Person:
Linares Gómez, María

First Name

María

Last Name

Linares Gómez

URI

https://hdl.handle.net/20.500.14352/77685

Affiliation

Universidad Complutense de Madrid

Faculty / Institute

Farmacia

Department

Bioquímica y Biología Molecular

Area

Bioquímica y Biología Molecular

Identifiers

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Now showing 1 - 10 of 45

Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma
(Cancers, 2021) Ortiz Ruiz, Alejandra; Ruiz Heredia, Yanira; Morales, María Luz; Aguilar Garrido, Pedro; García Ortiz, Almudena; Valeri Lozano, Antonio; Bárcena Asensio, Carmen; García Martín, Rosa María; Garrido, Vanesa; Moreno Gutiérrez, Laura; Gimenez, Alicia; Navarro Aguadero, Miguel Ángel; Velasco Estévez, María; Lospitao, Eva; Cedena, María Teresa; Barrio, Santiago; Martínez López, Joaquín; Linares Gómez, María; Gallardo, Miguel
Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitochondrial inhibitor, tigecycline, to overcome MM proliferation. COXII expression, COX activity, mitochondrial mass, and mitochondrial membrane potential demonstrated a progressive increase of mitochondrial features as the disease progresses. In vitro and in vivo therapeutic targeting using the mitochondrial inhibitor tigecycline showed promising efficacy and cytotoxicity in monotherapy and combination with the MM frontline treatment bortezomib. Overall, our findings demonstrate how mitochondrial activity emerges in MM transformation and disease progression and the efficacy of therapies targeting these novel vulnerabilities.
Editorial: The Role of Microorganisms in Multiple Myeloma
(Frontiers in Immunology, 2022) Linares Gómez, María; Hermouet, Sylvie
A broad analysis of resistance development in the malaria parasite
(Nature Communications, 2016) Corey, Victoria; Lukens, Amanda; Istvan, Eva; Lee, Marcus; Franco, Virginia; Magistrado, Pamela; Coburn-Flynn, Olivia; Sakata-Kato, Tomoyo ; Fuchs, Olivia; Gnädig, Nina; Goldgof, Greg; Linares Gómez, María; Gomez-Lorenzo, Maria ; Cózar, Cristina De; Lafuente-Monasterio, Maria Jose; Prats, Sara; Meister, Stefan; Tanaseichuk, Olga; Wree, Melanie; Zhou, Yingyao ; Willis, Paul; Gamo, Francisco-Javier; Goldberg, Daniel; Fidock, David; Wirth, Dyann; Winzeler, Elizabeth
Microbial resistance to chemotherapy has caused countless deaths where malaria is endemic. Chemotherapy may fail either due to pre-existing resistance or evolution of drug-resistant parasites. Here we use a diverse set of antimalarial compounds to investigate the acquisition of drug resistance and the degree of cross-resistance against common resistance alleles. We assess cross-resistance using a set of 15 parasite lines carrying resistance-conferring alleles in pfatp4, cytochrome bc1, pfcarl, pfdhod, pfcrt, pfmdr, pfdhfr, cytoplasmic prolyl t-RNA synthetase or hsp90. Subsequently, we assess whether resistant parasites can be obtained after several rounds of drug selection. Twenty-three of the 48 in vitro selections result in resistant parasites, with time to resistance onset ranging from 15 to 300 days. Our data indicate that pre-existing resistance may not be a major hurdle for novel-target antimalarial candidates, and focusing our attention on fast-killing compounds may result in a slower onset of clinical resistance.
Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma
(Blood, 2017) Fulciniti, Mariateresa ; Martínez López, Joaquín; Senapedis, William ; Oliva, Stefania ; Bandi, Rajya Lakshmi ; Amodio, Nicola ; Xu, Yan ; Szalat, Raphael ; Gulla, Annamaria ; Samur, Mehmet K.; Roccaro, Aldo ; Linares Gómez, María; Cea, Michele ; Baloglu, Erkan ; Argueta, Christian ; Landesman, Yosef ; Shacham, Sharon ; Liu, Siyuan ; Schenone, Monica ; Wu, Shiaw-Lin ; Karger, Barry ; Prabhala, Rao ; Anderson, Kenneth C. ; Munshi, Nikhil C.
Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4) and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-extracellular signal-regulated kinase pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. This set of data supports PAK4 as an oncogene in myeloma and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.
Collaborative intelligence and gamification for on-line malaria species differentiation
(Malaria Journal, 2019) Linares Gómez, María; Postigo, María; Cuadrado, Daniel; Ortiz-Ruiz, Alejandra; Gil-Casanova, Sara; Vladimirov, Alexander; García-Villena, Jaime; Nuñez-Escobedo, José María; Martínez López, Joaquín; Rubio, José Miguel; Ledesma-Carbayo, María Jesús; Santos, Andrés; Bassat, Quique; Luengo-Oroz, Miguel
Background: Current World Health Organization recommendations for the management of malaria include the need for a parasitological confrmation prior to triggering appropriate treatment. The use of rapid diagnostic tests (RDTs) for malaria has contributed to a better infection recognition and a more targeted treatment. Nevertheless, low-density infections and parasites that fail to produce HRP2 can cause false-negative RDT results. Microscopy has traditionally been the methodology most commonly used to quantify malaria and characterize the infecting species, but the wider use of this technique remains challenging, as it requires trained personnel and processing capacity. Objective: In this study, the feasibility of an on-line system for remote malaria species identifcation and diferentia‑ tion has been investigated by crowdsourcing the analysis of digitalized infected thin blood smears by non-expert observers using a mobile app. Methods: An on-line videogame in which players learned how to diferentiate the young trophozoite stage of the fve Plasmodium species has been designed. Images were digitalized with a smartphone camera adapted to the ocular of a conventional light microscope. Images from infected red blood cells were cropped and puzzled into an on-line game. During the game, players had to decide the malaria species (Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax, Plasmodium ovale, Plasmodium knowlesi) of the infected cells that were shown in the screen. After 2 months, each player’s decisions were analysed individually and collectively. Results: On-line volunteers playing the game made more than 500,000 assessments for species diferentiation. Statistically, when the choice of several players was combined (n>25), they were able to signifcantly discriminate Plasmodium species, reaching a level of accuracy of 99% for all species combinations, except for P. knowlesi (80%). Non-expert decisions on which Plasmodium species was shown in the screen were made in less than 3 s. Conclusion: These fndings show that it is possible to train malaria-naïve non-experts to identify and diferentiate malaria species in digitalized thin blood samples. Although the accuracy of a single player is not perfect, the combination of the responses of multiple casual gamers can achieve an accuracy that is within the range of the diagnostic accuracy made by a trained microscopist.
Ruxolitinib in combination with prednisone and nilotinib exhibit synergistic effects in human cells lines and primary cells from myeloproliferative neoplasms
(Haematologica, 2019) Arenas Cortés, Alicia; Ayala Díaz, Rosa María; Hernández-Campo, Pilar; Gorrochategui, Julián; Primo Niembro, Daniel Arturo; Robles, Alicia; Morales, María Luz; Ballesteros, Joan; Rapado, Inmaculada; Gallardo, Miguel; Linares Gómez, María; Martínez López, Joaquín
Ruxolitinib is the front-line non-palliative treatment for myelofibrosis (MF). However, a significant number of patients lose or present suboptimal response, are resistant or have unacceptable toxicity. In an attempt to improve response and avoid the adverse effects of this drug, we evaluated the combination of 17 drugs with ruxolitinib in ex vivo models of peripheral blood mononuclear cells from MF patients and cell lines. We found that the combination ruxolitinib and nilotinib had a synergistic effect against MF cells (ΔEC50 nilotinib, −21.6%). Moreover, the addition of prednisone to combined ruxolitinib/nilotinib improved the synergistic effect in all MF samples studied. We evaluated the molecular mechanisms of combined ruxolitinib/nilotinib/prednisone and observed inhibition of JAK/STAT (STAT5, 69.2+11.8% inhibition) and MAPK (ERK, 29.4+4.5% inhibition) signaling pathways. Furthermore, we found that the triple therapy combination inhibited collagen protein and COL1A1 gene expression in human bone marrow mesenchymal cells. Taken together, we provide evidence that combined ruxolitinib/nilotinib/prednisone is a potential therapy for MF, possibly through the anti-fibrotic effect of nilotinib, the immunomodulatory effect of ruxolitinib and prednisone, and the anti-proliferative effect of ruxolitinib. This combination will be further investigated in a phase Ib/II clinical trial in MF.
Cine en compañía para prevenir enfermedades
(2022) Linares Gómez, María; Valderrama Conde, María José; de Juan Chocano, Carmen; García Redondo, Alberto; López Vázquez, María de la O; Martín Saavedra, Mª Dolores; Navarro González de Mesa, Elisa; Alonso Monge, Rebeca; Rodríguez Escudero, Isabel; Velasco Estévez, María; Aguilar Garrido, Pedro; álvarez Sánchez-Redondo, Noemí; Morales Fernández, Mª Luz; Ortíz Ruiz, Mª Alejandra; Rodríguez García, Alba; García Vicente, Roberto; Díaz Noval, Nerea; Hernando Ospina, Natalia; Pérez García, Covadonga; Pulido Vadillo, Mario; Rodríguez Solana, Patricia; Vellisca Cruz, Pilar
El proyecto “Cine en compañía para prevenir enfermedades” es continuación del proyecto iniciado en 2017 (INNOVA-Docencia 18/2018, ApS-UCM 18/2019) y se encuadra en el campo de Salud Pública, higiene y prevención de enfermedad, dirigido a personas desfavorecidas o en riesgo de exclusión social. En esta edición se ha ampliado el área de conocimiento y profesores participantes, incluyendo no solo enfermedades infecciosas, como en ediciones anteriores, sino otras del ámbito de la Bioquímica y Biología Molecular. El proyecto es multidisciplinar e interfacultativo (21 tutores: profesores, colaboradores postdoctorales, doctorandos, estudiantes participantes en ediciones anteriores y técnico de laboratorio, de las Facultades de Farmacia, Biología y Medicina y del Hospital 12 de Octubre) y en él han participado 41 estudiantes de distintos Grados (Biología, Bioquímica, Ciencia y Tecnología de los Alimentos, Derecho, Farmacia, Ingeniería Electrónica) y Postgrados (Máster en Biología Sanitaria, y en Microbiología y Parasitología: Investigación y Desarrollo; Doctorado en Bioquímica y Biología Molecular) y participantes en la asignatura Transversal “Ciencia para la Sociedad”. La necesidad social detectada y atendida es la situación de algunos colectivos, por ejemplo, personas sin hogar, mujeres en exclusión, adictos a drogas, presidiarios o familias residentes en áreas no salubres, de una mayor exposición a determinadas enfermedades debido a sus condiciones de vida (enfermedades infecciosas, mentales, metabólicas derivadas de adicciones o alcoholismo), además de que encuentran escasas posibilidades de conocer cómo prevenirlas y la forma adecuada de recibir tratamiento. Adicionalmente, y no menos importante, acusan una carencia severa de compañía, atención y escucha de sus necesidades. Los estudiantes de universidad que cursan estudios en el campo de Ciencias y Ciencias de la Salud estudian estas enfermedades, por lo que pueden ayudar a estos colectivos en la mejora de prácticas higiénico-sanitarias, así como al acceso a la información para su prevención y tratamiento. Las actividades desarrolladas en el proyecto han consistido en el acompañamiento y desarrollo de una actividad lúdica mediante la proyección de películas comerciales que traten una enfermedad de interés en el colectivo a atender, seguida de coloquio para ayudar a conocer las formas adecuadas de prevención y tratamiento. Los equipos de 4-5 estudiantes (de distintas titulaciones y cursos) y dos tutores (senior y junior) han realizado varias visitas a centros sociales atendidos por Fundaciones con las que existe convenio de la UCM (centros de día para personas sin hogar, mujeres en exclusión, discapacitados o presidiarios, gestionados por Cáritas, Hogar-Sí, Diaconía, Medinacelli). Han investigado en profundidad las enfermedades que afectan y de interés del grupo atendido, seleccionado y analizado críticamente películas adecuadas, preparado materiales divulgativos (carteles, juegos) y diseñado y analizado encuestas para evaluar su actividad por parte de las personas atendidas y los coordinadores de los centros. Los resultados de las encuestas a todos los participantes (tutores, estudiantes, centros) y la recogida de opiniones y memorias de los estudiantes muestran una alta consecución de los objetivos de aprendizaje previstos, refuerzo de contenidos específicos de los estudios y, sobre todo, trabajo y adquisición de competencias transversales como trabajo en equipo, coordinación y asunción de responsabilidades, análisis crítico o expresión científica divulgativa. En cuanto a los objetivos de servicio, destaca la utilidad del proyecto en atención e información a los colectivos, la aplicación de los estudios a situaciones reales en atención a personas desfavorecidas y el valor social del proyecto.
Glutathione peroxidase contributes with heme oxygenase-1 to redox balance in mouse brain during the course of cerebral malaria
(Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2013) Linares Gómez, María; Marín-García, Patricia; Martínez-Chacón, Gabriela; Pérez-Benavente, Susana; Puyet Catalina, Antonio; Díez Martín, Amalia; Bautista Santa Cruz, José Manuel
Oxidative stress has been attributed both a key pathogenic and rescuing role in cerebral malaria (CM). In a Plasmodium berghei ANKA murine model of CM, host redox signaling and functioning were examined during the course of neurological damage. Host antioxidant defenses were early altered at the transcriptional level indicated by the gradually diminished expression of superoxide dismutase-1 (sod-1), sod-2, sod-3 and catalase genes. During severe disease, this led to the dysfunctional activity of superoxide dismutase and catalase enzymes in damaged brain regions. Vitagene associated markers (heat shock protein 70 and thioredoxin-1) also showed a decaying expression pattern that paralleled reduced expression of the transcription factors Parkinson disease 7, Forkhead box O 3 and X-box binding protein 1 with a role in preserving brain redox status. However, the oxidative stress markers reactive oxygen/nitrogen species were not accumulated in the brains of CM mice and redox proteomics and immunohistochemistry failed to detect quantitative or qualitative differences in protein carbonylation. Thus, the loss of antioxidant capacity was compensated for in all cerebral regions by progressive upregulation of heme oxygenase-1, and in specific regions by early glutathione peroxidase-1 induction. This study shows for the first time a scenario of cooperative glutathione peroxidase and heme oxygenase-1 upregulation to suppress superoxide dismutase, catalase, heat shock protein-70 and thioredoxin-1 downregulation effects in experimental CM, counteracting oxidative damage and maintaining redox equilibrium. Our findings reconcile the apparent inconsistency between the lack of oxidative metabolite build up and reported protective effect of antioxidant therapy against CM.
Factores neuroprotectores y redox en el desarrollo del fenotipo neurológico de la malaria cerebral murina
(2014) Linares Gómez, María; Bautista Santa Cruz, José Manuel; Díez Martín, Amalia
Proteomic Approaches to Identifying Carbonylated Proteins in Brain Tissue
(Journal of Proteome Research (JPR), 2011) Linares Gómez, María; Marín-García, Patricia ; Méndez, Darío ; Puyet Catalina, Antonio; Díez Martín, Amalia; Bautista Santa Cruz, José Manuel
Oxidative stress plays a critical role in the pathogenesis of a number of diseases. The carbonyl end products of protein oxidation are among the most commonly measured markers of oxidation in biological samples. Protein carbonyl functional groups may be derivatized with 2,4-dinitrophenylhydrazine (DNPH) to render a stable 2,4-dinitrophenylhydrazone-protein (DNP-protein) and the carbonyl contents of individual proteins then determined by two-dimensional electrophoresis followed by immunoblotting using specific anti-DNP antibodies. Unfortunately, derivatization of proteins with DNPH could affect their mass spectrometry (MS) identification. This problem can be overcome using nontreated samples for protein identification. Nevertheless, derivatization could also affect their mobility, which might be solved by performing the derivatization step after the initial electrophoresis. Here, we compare two-dimensional redox proteome maps of mouse cerebellum acquired by performing the DNPH derivatization step before or after electrophoresis and detect differences in protein patterns. When the same approach is used for protein detection and identification, both methods were found to be useful to identify carbonylated proteins. However, whereas pre-DNPH derivatized proteins were successfully analyzed, high background staining complicated the analysis when the DNPH reaction was performed after transblotting. Comparative data on protein identification using both methods are provided.