Person: Ortega Gutiérrez, Silvia
Universidad Complutense de Madrid
Faculty / Institute
Now showing 1 - 10 of 12
PublicationSMARTeaching: Uso de dispositivos móviles en el aula y eficacia de las clases presenciales(2018-06-30) García Segura, Juan Manuel; Feito Castellano, María José; Lacadena García-Gallo, Javier; Lainez Ferrando, Alfredo; Luque García, José Luis; OñaderraA Sánchez, Mercedes; Ortega Gutiérrez, Silvia; Pérez-Gil, Jesús; Sánchez García, Cristina PublicationUnique pharmacological properties of serotoninergic G-protein coupled receptors from cestodes(Public Library Science, 2018-02-09) Camicia, Federico; Celentano, Ana M.; Johns, Malcolm E.; Chan, John D.; Maldonado, Lucas; Vaca, Hugo; Siervi, Nicolás Di; Kamenetzky, Laura; Gamo Albero, Ana María; Ortega Gutiérrez, Silvia; Martín Fontecha, María del Mar; Davio, Carlos; Marchant, Jonathan S.; Rosenzvit, Mara C.Background: Cestodes are a diverse group of parasites, some of them being agents of neglected diseases. In cestodes, little is known about the functional properties of G protein coupled receptors (GPCRs) which have proved to be highly druggable targets in other organisms. Notably, serotoninergic G-protein coupled receptors (5-HT GPCRs) play major roles in key functions like movement, development and reproduction in parasites. Methodology/Principal findings: Three 5-HT GPCRs from Echinococcus granulosus and Mesocestoides corti were cloned, sequenced, bioinformatically analyzed and functionally characterized. Multiple sequence alignment with other GPCRs showed the presence of seven transmembrane segments and conserved motifs but interesting differences were also observed. Phylogenetic analysis grouped these new sequences within the 5-HT7 clade of GPCRs. Molecular modeling showed a striking resemblance in the spatial localization of key residues with their mammalian counterparts. Expression analysis using available RNAseq data showed that both E. granulosus sequences are expressed in larval and adult stages. Localization studies performed in E. granulosus larvae with a fluorescent probe produced a punctiform pattern concentrated in suckers. E. granulosus and M. corti larvae showed an increase in motility in response to serotonin. Heterologous expression revealed elevated levels of cAMP production in response to 5-HT and two of the GPCRs showed extremely high sensitivity to 5-HT (picomolar range). While each of these GPCRs was activated by 5-HT, they exhibit distinct pharmacological properties (5-HT sensitivity, differential responsiveness to ligands). Conclusions/Significance: These data provide the first functional report of GPCRs in parasitic cestodes. The serotoninergic GPCRs characterized here may represent novel druggable targets for antiparasitic intervention. PublicationNovel Antagonist of the Type 2 Lysophosphatidic Acid Receptor (LPA2), UCM-14216, Ameliorates Spinal Cord Injury in Mice(ACS Publications, 2022-08-10) Khiar Fernández, Nora; Zian, Debora; Vázquez Villa, Henar; Martínez, R. Fernando; Escobar Peña, Andrea; Foronda Sainz, Román; Ray, Manisha; Puigdomenech Poch, Maria; Cincilla, Giovanni; Sánchez Martínez, Melchor; Kihara, Yasuyuki; Chun, Jerold; López Vales, Rubèn; López Rodríguez, María L.; Ortega Gutiérrez, SilviaSpinal cord injuries (SCIs) irreversibly disrupt spinal connectivity, leading to permanent neurological disabilities. Current medical treatments for reducing the secondary damage that follows the initial injury are limited to surgical decompression and anti-inflammatory drugs, so there is a pressing need for new therapeutic strategies. Inhibition of the type 2 lysophosphatidic acid receptor (LPA2) has recently emerged as a new potential pharmacological approach to decrease SCIassociated damage. Toward validating this receptor as a target in SCI, we have developed a new series of LPA2 antagonists, among which compound 54 (UCM14216) stands out as a potent and selective LPA2 receptor antagonist (Emax = 90%, IC50 = 1.9 μM, KD = 1.3 nM; inactive at LPA1,3−6 receptors). This compound shows efficacy in an in vivo mouse model of SCI in an LPA2-dependent manner, confirming the potential of LPA2 inhibition for providing a new alternative for treating SCI. PublicationThe status of the lysophosphatidic acid receptor type 1 (LPA1R)(Royal Society of Chemistry (UK), 2015) González Gil, Inés; Zian, Debora; Vázquez Villa, Henar; Ortega Gutiérrez, Silvia; López Rodríguez, María L.Lysophospholipids are lipid molecules that are receiving growing attention because, in addition to their structural function in the cell membrane, they are now regarded as important regulators for diverse biological functions through activation of specific receptors. These receptors have been characterized during the last two decades as G protein-coupled receptors (GPCRs) and, among them, two families stand out: lysophosphatidic acid (LPA1–6) and sphingosine 1-phoshate (S1P1–5) receptors. Despite their interest, the high structural similarity between them has restrained the development of selective and high affinity ligands and therefore the elucidation of the role of these receptors in the central nervous system (CNS). This review provides an overview about the different LPA receptors with a special focus on the LPA1 subtype from a medicinal chemistry perspective. It summarizes the most recent developments in the search for selective and specific agonists and antagonists of the LPA1 receptor and highlights their current status in the drug development pipeline. PublicationNew Trends in Aging Drug Discovery(MDPI, 2022-08-15) Benhamú Salama, Bellinda; Martín Fontecha, María del Mar; Vázquez Villa, Henar; López Rodríguez, María Luz; Ortega Gutiérrez, SilviaAging is considered the main risk factor for many chronic diseases that frequently appear at advanced ages. However, the inevitability of this process is being questioned by recent research that suggests that senescent cells have specific features that differentiate them from younger cells and that removal of these cells ameliorates senescent phenotype and associated diseases. This opens the door to the design of tailored therapeutic interventions aimed at reducing and delaying the impact of senescence in life, that is, extending healthspan and treating aging as another chronic disease. Although these ideas are still far from reaching the bedside, it is conceivable that they will revolutionize the way we understand aging in the next decades. In this review, we analyze the main and well-validated cellular pathways and targets related to senescence as well as their implication in aging-associated diseases. In addition, the most relevant small molecules with senotherapeutic potential, with a special emphasis on their mechanism of action, ongoing clinical trials, and potential limitations, are discussed. Finally, a brief overview of alternative strategies that go beyond the small molecule field, together with our perspectives for the future of the field, is provided. PublicationOperaciones básicas de laboratorio en el contexto de los objetivos de desarrollo sostenible (ODS)(2023-07-27) Ortega Gutiérrez, Silvia; Benhamú Salama, Bellinda; Canales Mayordomo, Mª Ángeles; Gámez Márquez, Francisco de Asís; Muñoz Oliva, Mª Riansares; Pérez Corona, Mª Teresa; Cilleros Prados, Olga; Sobrino Díaz, Mª Lourdes; Fernández Cabellos, Daniel; Sánchez Merino, AnabelEn este proyecto se pretende sensibilizar a los estudiantes en la importancia de los objetivos de desarrollo sostenible (ODS), fomentar su compromiso con los mismos y mostrar como la química puede contribuir de forma concreta y significativa a la consecución de los ODS. PublicationDevelopment of a Fluorescent Bodipy Probe for Visualization of the Serotonin 5-HT1A Receptor in Native Cells of the Immune System(American Chemical Society (ACS), 2018-05-07) Hernández Torres, Gloria; Enríquez Palacios, Ernesto; Mecha Rodríguez, Miriam; Feliú Martínez, Ana; Rueda Zubiaurre, Ainoa; Angelina Querencias, Alba; Martín Cruz, Leticia; Martín Fontecha, María del Mar; Palomares, Oscar; Guaza Rodríguez, Carmen; Peña Cabrera, Eduardo; López Rodríguez, María L.; Ortega Gutiérrez, SilviaSerotonin (5-HT) modulates key aspects of the immune system. However, its precise function and the receptors involved in the observed effects have remained elusive. Among the different serotonin receptors, 5-HT1A plays an important role in the immune system given its presence in cells involved in both the innate and adaptive immune responses, but its actual levels of expression under different conditions have not been comprehensively studied due to the lack of suitable tools. To further clarify the role of 5-HT1A receptor in the immune system, we have developed a fluorescent small molecule probe that enables the direct study of the receptor levels in native cells. This probe allows direct profiling of the receptor expression in immune cells using flow cytometry. Our results show that important subsets of immune cells including human monocytes and dendritic cells express functional 5-HT1A and that its activation is associated with anti-inflammatory signaling. Furthermore, application of the probe to the experimental autoimmune encephalomyelitis model of multiple sclerosis demonstrates its potential to detect the specific overexpression of the 5-HT1A receptor in CD4+ T cells. Accordingly, the probe reported herein represents a useful tool whose use can be extended to study the levels of 5-HT1A receptor in ex vivo samples of different immune system conditions. PublicationDevelopment of a Nucleotide Exchange Inhibitor That Impairs Ras Oncogenic Signaling(Wiley, 2017-01-31) Marín Ramos, Nagore Isasbel; Piñar Pinedo, María del Carmen; Vázquez Villa, Henar; Martín Fontecha, María del Mar; Gonzalez Wong, Ángel; Canales Mayordomo, Ángeles; Algar Lizana, Sergio; Mayo Mariscal de Gante, Paloma P.; Jiménez-Barbero, Jesús; Gajate Fraile, Consuelo; Mollinedo García, Faustino; Pardo Carrasco, Leonardo; Ortega Gutiérrez, Silvia; Viso Beronda, Alma; López Rodríguez, María LuzDespite more than three decades of intense effort, no anti-Ras therapies have reached clinical application. Contributing to this failure has been an underestimation of Ras complexity and a dearth of structural information. In this regard, recent studies have revealed the highly dynamic character of the Ras surface and the existence of transient pockets suitable for small-molecule binding, opening up new possibilities for the development of Ras modulators. Herein, a novel Ras inhibitor (compound 12) is described that selectively impairs mutated Ras activity in a reversible manner without significantly affecting wild-type Ras, reduces the Ras–guanosine triphosphate (GTP) levels, inhibits the activation of the mitogen-activated protein kinase (MAPK) pathway, and exhibits remarkable cytotoxic activity in Ras-driven cellular models. The use of molecular dynamics simulations and NMR spectroscopy experiments has enabled the molecular bases responsible for the interactions between compound 12 and Ras protein to be explored. The new Ras inhibitor binds partially to the GTP-binding region and extends into the adjacent hydrophobic pocket delimited by switch II. Hence, Ras inhibitor 12 could represent a new compound for the development of more efficacious drugs to target Ras-driven cancers; a currently unmet clinical need. PublicationA Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia(American chemical Society (ACS), 2019-06-10) Marín Ramos, Nagore Isasbel; Balabasquer Peña, Moisés; Ortega Nogales, Francisco Jesús; Torrecillas, Iván R.; Gil Ordoñez, Ana; Marcos Ramiro, Beatriz; Aguilar Garrido, Pedro; Cushman, Ian; Romero, Antonio; Medrano, Francisco J.; Gajate Fraile, Consuelo; Mollinedo García, Faustino; Philips, Mark R.; Campillo, Mercedes; Gallardo Delgado, Miguel; Martín Fontecha, Mar; López Rodríguez, María Luz; Ortega Gutiérrez, SilviaBlockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 μM], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors. PublicationDeregulation of the endocannabinoid system and therapeutic potential of ABHD6 blockade in the cuprizone model of demyelination(Elsevier, 2018-08) Manterola, Andrea; Bernal Chico, Ana; Cipriani, Raffaela; Canedo Antelo, Manuel; Moreno García, Álvaro; Martín Fontecha, Mar; Pérez Cerdá, Fernando; Sánchez Gómez, María Victoria; Ortega Gutiérrez, Silvia; Brown, J. Mark; Hsu, Ku-Lung; Cravatt, Benjamin; Matute, Carlos; Mato, SusanaMultiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology in which tissue pathology suggests both immune-dependent attacks to oligodendroglia and primary oligodendrocyte demise. The endocannabinoid system has been crucially involved in the control of autoimmune demyelination and cannabinoid-based therapies exhibit therapeutic potential, but also limitations, in MS patients. In this context, growing evidence suggests that targeting the hydrolysis of the main endocannabinoid 2-arachidonoylglycerol (2-AG) may offer a more favorable benefit-to-risk balance in MS than existing cannabinoid medicines. Here we evaluated the modulation of endocannabinoid signaling and the therapeutic potential of targeting the 2-AG hydrolytic enzyme alpha/beta-hydrolase domain-containing 6 (ABHD6) in the cuprizone model of non-immune dependent demyelination. The concentrations of N-arachidonoylethanolamine (anandamide, AEA) and its congener N-palmitoylethanolamine (PEA) were reduced following 6 weeks of cuprizone feeding. Deregulation of AEA and PEA levels was not due to differences in the expression of the hydrolytic and biosynthetic enzymes fatty acid amide hydrolase and N-acylphosphatidylethanolamine-phospholipase D, respectively. Conversely, we measured elevated transcript levels of 2-AG hydrolytic enzymes monoacylglycerol lipase, ABHD6 and ABHD12 without changes in bulk 2-AG concentration. Upregulated CB1 and CB2 receptors expression, ascribed in part to microglia, was also detected in the brain of cuprizone-treated mice. Administration of an ABHD6 inhibitor partially attenuated myelin damage, astrogliosis and microglia/macrophage reactivity associated to cuprizone feeding. However, ABHD6 blockade was ineffective at engaging protective or differentiation promoting effects in oligodendrocyte cultures. These results show specific alterations of the endocannabinoid system and modest beneficial effects resulting from ABHD6 inactivation in a relevant model of primary demyelination.