Marina Benito

Universidad Complutense de Madrid

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Jesús Ruíz‐Cabello

Ikerbasque

Manuel Desco

Universidad Carlos III de Madrid

Sebastián Cerdán

Instituto de Investigaciones Biomédicas Sols-Morreale

Paloma Ballesteros

National University of Distance Education

Fernando Herranz

Instituto de Química Médica

Ana Victoria Lechuga‐Vieco

University of Oxford

Rafael Enrı́quez de Salamanca

Research Institute Hospital 12 de Octubre

Juan Pellico

St Thomas' Hospital

Antonio Fontanellas

Universidad de Navarra

Tiago B. Rodrigues

Cancer Research UK

Cooperative Institutions

Spanish National Centre for Cardiovascular Research

Instituto de Salud Carlos III

Consejo Superior de Investigaciones Científicas

Centro de Investigación Biomédica en Red

Universidad Complutense de Madrid

Universidad Autónoma de Madrid

Universidad de Navarra

Navarre Institute of Health Research

Clinica Universidad de Navarra

Centro de Investigación Biomédica en Red de Enfermedades Respiratorias

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Bases moleculares y fisiopatológicas del contraste por transferencia de magnetización en imágenes por resonancia magnática

Marina Benito

Esta Tesis investiga, in vitro e in vivo, las bases moleculares y fisiopatologicas de los procesos de Transferencia de Magnetizacion entre protones de macromoleculas y el agua circundante, mediante espectroscopia de alta resolucion 1H-RMN e imagen por Resonancia Magnetica (IRM). Se ha empleado como sistema modelo in vitro, soluciones acuosas de glutation oxidado, un dipeptido formado por dos cadenas de glutamico, cisteina y glicina, unidas por un puente disulfuro. Este peptido presenta grupos NH2 y NH que intercambian su magnetizacion intramolecularmente y con los protones del agua libre presentes en la disolucion. Nuestro estudio ha investigado la dependencia del intercambio de magnetizacion con el pH, la temperatura y la microviscosidad. La termodinamica del intercambio se estudio empleando espectros z y las ecuaciones de Van?t Hoff. Los resultados indican que el intercambio de magnetizacion es un proceso reversible dirigido entropicamente a pH 4.0 y 9.0, y entalpicamente a pH 6.5, en el caso de las moleculas de agua. Sin embargo, los intercambios entre los protones de los grupos NH y las moleculas de agua estan dirigidos entropicamente en todos los casos. Mediante experimentos de pulso y gradiente se investigo la variacion en el coeficiente de difusion aparente del agua. Un aumento de la viscosidad de la solucion reduce el intercambio de magnetizacion hasta en un 45%, lo que indica que en estos procesos, los movimientos translacionales de las especies en intercambio juegan un papel importante. Nuestros resultados tambien demuestran que los procesos de intercambio dependen del pH y del pKa de los grupos intercambiables, resultando cinetica y termodinamicamente mas favorables entre los protones de las moleculas de agua de la solucion que entre los protones del glutation o entre el glutation y el agua. Paralelamente se investigo mediante quimica computacional la energia de interaccion entre diversas regiones

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Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice

Cancers (2021)

Yolanda Aguilera Nuria Mellado-Damas Laura Olmedo-Moreno Víctor López Concepción Panadero‐Morón

Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials.

Cell therapy

Ex vivo

Biodistribution

Stem Cell Therapy

10.3390/cancers13051169

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Nrg1 haploinsufficiency alters inhibitory cortical circuits

Neurobiology of Disease (2021)

Carmen Navarro-González Héctor Carceller Marina Benito Irene Serra Marta Navarrete

Neuregulin 1 (NRG1) and its receptor ERBB4 are schizophrenia (SZ) risk genes that control the development of both excitatory and inhibitory cortical circuits. Most studies focused on the characterization ErbB4 deficient mice. However, ErbB4 deletion concurrently perturbs the signaling of Nrg1 and Neuregulin 3 (Nrg3), another ligand expressed in the cortex. In addition, NRG1 polymorphisms linked to SZ locate mainly in non-coding regions and they may partially reduce Nrg1 expression. Here, to study the relevance of Nrg1 partial loss-of-function in cortical circuits we characterized a recently developed haploinsufficient mouse model of Nrg1 (Nrg1tm1Lex). These mice display SZ-like behavioral deficits. The cellular and molecular underpinnings of the behavioral deficits in Nrg1tm1Lex mice remain to be established. With multiple approaches including Magnetic Resonance Spectroscopy (MRS), electrophysiology, quantitative imaging and molecular analysis we found that Nrg1 haploinsufficiency impairs the inhibitory cortical circuits. We observed changes in the expression of molecules involved in GABAergic neurotransmission, decreased density of Vglut1 excitatory buttons onto Parvalbumin interneurons and decreased frequency of spontaneous inhibitory postsynaptic currents. Moreover, we found a decreased number of Parvalbumin positive interneurons in the cortex and altered expression of Calretinin. Interestingly, we failed to detect other alterations in excitatory neurons that were previously reported in ErbB4 null mice suggesting that the Nrg1 haploinsufficiency does not entirely phenocopies ErbB4 deletions. Altogether, this study suggests that Nrg1 haploinsufficiency primarily affects the cortical inhibitory circuits in the cortex and provides new insights into the structural and molecular synaptic impairment caused by NRG1 hypofunction in a preclinical model of SZ.

Haploinsufficiency

neuregulin 1

ERBB4

10.1016/j.nbd.2021.105442

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Brain ventricular enlargement in human and murine acute intermittent porphyria

Human Molecular Genetics (2020)

Daniel Jericó Elkin O. Luís Lorena Cussó María A. Fernández‐Seara Xabier Morales

The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyze brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.

10.1093/hmg/ddaa204

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Unambiguous detection of atherosclerosis using bioorthogonal nanomaterials

Nanomedicine Nanotechnology Biology and Medicine (2019)

Juan Pellico Irene Fernández‐Barahona Marina Benito Ángel Gaitán Simón Lucía Gutiérrez

Bioorthogonal Chemistry

Molecular Imaging

Tetrazine

Pretargeting

Nuclear imaging

Biomolecule

10.1016/j.nano.2018.12.015

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Citations (24)

Espectroscopía e imagen del pH intra y extracelular mediante métodos de resonancia magnética. Implicaciones clínicas

Radiología (2008)

Paloma Ballesteros Elena Pérez‐Mayoral Marina Benito Sebastián Cerdán

Proton magnetic resonance

10.1016/s0033-8338(08)76333-1

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Phosphatidylcholine‐Coated Iron Oxide Nanomicelles for In Vivo Prolonged Circulation Time with an Antibiofouling Protein Corona

Chemistry - A European Journal (2014)

Hugo Groult Jesús Ruíz‐Cabello Ana Victoria Lechuga‐Vieco Jesús Mateo Marina Benito

Abstract We report the synthesis of micellar phosphatidylcholine‐coated superparamagnetic iron oxide nanoparticles as a new long circulation contrast agents for magnetic resonance imaging. Oleic acid‐coated Fe 3 O 4 nanoparticles were first prepared through thermal degradation and then encapsulated into small clusters with a phosphatidylcholine coating to obtain hydrophilic nanomicelles. A thorough characterization confirmed the chemical nature of the coating and the excellent colloidal stability of these nanomicelles in aqueous media. Magnetization and relaxivity properties proved their suitability as magnetic resonance imaging (MRI) contrast agent and in vitro cell viability data showed low toxicity. Vascular lifetime and elimination kinetics in the liver were assessed by blood relaxometry and by in vivo MRI in rats and compared with “control” particles prepared with a polyethylene glycol derivative. These micellar particles had a lifetime in blood of more than 10 h, much longer than the control nanoparticles (≈2 h), which is remarkable considering that the coating molecule is a small biocompatible zwitterionic phospholipid. The protein corona was characterized after incubation with rat serum at different times by high‐throughput proteomics, showing a higher proportion of bound apolipoproteins and other dysopsonins for the phosphatidylcholine particles. The antibiofouling properties of this corona and its resistance to the adsorption of proteins corroborate the observed enhanced stability and prolonged systemic circulation.

10.1002/chem.201404221

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Citations (27)

[Auditory evoked brainstem potentials, magnetic resonance and computerized tomography in the diagnosis of acoustic neurinoma].

PubMed (1985)

E García-Ibáñez Patricia Ivonne Chávez Rivas G Corradino Marina Benito Francesco Galletti

Acoustic neurinoma

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Detection of mouse endogenous type B astrocytes migrating towards brain lesions

Stem Cell Research (2015)

Gema Elvira Isabel Garcı́a Juan Gallo Marina Benito Paula Montesinos

Neuroblasts represent the predominant migrating cell type in the adult mouse brain. There are, however, increasing evidences of migration of other neural precursors. This work aims at identifying in vivo endogenous early neural precursors, different from neuroblasts, able to migrate in response to brain injuries. The monoclonal antibody Nilo1, which unequivocally identifies type B astrocytes and embryonic radial glia, was coupled to magnetic glyconanoparticles (mGNPs). Here we show that Nilo1–mGNPs in combination with magnetic resonance imaging in living mice allowed the in vivo identification of endogenous type B astrocytes at their niche, as well as their migration to the lesion site in response to glioblastoma, demyelination, cryolesion or mechanical injuries. In addition, Nilo1+ adult radial glia-like structures were identified at the lesion site a few hours after damage. For all damage models used, type B astrocyte migration was fast and orderly. Identification of Nilo1+ cells surrounding an induced glioblastoma was also possible after intraperitoneal injection of the antibody. This opens up the possibility of an early identification of the initial damage site(s) after brain insults, by the migration of type B astrocytes.

Neuroblast

Neuroglia

Cell type

10.1016/j.scr.2014.11.006

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Citations (8)

Decreased glucose-derivate uptake in primary somatosensorial cortex in the brain of female AIP mice. | International Porphyrins and Porphyria Meeting (10-13 April 2011. Cardiff, Wales, UK)

Marina Benito F. Molinet-Dronda Inés González Rodríguez Margarida Delgado María Collantes

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