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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Evaluation of different prophylactic methods against selenium deficiency in sheep grazing on range in Southwestern Spain

Small Ruminant Research (1998)

Antonio Jiménez S. Andrés J. Sánchez Rafael Barrera Chacón Marina Benito

Blood sampling

10.1016/s0921-4488(97)00127-2

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Citations (3)

Surface‐Functionalized Nanoparticles by Olefin Metathesis: A Chemoselective Approach for In Vivo Characterization of Atherosclerosis Plaque

Chemistry - A European Journal (2015)

Beatriz Salinas Jesús Ruíz‐Cabello Ana Victoria Lechuga‐Vieco Marina Benito Fernando Herranz

Abstract The use of click chemistry reactions for the functionalization of nanoparticles is particularly useful to modify the surface in a well‐defined manner and to enhance the targeting properties, thus facilitating clinical translation. Here it is demonstrated that olefin metathesis can be used for the chemoselective functionalization of iron oxide nanoparticles with three different examples. This approach enables, in one step, the synthesis and functionalization of different water‐stable magnetite‐based particles from oleic acid‐coated counterparts. The surface of the nanoparticles was completely characterized showing how the metathesis approach introduces a large number of hydrophilic molecules on their coating layer. As an example of the possible applications of these new nanocomposites, a focus was taken on atherosclerosis plaques. It is also demonstrated how the in vitro properties of one of the probes, particularly its Ca 2+ ‐binding properties, mediate their final in vivo use; that is, the selective accumulation in atherosclerotic plaques. This opens promising new applications to detect possible microcalcifications associated with plaque vulnerability. The accumulation of the new imaging tracers is demonstrated by in vivo magnetic resonance imaging of carotids and aorta in the ApoE −/− mouse model and the results were confirmed by histology.

Surface Modification

10.1002/chem.201500458

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Uso del método de Split Bregman para la resolución del problema de compressed sensing en imagen de resonancia magnética dinámica cardiaca para pequeño animal

P. Montesisnos Juan Abascal Judit Chamorro Servent Cristina Chavarrías Marina Benito

Actas de: XXIX Congreso Anual de la Sociedad Espnaola de Ingenieria Biomedica (CASEIB 2011). Caceres, 16-18 Noviembre 2011.

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Futile cycling of lactate through the plasma membrane of C6 glioma cells as detected by (¹³C, ²H) NMR

Journal of Neuroscience Research (2004)

Tiago B. Rodrigues Heather Gray Marina Benito Susana Garrido Alejandra Sierra

Abstract We report a novel ( 13 C, 2 H) nuclear magnetic resonance (NMR) procedure to investigate lactate recycling through the monocarboxylate transporter of the plasma membrane of cells in culture. C6 glioma cells were incubated with [3‐ 13 C]lactate in Krebs‐Henseleit Buffer containing 50% 2 H 2 O (vol/vol) for up to 30 hr. 13 C NMR analysis of aliquots progressively taken from the medium, showed: (1) a linearly decreasing singlet at ∼20.85 parts per million (ppm; −0.119 μmol/mg protein/hr) derived from the methyl carbon of [3‐ 13 C]lactate; and (2) an exponentially increasing shifted singlet at ∼20.74 ppm (0.227 μmol/ mg protein/hr) from the methyl carbon of [3‐ 13 C, 2‐ 2 H]lactate. The shifted singlet appears because during its transit through the cytosol, [3‐ 13 C]lactate generates [3‐ 13 C, 2‐ 2 H]lactate in the lactate dehydrogenase (LDH) equilibrium, which may return to the incubation medium through the reversible monocarboxylate carrier. The methyl group of [3‐ 13 C, 2‐ 2 H]lactate is shifted −0.11 ppm with respect to that of [3‐ 13 C]lactate, making it possible to distinguish between both molecules by 13 C NMR. During incubations with 2.5 mM [1‐ 13 C]glucose and 3.98 mM [U‐ 13 C 3 ]lactate or with 2.5 mM [1‐ 13 C]glucose and 3.93 mM [2‐ 13 C]pyruvate, C2‐deuterated lactate was produced only from [1‐ 13 C]glucose or [U‐ 13 C 3 ]lactate, revealing that this deuteration process is redox sensitive. When [1‐ 13 C]glucose and [U‐ 13 C 3 ]lactate were used as substrates, no significant [3‐ 13 C]lactate production from [1‐ 13 C]glucose was detected, suggesting that glycolytic lactate production may be stopped under the high lactate concentrations prevailing under mild hypoxic or ischemic episodes or during cerebral activation. © 2004 Wiley‐Liss, Inc.

10.1002/jnr.20308

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Citations (26)

Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency

Human Molecular Genetics (2016)

María Collantes Irantzu Serrano-Mendioroz Marina Benito F. Molinet-Dronda Mercedes Delgado

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks when hepatic heme synthesis is activated by endogenous or environmental factors including fasting. While the molecular mechanisms underlying the nutritional regulation of hepatic heme synthesis have been described, glucose homeostasis during fasting is poorly understood in porphyria. Our study aimed to analyse glucose homeostasis and hepatic carbohydrate metabolism during fasting in PBGD-deficient mice. To determine the contribution of hepatic PBGD deficiency to carbohydrate metabolism, AIP mice injected with a PBGD-liver gene delivery vector were included. After a 14 h fasting period, serum and liver metabolomics analyses showed that wild-type mice stimulated hepatic glycogen degradation to maintain glucose homeostasis while AIP livers activated gluconeogenesis and ketogenesis due to their inability to use stored glycogen. The serum of fasted AIP mice showed increased concentrations of insulin and reduced glucagon levels. Specific over-expression of the PBGD protein in the liver tended to normalize circulating insulin and glucagon levels, stimulated hepatic glycogen catabolism and blocked ketone body production. Reduced glucose uptake was observed in the primary somatosensorial brain cortex of fasted AIP mice, which could be reversed by PBGD-liver gene delivery. In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver.

Porphobilinogen deaminase

Ketogenesis

Carbohydrate Metabolism

Gluconeogenesis

10.1093/hmg/ddw013

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Citations (23)

Live Imaging of Mouse Endogenous Neural Progenitors Migrating in Response to an Induced Tumor

PLoS ONE (2012)

Gema Elvira Isabel Garcı́a Marina Benito Juan Gallo Manuel Desco

Adult neurogenesis is restricted to specific brain regions. Although involved in the continuous supply of interneurons for the olfactory function, the role of neural precursors in brain damage-repair remains an open question. Aiming to in vivo identify endogenous neural precursor cells migrating towards a brain damage site, the monoclonal antibody Nilo2 recognizing cell surface antigens on neuroblasts, was coupled to magnetic glyconanoparticles (mGNPs). The Nilo2-mGNP complexes allowed, by magnetic resonance imaging in living animals, the in vivo identification of endogenous neural precursors at their niche, as well as their migration to a lesion site (induced brain tumor), which was fast (within hours) and orderly. Interestingly, the rapid migration of neuroblasts towards a damage site is a characteristic that might be exploited to precisely localize early damage events in neurodegenerative diseases. In addition, it might facilitate the study of regenerative mechanisms through the activation of endogenous neural cell precursors. A similar approach, combining magnetic glyconanoparticles linked to appropriate antibodies could be applied to flag other small cell subpopulations within the organism, track their migration, localize stem cell niches, cancer stem cells or even track metastatic cells.

Neuroblast

Rostral migratory stream

10.1371/journal.pone.0044466

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Citations (21)

Heteroplasmy of Wild-Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty

Circulation (2022)

Ana Victoria Lechuga‐Vieco Ana Latorre Enrique Calvo Carlos Torroja Juan Pellico

In most eukaryotic cells, the mitochondrial DNA (mtDNA) is transmitted uniparentally and present in multiple copies derived from the clonal expansion of maternally inherited mtDNA. All copies are therefore near-identical, or homoplasmic. The presence of >1 mtDNA variant in the same cytoplasm can arise naturally or result from new medical technologies aimed at preventing mitochondrial genetic diseases and improving fertility. The latter is called divergent nonpathologic mtDNA heteroplasmy (DNPH). We hypothesized that DNPH is maladaptive and usually prevented by the cell.We engineered and characterized DNPH mice throughout their lifespan using transcriptomic, metabolomic, biochemical, physiologic, and phenotyping techniques. We focused on in vivo imaging techniques for noninvasive assessment of cardiac and pulmonary energy metabolism.We show that DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death. Symptom severity is strongly modulated by the nuclear context.Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA.

Heteroplasmy

Mitochondrial disease

Exercise intolerance

10.1161/circulationaha.121.056286

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Citations (18)

Serial In vivo Spectroscopic Nuclear Magnetic Resonance Imaging of Lactate and Extracellular pH in Rat Gliomas Shows Redistribution of Protons Away from Sites of Glycolysis

Cancer Research (2007)

Peggy Provent Marina Benito Bassem Hiba Régine Farion Pilar López‐Larrubia

Abstract The acidity of the tumor microenvironment aids tumor growth, and mechanisms causing it are targets for potential therapies. We have imaged extracellular pH (pHe) in C6 cell gliomas in rat brain using 1H magnetic resonance spectroscopy in vivo. We used a new probe molecule, ISUCA [(±)2-(imidazol-1-yl)succinic acid], and fast imaging techniques, with spiral acquisition in k-space. We obtained a map of metabolites [136 ms echo time (TE)] and then infused ISUCA in a femoral vein (25 mmol/kg body weight over 110 min) and obtained two consecutive images of pHe within the tumor (40 ms TE, each acquisition taking 25 min). pHe (where ISUCA was present) ranged from 6.5 to 7.5 in voxels of 0.75 μL and did not change detectably when [ISUCA] increased. Infusion of glucose (0.2 mmol/kg·min) decreased tumor pHe by, on average, 0.150 (SE, 0.007; P < 0.0001, 524 voxels in four rats) and increased the mean area of measurable lactate peaks by 54.4 ± 3.4% (P < 0.0001, 287 voxels). However, voxel-by-voxel analysis showed that, both before and during glucose infusion, the distributions of lactate and extracellular acidity were very different. In tumor voxels where both could be measured, the glucose-induced increase in lactate showed no spatial correlation with the decrease in pHe. We suggest that, although glycolysis is the main source of protons, distributed sites of proton influx and efflux cause pHe to be acidic at sites remote from lactate production. [Cancer Res 2007;67(16):7638–45]

Intracellular pH

10.1158/0008-5472.can-06-3459

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Citations (76)

The redox switch/redox coupling hypothesis

Neurochemistry International (2006)

Sebastián Cerdán Tiago B. Rodrigues Alejandra Sierra Marina Benito Luís L. Fonseca

Neuroglia

Transcellular

10.1016/j.neuint.2005.12.036

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Citations (147)

Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARβ/δ Activation

Blanca Rubio Cristina Pintado Lorena Mazuecos Marina Benito Antonio Andrés

Leptin, acting centrally or peripherally, has complex effects on cardiac remodeling and heart function. We previously reported that central leptin exerts an anti-hypertrophic effect in the heart via cardiac PPARβ/δ activation. Here, we assessed the impact of central leptin administra-tion and PPARβ/δ inhibition on cardiac function. Various cardiac properties, including QRS du-ration, R wave amplitude, heart rate (HR), ejection fraction (EF), end-diastolic left ventricular mass (EDLVM), end-diastolic volume (EDV), and cardiac output (CO) were analyzed. Central leptin infusion increased cardiac PPARβ/δ protein content and decreased HR, QRS duration and R wave amplitude. These changes induced by central leptin suggested a decrease in the ventricu-lar wall growth which was confirmed by MRI. In fact, the EDLVM was reduced by central leptin, while increased in rats co-treated with leptin and GSK0660, a selective antagonist of PPARβ/δ ac-tivity. In summary, central leptin plays a dual role in cardiac health, potentially leading to ven-tricular atrophy and improving heart function when PPARβ/δ signaling is intact. The protective effects of leptin are lost by PPARβ/δ inhibition, underscoring the importance of this pathway. These findings highlight the therapeutic potential of targeting leptin and PPARβ/δ pathways to combat cardiac alterations and heart failure, particularly, in the context of obesity

10.20944/preprints202406.1683.v1

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Citations (1)