Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19617

La Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC) es creada por la Dirección del Instituto de Salud Carlos III (ISCIII) en diciembre de 2012 con categoría interna de Centro a todos los efectos. La misión específica de UFIEC es desarrollar actividades de investigación básica y traslacional, diagnóstico diferencial y formación en enfermedades crónicas, constituyéndose así en un recurso de soporte científico-técnico para la prevención, diagnóstico y tratamiento de las enfermedades crónicas más prevalentes.

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The Two Faces of SHOC2: Skin Homeostasis Regulator and RAS-MAPK Pathway Enhancer.
(Athenaeum, 2025-11-24) Ortiz-Gutiérrez, Cristina; Zarich-Dimitrievich, Natasha; Camara, Ana Belen; de Lucas, Maria Pilar; Anta-Felez, Berta
The signaling pathway composed of RAS-RAF-MEK-ERK proteins regulates essential cellular processes such as cell differentiation, proliferation and migration. This pathway is crucial for embryonic development and tissue homeostasis and it is frequently dysregulated in cancer. The scaffold protein SHOC2 is a key modulator of ERK1/2 signals whose activity depends on its subcellular localization. Recently, SHOC2 has been proposed as a therapeutic target for the treatment of several cancers, either alone or in combination with MEK inhibitors. In this review we focus on the role of SHOC2 in the epithelial skin biology and its interaction with other partners to better understand the potential consequences of SHOC2 inhibition, particularly regarding skin toxicities. SHOC2 interacts with RAPTOR to limit mTORC1 activation, thereby promoting autophagy and limiting cell growth. Through its association with MRAS and PP1C, SHOC2 controls RAF1 dephosphorylation and modulates ERK output. Loss of SHOC2 disrupts E-cadherin turnover, impairing junctional dynamics and epithelial migration. In vivo, SHOC2 is essential for tissue development as complete knockout in mice results in embryonic lethality. We also discuss other important SHOC2 interactions in the epidermis including SCRIBBLE and ERBIN. SHOC2 acts as a signaling hub connecting RAS-MAPK pathways with epithelial polarity and differentiation. Its spatial regulation ensures proper tissue homeostasis, whereas mutation or mis-localization drives cancer and developmental disorders such as Noonan- like syndrome with loose anagen hair (NSLH) which has ectodermal manifestations. Finally, we review the context-dependent role of SHOC2 in cancer where it can be either upregulated or downregulated. Reduced SHOC2 activity in tumors addicted to ERK signaling may activate compensatory pathways highlighting the essential importance of SHOC2 in skin homeostasis and the potential cutaneous toxicities of SHOC2- targeted therapies.
IDP-410: a Novel Therapeutic Peptide that Alters N-MYC Stability and Reduces Angiogenesis and Tumor Progression in Glioblastomas.
(https://doi.org/10.1007/s13311-021-01176-6, 2022-01) Gargini, Ricardo; Segura-Collar, Berta; Garranzo-Asensio, Maria; Hortigüela, Rafael; Iglesias-Hernandez, Patricia; Lobato-Alonso, Daniel; Moreno-Raja, Miguel; Esteban-Martin, Santiago; Sepúlveda-Sánchez, Juan M; Nevola, Laura; Sánchez-Gómez, Pilar
Glioblastomas (GBMs) are the most frequent and highly aggressive brain tumors, being resistant to all cytotoxic and molecularly targeted agents tested so far. There is, therefore, an urgent need to find novel therapeutic approaches and/or alternative targets to bring treatment options to patients. Here, we first show that GBMs express high levels of N-MYC protein, a transcription factor involved in normal brain development. A novel stapled peptide designed to specifically target N-MYC protein monomer, IDP-410, is able to impair the formation of N-MYC/MAX complex and reduce the stability of N-MYC itself. As a result, the viability of GBM cells is compromised. Moreover, the efficacy is found dependent on the levels of expression of N-MYC. Finally, we demonstrate that IDP-410 reduces GBM growth in vivo when administered systemically, both in subcutaneous and intracranial xenografts, reducing the vascularization of the tumors, highlighting a potential relationship between the function of N-MYC and the expression of mesenchymal/angiogenic genes. Overall, our results strengthen the view of N-MYC as a therapeutic target in GBM and strongly suggest that IDP-410 could be further developed to become a first-in-class inhibitor of N-MYC protein, affecting not only tumor cell proliferation and survival, but also the interplay between GBM cells and their microenvironment.
The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas.
(American Association for the Advancement of Science (AAAS), 2020-01-22) Gargini, Ricardo; Sánchez-Gómez, Pilar; Segura-Collar, Berta; Herránz, Beatriz; García-Escudero, Vega; Romero-Bravo, Andrés; Núñez, Felipe J; García-Pérez, Daniel; Gutiérrez-Guamán, Jacqueline; Ayuso-Sacido, Angel; Seoane, Joan; Pérez-Núñez, Angel; Sepúlveda-Sánchez, Juan M; Hernández-Laín, Aurelio; Castro, María G; García-Escudero, Ramón; Ávila, Jesús; Sánchez-Gómez, Pilar
Gliomas that express the mutated isoforms of isocitrate dehydrogenase 1/2 (IDH1/2) have better prognosis than wild-type (wt) IDH1/2 gliomas. However, how these mutant (mut) proteins affect the tumor microenvironment is still a pending question. Here, we describe that the transcription of microtubule-associated protein TAU (), a gene that has been classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wt and mut IDH1/2 in mouse and human gliomas. In IDH1/2 mut tumors, we found high expression of TAU that decreased with tumor progression. Furthermore, was almost absent from tumors with epidermal growth factor receptor () mutations, whereas its trancription negatively correlated with overall survival in gliomas carrying wt or amplified (amp) We demonstrated that the overexpression of TAU, through the stabilization of microtubules, impaired the mesenchymal/pericyte-like transformation of glioma cells by blocking EGFR, nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) and the transcriptional coactivator with PDZ-binding motif (TAZ). Our data also showed that mut EGFR induced a constitutive activation of this pathway, which was no longer sensitive to TAU. By inhibiting the transdifferentiation capacity of EGFRamp/wt tumor cells, TAU protein inhibited angiogenesis and favored vascular normalization, decreasing glioma aggressiveness and increasing their sensitivity to chemotherapy.
Cognitive Screening Tools in Spanish for Mild Cognitive Impairment: A Systematic Review and Meta-analysis
(2025-05-28) Barderas Manchado, Rodrigo; Ropero-Sánchez, Andrea; Escudero Pérez, Guillermo; Lozano González, Pilar; Alonso-del-Cura, Olatz; Camacho-Montaño, Lucia; Pascual García, Marcos; Sánchez Ruano, Raquel; Martín Saborido, Carlos; Moreno-Casbas, Teresa; Instituto de Salud Carlos III
Mild Cognitive Impairment (MCI) represents the earliest stage of a chronic and degenerative condition, often undetected, impacting individuals, families, and healthcare systems. Early identification is critical. This study evaluates the diagnostic accuracy of MCI screening tools in Spanish-speaking populations, aiming to enhance early detection, reduce misdiagnosis and underdiagnosis, and improve clinical outcomes. This systematic review stems from the Project Dendrite (PMP22/00084 - "Personalized Medicine in the Identification of Preclinical Cognitive Impairment: Development of a Predictive Risk Model") in which it was demonstrated that the five screening tests employed in the study (MMSE, MoCA, Fototest, MiniCog, T@M) lacked consistency and yielded variable results, even in the same participant. This finding highlights the need to evaluate the diagnostic accuracy of the screening tools and their applicability in early cognitive decline detection.
Early detection of cognitive impairment in primary care: a mixed-methods protocol integrating data from multiple sources (DENDRITE study)
(2025-09-16) Almeida-Parra, Ángeles; Ropero-Sánchez, Andrea; Zamora Romero, Javier; Docío-Fernández, Laura; Fatjó-Vilas Mestre, Mar; Campuzano Ruiz, Susana; Lozano González, Pilar; Alonso-del-Cura, Olatz; Montero Calle, Ana; Barderas Manchado, Rodrigo; Moreno-Casbas, Teresa; MedPer_DC Project Working Group; Unión Europea. Comisión Europea. NextGenerationEU
Globally, over half of cognitive impairment cases identified in population-based studies remain undetected, and up to 90% of mild cases go undiagnosed. This represents a major public health challenge with significant implications for ageing populations and health systems. The present protocol outlines the integration of clinical, multiomic, healthcare, social, environmental, voice, and behavioral data, using artificial intelligence and advance statistical modeling, to develop a predictive risk model for the preclinical detection of cognitive impairment in adults aged 55–70 years. This is an observational, multicenter, non-interventional study employing a convergent mixed-methods approach. The design combines a prospective quantitative phase with a qualitative one based on discussion groups. The study will be conducted across six Spanish regions and seven primary healthcare centers located in different geographic areas. Each center will recruit 150 cognitively unimpaired participants, resulting in a total sample of 1050 participants. In addition, a calibration group of 100 participants diagnosed with mild cognitive impairment will be included. This protocol has been developed in accordance with the STROBE guidelines to ensure methodological rigor, transparency, and reproducibility. This research aims to develop a simple, cost-effective, and actionable tool for early preclinical detection of individuals at risk of cognitive impairment, enabling its integration into primary care and supporting timely, targeted interventions. This approach has the potential to reduce diagnostic delays, optimize healthcare resources, and promote equitable access to timely interventions, ultimately improving population health and quality of life.
Papel de SPRY2 y SUR8 en cáncer colorrectal (SPRYSURCOL). Data Management Plan V1.0
(Instituto de Salud Carlos III. Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), 2025-05-05) Rojas-Cabañeros, Jose Maria; Instituto de Salud Carlos III
Plan de Gestión de Datos del proyecto SPRYSURCOL. El proyecto tiene un enfoque preclínico, basado en estudios previos -con resultados avanzados que sostienen su viabilidad- sobre proteínas (Spry2 y Sur8) que intervienen en procesos bioquímicos alterados en el cáncer colorrectal, y en la que se intentará responder si estas proteínas pueden representar nuevas dianas para las actuaciones terapéuticas o si pueden ayudar a entender por qué los tratamientos convencionales no siempre son útiles. Los potenciales resultados del proyecto pueden suponer un notable impacto sobre la mejora en salud y calidad de vida de los pacientes con cáncer colorrectal, al abordar aspectos que pueden dar lugar a nuevos enfoques terapéuticos o mejoras en la estratificación de los pacientes para conseguir terapias más personalizadas e eficaces.
Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses
(Frontiers Media, 2024) Coronel Lopez, Raquel; García-Moreno, Enrique; Siendones, Emilio; Barrero, Maria; Martinez-Delgado, Beatriz; Santos-Ocaña, Carlos; Liste-Noya, Isabel; Cascajo-Almenara, M V; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Mitochondrial diseases are a group of severe pathologies that cause complex neurodegenerative disorders for which, in most cases, no therapy or treatment is available. These organelles are critical regulators of both neurogenesis and homeostasis of the neurological system. Consequently, mitochondrial damage or dysfunction can occur as a cause or consequence of neurodevelopmental or neurodegenerative diseases. As genetic knowledge of neurodevelopmental disorders advances, associations have been identified between genes that encode mitochondrial proteins and neurological symptoms, such as neuropathy, encephalomyopathy, ataxia, seizures, and developmental delays, among others. Understanding how mitochondrial dysfunction can alter these processes is essential in researching rare diseases. Three-dimensional (3D) cell cultures, which self-assemble to form specialized structures composed of different cell types, represent an accessible manner to model organogenesis and neurodevelopmental disorders. In particular, brain organoids are revolutionizing the study of mitochondrial-based neurological diseases since they are organ-specific and model-generated from a patient's cell, thereby overcoming some of the limitations of traditional animal and cell models. In this review, we have collected which neurological structures and functions recapitulate in the different types of reported brain organoids, focusing on those generated as models of mitochondrial diseases. In addition to advancements in the generation of brain organoids, techniques, and approaches for studying neuronal structures and physiology, drug screening and drug repositioning studies performed in brain organoids with mitochondrial damage and neurodevelopmental disorders have also been reviewed. This scope review will summarize the evidence on limitations in studying the function and dynamics of mitochondria in brain organoids.
Genome wide association study of clinical duration and age at onset of sporadic CJD
(Public Library of Science (PLOS), 2024) Hummerich, Holger; Speedy, Helen; Campbell, Tracy; Darwent, Lee; Hill, Elizabeth; Collins, Steven; Stehmann, Christiane; Kovacs, Gabor G; Geschwind, Michael D; Frontzek, Karl; Budka, Herbert; Gelpi, Ellen; Aguzzi, Adriano; van der Lee, Sven J; van Duijn, Cornelia M; Liberski, Pawel P; Calero, Miguel; Sánchez-Juan, Pascual; Bouaziz-Amar, Elodie; Laplanche, Jean-Louis; Haïk, Stéphane; Brandel, Jean-Philippe; Mammana, Angela; Capellari, Sabina; Poleggi, Anna; Ladogana, Anna; Pocchiari, Maurizio; Zafar, Saima; Booth, Stephanie; Jansen, Gerard H; Areškevičiūtė, Aušrinė; Løbner Lund, Eva; Glisic, Katie; Parchi, Piero; Hermann, Peter; Zerr, Inga; Appleby, Brian S; Safar, Jiri; Gambetti, Pierluigi; Collinge, John; Mead, Simon; Medical Research Council (Reino Unido); National Institute for Health Research (Reino Unido); Ministero della Salute (Italia); Ministry of Health Welfare and Sport (Países Bajos); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Plan Nacional de I+D+i (España); NIH - National Institute on Aging (NIA) (Estados Unidos); Centers for Disease Control and Prevention (Estado Unidos); Austrian Agency for Health and Food Safety; National Prion Monitoring Cohort (Reino Unido); University of Łódź (Polonia); Robert Koch Institute; Santé Publique France; Austrian Reference Center for Prion Diseases; Commonwealth Fund; National Institute for Public Health and the Environment (Países Bajos); Unión Europea. EU Joint Programme-Neurodegenerative Disease Research
Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci.
Structural and mechanistic insights into Streptococcus pneumoniae NADPH oxidase
(Nature Publishing Group, 2024-11) Dubach, Victor R A; Segundo-Acosta, Pablo San; Murphy, Bonnie J; Max Planck Society
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) have a major role in the physiology of eukaryotic cells by mediating reactive oxygen species production. Evolutionarily distant proteins with the NOX catalytic core have been found in bacteria, including Streptococcus pneumoniae NOX (SpNOX), which is proposed as a model for studying NOXs because of its high activity and stability in detergent micelles. We present here cryo-electron microscopy structures of substrate-free and nicotinamide adenine dinucleotide (NADH)-bound SpNOX and of NADPH-bound wild-type and F397A SpNOX under turnover conditions. These high-resolution structures provide insights into the electron-transfer pathway and reveal a hydride-transfer mechanism regulated by the displacement of F397. We conducted structure-guided mutagenesis and biochemical analyses that explain the absence of substrate specificity toward NADPH and suggest the mechanism behind constitutive activity. Our study presents the structural basis underlying SpNOX enzymatic activity and sheds light on its potential in vivo function.
Proteomics Analyses of Small Extracellular Vesicles of Aqueous Humor: Identification and Validation of GAS6 and SPP1 as Glaucoma Markers
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-06-26) Rejas-González, Raquel; Montero-Calle, Ana Maria; Valverde, Alejandro; Salvador, Natalia Pastora; Carballés, María José Crespo; Ausín-González, Emma; Sánchez-Naves, Juan; Campuzano, Susana; Barderas Manchado, Rodrigo; Guzman-Aranguez, Ana; Complutense University of Madrid (España); Banco Santander; Instituto de Salud Carlos III; Agencia Estatal de Investigación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Cataracts and glaucoma account for a high percentage of vision loss and blindness worldwide. Small extracellular vesicles (sEVs) are released into different body fluids, including the eye's aqueous humor. Information about their proteome content and characterization in ocular pathologies is not yet well established. In this study, aqueous humor sEVs from healthy individuals, cataracts, and glaucoma patients were studied, and their specific protein profiles were characterized. Moreover, the potential of identified proteins as diagnostic glaucoma biomarkers was evaluated. The protein content of sEVs from patients' aqueous humor with cataracts and glaucoma compared to healthy individuals was analyzed by quantitative proteomics. Validation was performed by western blot (WB) and ELISA. A total of 828 peptides and 192 proteins were identified and quantified. After data analysis with the R program, 8 significantly dysregulated proteins from aqueous humor sEVs in cataracts and 16 in glaucoma showed an expression ratio ≥ 1.5. By WB and ELISA using directly aqueous humor samples, the dysregulation of 9 proteins was mostly confirmed. Importantly, GAS6 and SPP1 showed high diagnostic ability of glaucoma, which in combination allowed for discriminating glaucoma patients from control individuals with an area under the curve of 76.1% and a sensitivity of 65.6% and a specificity of 87.7%.
Magneto-controlled electrochemical immunosensing platform to assess the senescence-associated GDF-15 marker in colorectal cancer
(Royal Society of Chemistry (RSC), 2024) Tejerina-Miranda, Sandra; Pérez-Ginés, Víctor; Torrente-Rodríguez, Rebeca M; Pedrero, María; Montero-Calle, Ana Maria; Pingarrón, José M; Barderas Manchado, Rodrigo; Campuzano, Susana; Agencia Estatal de Investigación (España); Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. H2020; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; Complutense University of Madrid (España)
In this study, we report a novel electrochemical immunoplatform using magnetic micro-supports and screen-printed carbon electrodes (SPCEs), overcoming limitations of the methods reported to date, for the rapid and sensitive determination of GDF-15, a molecular marker associated with cellular senescence in aging and cancer development and prognosis. The immunoplatform incorporated a sandwich-type configuration with specific capture and biotinylated-detection antibodies and used a streptavidin–peroxidase (strep–HRP) enzymatic conjugate as label. After magnetic capturing the micro-supports with the sandwich HRP-labeled immunocomplexes onto the surface of a SPCE, the change in cathodic current was quantified in the presence of H2O2 and hydroquinone (HQ), showing a direct correlation with the GDF-15 concentration. The proposed bioplatform exhibited attractive performance characteristics, including a good reproducibility (RSD 4.3%), and a wide linear concentration dynamic range from 140 to 10 000 pg mL−1 with a low limit of detection (LOD) of 42 pg mL−1 for GDF-15 standards in buffered solutions. The selectivity of the developed method and the storage stability of the capturing immunoconjugates were noteworthy. Indeed, the immunoconjugates showed a reliable performance for over 28 days when stored in a refrigerator. The immunoplatform was applied to a cohort of 19 plasma samples representing the different stages of colorectal cancer (CRC). The method allowed efficient discrimination between healthy individuals and CRC patients, particularly those in advanced stages, within a rapid 75-minute timeframe. The immunoplatform also presents substantial advantages in terms of cost-effectiveness, assay time reduction, and simplicity compared to other available techniques.
A genome-wide association meta-analysis of all-cause and vascular dementia
(Wiley, 2024-09) Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium; Calero, Miguel; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); NIH - National Institute on Aging (NIA) (Estados Unidos); NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos)
Introduction: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. Methods: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. Results: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Discussion: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.
Guidelines for the standardization of pre-analytical variables for salivary biomarker studies in Alzheimer's disease research: An updated review and consensus of the Salivary Biomarkers for Dementia Research Working Group.
(Wiley, 2024-12-30) Ng, Ted K S; Udeh-Momoh, Chinedu; Lim, Mei-Ann; Gleerup, Helena Sophia; Leifert, Wayne; Ajalo, Catherine; Ashton, Nicholas; Zetterberg, Henrik; Rissman, Robert A; Winston, Charisse N; O' Bryant, Sid; Jenkins, Robert; Carro, Eva; Orive, Gorka; Tamburin, Stefano; Olvera-Rojas, Marcos; Solis-Urra, Patricio; Esteban-Cornejo, Irene; Santos, Gustavo Alves Andrade Dos; Rajan, Kumar B; Koh, David; Simonsen, Anja Hviid; Slowey, Paul D; Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment: Biofluid Based Biomarkers Professional Interest Area Salivary Biomarkers for Dementia Research Working Group (ISTAART‐BBB‐PIA‐SWG)
There is a pressing need for accessible biomarkers with high diagnostic accuracy for Alzheimer's disease (AD) diagnosis to facilitate widespread screening, particularly in underserved groups. Saliva is an emerging specimen for measuring AD biomarkers, with distinct contexts of use that could complement blood and cerebrospinal fluid and detect various analytes. An interdisciplinary, international group of AD and related dementias (ADRD) researchers convened and performed a narrative review of published studies on salivary AD biomarkers. We critically appraised the current state of the literature, examining both consistencies and discrepancies in existing pre-analytical variables and methodologies. We discussed how various pre-analytical variables could influence the detection and quantification of salivary biomarkers, showed technologies available to standardize collection procedures, and proposed a standardized pre-analytical protocol to guide future studies on salivary AD biomarker examinations. We identified potential contexts of use, gaps, and priorities and proposed future research directions. HIGHLIGHTS: Given its non-invasive nature, wider accessibility, and cultural acceptability, particularly in low-resourced settings, saliva is a biofluid complementary to blood and CSF. Current salivary AD biomarker studies do not control for many confounding pre-analytical variables during the sampling process, potentially leading to inaccurate salivary biomarker readings and conclusions, contributing to conflicting findings. Reviewing the current literature, including the consistencies and non-consistencies observed in the existing parameters and methodologies, discussing how they can affect salivary AD biomarker detection and quantification. Proposing a standardized salivary pre-analytical protocol, identifying the gaps and prioritizations needed to move this area forward, proposing future directions and potential contexts of use.
Functional ultrasound and brain connectivity reveal central nervous system compromise in Trembler-J mice model of Charcot-Marie-Tooth disease
(Nature Publishing Group, 2024-12-03) Anzibar Fialho, Maximiliano; Martínez Barreiro, Mariana; Vázquez Alberdi, Lucia; Damián, Juan Pablo; Di Tomaso, María Vittoria; Baranger, Jérôme; Tanter, Mickael; Calero, Miguel; Negreira, Carlos; Rubido, Nicolás; Kun, Alejandra; Brum, Javier; Agencia Nacional de Investigación e Innovación (Uruguay); University of the Republic (Uruguay); Consejo Superior de Investigaciones Científicas (España)
The Charcot-Marie-Tooth-1E (CMT1E) disease is typically described as a peripheral neuropathy in humans, causing decreased nerve conduction, spastic paralysis, and tremor. The Trembler-J (TrJ) mice serve as a high fidelity model of this disease. Here, we use functional ultrasound (fUS) and functional connectivity (FC) to analyze TrJ mice's brain activity during sensory stimulation and resting state experiments against wild type (WT) mice - the healthy counterpart. fUS is an imaging technique that measures cerebral blood volume (CBV) temporal changes. We study these changes in the primary somatosensory cortex barrel field (S1BF) of both mice populations during periodic vibrissae stimulation, measuring the number of pixels that correlate to the stimulation (i.e., the size of the activation area), the average correlation of these pixels (i.e., the response strength), and the CBV's rate of change for each stimulation (i.e., the hemodynamic response). Then, we construct a FC matrix for each genotype and experiment by correlating the CBV signals from the eight cortical regions defined by the Paxinos and Franklin atlas. Our results show that TrJ mice have significantly diminished neurovascular responses and altered brain connectivity with respect to WT mice, pointing to central nervous system effects that could shift our understanding of the CMT1E disease.
Dual on-the-move electrochemical immunoassays for the simultaneous determination of amyloid-β (1−42) and Tau in Alzheimer's patient samples
(Elsevier, 2025-01) Gordón Pidal, José M; Moreno-Guzmán, María; Montero-Calle, Ana Maria; Barderas Manchado, Rodrigo; López, Miguel Ángel; Escarpa, Alberto; Agencia Estatal de Investigación (España); Comunidad de Madrid (España); Ministerio de Educación, Cultura y Deporte (España)
Here, we report catalytic micromotors (MM)-based electrochemical immunoassays for the on-the-move dual and simultaneous determination of Amyloid-β (Aβ-42) and Tau protein (Tau) (MMAβ-42-MMTau) as relevant Alzheimer’s disease biomarkers in brain tissue, cerebrospinal fluid, and plasma diagnosed samples. Combining the binding capacity of the antibody's functionalized polypyrrole (PPy) layer of MM with the self-propulsion from the PtNPs layer thanks to the decomposition of hydrogen peroxide, the approach yielded excellent detection limits (LODAβ-42=0.04 ng/mL, LODTau= 0.4 pg/mL) using low sample volumes (30 µL) and short analysis times (15 min) to detect both biomarkers. Quantitative analysis by MMAβ-42-MMTau was carried out without any clinical sample dilution (linear ranges are between 0.1 and 5 ng/mL for Aβ-42 and from 1 to 106 pg/mL in the case of Tau), highlighting the versatility of the approach to quantify Aβ-42 and Tau levels at different dynamic ranges. MMAβ-42-MMTau showed superior analytical capabilities to the single molecule counting technology (SMCx) during quantitative analysis in all sample classes tested, reporting a difference in quantitative levels for both biomarkers between healthy and diseased individuals and an increase in the levels with disease progression, except in plasma samples where no relationship between biomarker levels and disease progression was found.
Señalización por Ras
(Universidad Nacional de Quilmes (Argentina), 2000) Rojas-Cabañeros, Jose Maria; Jorge, Rocío; Zarich-Dimitrievich, Natasha; Gil, L; Oliva-Martinez, Jose Luis; Azañedo, M
El libro se exponen las bases de los mecanismos de activación de receptores y la farmacología molecular, junto con los últimos hallazgos de las rutas intracelulares que se activan por fármacos, hormonas, neurotransmisores y distintos factores de crecimiento. La información que se proporciona es fundamental para médicos, biólogos, bioquímicos y farmacólogos interesados en comprender las bases moleculares de la farmacología, la biología molecular y la bioquímica celular.
Regulation of CBP and Tip60 coordinates histone acetylation at local and global levels during Ras-induced transformation.
(Oxford University Press, 2014-10) Sánchez-Molina, Sara; Estarás, Conchi; Oliva-Martinez, Jose Luis; Akizu, Naiara; Asensio-Juan, Elena; Rojas-Cabañeros, Jose Maria; Martínez-Balbás, Marian A; Ministerio de Educación y Ciencia (España); Fundación La Marató TV3; Instituto de Salud Carlos III; Red Temática de Investigación Cooperativa en Cáncer (RTICC) (España); Government of Catalonia (España); Innovate UK; Fondation Jérôme-Lejeune
Cell transformation is clearly linked to epigenetic changes. However, the role of the histone-modifying enzymes in this process is still poorly understood. In this study, we investigated the contribution of the histone acetyltransferase (HAT) enzymes to Ras-mediated transformation. Our results demonstrated that lysine acetyltransferase 5, also known as Tip60, facilitates histone acetylation of bulk chromatin in Ras-transformed cells. As a consequence, global H4 acetylation (H4K8ac and H4K12ac) increases in Ras-transformed cells, rendering a more decompacted chromatin than in parental cells. Furthermore, low levels of CREB-binding protein (CBP) lead to hypoacetylation of retinoblastoma 1 (Rb1) and cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27Kip1) tumour suppressor gene promoters to facilitate Ras-mediated transformation. In agreement with these data, overexpression of Cbp counteracts Ras transforming capability in a HAT-dependent manner. Altogether our results indicate that CBP and Tip60 coordinate histone acetylation at both local and global levels to facilitate Ras-induced transformation.
Toxicity of nanoplastics for zebrafish embryos, what we know and where to go next
(Elsevier, 2021-11-25) Torres-Ruiz, Mónica; De la Vieja, Antonio; De Alba-González, Mercedes; Esteban-Lopez, Marta; Castaño, Argelia; Cañas Portilla, Ana Isabel; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Nanoplastics (NP) are an emerging threat to human health and there is a need to understand their toxicity. Zebrafish (ZF) is extensively used as a toxicology model due to its power to com-bine genetic, cellular, and whole organism endpoints. The present review integrates results regarding polystyrene NP effects on ZF embryo development. Study design was evaluated against NP effects. NP size, concentration, and exposure time did not affect organism responses (mortality, development, heart rate, locomotion) or cellular responses (gene expression, enzymes, metabolites). However, NP accumulation depended on size. Smaller NP can reach internal organs (brain, eyes, liver, pancreas, heart) but larger (>200 nm) accumulate mainly in gut, gills and skin. Locomotion and heart rate were commonly affected with hypoactivity and bradycardia being more prevalent. Effects on genetic/enzymatic/metabolic pathways were thoroughly analyzed. Immunity genes were generally upregulated whereas oxidative stress response genes varied. Central nervous system genes and visual related genes were generally downregulated. Results of genetic and enzymatic analyses coincided only for some genes/enzyme pairs. Reviewed studies provide a basis for understanding NP toxicity but results are hard to integrate. We propose key recommendations and future directions with regard to experimental design that may allow greater comparability across future studies.
Internalization and toxicity of polystyrene nanoplastics on inmortalized human neural stem cells
(Elsevier, 2024-05) González-Caballero, MCarmen; De Alba-González, Mercedes; Torres-Ruiz, Mónica; Iglesias-Hernandez, Patricia; Zapata, Verónica; Terrón-Orellana, Maria Carmen; Sachse, Martin; Morales, Mónica; Martin-Folgar, Raquel; Liste-Noya, Isabel; Cañas Portilla, Ana Isabel; Instituto de Salud Carlos III; Agencia Estatal de Investigación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Global plastic production has increased exponentially in recent decades, and a significant part of it persists in the environment, where it degrades into microplastics and nanoplastics (MPs and NPs). These can enter in humans by ingestion, inhalation, and dermal routes, and there is scientific evidence that they are able to reach the systemic circulation and penetrate and accumulate in various tissues and organs. Neurodevelopmental toxicity of NPs is one of the most worrying effects, as they can cross the blood-brain barrier. In the following study, we analyzed, by transmission electron microscopy, the in vitro uptake of 30-nm polystyrene nanoplastics (PS-NPs) into human neural stem cells (NSCs), their accumulation and subcellular localization within the cell. Furthermore, we studied the effects of different concentrations of PS-NPs on cell death, proliferation, and cell differentiation using immunocytochemistry and quantitative real time PCR for specific markers. This study demonstrated that PS-NPs were able to enter the cell, probably by endocytosis, accumulate, and aggregated in human NSCs, without being detected in the nucleus, causing cell death by apoptosis and decreased cell proliferation. This study provides new insights into the interaction and effects of PS-NPs in human NSC and supports the scientific evidence for the involvement of nanoplastic in neurodevelopmental disorders.
Mitochondrial RNA methyltransferase TRMT61B is a new, potential biomarker and therapeutic target for highly aneuploid cancers
(Nature Publishing Group, 2023-01) Martin, Alberto; Epifano, Carolina; Vilaplana-Marti, Borja; Hernández Martínez, Iván; Macías, Rocío I R; Martínez-Ramírez, Ángel; Cerezo, Ana; Cabezas-Sainz, Pablo; Garranzo-Asensio, Maria; Amarilla-Quintana, Sandra; Gomez-Dominguez, Deborah; Caleiras, Eduardo; Camps, Jordi; Gomez Lopez, Gonzalo; Gómez de Cedrón, Marta; Ramírez de Molina, Ana; Barderas Manchado, Rodrigo; Sánchez, Laura; Velasco-Miguel, Susana; Perez de Castro, Ignacio; Asociación Española Contra el Cáncer; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III
Despite being frequently observed in cancer cells, chromosomal instability (CIN) and its immediate consequence, aneuploidy, trigger adverse effects on cellular homeostasis that need to be overcome by anti-stress mechanisms. As such, these safeguard responses represent a tumor-specific Achilles heel, since CIN and aneuploidy are rarely observed in normal cells. Recent data have revealed that epitranscriptomic marks catalyzed by RNA-modifying enzymes change under various stress insults. However, whether aneuploidy is associated with such RNA modifying pathways remains to be determined. Through an in silico search for aneuploidy biomarkers in cancer cells, we found TRMT61B, a mitochondrial RNA methyltransferase enzyme, to be associated with high levels of aneuploidy. Accordingly, TRMT61B protein levels are increased in tumor cell lines with an imbalanced karyotype as well as in different tumor types when compared to control tissues. Interestingly, while TRMT61B depletion induces senescence in melanoma cell lines with low levels of aneuploidy, it leads to apoptosis in cells with high levels. The therapeutic potential of these results was further validated by targeting TRMT61B in transwell and xenografts assays. We show that TRM61B depletion reduces the expression of several mitochondrial encoded proteins and limits mitochondrial function. Taken together, these results identify a new biomarker of aneuploidy in cancer cells that could potentially be used to selectively target highly aneuploid tumors.

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