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Circulating metabolic markers after surgery identify patients at risk for severe postoperative complications: a prospective cohort study in colorectal cancer
(Elsevier, 2024-03-01) Montcusí, Blanca; Pera Román, Miguel; Madrid Gambín, Francisco Javier; Pozo Mendoza, Óscar J., 1975-; Marco Colás, Santiago; Marín Martínez, Silvia; Mayol, Xavier; Pascual Damieta, Marta; Alonso-Gonçalves, Sandra; Silvia Salvans Ruiz; Jiménez-Toscano, Marta; Cascante i Serratosa, Marta
Background: Early detection of postoperative complications after colorectal cancer (CRC) surgery is associated with improved outcomes. The aim was to investigate early metabolomics signatures capable to detect patients at risk for severe postoperative complications after CRC surgery. Materials and methods: Prospective cohort study of patients undergoing CRC surgery from 2015 to 2018. Plasma samples were collected before and after surgery, and analyzed by mass spectrometry obtaining 188 metabolites and 21 ratios. Postoperative complications were registered with Clavien–Dindo Classification and Comprehensive Complication Index. Results: One hundred forty-six patients were included. Surgery substantially modified metabolome and metabolic changes after surgery were quantitatively associated with the severity of postoperative complications. The strongest positive relationship with both Clavien–Dindo and Comprehensive Complication Index (β=4.09 and 63.05, P<0.001) corresponded to kynurenine/tryptophan, against an inverse relationship with lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs). Patients with LPC18:2/PCa36:2 below the cut-off 0.084 µM/µM resulted in a sevenfold higher risk of major complications (OR=7.38, 95% CI: 2.82–21.25, P<0.001), while kynurenine/tryptophan above 0.067 µM/µM a ninefold (OR=9.35, 95% CI: 3.03–32.66, P<0.001). Hexadecanoylcarnitine below 0.093 µM displayed a 12-fold higher risk of anastomotic leakage-related complications (OR=11.99, 95% CI: 2.62–80.79, P=0.004). Conclusion: Surgery-induced phospholipids and amino acid dysregulation is associated with the severity of postoperative complications after CRC surgery, including anastomotic leakage-related outcomes. The authors provide quantitative insight on metabolic markers, measuring vulnerability to postoperative morbidity that might help guide early decision-making and improve surgical outcomes.
Transcriptomic profiling of endothelial progenitor cells in post-COVID-19 patients: Insights at 3- and 6-month post-infection
(Elsevier, 2025-11-21) Poyatos Dorado, Paula; Gratacòs-Aurich, Miquel; Aguilar, Daniel; Luque, Neus; Bonnin Vilaplana, Marc; Eizaguirre, Saioa; Cascante i Serratosa, Marta; Orriols Martínez, Ramon; Tura-Ceide, Olga
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused significant global morbidity since 2019. Long COVID, characterized by persistent symptoms after acute infection, may involve endothelial injury. We analyzed endothelial colony-forming cells (ECFCs) from post-COVID-19 patients at 3- and 6-month post-infection, comparing them with healthy controls and stratifying by prior pulmonary embolism (PE). Transcriptomic profiling identified differentially expressed genes (DEGs) associated with endothelial homeostasis, inflammation, oxidative stress, and thrombosis. Post-COVID ECFCs showed downregulation of NOS3, KLF2, ANGPT1, PIK3R3, GBX2, GDF6, SMAD6, SRC, and TGFB1, and upregulation of CASP1, CXCL5, IL12A, SOD2, TIMP3, and TLR2. Minimal differences were observed between 3 and 6-month samples. PE patients showed downregulation of thrombosis-related genes such as PTGS2 and ACKR3. These findings indicate sustained endothelial dysfunction and inflammation up to 6 months post-infection, highlighting the importance of long-term monitoring and potential therapeutic strategies to support vascular health in post-COVID-19 patients.
Design of a true bivalent ligand with picomolar affinity for a G protein-coupled receptor homodimer
(American Chemical Society, 2018-10-25) Pulido, Daniel; Casadó Anguera, Verònica; Pérez-Benito, Laura; Moreno Guillén, Estefanía; Cordomí, Arnau; López, Laura; Cortés Tejedor, Antonio; Ferré, Sergi; Pardo, Leonardo; Casadó, Vicent; Royo Expósito, Miriam
Bivalent ligands have emerged as chemical tools to study G protein-coupled receptor dimers. Using a combination of computational, chemical, and biochemical tools, here we describe the design of bivalent ligand 13 with high affinity (KDB1=21 pM) for the dopa-mine D2 receptor (D2R) homodimer. Bivalent ligand 13 enhances the binding affinity relative to monovalent compound 15 by 37-fold, indicating simultaneous binding at both protomers. Using synthetic peptides with amino acid sequences of transmembrane (TM) domains of D2R, we provide evidence that TM6 forms the interface of the homodimer. Notably, the disturber peptide TAT-TM6 decreased the binding of bivalent ligand 13 by 52-fold and had no effect on monovalent compound 15, confirming the D2R homodimer through TM6 ex-vivo. In conclusion, using a versatile multivalent chemical platform, we have developed a precise strategy to generate a true bivalent ligand that simultaneously targets both orthosteric sites of the D2R homodimer
A heterobivalent ligand for the adenosine A2A-dopamine D2 receptor heteromer
(American Chemical Society, 2022-01-04) Pulido, Daniel; Casadó Anguera, Verònica; Gómez-Autet, Marc; Llopart, Natàlia; Moreno Guillén, Estefanía; Casajuana-Martin, Nil; Ferré, Sergi; Pardo, Leonardo; Casadó, Vicent; Royo Expósito, Miriam
A G protein-coupled receptor heteromer that fulfills the established criteria for its existence in vivo is the complex between adenosine A2A (A2AR) and dopamine D2 (D2R) receptors. Here, we have designed and synthesized heterobivalent ligands for the A2AR−D2R heteromer with various spacer lengths. The indispensable simultaneous binding of these ligands to the two different orthosteric sites of the heteromer has been evaluated by radioligand competition-binding assays in the absence and presence of specific peptides that disrupt the formation of the heteromer, label-free dynamic mass redistribution assays in living cells, and molecular dynamic simulations. This combination of techniques has permitted us to identify compound 26 [KDB1 (A2AR) = 2.1 nM, KDB1 (D2R) = 0.13 nM], with a spacer length of 43-atoms, as a true bivalent ligand that simultaneously binds to the two different orthosteric sites. Moreover, bioluminescence resonance energy transfer experiments indicate that 26 favors the stabilization of the A2AR−D2R heteromer.
Reinterpreting anomalous competitive binding experiments within G protein-coupled receptor homodimers using a dimer receptor model
(Elsevier B.V., 2019-01-01) Casadó Anguera, Verònica; Moreno Guillén, Estefanía; Mallol Montero, Josefa; Ferré, Sergi; Canela Campos, Enric I. (Enric Isidre), 1949-; Cortés Tejedor, Antonio; Casadó, Vicent
An increasing number of G protein-coupled receptors (GPCRs) have been reported to be expressed in the plasma membrane as dimers. Since most ligand binding data are currently fitted by classical equations developed only for monomeric receptors, the interpretation of data could be misleading in the presence of GPCR dimers. On the other hand, the equations developed from dimer receptor models assuming the existence of two orthosteric binding sites within the dimeric molecule offer the possibility to directly calculate macroscopic equilibrium dissociation constants for the two sites, an index of cooperativity (DC) that reflects the molecular communication within the dimer and, importantly, a constant of radioligand-competitor allosteric interaction (KDAB) in competitive assays. Here, we provide a practical way to fit competitive binding data that allows the interpretation of apparently anomalous results, such as competition curves that could be either bell-shaped, monophasic or biphasic depending on the assay conditions. The consideration of a radioligand-competitor allosteric interaction allows fitting these curve patterns both under simulation conditions and in real radioligand binding experiments, obtaining competitor affinity parameters closer to the actual values. Our approach is the first that, assuming the formation of receptor homodimers, is able to explain several experimental results previously considered erroneous due to their impossibility to be fitted. We also deduce the radioligand concentration responsible for the conversion of biphasic to monophasic or to bell-shaped curves in competitive radioligand binding assays. In conclusion, bell-shaped curves in competitive binding experiments constitute evidence for GPCR homodimerization.
Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone
(Nature Publishing Group, 2024-03-01) Walther, Donna; Glatfelter, Grant C.; Weinshenker, David; Zarate, Carlos A.; Casadó, Vicent; Baumann, Michael H.; Pardo, Leonardo; Ferré, Sergi; Michaelides, Michael; Levinstein, Marjorie; De Oliveira, Paulo A.; Casajuana-Martin, Nil; Quiroz, César; Budinich, Reece C.; Rais, Rana; Rea, William; Ventriglia, Emilya; Llopart, Natàlia; Casadó Anguera, Verònica; Moreno Guillén, Estefanía
(R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal1 receptor (Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use. One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal1R heteromer, decreasing its abuse liability.
Towards biomimetic electrochromatography: Fast method for the Abraham's characterization of solute-solvent interactions in micellar and microemulsion electrokinetic systems
(Elsevier B.V., 2025-09-13) Idrees, Rabia; Subirats i Vila, Xavier; Amézqueta, Susana; Rosés Pascual, Martí
This study presents a fast method for the characterization of solute-solvent interactions in micellar and microemulsion electrokinetic chromatography based on the linear solvation energy relationships proposed by Abraham. The magnitude of the different types of interactions between solutes and chromatographic phases is determined from the differences in migration observed for pairs of solutes, and the effect of the different cohesion of the dispersed phase and the dispersive medium is determined from the injection of a mixture of homologous compounds, using in all injections nonanophenone as dispersed phase marker. For excess polarizability interactions (e), the compounds 8-hydroxyquinoline and 1,2-dimethoxybenzene are used. The dipolarity/polarizability coefficient (s) is assessed with 1,4- or 1,2-dicyanobenzene and 2-methylbenzaldehyde. To evaluate the solute hydrogen bond acceptor capacity (a), 3-ethoxyphenol and 2-chloroacetophenone are employed, and the hydrogen bond donor capacity (b) is characterized using 2,3,5,6-tetramethylpyrazine and 2,6-dimethylanisole. Finally, the cavity term (v) is determined using a mixture of n-alkyl phenone homologues in the range of acetophenone to heptanophenone, depending on the nature of the electrokinetic system. This fast approach allows for results comparable to the conventional methodology, which is based on the injection of a relatively large number of solutes and subsequent analysis using multiple linear regressions, but significantly reducing the time and resources invested in the characterization of electrokinetic chromatography systems. This novel method was assayed with micellar solutions prepared from bile salts (SC, SDC), anionic surfactants (SDS, LDS), and cationic surfactants (CTAB, TTAB), and microemulsions consisting of heptane, 1-butanol, and surfactants (SDS, SC, and TTAB) at different concentrations and pH values. Provided that electrokinetic chromatography has a high potential mimicking biological systems due to the availability of surfactants and cosurfactants of different natures and the wide operational pH range, this study aims to contribute to the development of biomimetic chromatography by proposing a screening method based on the Abraham’s solvation parameter model, widely used in the characterization of biological systems.
rbfox1 LoF mutants show disrupted bdnf/trkb2 and crhb/nr3c2 expression and increased cortisol levels during development coupled with signs of allostatic overload in adulthood
(Nature Publishing Group, 2025-11-19) Leggieri, Adele; García-González, Judit; Hosseinian, Saeedeh; Ashdown, Peter; Anagianni, Sofia; Wang, Xian; Havelange, William; Fernàndez Castillo, Noèlia; Cormand Rifà, Bru; Brennan, Caroline H.
Mutations in the RBFOX1 gene are associated with psychiatric disorders but how RBFOX1 influences psychiatric disorder vulnerability remains unclear. Recent studies showed that RBFOX proteins mediate the alternative splicing of PAC1, a critical HPA axis activator. Further, RBFOX1 dysfunction is linked to dysregulation of BDNF/TRKB, a pathway promoting neuroplasticity, neuronal survival and stress resilience. Hence, RBFOX1 dysfunction may increase psychiatric disorder vulnerability via HPA axis dysregulation, leading to disrupted development and allostatic overload. To test this hypothesis, we generated a zebrafish rbfox1 loss of function (LoF) line and examined behavioural and molecular effects during development. We found that rbfox1 LoF mutants exhibited hyperactivity, impulsivity and heightened arousal, alongside alterations in proliferation – traits associated with neurodevelopmental and stress-related disorders. In adults, loss of rbfox1 function led to decreased fertility and survival, consistent with allostatic overload. At the molecular level, at larval stages rbfox1 mutants showed increased cortisol levels and disrupted expression of key stress-related genes (bdnf, trkb2, pac1a-hop, crhb, nr3c2). Pharmacological intervention targeting TRKB restored crhb and nr3c2 gene expression and hyperactive and hyperarousal behaviours. In adults, dysregulation of crhb, nr3c2 and bdnf/trkb2 genes was only seen following acute stress exposure. Our findings reveal a fundamental role for RBFOX1 in integrating stress responses through its regulation of BDNF/TRKB and neuroendocrine signalling.
Neuropilin-2 upregulation by stromal TGFβ1 induces lung disseminated tumor cells dormancy escape and promotes metastasis outgrowth
(Elsevier, 2025-10-01) Recalde Percaz, Leire; de la Guía López, Inés; Linzoain-Agos, Paula; Noguera Castells, Aleix; Rodrigo-Faus, María; Jauregui, Patricia; López Plana, Anna; Fernández Nogueira, Patricia; Iniesta-González, Minerva; Cueto-Remacha, Mateo; Manzano, Sara; Alonso, Rodrigo; Moragas, Núria; Baquero, Cristina; Palao, Nerea; Dalla, Erica; Avilés Jurado, Francesc Xavier; Vilaseca González, Isabel; Leon Vintro, Xavier; Camacho, Mercedes; Fuster Orellana, Gemma; Alcaraz Casademunt, Jordi; Aguirre-Ghiso, Julio; Gascón, Pere; Porras, Almudena; Gutiérrez-Uzquiza, Álvaro; Carbó Carbó, Neus; Bragado Domingo, Paloma
Metastasis is the main cause of death from solid tumors. Therefore, identifying the mechanisms that govern metastatic growth poses a major biomedical challenge. Tumor microenvironment signals regulate the fate and survival of disseminated tumor cells (DTCs) in secondary organs. However, very little is known about the role of nervous system mediators in this process. We have previously reported that neuropilin-2 (NRP2) expression in breast cancer correlates with poor prognosis. Here, we show that NRP2 positively regulates the proliferation, invasion, and survival of breast and head and neck cancer cells in vitro. NRP2 deletion in tumor cells inhibits tumor growth in vivo and decreases the number and size of lung metastases by promoting lung DTCs quiescence. NRP2 deletion upregulates dormancy and cell cycle regulators expression and promotes DTCs reprograming into quiescence. Moreover, lung fibroblasts and macrophages induce NRP2 upregulation in DTCs through the secretion of TGFβ1. NRP2 facilitates lung DTC interaction with the extracellular matrix and promotes lung DTCs activation and metastasis. Therefore, we conclude that the TGFβ1-NRP2 axis is a new key dormancy-awakening inducer that promotes DTCs proliferation and lung metastasis development.
Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation
(Springer Verlag, 2024-07-06) Hernández-Hernández, Irene; Rosa, Juan V. de la; Martín-Rodríguez, Patricia; Díaz-Sarmiento, Mercedes; Recio, Carlota; Guerra, Borja; Fernández-Pérez, Leandro; León Moreno, Theresa Elizabeth; Torres, Rosa; Font Díaz, Joan; Roig, Angela; Mora, Fernando de; Boscá, Lisardo; Díaz, Mario; Valledor Fernández, Annabel; Castrillo, Antonio; Tabraue, Carlos
Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRβ, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRβ as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases.
Liver X receptors and inflammatory-induced C/EBPβ selectively cooperate to control CD38 transcription
(Karger, 2024-12-19) Glaría Percaz, Estibaliz; Rodríguez Martínez, Pol; Font Díaz, Joan; Rosa, Juan Vladimir de la; Castrillo, Antonio; Crawshaw, Dylan J.; Vidal Taboada, José Manuel; Saura Martí, Josep; Matalonga, Jonathan; Nunes Chini, Eduardo; Caelles Franch, Carme; Valledor Fernández, Annabel
Introduction: Macrophages abundantly express liver X receptors (LXRs), which are ligand-dependent transcription factors and sensors of several cholesterol metabolites. In response to agonists, LXRs promote the expression of key lipid homeostasis regulators. Cross talk between LXRs and inflammatory signals exists in a cell type- and gene-specific manner. A common feature in the macrophage response to inflammatory mediators is the induction of CCAAT/enhancer-binding protein beta (C/EBPβ), a master transcriptional regulator and lineage-determining transcription factor in monocytes/macrophages. Methods: Quantitative real-time PCR in control and C/EBPβ-deficient macrophages was used to explore the role of C/EBPβ in the cross talk between inflammatory mediators and the macrophage response to pharmacological LXR activation. The functional interaction between C/EBPβ and LXRs on selected genomic regions was further characterized by chromatin-immunoprecipitation (ChIP) and gene reporter studies. Results: Whereas inflammatory signaling repressed several LXR-regulated genes involved in lipid metabolism, these effects were conserved after deletion of C/EBPβ. In contrast, inflammatory mediators and LXRs synergistically induced the expression of the multifunctional protein CD38 in a C/EBPβ-dependent manner. C/EBPβ and LXRs bound to several regions with enhancer activity upstream and within the mouse Cd38 gene and their functional cooperation in macrophages required intact binding sites for LXR and C/EBPβ. Conclusion: This study reveals positive cross talk between C/EBPβ and LXRs during the macrophage inflammatory response, which selectively impacts CD38 expression.
LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based Parkinson’s disease model
(Springer Science and Business Media LLC, 2025-08-12) Blasco Agell, Lucas; Pons Espinal, Meritxell; Testa, Veronica; Roch, Gerard; Montero-Muñoz, Jara; Fernández Carasa, Irene; Baruffi, Valentina; Gonzalez-Sepulveda, Marta; Richaud-Patin, Yvonne; Jimenez, Senda; Cuadros, Thais; Cladera-Sastre, Joana M.; Compte, Joan; Manglano-Artuñedo, Zoe; Ventura, Salvador; Juan, Manel; Tolosa, Eduardo; Raya Chamorro, Ángel; Vila, Miquel; Consiglio, Antonella
Parkinson's disease (PD) is a progressive, incurable neurodegenerative disorder characterized by the loss of neuromelanin (NM)-containing dopamine neurons (DAn) in the substantia nigra of the midbrain. Non-neuronal cells are increasingly recognized as contributors to PD. We generated human microglia-like cells (hMG) from induced pluripotent stem cells (iPSC) derived from patients with LRRK2 PD-causing mutations, gene-corrected isogenic controls, and healthy donors. While neither genotype induced neurodegeneration in healthy DAn, LRRK2 hMG become hyperreactive to LPS stimulation, exhibiting increased cytokine expression, reactive oxygen species, and phagocytosis. When exposed to NM-containing particles, but not alpha-synuclein fibrils, LRRK2 hMG trigger DAn degeneration, in a process that is prevented by pre-treatment with the immunomodulatory drug ivermectin. Finally, post-mortem analysis of midbrain tissue of LRRK2-PD patients show increased microglia activation around NM-containing neurons, confirming our in vitro findings. Overall, our work highlights NM-activated microglia's role in PD progression, and provides a model for testing therapeutic targets.
A Nanoencapsulated Ir(III)-Phthalocyanine Conjugate as a Promising Photodynamic Therapy Anticancer Agent
(American Chemical Society, 2024-07-23) Bonelli Blasco, Joaquin Daniel; Ortega-Forte, Enrique; Vigueras, Gloria; Follana-Berná, Jorge; Ashoo, Pezhman; Abad-Montero, Diego; Isidro, Neus; López-Corrales, Marta; Hernández, Adrián; Ortiz, Javier; Izquierdo García, Eduardo; Bosch, Manel; Rocas, Josep; Sastre-Santos, Ángela; Ruiz, José; Marchán Sancho, Vicente
Despite the potential of photodynamic therapy (PDT) in cancer treatment, the development of efficient and photostable photosensitizing molecules that operate at long wavelengths of light has become a major hurdle. Here, we report for the first time an Ir(III)-phthalocyanine conjugate (Ir-ZnPc) as a novel photosensitizer for high-efficiency synergistic PDT treatment that takes advantage of the longwavelength excitation and near infrared (NIR) emission of the phthalocyanine scaffold and the known photostability and high phototoxicity of cyclometalated Ir(III) complexes. In order to increase water solubility and cell membrane permeability, the conjugate and parent zinc phthalocyanine (ZnPc) were encapsulated in amphoteric redox-responsive polyurethane-polyurea hybrid nanocapsules (Ir-ZnPc-NCs and ZnPc-NCs, respectively). Photobiological evaluations revealed that the encapsulated Ir-ZnPc conjugate achieved high photocytotoxicity in both normoxic and hypoxic conditions under 630 nm light irradiation, which can be attributed to dual Type I and Type II reactive oxygen species (ROS) photogeneration. Interestingly, PDT treatments with Ir-ZnPc-NCs and ZnPc-NCs significantly inhibited the growth of three-dimensional (3D) multicellular tumor spheroids. Overall, the nanoencapsulation of Zn phthalocyanines conjugated to cyclometalated Ir(III) complexes provides a new strategy for obtaining photostable and biocompatible red-light-activated nano-PDT agents with efficient performance under challenging hypoxic environments, thus offering new therapeutic opportunities for cancer treatment.
Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers
(Elsevier, 2025-07-09) Llorens-Giralt, Palmira; Ruiz Romero, Marina; Nurtdinov, Ramil; Herranz Itúrbide, Macarena; Vicent, Guillermo Pablo; Serras Rigalt, Florenci; Fabregat Romero, Isabel; Corominas, Montserrat (Corominas Guiu)
The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice. We show that the expression of crucial regeneration genes is orchestrated by a diverse array of cis-regulatory elements, including regeneration-specific enhancers and enhancers repurposed from various developmental stages. These enhancers collaborate to activate the transcriptional programs required for hepatocyte priming and proliferation, with their activity initially regulated by the activator protein-1 (AP-1) complex and ATF3, and subsequently by nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) during proliferation. Our results also indicate that hepatic regeneration involves the repression of enhancers regulating liver-specific metabolic functions, particularly those involved in lipid metabolism. This study provides a genome-wide atlas of enhancer-gene interactions, offering new insights into the regulatory mechanisms underlying liver regeneration.
Lifetime suicidal thoughts, attempts, and lethality of attempts as major outcome domains of psychotic disorders: a 21-year prospective cohort study after a first-episode psychosis
(Cambridge University Press (CUP), 2025-03-04) Peralta, Víctor; Moreno-Izco, Lucía; García de Jalón, Elena; Sánchez Torres, Ana M.; Peralta, David; Janda, Lucía; Cuesta, Manuel J.; SEGPEPs group; Ansorena, Xabier; Ballesteros, Alejandro; Chato, Julen; Fañanás Saura, Lourdes; Gil-Berrozpe, Gustavo; Giné-Servé, Eloi; Lorente, Ruth; Papiol, Sergi; Ribeiro, María; Rosado, Esther; Rosero, Ángela
Background: Suicidal thoughts and behaviors (STBs) are a major concern in people with psychotic disorders. There is a need to examine their prevalence over long-term follow-up after first-episode psychosis (FEP) and determine their early predictors. Methods: Of 510 participants with FEP evaluated on 26 risk factors for later outcomes, 260 were reassessed after 21 years of follow-up for lifetime ratings of most severe suicidal ideation, number of suicide attempts, and lethality of the most severe attempt. Risk factors and STB outcomes were modeled using hierarchical linear regression analysis. Results: Over the 21-year follow-up period, 62.7% of participants experienced suicidal thoughts, 40.8% attempted suicide, and 18 died of suicide (3.5% case fatality and 20.6% proportionate mortality). Suicidal ideation was independently predicted by parental socioeconomic status, familial load of major depression, neurodevelopmental delay, poor adolescence social networks, and suicidal thoughts/behavior at FEP. The number of suicide attempts was independently predicted by years of follow-up, familial load of major depression, obstetric complications, childhood adversity, and suicidal thoughts/behavior at FEP. Lethality was independently predicted by familial load of major depression, obstetric complications, neurodevelopmental delay, and poor adolescence social networks. The proportion of variance in suicidal ideation, attempts, and lethality explained by the independent predictors was 29.3%, 21.2%, and 18.1%, respectively. Conclusions: STBs are highly prevalent in psychotic disorders and leads to substantial morbidity and mortality. They were predicted by a number of early risk factors, whose clinical recognition should contribute to improved prediction and prevention in people with psychotic disorders.
Decreased brain serotonin in rbfox1 mutant zebrafish and partial reversion of behavioural alterations by the SSRI fluoxetine
(MDPI, 2024-02-16) Adel, Maja R.; Antón Galindo, Ester; Gago-Garcia, Edurne; Arias-Dimas, Ángela; Arenas Solà, Concepción; Artuch, Rafael; Cormand Rifà, Bru; Fernàndez Castillo, Noèlia
RBFOX1 functions as a master regulator of thousands of genes, exerting a pleiotropic effect on numerous neurodevelopmental and psychiatric disorders. A potential mechanism by which RBFOX1 may impact these disorders is through its modulation of serotonergic neurotransmission, a common target for pharmacological intervention in psychiatric conditions linked to RBFOX1. However, the precise effects of RBFOX1 on the serotonergic system remain largely unexplored. Here we show that homozygous rbfox1sa15940 zebrafish, which express a shorter, aberrant rbfox1 mRNA, have significantly reduced serotonin levels in telencephalon and diencephalon. We observed that the acute administration of fluoxetine partially reverses the associated behavioural alterations. The hyperactive phenotype and altered shoaling behaviour of the rbfox1sa15940/sa15940 zebrafish could be reversed with acute fluoxetine exposure in the Open Field and the Shoaling test, respectively. However, in the other paradigms, hyperactivity was not diminished, suggesting a distinct intrinsic motivation for locomotion in the different paradigms. Acute fluoxetine exposure did not reverse the alterations observed in the aggression and social novelty tests, suggesting the involvement of other neurological mechanisms in these behaviours. These findings underscore the importance of investigating the intricate working mechanisms of RBFOX1 in neurodevelopmental and psychiatric disorders to gain a better understanding of the associated disorders along with their pharmacological treatment.
Reactive oxygen species activate the Drosophila TNF receptor Wengen for damage-induced regeneration
(EMBO Press, 2024-09-02) Esteban-Collado, José; Fernández Mañas, Mar; Fernández Moreno, Manuel; Maeso, Ignacio; Corominas, Montserrat (Corominas Guiu); Serras Rigalt, Florenci
Tumor necrosis factor receptors (TNFRs) control pleiotropic pro-inflammatory functions that range from apoptosis to cell survival. The ability to trigger a particular function will depend on the upstream cues, association with regulatory complexes, and downstream pathways. In Drosophila melanogaster, two TNFRs have been identified, Wengen (Wgn) and Grindelwald (Grnd). Although several reports associate these receptors with JNK-dependent apoptosis, it has recently been found that Wgn activates a variety of other functions. We demonstrate that Wgn is required for survival by protecting cells from apoptosis. This is mediated by dTRAF1 and results in the activation of p38 MAP kinase. Remarkably, Wgn is required for apoptosis-induced regeneration and is activated by the reactive oxygen species (ROS) produced following apoptosis. This ROS activation is exclusive for Wgn, but not for Grnd, and can occur after knocking down Eiger/TNFα. The extracellular cysteine-rich domain of Grnd is much more divergent than that of Wgn, which is more similar to TNFRs from other animals, including humans. Our results show a novel TNFR function that responds to stressors by ensuring p38-dependent regeneration.
In search of radical transformations from metal enolates. Direct reactions of N‑acyl-1,3-oxazolidin-2-ones with TEMPO catalyzed by copper(II) acetate
(American Chemical Society, 2025-05-27) Balaguer Garcia, Eduard; Pérez-Palau, Marina; Bello Quiñones, Cristina; Costa, Ana Maria; Romea, Pedro; Urpí Tubella, Fèlix
The direct reactions of a diverse range of N-acyl-1,3-oxazolidin-2-ones with TEMPO, catalyzed by copper(II) acetate and 4,7-dimethyl-1,10-phenanthroline without the need for any base, are herein described. These reactions afford the corresponding aminoxylated derivatives with high chemoselectivity and complete regioselectivity, achieving excellent yields under mild conditions. Further treatment of the resulting imides enables access to a variety of formally protected hydroxy compounds, which can be regarded as valuable synthetic intermediates. The efficient formal synthesis of isoproterenol highlights the potential of this methodology and sets the stage for further advancements in the catalytic chemistry of metal enolates.
YAT2150: Overcoming limitations of traditional amyloid dyes in aggregation studies
(Elsevier Ltd., 2025-03-19) Espargaró Colomé, Alba; Álvarez-Berbel, Irene; Llabrés Prat, Salomé; Domènech Cabrera, Òscar; Busquets i Viñas, Ma. Antonia; Fernàndez Busquets, Xavier; Arce, Elsa M.; Gavín Marín, Rosalina; Río Fernández, José Antonio del; Muñoz-Torrero López-Ibarra, Diego; Luque Garriga, F. Xavier; Sabaté Lagunas, Raimon
Amyloid fibrils, which are aggregates of misfolded proteins characterized by β-sheet-rich structures, are implicated in several neurodegenerative and systemic pathologies, including Alzheimer’s and Parkinson’s diseases and type II diabetes mellitus. Traditional amyloid markers, such as Congo Red and Thioflavin T, are widely used for amyloid detection but present limitations, particularly in cellular assays, due to spectral interference and aggregation inhibition. This study investigates YAT2150, a novel fluorescent dye with enhanced amyloid-binding specificity and sensitivity, as a potential alternative to conventional dyes. We evaluated YAT2150’s efficacy for detecting amyloid aggregates in both in vitro and in cellula assays. First, we compared its fluorescence intensity and binding specificity to that of Thioflavin T in amyloid fibril assays, demonstrating that YAT2150 exhibits high affinity and selectivity for amyloid structures, with minimal interference from non-aggregated proteins. Furthermore, we explored YAT2150’s utility in Escherichia coli as a model system for studying protein aggregation and amyloid formation in a procaryotic cellular context. Our findings indicate that YAT2150 effectively labels amyloid-like inclusion bodies in E. coli, producing a robust fluorescence signal with low background noise. These results suggest that YAT2150 is a promising new tool for amyloid research, offering greater sensitivity compared to traditional dyes, even in complex cellular environments.
Influence of Ionization and the Addition of Cyclodextrins andHydrophilic Excipients on the Solubility of Benzthiazide,Isoxicam, and Piroxicam
(MDPI, 2025-04-25) Lucero Borja, Diego Sebastián; Ruiz, Rebeca; Fuguet i Jordà, Elisabet; Ràfols Llach, Clara
Background: The bioavailability of a drug depends, among other parameters,on solubility. One of the strategies used to enhance the solubility of sparingly solubledrugs is the use of excipients. Excipients can interact with the drug by increasing its solubilityand/or stabilizing supersaturated solutions. Some of the most common excipientsare cyclodextrins and hydrophilic polymers. Objectives: The effect of two cyclodextrins(captisol and cavasol) and three hydrophilic polymers (klucel, kollidon and plasdoneS630) on the solubility of three ionizable drugs (benzthiazide, isoxicam, and piroxicam) isevaluated at biorelevant pH values, using two complementary techniques. Methods: Thesolubility enhancement was evaluated by the comparison of the solubility with and withoutthe presence of excipients through the shake-flask and CheqSol methodology. Results:Captisol and cavasol slightly increase the concentration of the neutral species of the drugsin the solution before precipitation begins, although they do not enhance the supersaturationduration nor the thermodynamic solubility of the drugs. The increase in solubilityin the presence of cyclodextrins is mainly caused by the ionization state of the drug. Hydrophilicpolymers not only improve thermodynamic solubility but also the extent andthe duration of the supersaturation. Some metastable forms are observed for benzthiazideand isoxicam in the presence of kollidon and plasdone S630. Conclusions: The shake-flaskmethod enabled the evaluation of thermodynamic solubility both in the absence and presenceof excipients. Meanwhile, the CheqSol method provided insights into the presenceof supersaturated solutions. Different behavior is observed depending on the nature ofthe excipient.

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