final section with our view on future progress and wider consensus in the use of graphene in catalysis.Financial support by the Spanish Ministry of Economy and Competitiveness (Severo Ochoa and CTQ2014-53292-R) is gratefully acknowledged. Generalidad Valenciana is also thanked for funding (Prometeo 2013/014). SN is thankful for financial support by the Fundacion Ramon Areces (XVIII Concurso Nacional para la Adjudicacion de Ayudas a la Investigacion en Ciencias de la Vida y de la Materia, 2016). Financial support by Fundacion Ramon Areces (XVII Concurso Nacional para la adjudicacion de Ayudas a la Investigacion en Ciencias de la Vida y de la Materia).Navalón Oltra, S.; Herance, JR.; Alvaro Rodríguez, MM.; García Gómez, H. (2018). General aspects in the use of graphenes in catalysis. Materials Horizons (Online). 5(3):363-378. https://doi.org/10.1039/c8mh00066bS3633785

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

Radiomics and Machine Learning for Skeletal Muscle Injury Recovery Prediction

Injuries; Muscles; RadiomicsLesions; Músculs; RadiòmicaLesiones; Músculos; RadiómicaRadiomics as a novel quantitative approach to medical imaging is an emerging area in the field of radiology. Artificial intelligence offers promising tools for exploiting and analyzing radiomics. The objective of the present study is to propose a methodology for the design, development, and evaluation of machine learning (ML) models for the prediction of the recovery progress of skeletal muscle injury over time in rats using radiomics. Radiomics were extracted from contrast enhanced computed tomography (CT) data and ML algorithms were trained and compared for their predictive value based on different CT imaging parameters. Ten different ML regression algorithms were tested and the optimal combination of radiomics for each algorithm and CT imaging parameter settings combination was studied. The best ensemble learning model, trained on the 70 kVp, 100 mA imaging parameter dataset, achieved a mean absolute error score of 1.22. The results suggest that radiomics extracted from CT images can be used as input in ML regression algorithms to predict the volume of a skeletal muscle injury in rats. Moreover, the results show that CT imaging settings impact the predictive performance of the ML regression models, indicating that lower values of tube current and peak kilovoltage contribute to more accurate predictions.10.13039/100010671-European Union’s Horizon Research and Innovation Program (Grant Number: 761031

A translational approach to assess the metabolomic impact of stabilized gold nanoparticles by NMR spectroscopy

[EN] Gold nanoparticles have high potential in the biomedical area, especially in disease diagnosis and treatment. The application of these nanoparticles requires the presence of stabilizers to avoid their agglomeration. Nowadays, there is a lack of reliable methods for characterising the effect of stabilised nanoparticles on biological systems. To this end, in this study, we apply an experimental approach based on nuclear magnetic resonance spectroscopy to study the effect of gold nanoparticles, stabilised with cerium oxide or chitosan, on a human cancer cell model. The results showed that both systems have a significant effect, even at non-toxic levels, on the cellular antioxidant system. However, although particles functionalised with chitosan exerted a strong effect on the aerobic respiration, nanoparticles stabilised with cerium oxide had a higher impact on the mechanisms associated with anaerobic energy production. Therefore, even though both systems contained similar gold nanoparticles, the presence of different stabilizers strongly influenced their mode of action and potential applications in biomedicine.This work was supported by the Carlos III Health Institute, the European Regional Development Fund (PI16/02064 and CP13/00252) and the Spanish Ministerio de Economia y Competitividad (SAF2014-53977-R, SAF2017-89229-R and RD12/0036/0025). In addition, JRH is a recipient of a contract from the Ministry of Health of the Carlos III Health Institute.Herance, JR.; García Gómez, H.; Guitierrez Carcedo, P.; Navalón Oltra, S.; Pineda-Lucena, A.; Palomino-Schätzlein, M. (2019). A translational approach to assess the metabolomic impact of stabilized gold nanoparticles by NMR spectroscopy. The Analyst. 144(4):1265-1274. https://doi.org/10.1039/c8an01827hS126512741444Shi, J., Kantoff, P. W., Wooster, R., & Farokhzad, O. C. (2016). Cancer nanomedicine: progress, challenges and opportunities. Nature Reviews Cancer, 17(1), 20-37. doi:10.1038/nrc.2016.108Gioria, S., Lobo Vicente, J., Barboro, P., La Spina, R., Tomasi, G., Urbán, P., … Chassaigne, H. (2016). A combined proteomics and metabolomics approach to assess the effects of gold nanoparticlesin vitro. Nanotoxicology, 10(6), 736-748. doi:10.3109/17435390.2015.1121412Beik, J., Khademi, S., Attaran, N., Sarkar, S., Shakeri-Zadeh, A., Ghaznavi, H., & Ghadiri, H. (2017). A Nanotechnology-based Strategy to Increase the Efficiency of Cancer Diagnosis and Therapy: Folate-conjugated Gold Nanoparticles. Current Medicinal Chemistry, 24(39). doi:10.2174/0929867324666170810154917Nagi, N. M. S., Khair, Y. A. M., & Abdalla, A. M. E. (2017). Capacity of gold nanoparticles in cancer radiotherapy. Japanese Journal of Radiology, 35(10), 555-561. doi:10.1007/s11604-017-0671-6Gharatape, A., & Salehi, R. (2017). Recent progress in theranostic applications of hybrid gold nanoparticles. European Journal of Medicinal Chemistry, 138, 221-233. doi:10.1016/j.ejmech.2017.06.034Fang, J., Nakamura, H., & Maeda, H. (2011). The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Advanced Drug Delivery Reviews, 63(3), 136-151. doi:10.1016/j.addr.2010.04.009Haume, K., Rosa, S., Grellet, S., Śmiałek, M. A., Butterworth, K. T., Solov’yov, A. V., … Mason, N. J. (2016). Gold nanoparticles for cancer radiotherapy: a review. Cancer Nanotechnology, 7(1). doi:10.1186/s12645-016-0021-xAzevedo, R. S. S., de Sousa, J. R., Araujo, M. T. F., Martins Filho, A. J., de Alcantara, B. N., Araujo, F. M. C., … Vasconcelos, P. F. C. (2018). In situ immune response and mechanisms of cell damage in central nervous system of fatal cases microcephaly by Zika virus. Scientific Reports, 8(1). doi:10.1038/s41598-017-17765-5Lin, Y., Wu, Z., Wen, J., Ding, K., Yang, X., Poeppelmeier, K. R., & Marks, L. D. (2015). Adhesion and Atomic Structures of Gold on Ceria Nanostructures: The Role of Surface Structure and Oxidation State of Ceria Supports. Nano Letters, 15(8), 5375-5381. doi:10.1021/acs.nanolett.5b02694Menchón, C., Martín, R., Apostolova, N., Victor, V. M., Álvaro, M., Herance, J. R., & García, H. (2012). Gold Nanoparticles Supported on Nanoparticulate Ceria as a Powerful Agent against Intracellular Oxidative Stress. Small, 8(12), 1895-1903. doi:10.1002/smll.201102255Tiwari, P., Vig, K., Dennis, V., & Singh, S. (2011). Functionalized Gold Nanoparticles and Their Biomedical Applications. Nanomaterials, 1(1), 31-63. doi:10.3390/nano1010031Fathy, M. M., Mohamed, F. S., Elbialy, N., & Elshemey, W. M. (2018). Multifunctional Chitosan-Capped Gold Nanoparticles for enhanced cancer chemo-radiotherapy: An invitro study. Physica Medica, 48, 76-83. doi:10.1016/j.ejmp.2018.04.002Guo, X., Zhuang, Q., Ji, T., Zhang, Y., Li, C., Wang, Y., … Du, L. (2018). Multi-functionalized chitosan nanoparticles for enhanced chemotherapy in lung cancer. Carbohydrate Polymers, 195, 311-320. doi:10.1016/j.carbpol.2018.04.087Lee, Y.-H., Kim, J.-S., Kim, J.-E., Lee, M.-H., Jeon, J.-G., Park, I.-S., & Yi, H.-K. (2017). Nanoparticle mediated PPARγ gene delivery on dental implants improves osseointegration via mitochondrial biogenesis in diabetes mellitus rat model. Nanomedicine: Nanotechnology, Biology and Medicine, 13(5), 1821-1832. doi:10.1016/j.nano.2017.02.020Sun, I.-C., Na, J. H., Jeong, S. Y., Kim, D.-E., Kwon, I. C., Choi, K., … Kim, K. (2013). Biocompatible Glycol Chitosan-Coated Gold Nanoparticles for Tumor-Targeting CT Imaging. Pharmaceutical Research, 31(6), 1418-1425. doi:10.1007/s11095-013-1142-0Costa, P. M., & Fadeel, B. (2016). Emerging systems biology approaches in nanotoxicology: Towards a mechanism-based understanding of nanomaterial hazard and risk. Toxicology and Applied Pharmacology, 299, 101-111. doi:10.1016/j.taap.2015.12.014Lv, M., Huang, W., Chen, Z., Jiang, H., Chen, J., Tian, Y., … Xu, F. (2015). Metabolomics techniques for nanotoxicity investigations. Bioanalysis, 7(12), 1527-1544. doi:10.4155/bio.15.83Nagana Gowda, G. A., Barding, G. A., Dai, J., Gu, H., Margineantu, D. H., Hockenbery, D. M., & Raftery, D. (2018). A Metabolomics Study of BPTES Altered Metabolism in Human Breast Cancer Cell Lines. Frontiers in Molecular Biosciences, 5. doi:10.3389/fmolb.2018.00049Ali, M. R. K., Wu, Y., Han, T., Zang, X., Xiao, H., Tang, Y., … El-Sayed, M. A. (2016). Simultaneous Time-Dependent Surface-Enhanced Raman Spectroscopy, Metabolomics, and Proteomics Reveal Cancer Cell Death Mechanisms Associated with Gold Nanorod Photothermal Therapy. Journal of the American Chemical Society, 138(47), 15434-15442. doi:10.1021/jacs.6b08787Esumi, K., Takei, N., & Yoshimura, T. (2003). Antioxidant-potentiality of gold–chitosan nanocomposites. Colloids and Surfaces B: Biointerfaces, 32(2), 117-123. doi:10.1016/s0927-7765(03)00151-6Du, S., Kendall, K., Toloueinia, P., Mehrabadi, Y., Gupta, G., & Newton, J. (2012). Aggregation and adhesion of gold nanoparticles in phosphate buffered saline. Journal of Nanoparticle Research, 14(3). doi:10.1007/s11051-012-0758-zUlrich, E. L., Akutsu, H., Doreleijers, J. F., Harano, Y., Ioannidis, Y. E., Lin, J., … Markley, J. L. (2007). BioMagResBank. Nucleic Acids Research, 36(Database), D402-D408. doi:10.1093/nar/gkm957Wishart, D. S., Feunang, Y. D., Marcu, A., Guo, A. C., Liang, K., Vázquez-Fresno, R., … Scalbert, A. (2017). HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Research, 46(D1), D608-D617. doi:10.1093/nar/gkx1089Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1-2), 55-63. doi:10.1016/0022-1759(83)90303-4Yang, L., Shang, L., & Nienhaus, G. U. (2013). Mechanistic aspects of fluorescent gold nanocluster internalization by live HeLa cells. Nanoscale, 5(4), 1537. doi:10.1039/c2nr33147kZhitomirsky, B., Farber, H., & Assaraf, Y. G. (2018). LysoTracker and MitoTracker Red are transport substrates of P‐glycoprotein: implications for anticancer drug design evading multidrug resistance. Journal of Cellular and Molecular Medicine, 22(4), 2131-2141. doi:10.1111/jcmm.13485Chong, J., Soufan, O., Li, C., Caraus, I., Li, S., Bourque, G., … Xia, J. (2018). MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Research, 46(W1), W486-W494. doi:10.1093/nar/gky310Stepanenko, A. A., & Dmitrenko, V. V. (2015). Pitfalls of the MTT assay: Direct and off-target effects of inhibitors can result in over/underestimation of cell viability. Gene, 574(2), 193-203. doi:10.1016/j.gene.2015.08.009Choi, S. Y., Jang, S. H., Park, J., Jeong, S., Park, J. H., Ock, K. S., … Lee, S. Y. (2012). Cellular uptake and cytotoxicity of positively charged chitosan gold nanoparticles in human lung adenocarcinoma cells. Journal of Nanoparticle Research, 14(12). doi:10.1007/s11051-012-1234-5De Carvalho, T. G., Garcia, V. B., de Araújo, A. A., da Silva Gasparotto, L. H., Silva, H., Guerra, G. C. B., … de Araújo Júnior, R. F. (2018). Spherical neutral gold nanoparticles improve anti-inflammatory response, oxidative stress and fibrosis in alcohol-methamphetamine-induced liver injury in rats. International Journal of Pharmaceutics, 548(1), 1-14. doi:10.1016/j.ijpharm.2018.06.008Carrola, J., Bastos, V., Ferreira de Oliveira, J. M. P., Oliveira, H., Santos, C., Gil, A. M., & Duarte, I. F. (2016). Insights into the impact of silver nanoparticles on human keratinocytes metabolism through NMR metabolomics. Archives of Biochemistry and Biophysics, 589, 53-61. doi:10.1016/j.abb.2015.08.022Fröhlich, E. (2012). The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles. International Journal of Nanomedicine, 5577. doi:10.2147/ijn.s36111Gürer, H., Özgünes, H., Saygin, E., & Ercal, N. (2001). Antioxidant Effect of Taurine Against Lead-Induced Oxidative Stress. Archives of Environmental Contamination and Toxicology, 41(4), 397-402. doi:10.1007/s002440010265Lee, S.-H., Wang, T.-Y., Hong, J.-H., Cheng, T.-J., & Lin, C.-Y. (2016). NMR-based metabolomics to determine acute inhalation effects of nano- and fine-sized ZnO particles in the rat lung. Nanotoxicology, 10(7), 924-934. doi:10.3109/17435390.2016.1144825Saborano, R., Wongpinyochit, T., Totten, J. D., Johnston, B. F., Seib, F. P., & Duarte, I. F. (2017). Metabolic Reprogramming of Macrophages Exposed to Silk, Poly(lactic-co-glycolic acid), and Silica Nanoparticles. Advanced Healthcare Materials, 6(14), 1601240. doi:10.1002/adhm.201601240Bo, Y., Jin, C., Liu, Y., Yu, W., & Kang, H. (2014). Metabolomic analysis on the toxicological effects of TiO2nanoparticles in mouse fibroblast cells: from the perspective of perturbations in amino acid metabolism. Toxicology Mechanisms and Methods, 24(7), 461-469. doi:10.3109/15376516.2014.939321Shea, T. B., Ekinci, F. J., Ortiz, D., Dawn-Linsley, M., Wilson, T. O., & Nicolosi, R. J. (2002). Efficacy of vitamin E, phosphatidyl choline, and pyruvate on buffering neuronal degeneration and oxidative stress in cultured cortical neurons and in central nervous tissue of apolipoprotein E-deficient mice. Free Radical Biology and Medicine, 33(2), 276-282. doi:10.1016/s0891-5849(02)00872-9Schätzlein, M. P., Becker, J., Schulze-Sünninghausen, D., Pineda-Lucena, A., Herance, J. R., & Luy, B. (2018). Rapid two-dimensional ALSOFAST-HSQC experiment for metabolomics and fluxomics studies: application to a 13C-enriched cancer cell model treated with gold nanoparticles. Analytical and Bioanalytical Chemistry, 410(11), 2793-2804. doi:10.1007/s00216-018-0961-6HUNTER, A. (2006). Molecular hurdles in polyfectin design and mechanistic background to polycation induced cytotoxicity☆. Advanced Drug Delivery Reviews, 58(14), 1523-1531. doi:10.1016/j.addr.2006.09.008Ratnasekhar, C., Sonane, M., Satish, A., & Mudiam, M. K. R. (2015). Metabolomics reveals the perturbations in the metabolome ofCaenorhabditis elegansexposed to titanium dioxide nanoparticles. Nanotoxicology, 9(8), 994-1004. doi:10.3109/17435390.2014.99334

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)

Simultaneous Dual-tracer PET Imaging of the Rat Brain and its Application in the Study of Cerebral Ischemia

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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

Alteration of the Mitochondrial Effects of Ceria Nanoparticles by Gold: An Approach for the Mitochondrial Modulation of Cells Based on Nanomedicine

[EN] Ceria nanoparticles are cell compatible antioxidants whose activity can be enhanced by gold deposition and by surface functionalization with positive triphenylphosphonium units to selectively target the mitochondria. The antioxidant properties of these nanoparticles can serve as the basis of a new strategy for the treatment of several disorders exhibiting oxidative stress, such as cancer, diabetes or Alzheimer's disease. However, all of these pathologies require a specific antioxidant according with their mechanism to remove oxidant species excess in cells and diminish their effect on mitochondrial function. The mechanism through which ceria nanoparticles neutralize oxidative stress and their effect on mitochondrial function have not been characterized yet. In the present study, the mitochondria antioxidant effect of ceria and ceria-supported gold nanoparticles, with or without triphenylphosphonium functionalization, was assessed in HeLa cells. The effect caused by ceria nanoparticles on mitochondria function in terms of mitochondrial membrane potential (Delta Psi m), adenosine triphosphate (ATP) production, nuclear respiratory factor 1 (NRF1) and nuclear factor erythroid-2 like 1 (NFE2L1) was reversed by the presence of gold. Furthermore, this effect was enhanced when nanoparticles were functionalized with triphenylphosphonium. Our study illustrates how the mitochondrial antioxidant effect induced by ceria nanoparticles can be modulated by the presence of gold.This research was funded by Carlos III Health Institute and the European Regional Development Fund, grant number CP13/00252 and PI16/1083; the Catalonian Agency for Management of University and Research Grants, grant number 2017SGR1303; the Ministry of Education of the Valencian Regional Government, grant number PROMETEO/2019/027, The Foundation for the Promotion of Health and Biomedical Research of Valencia Region, grant number Nanobetes2.Gutiérrez-Carcedo, P.; Navalón Oltra, S.; Simó, R.; Setoain, X.; Aparicio-Gómez, C.; Abasolo, I.; Victor, VM.... (2020). Alteration of the Mitochondrial Effects of Ceria Nanoparticles by Gold: An Approach for the Mitochondrial Modulation of Cells Based on Nanomedicine. Nanomaterials. 10(4):1-16. https://doi.org/10.3390/nano10040744S11610

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