Artículos (Biología Celular)

URI permanente para esta colecciónhttps://hdl.handle.net/11441/10814

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Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support
(BioMed Central, 2025-12-12) Cáceres Palomo, Laura; Sánchez Mejías, Elisabeth; Trujillo Estrada, Laura; Pérez Moreno, Juan José; López Oliva, Elba; Lim, Tau En; DeFlitch, Leah; Vitorica Ferrández, Francisco Javier; García León, Juan Antonio; Gutiérrez, Antonia; Biología Celular; Bioquímica y Biología Molecular; Instituto de Salud Carlos III; European Union (UE)
Alzheimer´s disease (AD) is dominated by a complex cellular pathology which involves most brain cell types with glial cells increasingly recognized as playing fundamental roles in neurodegeneration. Astrocytes, which perform essential functions in preserving brain homeostasis, present a reactive phenotype in the AD brains with still unknown consequences. In this study, we generated and characterized human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients harboring the APOE4/4 genotype, the greatest genetic risk factor for late-onset AD. Disease astrocytes showed a reactive phenotype. In addition, they showed altered mitochondrial network including perinuclear clustering of mitochondria, enhanced mitochondrial fusion and higher production of reactive oxygen species which, unexpectedly, were coincident with increased oxidative phosphorylation and glycolysis. As these mitochondrial features are related to the acquisition of cell senescence, we evaluated this at the transcriptome level and found that these AD-derived astrocytes significantly upregulated gene signatures of cellular senescence and displayed a senescence-associated secretory phenotype (SASP). To verify this finding, we observed senescence-related DNA damage response in a significant proportion of cells in the cerebral cortex of AD patients, with most of these cells being astrocytes. Finally, we confirmed that this astrocytic senescent and proinflammatory phenotype is associated with a reduced neuronal support, evidencing that APOE4/4 AD astrocytes present intrinsic features that may compromise brain homeostasis and promote neurodegeneration. Addressing the causes and consequences of this astrocytic dysfunctionality should help to elucidate novel therapeutic targets able to modify the neurodegeneration present in AD.
Neuroprotection with Bioactive Compounds
(MDPI, 2026-10-30) Río Mercado, Carmen del; Segura Carretero, Antonio; Biología Celular
Analysis and removal of matrine in liquorice raw materials by good manufacturing practices
(Elsevier, 2026-01-13) Millán Linares, Carmen; Martín Rubio, María Esther; Biología Celular
The quinolizidine alkaloids matrine and its N-oxide oxymatrine, naturally occurring in plants of the genus Sophora, have recently been detected sporadically in liquorice (Glycyrrhiza sp.) products. This contamination is primarily attributed to the morphological similarity between the liquorice plant and Sophora species (sp.) leading to confusion during harvesting. While the use of matrine as a pesticide has been reported, the primary concern stems from its unintentional presence in liquorice products. The detection of matrine in liquorice raised concerns due to some studies suggesting potential genotoxic activity of matrine and oxymatrine. An LC-MS/MS measurement (QuPPe-PO-Method) was successfully developed and applied used for the identification of matrine/SOP 2887 by SGS in 31 samples selected throughout the liquorice production process. No contamination was obtained in any of the samples analyzed after the application of the internal process model designed by Mafco Worldwide LLC. Microscopic and spectroscopic analysis of the manually separated plants demonstrated not only the effectiveness of the procedure for the control of matrine contamination but also showed for the first time that between the two species can be a valuable and less costly alternative or complementary methodology to quantitative methods.
Ceramide sorting into non-vesicular transport is independent of acyl chain length in budding yeast
(Elsevier, 2024-01) Schlarmann, Philipp; Hanaoka, Kazuki; Ikeda, Atsuko; Muñiz Guinea, Manuel; Funato, Kouichi; Biología Celular
The transport of ceramide from the endoplasmic reticulum (ER) to the Golgi is a key step in the synthesis of complex sphingolipids, the main building blocks of the plasma membrane. In yeast, ceramide is transported to the Golgi either through ATP-dependent COPII vesicles of the secretory pathway or by ATP-independent non-vesicular transport that involves tethering proteins at ER-Golgi membrane contact sites. Studies in both mammalian and yeast cells reported that vesicular transport mainly carries ceramide containing very long chain fatty acids, while the main mammalian non-vesicular ceramide transport protein CERT only transports ceramides containing short chain fatty acids. However, if non-vesicular ceramide transport in yeast similarly favors short chain ceramides remained unanswered. Here we employed a yeast GhLag1 strain in which the endogenous ceramide synthase is replaced by the cotton-derived GhLag1 gene, resulting in the production of short chain C18 rather than C26 ceramides. We show that block of vesicular transport through ATP-depletion or the use of temperature-sensitive sec mutants caused a reduction in inositolphosphorylceramide (IPC) synthesis to similar extent in WT and GhLag1 backgrounds. Since the remaining IPC synthesis is a readout for non-vesicular ceramide transport, our results indicate that non-vesicular ceramide transport is neither blocked nor facilitated when only short chain ceramides are present. Therefore, we propose that the sorting of ceramide into non-vesicular transport is independent of acyl chain length in budding yeast.
Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia
(Taylor & Francis Inc., 2025-12-15) Klootsema, Yolande; Tsesmetzis, Nikolaos; Sharma, Sushma; Hofmann, Sophia; Thier, Jonas; Dirks, Christopher; Hormann, Femke M.; Yagüe Capilla, Miriam; Herold, Nikolas; Biología Celular; Swedish Society for Medical Research; Swedish Cancer Society; Swedish Childhood Cancer Foundation; Swedish Society of Medicine; Sjöberg Foundation; Swedish Research Council
Cytarabine (ara-C) and fludarabine (F-ara-A) are key drugs in leukaemia treatment. SAMHD1 is known to confer resistance to ara-C and F-ara-A, and we previously identified ribonucleotide reductase inhibitors as indirect SAMHD1 inhibitors in a phenotypic screen. The inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolic acid (MPA) was also a hit in this screen. IMPDH inhibitors (IMPDHi) have previously shown efficacy against KMT2A-rearranged (KMT2Ar) acute myeloid leukaemia (AML). We investigated whether IMPDH inhibition could enhance the effect of ara-C and F-ara-A in AML cell lines and primary AML samples, and whether this effect was linked to KMT2A status. We found that sensitivity to IMPDHi was independent of KMT2A status. IMPDHi synergized with ara-C and F-ara-A in a SAMHD1-dependent manner in a subset of AML cells, but not in acute lymphoblastic leukaemia cell lines. Mechanistically, IMPDHi depleted allosteric SAMHD1 activators GTP and dGTP, thereby increasing active triphosphate metabolites in SAMHD1-proficient, but not SAMHD1-deficient, cells. Our findings suggest that the addition of IMPDHi to ara-C and F-ara-A may have therapeutic benefits in some AML cases.
Mechanisms of growth-dependent regulation of the Gin4 kinase
(American Society for Cell Biology, 2025-07-28) Méndez Díaz, Francisco; Sánchez -Godínez, David; Solano, Francisco; Jasani, Akshi; Alcaide Gavilán, María; Prichard, Beth E.; Kellogg, Douglas R.; Biología Celular; University of California Santa Cruz, Santa Cruz, CA, United States
Cell cycle progression is dependent upon cell growth. Cells must therefore translate growth into a proportional signal that indicates when there has been sufficient growth for cell cycle progression. In budding yeast, the protein kinase Gin4 is required for normal control of bud growth and undergoes gradual multi-site hyperphosphorylation and activation that are dependent upon bud growth and correlated with the extent of growth. Together, these observations suggest that Gin4 functions in mechanisms that measure cell growth. Here, we searched for signals that link Gin4 hyperphosphorylation to cell growth. We found that Elm1, a yeast homolog of mammalian Lkb1 kinases, is sufficient in vitro to induce full hyperphosphorylation of Gin4, and likely works by stimulating extensive autophosphorylation of Gin4. We further discovered that casein kinase I, encoded by the YCK1 and YCK2 genes, is required for growth-dependent phosphorylation of Gin4. Yck1/2 are delivered to the growing plasma membrane by post-Golgi vesicles that drive membrane growth, and they are required for normal control of growth. The data suggest that delivery of Yck1/2 to the plasma membrane could play an important role in generating a growth-dependent signal that provides a measure of bud growth.
Casein kinase 1 controls components of a TORC2 signaling network in budding yeast
(The Company of Biologists, 2024-12-20) Lucena Hernández, Rafael; Jasani, Akshi; Anastasia, Steph; Kellogg, Douglas; Alcaide Gavilán, María; Biología Celular
Tor kinases play diverse and essential roles in control of nutrient signaling and cell growth. These kinases are assembled into two multiprotein complexes known as TORC1 and TORC2. In budding yeast, TORC2 relays nutrient-dependent signals that strongly influence growth rate and cell size. However, the mechanisms that control TORC2 signaling are poorly understood. Activation of TORC2 requires Mss4, a phosphatidylinositol 4-phosphate 5-kinase that recruits and activates downstream targets of TORC2. Localization of Mss4 to the plasma membrane is thought to be controlled by phosphorylation, and previous work has suggested that yeast homologs of casein kinase 1, Yck1 and Yck2 (referred to here collectively as Yck1/2), Control phosphorylation of Mss4. Here, we generated a new analog-sensitive allele of YCK2 and used it to test whether Yck1/2 influence localization of Mss4 or signaling in the TORC2 network. We found that Yck1/2 strongly influence Mss4 phosphorylation and localization, as well as influencing regulation of multiple components of the TORC2 network. However, inhibition of Yck1/2 causes mild effects on the best-characterized signaling axis in the TORC2 pathway, suggesting that Yck1/2 might play a larger role in influencing less well-understood aspects of TORC2 signaling.
Very long-chain fatty acids drive 1-deoxySphingolipid toxicity
(Nature Research, 2025-11-26) Majcher, Adam; Karsai, Gergely; Yusifov, Elkhan; Schaettin, Martina; Malagola, Ermanno; Horvath, Peter J.; Li, Jinmei; Rodríguez Gallardo, Sofía; Dubey, Raghvendra; Hornemann, Thorsten; Biología Celular; Swiss National Science Foundation (SNFS)
1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids formed when serine palmitoyltransferase incorporates L-alanine instead of L-serine. Elevated 1-deoxySLs are associated with hereditary sensory neuropathy type 1 and diabetic neuropathy, but the molecular basis of their toxicity remains unclear. Here we show that toxicity is mediated by very long-chain (VLC) 1-deoxy-dihydroceramides (1-deoxyDHCer), particularly nervonyl-1-deoxyDHCer (m18:0/24:1) and lignoceryl-1-deoxyDHCer (m18:0/24:0). Using a CRISPR interference screen, we identify ELOVL1 and CERS2 as essential enzymes driving the formation of these toxic species. Genetic modulation or pharmacological inhibition of ELOVL1 prevents VLC 1-deoxyDHCer accumulation, rescuing the toxicity in cellular and neuronal models. Mechanistic studies reveal that m18:0/24:1 disrupts mitochondrial integrity and induces the mitochondrial permeability transition pore formation and BAX activation, leading to cell death. These findings establish a direct link between 1-deoxySL chemical structure and cytotoxicity and highlight ELOVL1 inhibition as a potential therapeutic strategy for 1-deoxySL-associated diseases.
Subchronic 90-days toxicity profile of Salicornia ramosissima extract in rats
(Elsevier, 2025-12-11) Romero Bernal, Marina; González Díaz, Ángela; Tripodi, Maria; Álvarez, Alba Zheli; Rodríguez, Jara; Núnez Jurado, David; Cádiz Gurrea, María de la Luz; Prieto Ortega, Ana Isabel; Díez-Quijada Jiménez, Leticia; Cantarero, Irene; Río Mercado, Carmen del; Montaner, Joan; Nutrición y Bromatología, Toxicología y Medicina Legal; Biología Celular; Instituto de Salud Carlos III
Salicornia ramosissima, a halophytic plant rich in bioactive compounds, has gained attention for its potential health benefits. However, its long-term safety profile remains underexplored. This study aimed to evaluate the subchronic 90-day toxicity of S. ramosissima extract in Wistar rats. Animals received daily oral doses of 100, 500 or 1.000 mg/kg/day of the extract or placebo, and key physiological, biochemical, and histopathological parameters were assessed. Results indicated no significant adverse effects on body weight, food and water intake, or organ weights. Hematological and biochemical analyses revealed no major toxicological concerns. Histopathological examination did not indicate any extract-induced lesions in any of the examined organs, which included gastrointestinal, respiratory, lymphoid, urinary, nervous, circulatory and reproductive systems. Complementary assays demonstrated absence of developmental toxicity in Drosophila melanogaster and no mutagenic activity in the Ames test. Overall, these results indicate that subchronic administration of S. ramosissima extract is well tolerated in rats and does not elicit genotoxic or developmental toxicity, supporting its potential safe use as a functional food or nutraceutical ingredient.
Influence of stromal neural crest progenitor cells on neuroblastoma radioresistance
(Taylor & Francis, 2025-01) Huertas Castaño, Carlos; Martínez López, Laura; Cabrera Roldán, Patricia; Pastor Carrillo, Nuria María; Mateos Pérez, Juan Carlos; Mateos Cordero, Santiago; Pardal Redondo, Ricardo; Domínguez García, Inmaculada; Orta Vázquez, Manuel Luis; Biología Celular; Fisiología Médica y Biofísica
Purpose A substantial proportion of children with high risk Neuroblastoma die within the first 5 years post-diagnosis despite the complex treatment applied. In the recent years, tumor environment has been revealed as key factor for cancer treatment efficacy. In this sense, non-tumorigenic Neural Crest progenitor cells from high risk patients, have been described as part of Neuroblastoma stroma, promoting tumor growth and contributing to mesenchyme formation. In this paper we wanted to study the radiobiological behavior of these cells (NB14t) and how they influence the growth of tumorigenic neuroblasts after radiotherapy. Materials and methods To achieve our aim, we employed a wide list of methods either using NB14t cells as well as commercial NB cells. We have analyzed viability, survival, cell cyle profiles and differentiation. In addition, cocultured experiments were performed to monitor the influence of stroma cells to tumorigenic neuroblasts. Results We found that stromal progenitor cells showed an extraordinary radio-resistance either cultured in attached or suspension conditions. In good agreement, we found an enhanced repair of irradiation-induced DNA lesions as compared with commercial cell lines. In addition, according to our data these cells differentiate into a Cancer Associated Fibroblasts (CAFs)-like phenotype, hence contributing to the formation of mesenchymal stroma enhancing the growth of tumor cells after irradiation. Conclusion Our data show that neural progenitor cells from high risk NB stroma are radio-resistant and promote cancer growth after irradiation. This paper can help to understand the complex cell relationships within a tumor that will determine patient prognosis after radiotherapy.
Plasma proteomics uncovers divergent molecular signatures in ischemic stroke and intracerebral hemorrhage
(BioMed Central, 2025-10-28) Núñez Jurado, David; Fernández Vega, Alejandro; Río Mercado, Carmen del; Penalba, Anna; Llucià Carol, Laia; Muiño Acuña, Elena; Ezcurra Díaz, Garbiñe; Guasch Jiménez, Marina; Cullell, Natalia; Montaner, Joan; Biología Celular; Instituto de Salud Carlos III; European Union (UE); Junta de Andalucía
Background. Timely differentiation between ischemic stroke (IS) and intracerebral hemorrhage (ICH) is critical for guiding appropriate acute management strategies. While neuroimaging is the diagnostic gold standard, its accessibility is often limited in urgent clinical settings. Blood biomarkers offer a promising, scalable diagnostic alternative; however, no validated panel is yet available for distinguishing stroke subtypes during the hyperacute phase. Methods. In a multicenter study, plasma samples were collected within 6 h of symptom onset. A total of 3,072 proteins were measured using Olink® proximity extension assays. We applied differential expression analysis, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and receiver operating characteristic (ROC) curve evaluation. To interpret the biological relevance of the findings, we conducted functional enrichment and protein–protein interaction (PPI) analyses. Results. Among the 388 patients (344 IS, 44 ICH), 2,531 proteins were retained; 878 reached nominal significance (p < 0.05), and 67 remained significant after multiple-testing correction (FDR-adjusted p < 0.05). Of these, 844 were overexpressed in ICH and 34 in IS. GFAP, a glial marker, emerged as the most discriminative biomarker for ICH versus IS (AUC = 0.887; sensitivity: 80%, specificity: 90%), followed by BCAN (AUC = 0.820), SNAP25 (AUC = 0.797), and SPOCK1 (AUC = 0.786). For IS, S100A12 (AUC = 0.677) and MNDA (AUC = 0.657) showed the best performance. Multivariate analyses confirmed the presence of distinct proteomic patterns, with enrichment revealing a significant overrepresentation of neurodevelopmental and synaptic pathways. In PPI networks, GFAP and LYN emerged as central hubs. Conclusion. This study reveals a robust plasma proteomic signature distinguishing IS from ICH within hours of onset. These results lay the groundwork for scalable, blood-based diagnostics to guide early stroke management when imaging is delayed or unavailable. Highlights. GFAP shows high accuracy in differentiating between ischemic stroke and intracerebral hemorrhage. - GFAP and LYN are central hubs in intracerebral hemorrhage-related protein networks. - Neuroinflammatory and synaptic remodeling proteins dominated intracerebral hemorrhage. - S100A12 and MNDA were key discriminative proteins in ischemic stroke.
PLAMseq enables the proteo-genomic characterization of chromatin-associated proteins and protein interactions in a single workflow
(American Association for the Advancement of Science, 2025-11-07) González Vinceiro, Lourdes; Espejo Serrano, Carmen; Soler Oliva, María Eugenia; Soto Hidalgo, Emily; Mateos Martín, María Luisa; Rico, Daniel; Gonzalez Aguilera, Cristina; González Prieto, Román; Biología Celular; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; European Union (UE); Junta de Andalucía
Chromatin immunoprecipitation and coimmunoprecipitation assays are common approaches to characterize thegenomic localization and protein interactors, respectively, for a protein of interest. However, these approachesrequire the use of specific antibodies, which often face sensitivity and specificity issues. On the basis of TurboID,we developed proximity-labeled affinity-purified mass spectrometry and sequencing (PLAMseq), which enables,in the same workflow, identification of the genomic loci and the interacting proteome of a protein of interest.Moreover, PLAMseq can also be applied to specifically map protein interactions and ubiquitin(-like)–modifiedproteins. We validated PLAMseq with two well-characterized proteins, RNA polymerase II, and CTCF, with excellentrobustness and reproducibility. Next, we applied PLAMseq to characterize histone H1 SUMOylation, in whichstudy has remained elusive due to the lack of specific reagents, and found that SETDB1 binds to SUMOylated his-tones H1.2 and H1.4 that also colocalize with H3K9me3 at repetitive regions of the genome.
Treatment with the senolytics dasatinib/quercetin reduces SARS-CoV-2-related mortality in mice
(Wiley, 2023-03) Pastor-Fernández, Andrés; Bertos, Antonio R.; Sierra-Ramírez, Arantzazu; del Moral-Salmoral, Javier; Merino, Javier; de Avila, Ana I.; Olague, Cristina; Rodríguez Hernández, María A.; Fernández-Marcos, Pablo José; von Kobbe, Cayetano; Biología Celular; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer; Ministerio de Ciencia e Innovación (MICIN). España; European Union (UE); Consejo Superior de Investigaciones Científicas (CSIC); European Commission (EC)
The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic tool.
Enhanced non-enzymatic H2S generation extends lifespan and healthspan in male mice
(Elsevier, 2025-12-19) Cáliz-Molina, María Ángeles; López-Fernández-Sobrino, Raúl; Pino-Pérez, Inmaculada; Panadero-Morón, Concepción; Vilches-Pérez, María del Carmen; Camacho-Cabrera, María; García-Ruiz, Almudena; Pérez-Rosendo, Leopoldo; Espadas, Isabel; Venegas Calerón, Mónica; Aroca Aguilar, Ángeles; González Prieto, Román; Bernabeu Wittel, Máximo; Martín-Montalvo, Alejandro; Fisiología Médica y Biofísica; Bioquímica Vegetal y Biología Molecular; Biología Celular; Medicina; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; Sociedad Española de Diabetes (SED); Instituto de Salud Carlos III
Hydrogen sulfide is a gasotransmitter with biological functions, including roles in antioxidant defenses, mitochondrial bioenergetics, and cellular signaling via cysteine persulfidation. Several longevity-promoting interventions enhance endogenous hydrogen sulfide generation. However, whether enhanced hydrogen sulfide generation extends healthspan and lifespan in mammals remains unknown. Here, we investigated the in vivo effects of the non-enzymatic hydrogen sulfide generation promoted by natural diallyl sulforated compounds. Diallyl sulforated compounds extended lifespan and improved the main aspects of healthspan, including glucoregulation, locomotor function, and neurocognition in wild-type male mice across their lifespan. At the histological and molecular levels, we observed reductions in hepatic lipid-droplet size, attenuation of transcriptional and proteomic signatures associated with mTOR and immune-related pathways, and increased cysteine persulfidation in proteins. In humans, greater protein persulfidation in individuals with polypathological conditions was associated with increased muscle strength and lower triglyceride levels, supporting its physiological relevance. Our findings uncover the potential of enhanced hydrogen sulfide generation to promote healthy aging.
CRISPR-RfxCas13d screening uncovers Bckdk as a post-translational regulator of maternal-to-zygotic transition in teleosts
(Springer Nature, 2025-11-18) Hernández Huertas, Luis; Moreno Sánchez, Ismael; Crespo-Cuadrado, Jesús; Vargas-Barco, Ana; da Silva Pescador, Gabriel; Zhang, Ying; Wen, Zhihui; Florens, Laurence; Santos Pereira, José María; Bazzini, Ariel A.; Moreno Mateos, Miguel Ángel; Biología Celular; EC | NextGenerationEU (NGEU)
The maternal-to-zygotic transition (MZT) is a reprograming process encompassing zygotic genome activation (ZGA) and the clearance of maternally-provided mRNAs. While some factors regulating MZT have been identified, there are thousands of maternal RNAs whose function has not been ascribed yet. Here, we have performed a proof-of-principle CRISPR-RfxCas13d maternal screen, in which we targeted mRNAs encoding kinases and phosphatases or proteins regulating them in zebrafish. This screen identified branched-chain ketoacid dehydrogenase kinase, Bckdk, as a novel post-translational regulator of MZT. Bckdk mRNA knockdown caused epiboly defects, ZGA deregulation, H3K27ac reduction and a partial impairment of miR-430 processing. Phospho-proteomic analysis revealed that Phf10/Baf45a, a chromatin remodeling factor, is less phosphorylated upon Bckdk depletion. Further, phf10 mRNA knockdown also altered ZGA, and expression of a phospho-mimetic mutant of Phf10 rescued the developmental defects observed after bckdk mRNA depletion, as well as restored H3K27ac levels. Altogether, our results demonstrate the competence of CRISPR-RfxCas13d screenings to uncover new regulators of early vertebrate development and shed light on the post-translational control of MZT mediated by protein phosphorylation.
Integrative multi-omic analysis reveals a PAX8-driven gene network linking tumor stemness to therapy response in ovarian cancer
(Oxford University Press, 2025-09) Santos Pereira, José María; Carnero, Amancio; Muñoz Galván, Sandra; Biología Celular; Junta de Andalucía; Ministerio de Ciencia e Innovación (MICIN). España; Centro de Investigación Biomédica en Red, Cáncer (CIBERONC); Ministerio de Ciencia, Innovación y Universidades (MICIU). España
The transcription factor PAX8 is expressed in most ovarian tumors, being associated with increased tumorigenesis. Although recent studies have addressed the gene regulatory functions of PAX8 in ovarian cancer, an integrative analysis of multi-omic and patient data is required to identify the core regulatory network of PAX8 and its prognostic and therapeutic value. Here, we integrate PAX8 chromatin binding and accessibility data in ovarian cancer cells with transcriptomic and patients’ data to gain insight into the core gene regulatory network orchestrated by PAX8 in ovarian tumors. Integration of differential chromatin accessibility, transcription factor binding, and gene expression upon PAX8 knockout provides a core regulatory network that explains most of the genes regulated by PAX8. We combine these target genes with patient expression data and find a PAX8 gene signature associated with tumor stemness, a property related to therapy resistance. Indeed, we show that the PAX8 gene signature predicts disease outcome and response to therapy in ovarian cancer patients. Finally, we validated experimentally our results from bioinformatic analyses, thus reassuring their robustness. Our findings uncover a PAX8 core network that represents a promising strategy for targeted antitumor therapies and open new pathways to fight against ovarian cancer resistance.
Optical Control of Membrane Viscosity Modulates ER-to-Golgi Trafficking
(American Chemical Society (ACS) publications, 2025-08-12) Jiménez Rojo, Noemi; Fen, Suihan; Morstein, Johannes; Pritzl, Stefanie D.; López Martín, Sergio; Muñiz Guinea, Manuel; Trauner, Dirk; Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); National Key R&D Program. China; National Science Foundation. Switzerland; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG); National Institutes of Health. United States
The lipid composition of cellular membranes is highly dynamic and undergoes continuous remodeling, affecting the biophysical properties critical to biological function. Here, we introduce an optical approach to manipulate membrane viscosity based on an exogenous synthetic fatty acid with an azobenzene photoswitch, termed FAAzo4. Cells rapidly incorporate FAAzo4 into phosphatidylcholine and phosphatidylethanolamine in a concentration- and cell type-dependent manner. This generates photoswitchable PC and PE analogs, which are predominantly located in the endoplasmic reticulum. Irradiation causes a rapid photoisomerization that decreases membrane viscosity with high spatiotemporal precision. We use the resulting “PhotoCells” to study the impact of membrane viscosity on ER-to-Golgi transport and demonstrate that this two-step process has distinct membrane viscosity requirements. Our approach provides an unprecedented way of manipulating membrane biophysical properties directly in living cells and opens novel avenues to probe the effects of viscosity in a wide variety of biological processes.
Role of Bioactive Compounds in Neuroprotection and Neurodegenerative Disease
(Multidisciplinary Digital Publishing Institute, 2025-09-26) Cantarero, Irene; Río Mercado, Carmen del; Biología Celular
Assessing small-sized D-fructose-functionalized micelles for active targeting of triple-negative breast cancer
(Elsevier, 2025-10) Castillejos Anguiano, María del Carmen; Zuliani, Alessio; Cova, Camilla María; Caro, Carlos; López Noriega, Livia; Comaills, Valentine; Khiar, Noureddine; Química Inorgánica; Biología Celular; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía; European Union (UE); Consejo Superior de Investigaciones Científicas (CSIC); Association against the Cancer AECC. Spain
Triple-negative breast cancer (TNBC) is one of the most aggressive and clinically challenging subtypes of breast cancer. Its high heterogeneity and lack of actionable molecular targets limit therapeutic options, leading to poor patient outcomes. Given the reported overexpression of the fructose transporter GLUT5 (Glucose Transporter type 5) in breast cancer cells, D-fructose (FRUC) has been proposed as a ligand for active targeting; however, its effectiveness remains uncertain. Here, we investigate passive and fructose-mediated active targeting of TNBC using small-sized supramolecular micelles in vitro and in vivo. We designed two micelle formulations, one incorporating a D-fructose headgroup, using amphiphiles composed of pentacosadiynoic acid as the hydrophobic core and polyethylene glycol as a spacer. These micelles (∼10 nm) were characterized by nuclear magnetic resonance, electron microscopy, and dynamic light scattering, and their stability was confirmed under various conditions. Cellular internalization studies, flow cytometry, and confocal microscopy revealed that PEGylated micelles exhibited superior intracellular accumulation compared to fructose-functionalized micelles, suggesting that D-fructose may hinder endocytic uptake rather than enhance it. In vivo biodistribution analysis in tumor-bearing mice showed similar tumor accumulation for both formulations, with FRUC-Mic exhibiting a transiently higher presence at 1-h post-administration, though this difference was not statistically significant. Although this study does not validate D-fructose as an effective ligand for active targeting, both micelle formulations showed key advantages, including Immunoglobulin G-sized particles, high stability, and facile synthesis, enabling scalable production and clinical translation. Moreover, their ability to solubilize, stabilize, and deliver hydrophobic dyes and cytotoxic agents underscores their potential as theranostic nanoplatforms for TNBC treatment.
Correction to: Differential effectiveness of tyrosine kinase inhibitors in 2D/3D culture according to cell differentiation, p53 status and mitochondrial respiration in liver cancer cells
(Springer Nature, 2024-08-20) Rodríguez Hernández, María A.; Chapresto Garzón, Raquel; Cadenas, Miryam; Navarro Villarán, Elena; Negrete, María; Gómez Bravo, Miguel Ángel; Victor, Victor M.; Padillo Ruiz, Francisco Javier; Muntané Relat, Jordi; Cirugía; Biología Celular; Fisiología Médica y Biofísica; CTS664: Cirugía Avanzada y Trasplantes. Terapia Celular y Bioingeniería Aplicada a la Cirugía; CTS1098: Mecanismos Moleculares del Hepatocarcinoma y Sus Estrategias Terapéuticas
In this article, the spheroid image obtained after 15 days of treatment of Hep3B with Cabozantinib was incorrectly duplicated from that obtained after 12 days. The new Fig. 1B shows the correct spheroid image at 15 days. The replacement does not change the results or conclusions of Fig. 1B. The authors apologize for the unexpected error in the preparation of Fig. 1B. (excerpt)

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