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3 results on '"Loza, María Isabel [0000-0003-4730-0863]"'

1. Supporting information Discovery and in Vivo Proof-of-Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

Author

Griñán-Ferré, Christian [0000-0002-5424-9130], Calvó-Tusell, Carla [0000-0003-2681-8460], Osuna, Sílvia [0000-0003-3657-6469], Bartolini, Manuela [0000-0002-2890-3856], Loza, María Isabel [0000-0003-4730-0863], Juárez-Jiménez, Jordi [0000-0003-1464-1397], Pallàs, Mercè [0000-0003-3095-4254], Vázquez, Santiago [0000-0002-9296-6026], Muñoz-Torrero, Diego [0000-0002-8140-8555], Vázquez, Santiago [svazquez@ub.edu] ; Muñoz-Torrero, Diego [dmunoztorrero@ub.edu], Codony, Sandra, Pont, Caterina, Griñán-Ferré, Christian, Di Pede-Mattatelli, Ania, Calvó-Tusell, Carla, Feixas, Ferran, Osuna, Sílvia, Jarné-Ferrer, Júlia, Naldi, Marina, Bartolini, Manuela, Loza, María Isabel, Brea, José Manuel, Pérez, Belén, Bartra Cabré, Clara, Sanfeliu, Coral, Juárez-Jiménez, Jordi, Morisseau, Christophe, Hammock, Bruce D., Pallàs, Mercè, Vázquez, Santiago, Muñoz-Torrero, Diego, Griñán-Ferré, Christian [0000-0002-5424-9130], Calvó-Tusell, Carla [0000-0003-2681-8460], Osuna, Sílvia [0000-0003-3657-6469], Bartolini, Manuela [0000-0002-2890-3856], Loza, María Isabel [0000-0003-4730-0863], Juárez-Jiménez, Jordi [0000-0003-1464-1397], Pallàs, Mercè [0000-0003-3095-4254], Vázquez, Santiago [0000-0002-9296-6026], Muñoz-Torrero, Diego [0000-0002-8140-8555], Vázquez, Santiago [svazquez@ub.edu] ; Muñoz-Torrero, Diego [dmunoztorrero@ub.edu], Codony, Sandra, Pont, Caterina, Griñán-Ferré, Christian, Di Pede-Mattatelli, Ania, Calvó-Tusell, Carla, Feixas, Ferran, Osuna, Sílvia, Jarné-Ferrer, Júlia, Naldi, Marina, Bartolini, Manuela, Loza, María Isabel, Brea, José Manuel, Pérez, Belén, Bartra Cabré, Clara, Sanfeliu, Coral, Juárez-Jiménez, Jordi, Morisseau, Christophe, Hammock, Bruce D., Pallàs, Mercè, Vázquez, Santiago, and Muñoz-Torrero, Diego

Published
2022

2. Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer's Disease

Author

Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Xunta de Galicia, European Commission, Generalitat de Catalunya, National Institute of Environmental Health Sciences (US), European Research Council, National Institute of Neurological Disorders and Stroke (US), National Institute of Diabetes and Digestive and Kidney Diseases (US), Ministerio de Educación, Cultura y Deporte (España), Griñán-Ferré, Christian [0000-0002-5424-9130], Calvó-Tusell, Carla [0000-0003-2681-8460], Osuna, Sílvia [0000-0003-3657-6469], Bartolini, Manuela [0000-0002-2890-3856], Loza, María Isabel [0000-0003-4730-0863], Juárez-Jiménez, Jordi [0000-0003-1464-1397], Pallàs, Mercè [0000-0003-3095-4254], Vázquez, Santiago [0000-0002-9296-6026], Muñoz-Torrero, Diego [0000-0002-8140-8555], Codony, Sandra, Pont, Caterina, Griñán-Ferré, Christian, Di Pede-Mattatelli, Ania, Calvó-Tusell, Carla, Feixas, Ferran, Osuna, Sílvia, Jarné-Ferrer, Júlia, Naldi, Marina, Bartolini, Manuela, Loza, María Isabel, Brea, José Manuel, Pérez, Belén, Bartra Cabré, Clara, Sanfeliu, Coral, Juárez-Jiménez, Jordi, Morisseau, Christophe, Hammock, Bruce D., Pallàs, Mercè, Vázquez, Santiago, Muñoz-Torrero, Diego, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Xunta de Galicia, European Commission, Generalitat de Catalunya, National Institute of Environmental Health Sciences (US), European Research Council, National Institute of Neurological Disorders and Stroke (US), National Institute of Diabetes and Digestive and Kidney Diseases (US), Ministerio de Educación, Cultura y Deporte (España), Griñán-Ferré, Christian [0000-0002-5424-9130], Calvó-Tusell, Carla [0000-0003-2681-8460], Osuna, Sílvia [0000-0003-3657-6469], Bartolini, Manuela [0000-0002-2890-3856], Loza, María Isabel [0000-0003-4730-0863], Juárez-Jiménez, Jordi [0000-0003-1464-1397], Pallàs, Mercè [0000-0003-3095-4254], Vázquez, Santiago [0000-0002-9296-6026], Muñoz-Torrero, Diego [0000-0002-8140-8555], Codony, Sandra, Pont, Caterina, Griñán-Ferré, Christian, Di Pede-Mattatelli, Ania, Calvó-Tusell, Carla, Feixas, Ferran, Osuna, Sílvia, Jarné-Ferrer, Júlia, Naldi, Marina, Bartolini, Manuela, Loza, María Isabel, Brea, José Manuel, Pérez, Belén, Bartra Cabré, Clara, Sanfeliu, Coral, Juárez-Jiménez, Jordi, Morisseau, Christophe, Hammock, Bruce D., Pallàs, Mercè, Vázquez, Santiago, and Muñoz-Torrero, Diego

Abstract

With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent of multitarget drug discovery has brought a new breath of hope. Here, we disclose a class of 6-chlorotacrine (huprine)-TPPU hybrids as dual inhibitors of the enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), a multitarget profile to provide cumulative effects against neuroinflammation and memory impairment. Computational studies confirmed the gorge-wide occupancy of both enzymes, from the main site to a secondary site, including a so far non-described AChE cryptic pocket. The lead compound displayed in vitro dual nanomolar potencies, adequate brain permeability, aqueous solubility, human microsomal stability, lack of neurotoxicity, and it rescued memory, synaptic plasticity, and neuroinflammation in an AD mouse model, after low dose chronic oral administration.

Published
2022

3. A Comprehensive Tyrosine Phosphoproteomic Analysis Reveals Novel Components of the Platelet CLEC-2 Signaling Cascade

Author

Lidia Hermida-Nogueira, Irene Izquierdo, Serena Lacerenza, Roberto Pinto-Llorente, Vivian de los Ríos, Luis A. Morán, Ángel García, María Isabel Loza, Johannes A. Eble, Joaquín Abián, Vanessa Casas, María N. Barrachina, J I Casal, Eduardo Domínguez, Montserrat Carrascal, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica, Ministerio de Economía y Competitividad (España), Xunta de Galicia, European Commission, Barrachina, Maria N. [0000-0002-1701-6899], Hermida-Nogueira, Lidia [0000-0001-7858-6046], Casas, Vanessa [0000-0001-7438-0323], Eble, Johannes A. [0000-0001-9156-2137], de los Ríos, Vivian [0000-0001-5582-6879], Domínguez, Eduardo [0000-0003-3359-5867], Loza, María Isabel [0000-0003-4730-0863], Casal, J. Ignacio [0000-0003-1085-2840], Carrascal, Montserrat [0000-0002-0205-2176], Barrachina, Maria N., Hermida-Nogueira, Lidia, Casas, Vanessa, Eble, Johannes A., de los Ríos, Vivian, Domínguez, Eduardo, Loza, María Isabel, Casal, J. Ignacio, and Carrascal, Montserrat

Subjects
Adult, Blood Platelets, Male, Platelets, 0301 basic medicine, Platelet Aggregation, Proteome, Syk, CLEC-2 signaling, 030204 cardiovascular system & hematology, Thromboxane A2, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Tyrosinephosphoproteome, Humans, Lectins, C-Type, Platelet activation, Phosphorylation, Tyrosine, Phosphotyrosine, Membrane Glycoproteins, Kinase, Hematology, Middle Aged, Phosphoproteins, Platelet Activation, 3. Good health, Cell biology, Adenosine Diphosphate, Kinetics, Adenosine diphosphate, 030104 developmental biology, chemistry, Tyrosine phosphoproteome, Calcium, Female, Signal transduction, Signal Transduction, Proto-oncogene tyrosine-protein kinase Src
Abstract

15 p.-7 fig.-2 tab., C-type lectin-like receptor 2 (CLEC-2) plays a crucial role in different platelet-related physiological and pathological processes. It signals through a tyrosine kinase-mediated pathway that is highly dependent on the positive feedback exerted by the platelet-derived secondary mediators, adenosine diphosphate (ADP) and thromboxane A2 (TXA2). Here, we aimed to analyze the tyrosine phosphoproteome of platelets activated with the CLEC-2 agonist rhodocytin to identify relevant phosphorylated tyrosine residues (p-Tyr) and proteins involved in platelet activation downstream of this receptor. We identified 363 differentially p-Tyr residues, corresponding to the majority of proteins previously known to participate in CLEC-2 signaling and also novel ones, including adaptors (e.g., DAPP1, Dok1/3, CASS4, Nck1/2), kinases/phosphatases (e.g., FAK1, FES, FGR, JAK2, SHIP2), and membrane proteins (e.g., G6F, JAM-A, PECAM-1, TLT-1). To elucidate the contribution of ADP and TXA2 at different points of the CLEC-2 signaling cascade, we evaluated p-Tyr levels of residues identified in the analysis and known to be essential for the catalytic activity of kinases Syk(p-Tyr525+526) and Src(p-Tyr419), and for PLCγ2 activity (p-Tyr759). We demonstrated that Syk phosphorylation at Tyr525+526 also happens in the presence of ADP and TXA2 inhibitors, which is not the case for Src-pTyr419 and PLCγ2-pTyr759. Kinetics studies for the three phosphoproteins show some differences in the phosphorylation profile. Ca2+ mobilization assays confirmed the relevance of ADP and TXA2 for full CLEC-2-mediated platelet activation. The present study provides significant insights into the intracellular events that take place following CLEC-2 activation in platelets, contributing to elucidate in detail the CLEC-2 signalosome., This study was supported by the Spanish Ministryof Economy and Competitiveness (MINECO) [grant No. SAF2016-79662-R], co-funded by the European Regional Develop-ment Fund (ERDF); and the Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia [ED431C2018/21; predoctoral grant Plan I2C 2014; and CentroSingular de investigación de Galicia accreditation 2016-2019, ED431G/05], co-funded by the European Regional Development Fund (ERDF). The study also received funding from the European Union’s Horizon 2020 research andinnovation programme under the Marie Skłodowska-Curiegrant agreement No 766118. J.A.E. is supported by DeutscheForschungsgemeinschaft [DFG grant: EB177/13-1]

Published
2020
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