Person:
Oset Gasque, María Jesús

First Name

María Jesús

Last Name

Oset Gasque

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Farmacia

Department

Bioquímica y Biología Molecular

Area

Bioquímica y Biología Molecular

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Now showing 1 - 10 of 11

Pyranopyrazolotacrines as nonneurotoxic, Aβ-anti-aggregating and neuroprotective agents for Alzheimer’s disease
(Future Science, 2015) Chioua, Mourad; Pérez Peña, Javier; García Font, Nuria; Moraleda, Ignacio; Iriepa, Isabel; Soriano, Elena; Marco Contelles, José; Oset Gasque, María Jesús
Aim: Due to the complex nature of Alzheimer’s disease, there is a renewed search for multipotent, nonhepatotoxic tacrines. Results: This paper describes the synthesis and in vitro biological evaluation of eight new racemic 3-methyl-4-aryl-2,4,6,7,8,9-hexahydropyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolin-5-amines (pyranopyrazolotacrines, PPT) as nonhepatotoxic multipotent tacrine analogs. Among these compounds, PPT4 is the less hepatotoxic in the cell viability assay on HepG2 cells, showing a good neuroprotective effect in the decreased cortical neuron viability induced by oligomycin A/rotenone analysis. PPT4 is a selective and good, noncompetitive EeAChE inhibitor, able to completely inhibit the Aβ1–40 aggregation induced by acetylcholinesterase. Conclusion: A new family of permeable tacrine analogs, have been discovered for the potential treatment of Alzheimer’s disease.
CXCR4/CXCR7 Molecular Involvement in Neuronal and Neural Progenitor Migration: Focus in CNS Repair
(Wiley, 2015) Merino, José Joaquín; Bellver Landete, Víctor; Oset Gasque, María Jesús; Cubelos, Beatriz
In the adult brain, neural progenitor cells (NPCs) reside in the subventricular zone (SVZ) of the lateral ventricles, the dentate gyrus and the olfactory bulb. Following CNS insult, NPCs from the SVZ can migrate along the rostral migratory stream (RMS), a migration of NPCs that is directed by proinflammatory cytokines. Cells expressing CXCR4 follow a homing signal that ultimately leads to neuronal integration and CNS repair, although such molecules can also promote NPC quiescence. The ligand, SDF1 alpha (or CXCL12) is one of the chemokines secreted at sites of injury that it is known to attract NSC-derived neuroblasts, cells that express CXCR4. In function of its concentration, CXCL12 can induce different responses, promoting NPC migration at low concentrations while favoring cell adhesion via EGF and the alpha 6 integrin at high CXCL12 concentrations. However, the preclinical effectiveness of chemokines and their relationship with NPC mobilization requires further study, particularly with respect to CNS repair. NPC migration may also be affected by the release of cytokines or chemokines induced by local inflammation, through autocrine or paracrine mechanisms, as well as through erythropoietin (EPO) or nitric oxide (NO) release. CXCL12 activity requires G-coupled proteins and the availability of its ligand may be modulated by its binding to CXCR7, for which it shows a stronger affinity than for CXCR4.
Synthesis, Neuroprotection, and Antioxidant Activity of 1,1′-Biphenylnitrones as α-Phenyl-N-tert-butylnitrone Analogues in In Vitro Ischemia Models
(MDPI, 2021-02-20) Chamorro, Beatriz; García-Vieira, David; Diez-Iriepa, Daniel; Garagarza, Estíbaliz; Chioua, Mourad; Hadjipavlou-Litina, Dimitra; López-Muñoz, Francisco; Marco-Contelles, José; Oset Gasque, María Jesús
Herein, we report the neuroprotective and antioxidant activity of 1,1′-biphenyl nitrones (BPNs) 1–5 as α-phenyl-N-tert-butylnitrone analogues prepared from commercially available [1,1′-biphenyl]-4-carbaldehyde and [1,1′-biphenyl]-4,4′-dicarbaldehyde. The neuroprotection of BPNs1-5 has been measured against oligomycin A/rotenone and in an oxygen–glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that BPNs 1–5 have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN), and they are quite similar to N-acetyl-L-cysteine (NAC), which is a well-known antioxidant agent. Among the nitrones studied, homo-bis-nitrone BPHBN5, bearing two N-tert-Bu radicals at the nitrone motif, has the best neuroprotective capacity (EC50 = 13.16 ± 1.65 and 25.5 ± 3.93 μM, against the reduction in metabolic activity induced by respiratory chain blockers and oxygen–glucose deprivation in an in vitro ischemia model, respectively) as well as anti-necrotic, anti-apoptotic, and antioxidant activities (EC50 = 11.2 ± 3.94 μM), which were measured by its capacity to reduce superoxide production in human neuroblastoma SH-SY5Y cell cultures, followed by mononitrone BPMN3, with one N-Bn radical, and BPMN2, with only one N-tert-Bu substituent. The antioxidant activity of BPNs1-5 has also been analyzed for their capacity to scavenge hydroxyl free radicals (82% at 100 μM), lipoxygenase inhibition, and the inhibition of lipid peroxidation (68% at 100 μM). Results showed that although the number of nitrone groups improves the neuroprotection profile of these BPNs, the final effect is also dependent on the substitutent that is being incorporated. Thus, BPNs bearing N-tert-Bu and N-Bn groups show better neuroprotective and antioxidant properties than those substituted with Me. All these results led us to propose homo-bis-nitrone BPHBN5 as the most balanced and interesting nitrone based on its neuroprotective capacity in different neuronal models of oxidative stress and in vitro ischemia as well as its antioxidant activity.
Toxicological and pharmacological evaluation, antioxidant, ADMET and molecular modeling of selected racemic chromenotacrines {11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ols} for the potential prevention and treatment of Alzheimer’s disease
(Elsevier, 2014-01-08) Oset Gasque, María Jesús; González Prieto, María Pilar; Pérez Peña, Javier; García Font, Nuria; Romero Martínez, Alejandro; Pino Sans, Javier del; Ramos, Eva; Hadjipavlou-Litina, Dimitra; Soriano, Elena; Chioua, Mourad; Samadi, Abdelouahid; Raghuvanshi, Dushyant S.; Singh, Krishna N.; Marco Contelles, José
The pharmacological analysis of racemic chromenotacrines (CT) 1e7, bearing the 11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ol ring skeleton, in a series of experiments targeted to explore their potential use for the treatment of Alzheimer’s disease (AD), is reported. The toxicological evaluation showed that among all these chromenotacrines, CT6 is much less hepatotoxic than tacrine in a range of concentrations from 1 to 300 mM, measured as cell viability in HepG2 cells. Moreover, CT6 did not significantly increase lactate dehydrogenase, aspartate transaminase, and alanine transaminase release in HepG2 cells. Besides,CT6treatment exerts a high protective effect against thelipid peroxidationinduced after H2O2-treated SHSY5Y cells, in a concentration-dependent manner. CT6 showed an excellent antioxidant profile in the AAPH test, and protects against the decrease in cell viability induced by respiratory chain inhibitors (Oligomicyn A/Rotenone)and NO donors in neuronal cultures. This effect could be due to a mixed antiapoptotic and antinecrotic neuroprotective effect at low and intermediate CT6 concentrations, respectively. CT1-7 are potent and selective inhibitors of EeAChE in the submicromolar range. CT3 [IC50 (EeAChE) ¼ 0.007 0.003 mM], and CT6 [IC50 (EeAChE) ¼ 0.041 0.001 mM] are the most potent AChE inhibitors. Kinetic studies on the non-toxic chromenotacrine CT6 showed that this compound behaves as a non-competitive inhibitor (Ki ¼ 0.047 0.003 mM),indicating that CT6 binds at the peripheral anionic site, a fact confirmed by molecular modeling analysis. In silico ADMET analysis showed also that CT6 should have a moderate BBB permeability. Consequently, non-toxic chromenotacrine CT6can be considered as an ttractivemultipotent molecule for the potential treatment of AD.
Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms
(MDPI, 2020-06-22) Abbruzzese, Giuseppe; Morón Oset, Javier; Díaz Castroverde, Sabela; García Font, Nuria; Roncero Romero, Cesáreo; López Muñoz, Francisco; Marco Contelles, José Luis; Oset Gasque, María Jesús
Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions. First, we found that autophagy initiation affords neuronal protection upon neuronal damage induced by OGD and OGDR. The mammalian target of rapamycin/ribosomal S6 kinase (mTOR/S6K) pathway is blocked in these conditions, and we provide evidence that this is mediated by modulation of both the 50 AMP-activated protein kinase (AMPK) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. These are dampened up or down, respectively, under OGDR-induced neuronal damage. In contrast, the MAPK-Erk kinase/extracellular signal-regulated kinase (MEK/ERK) pathway is increased under these conditions. Regarding the pathways affected by phytoestrogens, we show that their protective properties require autophagy initiation, but at later stages, they decrease mitogen-activated protein kinase (MAPK) and AMPK activation and increase mTOR/S6K activation. Collectively, our results put forward a novel mode of action where phytoestrogens play a dual role in the regulation of autophagy by acting as autophagy initiation enhancers when autophagy is a neuroprotective and pro-survival mechanism, and as autophagy initiation inhibitors when autophagy is a pro-death mechanism. Finally, our results support the therapeutic potential of phytoestrogens in brain ischemia by modulating autophagy.
Mejora de la docencia en Bioquímica Aplicada y Clínica: desarrollo de una revista digital sobre investigación en Medicina Molecular elaborado por los alumnos y puesta en marcha de la metodología didáctica mediante clases invertidas
(2020-09-29) Oset Gasque, María Jesús; Escrivá Pons, Fernando; Iniesta Serrano, María Pilar; Gómez Hernández, María de la Almudena; Escribano Illanes, Óscar; García Redondo, Alberto; Martínez Ruíz, Antonio; Roncero Romero, Cesáreo; Álvarez Escola, Carmen; Juan Chocano, María del Carmen de
Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia–Reperfusion
(MPDI, 2022-03-21) Chamorro, Beatriz; Głowacka, Iwona E.; Gotkowska, Joanna; Gulej, Rafał; Hadjipavlou Litina, Dimitra; López Muñoz, Francisco; Marco Contelles, José Luis; Piotrowska, Dorota G.; Oset Gasque, María Jesús
Herein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named 9a–i. The neuroprotective properties of nitrones, 9a–i, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, 9a–i, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone (PBN) and are similar to N-acetyl-L-cysteine (NAC), a well-known antioxidant and neuroprotective agent. The nitrones with the highest neuroprotective capacity were those containing purine nucleobases (nitrones 9f, g, B = adenine, theophylline), followed by nitrones with pyrimidine nucleobases with H or F substituents at the C5 position (nitrones 9a, c). All of these possess EC50 values in the range of 1–6 μM and maximal activities higher than 100%. However, the introduction of a methyl substituent (nitrone 9b, B = thymine) or hard halogen substituents such as Br and Cl (nitrones 9d, e, B = 5-Br and 5-Cl uracil, respectively) worsens the neuroprotective activity of the nitrone with uracil as the nucleobase (9a). The effects on overall metabolic cell capacity were confirmed by results on the high anti-necrotic (EC50′s ≈ 2–4 μM) and antioxidant (EC50′s ≈ 0.4–3.5 μM) activities of these compounds on superoxide radical production. In general, all tested nitrones were excellent inhibitors of superoxide radical production in cultured neuroblastoma cells, as well as potent hydroxyl radical scavengers that inhibit in vitro lipid peroxidation, particularly, 9c, f, g, presenting the highest lipoxygenase inhibitory activity among the tested nitrones. Finally, the introduction of two nitrone groups at 9a and 9d (bis-nitronas 9g, i) did not show better neuroprotective effects than their precursor mono-nitrones. These results led us to propose nitrones containing purine (9f, g) and pyrimidine (9a, c) nucleobases as potential therapeutic agents for the treatment of cerebral ischemia and/or neurodegenerative diseases, leading us to further investigate their effects using in vivo models of these pathologies.
Innovación Docente en la enseñanza de la Bioquímica y la Biología Molecular: Revistas digitales, clases invertidas y recursos didácticos para la enseñanza “en línea”
(E-Prints Complutense, 2021-12-27) Oset Gasque, María Jesús; Bragado Domingo, Paloma; Escribano Illanes, Óscar; Escrivá Pons, Fernando; Fernández Millán, Elisa; García Redondo, Alberto; Gómez Hernández, María de la Almudena; Herrera González, Blanca María; Iniesta Serrano, María Pilar; Juan Chocano, María del Carmen de; Linares Gómez, María; Martínez Ruíz, Antonio; Pacheco González, Beatriz; Roncero Romero, Cesáreo; Sánchez Muñoz, Aránzazu
En este Proyecto de Innovación Docente (PID 335/20) se han realizado tres tipos de actividades: 1. Elaboración de revistas digitales 2. Implantación de la metodología de clase invertida 3. Desarrollo de materiales docentes par la implantación de la enseñanza "en línea" y formación del profesorado. En ella han participado 15 profesores del Dpto. de Bioquímica y Biología Molecular (Sección Farmacia), de 4 asignaturas diferentes: Bioquímica Aplicada y Clínica, Bioquímica, Biología Molecular y Genética. Los resultados han sido muy satisfactorios, ya que se ha conseguido la participación de un enorme número de alumnos de todas estas asignaturas, los cuales han quedado muy contentos y satisfechos, ya que ha fomentado su autoaprendizaje, su trabajo en grupo, su conocimiento del método científico y sus habilidades como divulgadores de ciencia.
The Nitric Oxide Donor SNAP-Induced Amino Acid Neurotransmitter Release in Cortical Neurons. Effects of Blockers of Voltage-Dependent Sodium and Calcium Channels
(Public Library of Science, 2014) Merino, José Joaquín; Arce, Carmen; Naddaf, Ahmad; Bellver Landete, Víctor; González, María Pilar; Oset Gasque, María Jesús
Background: The discovery that nitric oxide (NO)functions as a signalling molecule in the nervous system has radically changed the concept of neuronal communication. NO induces the release of amino acid neurotransmitters but the underlying mechanisms remain to be elucidated. Findings: The aim of this work was to study the effect of NO on amino acid neurotransmitter release (Asp, Glu, Gly and GABA) in cortical neurons as well as the mechanism underlying the release of these neurotransmitters. Cortical neurons were stimulated with SNAP, a NO donor, and the release of different amino acid neurotransmitters was measured by HPLC. The involvement of voltage dependent Na+ and Ca2+ channels as well as cGMP in its mechanism of action was evaluated. Conclusions: Our results indicate that NO induces release of aspartate, glutamate, glycine and GABA in cortical neurons and that this release is inhibited by ODQ, an inhibitor of soluble guanylate cyclase. Thus, the NO effect on amino acid neurotransmission could be mediated by cGMP formation in cortical neurons. Our data also demonstrate that the Na+ and Ca2+ voltage- dependent calcium channels are involved in the NO effects on cortical neurons.
Antioxidant and Protective Mechanisms against Hypoxia and Hypoglycaemia in Cortical Neurons in Vitro
(MDPI, 2014-02-12) Merino, José Joaquín; Roncero Romero, César; Oset Gasque, María Jesús; Naddaf, Ahmad; González Prieto, María Pilar
In the present work, we have studied whether cell death could be induced in cortical neurons from rats subjected to different period of O2 deprivation and low glucose (ODLG). This “in vitro” model is designed to emulate the penumbra area under ischemia. In these conditions, cortical neurons displayed loss of mitochondrial respiratory ability however, nor necrosis neither apoptosis occurred despite ROS production. The absence of cellular death could be a consequence of increased antioxidant responses such as superoxide dismutase-1 (SOD1) and GPX3. In addition, the levels of reduced glutathione were augmented and HIF-1/3α overexpressed. After long periods of ODLG (12–24 h) cortical neurons showed cellular and mitochondrial membrane alterations and did not recuperate cellular viability during reperfusion. This could mean that therapies directed toward prevention of cellular and mitochondrial membrane imbalance or cell death through mechanisms other than necrosis or apoptosis, like authophagy, may be a way to prevent ODLG damage.