Articles publicats (Medicina Experimental)
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- ItemOpen AccessInhibition of acid sphingomyelinase increases SMN levels and connects sphingolipid metabolism to Spinal Muscular Atrophy(Elsevier, 2025-09) Brokate Llanos, Ana; Beltran Perelló, Maria; Garzón, Andrés; Garcera, Ana; Miralles, María; Celma Nos, Ferrán; Campoy López, Alejandro; Soler i Tatché , Rosa Ma.; Muñoz, Manuel; Pérez Pulido, AntonioSpinal Muscular Atrophy (SMA) is a moderately rare disease that causes progressive motor neuron degeneration and presents the highest neonatal death rate of all human genetic diseases. It is associated with the deletion or mutation of the SMN1 gene, encoding the SMN protein, mainly involved in the assembly of a ribonucleoprotein complex called Sm ring, essential for the splicing of mRNA molecules. In humans, there are usually multiple copies of another gene virtually identical in sequence, SMN2, which produces 10 % of complete SMN protein. It is known that increased expression of SMN2 improves the SMA phenotype. We have developed a multidisciplinary protocol, by which negative regulatory genes of SMN2 were discovered through an in silico approach based on analysis of gene expression profiles obtained from public transcriptomics experiments. We then knockdown these candidate genes in a Caenorhabditis elegans strain where the amount of SMN can be measured by fluorescence temporally and spatially. Thus, we have found that when a homolog of human SMPD1, a gene involved in sphingolipid metabolism, is inhibited by RNAi or specific drugs, SMN levels increase. We have also used motor neuron cultures of SMA patients, finding that the levels of SMPD1 mRNA and protein are increased in these cells. Furthermore, when they are treated with the SMPD1 inhibitor clomipramine, SMN levels also increase and a significant decrease in neurite degeneration is observed. Those results propose new therapeutic avenues for this devastating disease and represent a new method of finding modifiers and drugs for human diseases
- ItemOpen AccessExploring platelet metabolomics and fatty acid profiles for ALS prognosis and diagnosis(Springer Nature, 2025-09) Torres Cabestany, Pascual; Pradas, Irene; Fernández Bernal, Anna; Povedano, Mònica; Dominguez, Raul; Jové Font, Mariona; González Mingot, Cristina; Ayala Jové, Ma. Victoria (Maria Victoria); Ferrer, Isidre; Pamplona Gras, Reinald; Portero Otín, ManuelAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with heterogeneous clinical progression, reflecting distinct underlying pathological mechanisms. Early and accurate diagnosis and prognosis require reliable biomarkers to improve clinical management and therapeutic stratification. The present study explores the potential of platelet global metabolomics and fatty acid (FA) profiling as potential sources of diagnostic and prognostic biomarkers for ALS. We analysed platelets from 15 recently diagnosed ALS patients and 21 healthy controls (CTLs) using liquid chromatography-mass spectrometry (LC-MS) for metabolomics and gas chromatography-flame ionization detection (GC-FID) for FA profiling. ALS patients were classified as fast or slow progressors based on the median ALS Functional Rating Scale-Revised (ALSFRS-R) slope. While global metabolomic and FA profiles have shown limited potential for distinguishing ALS from CTL, preliminary molecular annotation based on mass and retention times disclosed specific metabolites with potential diagnostic value. Importantly, both global metabolomic and FA analyses demonstrated a marked capacity to differentiate fast progressors from slow progressors (receiver operating characteristic (ROC) curves of approximately 1), revealing distinct metabolic signatures associated with disease progression. Our findings demonstrate that platelet global metabolomics and FA profiling hold promise as prognostic biomarkers in ALS.
- ItemOpen AccessSafety, tolerability, immunogenicity, and efficacy of ABvac40 active immunotherapy against Aβ40 in patients with mild cognitive impairment or very mild Alzheimer's disease: A randomized, double-blind, placebo-controlled phase 2 study(Wiley, 2025-09) Pascual Lucas, María; Lacosta, Ana María; Montañés, María; Canudas, Jesús; Loscos, Jorge; Monleón, Inmaculada; Allué, José Antonio; Sarasa, Leticia; Fandos, Noelia; Romero, Judith; Sarasa, Manuel; Torres, Mireia; Whyms, Dermot; Terencio, Jose; Piñol Ripoll, Gerard; Boada, MercèIntroduction: ABvac40 is an investigational active immunotherapy (vaccine) targeting Aβ40. This study assessed the safety and immunogenicity of ABvac40 in patients with amnestic mild cognitive impairment or very mild Alzheimer's disease. Methods: AB1601 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients (n = 124) received five monthly injections plus a 10-month booster of ABvac40 or placebo, with 18-24 months of follow-up. Primary endpoints included safety, tolerability, and immunogenicity. Secondary endpoints assessed immune response, neuropsychological changes, and disease biomarkers. Results: Treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable between ABvac40 (90.6% and 26.6%) and placebo (93.3% and 26.7%). Amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were similar (12.5% ABvac40; 15.0% placebo), with no ARIA-edema (ARIA-E) or meningoencephalomyelitis. ABvac40 induced a specific, sustained immune response in plasma, with detectable antibodies in CSF. Discussion: These findings support further investigation of ABvac40 as a potential disease-modifying therapy. Clinical trial registration number: NCT03461276 (ClinicalTrials.gov) HIGHLIGHTS: ABvac40 was safe and well-tolerated in early-stage Alzheimer's disease patients. No amyloid-related imaging abnormalities-edema (ARIA-E) or encephalitis observed; ARIA-hemorrhage (ARIA-H) rates were similar across groups. Specific, sustained immune response to ABvac40 in plasma, with cerebrospinal fluid (CSF) antibody penetration. Cognitive scales and magnetic resonance imaging (MRI) volumetric data favored ABvac40 over placebo. Results support further development of ABvac40 as a disease-modifying therapy.
- ItemOpen AccessEndometrial cancer progression driven by PTEN-deficiency requires miR-424(322)~503(Springer Nature, 2025-10) Vidal Sabanés, Maria; Bonifaci, Núria; Navaridas, Raúl; Egea Navarro, Joaquim; Encinas Martín, Mario; Rodriguez-Barrueco, Ruth; Silva, Jose M.; Matias-Guiu, Xavier; Llobet Navas, David; Dolcet Roca, XavierEndometrial cancer is the most frequent type of cancer in the female reproductive tract. Loss-of-function alterations in PTEN, leading to enhanced PI3K/AKT activation, are among the most frequent molecular alterations in endometrial cancer. Increased PI3K/AKT signaling resulting from PTEN loss promotes cellular proliferation and confers resistance to TGFβ-mediated apoptosis, a key regulator of endometrial homeostasis. In this study, we have analyzed the role of miRNAs in driving these altered cellular responses. A comprehensive transcriptomic analysis of miRNA expression revealed the upregulation of several miRNAs caused by PTEN deficiency and/or TGFβ stimulation. The miR-424(322)~503 cluster drew our attention due to its involvement in regulating apoptosis and proliferation. However, miR-424(322)~503 cluster has a paradoxical role in cancer, exhibiting either oncogenic and tumor suppressive functions depending on cell type or context. To ascertain the function of miR-424(322)~503 in endometrial carcinogenesis caused by PTEN deficiency, we generated a double Pten/miR-424(322)~503 knock-out mice. We demonstrate that loss of miR-424(322)~503 impairs proliferation of both wild type or Pten deficient endometrial organoids by interfering with growth factor and PI3K/AKT signaling. Furthermore, the absence of miR-424(322)~503 restores TGFβ-induced apoptosis, which is otherwise compromised by PTEN deficiency. In vivo, Pten/miR-424(322)~503 knock-out mice exhibit reduced endometrial cancer progression compared to Pten deficient mice through a cell-autonomous mechanism.
- ItemOpen AccessPostnatal plasticity in the olfactory system of the juvenile swine brain(Springer, 2025-10-05T22:00:00Z) Freixes Vidal, Júlia; Abdel-Rahman, Fatma ElZahraa S.; Nebbia, Roberto; Medina Hernández, Loreta Mª; Desfilis, EsterSwine have an excellent sense of smell and highly complex olfactory brain structures, which play a crucial role in their complex social interactions. In other mammals the olfactory system is known to exhibit significant plasticity, even during adulthood. The aim of this study was to investigate postnatal plasticity in olfactory areas of juvenile swine brains by studying immature cells immunoreactive for the microtubule-associated protein doublecortin (DCX). Using immunofluorescence, we studied DCX coexpression with the cell proliferation marker Ki-67, and different neuronal markers. Our results show the existence of numerous DCX + cells throughout the olfactory pallial areas. In some of them, we found DCX+/Ki-67 + coexpressing cells, suggesting that they were proliferating. Some of these proliferating cells were grouped in tangentially-oriented migratory-like chains, forming the rostral migratory stream to anterior olfactory area and olfactory bulb. Moreover, chains of DCX + cells were found in the external capsule and white matter adjacent to the temporal horn of the ventricle. Chains of DCX + cells were observed crossing the internal layers of the piriform and entorhinal cortices. In layer II of these cortices, DCX + cells of varying maturity degrees and neuronal phenotypes (including NeuN expression) were present. This suggests the existence of multiple migratory streams along the anteroposterior axis. Most DCX + immature cells in the migratory chains and in the anterior olfactory area, piriform and entorhinal cortices expressed the transcription factor Brn2 (Pou3f2), suggesting the incorporation of new glutamatergic neurons in these areas. Together, these results highlight the interest of swine to study the role of postnatal brain plasticity and their potential for regeneration in large, gyrencephalic brains.