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Assessing the contribution of genes involved in monogenic bone disorders to the etiology of atypical femoral fractures
(BioMed Central, 2024-12-01) Garcia Giralt, Natàlia; Ovejero, Diana; Grinberg Vaisman, Daniel Raúl; Nogués Solán, Xavier; Castañeda, Santos; Balcells Comas, Susana; Rabionet Janssen, Raquel
Background: Recent studies suggested that genetic variants associated with monogenic bone disorders were involved in the pathogenesis of atypical femoral fractures (AFF). Here, we aim to identify rare genetic variants by whole exome sequencing in genes involved in monogenic rare skeletal diseases in 12 women with AFF and 4 controls without any fracture. Results: Out of 33 genetic variants identified in women with AFF, eleven (33.3%) were found in genes belonging to the Wnt pathway (LRP5, LRP6, DAAM2, WNT1, and WNT3A). One of them was rated as pathogenic (p.Pro582His in DAAM2), while all others were rated as variants of uncertain significance according to ClinVar and ACMG criteria. Conclusions: Osteoporosis, rare bone diseases, and AFFs may share the same genes, thus making it even more difficult to identify unique risk factors.
The Liver Clock Tunes Transcriptional Rhythms in Skeletal Muscle to Regulate Mitochondrial Function
(SAGE Publications, 2026-01-04) Sica, Valentina; Sato, Tomoki; Tsialtas, Ioannis; Hernandez, Sophia; Chen, Siwei; Baldi, Pierre; Muñoz Cánoves, Pura, 1962-; Sassone-Corsi, Paolo; Koronowski, Kevin B.; Smith, Jacob Anderson Giffen
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Inhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
(Nature Publishing Group, 2022-04-19) Erdem, Aysegül; Marín Martínez, Silvia; Pereira-Martins, Diego A.; Geugien, Marjan; Cunningham, Alan; Pruis, Maurien G.; Weinhäuser, Isabel; Gerding, Albert; Bakker, Barbara M.; Wierenga, Albertus; Rego, Eduardo; Huls, Gerwin; Cascante i Serratosa, Marta; Schuringa, Jan Jacob
Metabolic programs can differ substantially across genetically distinct subtypes of acute myeloid leukemia (AML). These programs are not static entities but can change swiftly as a consequence of extracellular changes or in response to pathway-inhibiting drugs. Here, we uncover that AML patients with FLT3 internal tandem duplications (FLT3-ITD+) are characterized by a high expression of succinate-CoA ligases and high activity of mitochondrial electron transport chain (ETC) complex II, thereby driving high mitochondrial respiration activity linked to the Krebs cycle. While inhibition of ETC complex II enhances apoptosis in FLT3-ITD+ AML, cells also quickly adapt by importing lactate from the extracellular microenvironment. 13C3-labelled lactate metabolic flux analyses reveal that AML cells use lactate as a fuel for mitochondrial respiration. Inhibition of lactate transport by blocking Monocarboxylic Acid Transporter 1 (MCT1) strongly enhances sensitivity to ETC complex II inhibition in vitro as well as in vivo. Our study highlights a metabolic adaptability of cancer cells that can be exploited therapeutically.
The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia
(Nature Publishing Group, 2022-03-01) Erdem, Aysegül; Marín Martínez, Silvia; Pereira-Martins, Diego A.; Cortes Giraldez, Roldan; Cunningham, Alan; Pruis, Maurien G.; de Boer, Bauke; van den Heuvel, Fiona; Geugien, Marjan; Wierenga, Albertus; Brouwers-Vos, Annet; Rego, Eduardo; Huls, Gerwin; Cascante i Serratosa, Marta; Schuringa, Jan Jacob
Acute myeloid leukemia remains difficult to treat due to strong genetic heterogeneity between and within individual patients. Here, we show that Pyruvate dehydrogenase kinase 1 (PDK1) acts as a targetable determinant of different metabolic states in acute myeloid leukemia (AML). PDK1low AMLs are OXPHOS-driven, are enriched for leukemic granulocyte-monocyte progenitor (L-GMP) signatures, and are associated with FLT3-ITD and NPM1cyt mutations. PDK1high AMLs however are OXPHOSlow, wild type for FLT3 and NPM1, and are enriched for stemness signatures. Metabolic states can even differ between genetically distinct subclones within individual patients. Loss of PDK1 activity releases glycolytic cells into an OXPHOS state associated with increased ROS levels resulting in enhanced apoptosis in leukemic but not in healthy stem/progenitor cells. This coincides with an enhanced dependency on glutamine uptake and reduced proliferation in vitro and in vivo in humanized xenograft mouse models. We show that human leukemias display distinct metabolic states and adaptation mechanisms that can serve as targets for treatment.
From Current Therapeutics to Multitarget Ligands: A Review of Diabetes Pharmacological Treatments
(MDPI, 2025-09-01) Cabré Vacas, Francesc; Centelles Serra, Josep Joan; Cascante i Serratosa, Marta
Diabetes is a chronic and complex pathological syndrome that includes a series of disorders and imbalances, whose first characterization is hyperglycemia, although, as it is a multifactorial phenomenon, it requires risk reduction strategies beyond glycemic control. Continuous education and support for diabetes self-management are essential to prevent acute complications and reduce the risk of long-term complications. Therefore, the guidelines for the treatment of diabetes emphasize the importance of lifestyle changes, including a reduced-calorie diet and increased physical activity. However, for many people, these changes can be difficult to maintain in the long term and eventually they must resort to pharmacological treatment that in most cases requires the combined use of two or more antidiabetic drugs with different mechanisms of action. This review explores the different pharmacological agents, authorized and used therapeutically, for the control of diabetes, especially type 2 diabetes, and analyzes the development strategies of multi-target agents whose effects, through distinct mechanisms and by acting on more than one receptor, could represent a promising alternative in the treatment of a multifactorial disease such as diabetes. As regards therapeutic uses, from metformin to glucose transporter inhibitors (SGLT2i), the potential mechanisms of action, pharmacological and clinical effects, safety, and use in therapeutics are described, presenting, as far as reasonably possible, diverse comparisons between them. In conclusion, although metformin remains the first-line agent for the treatment of type 2 diabetes, the choice of a second-line agent depends on several factors, in particular the cardiovascular risk profile, weight, and renal function of the patient; moreover, the ideal pharmacological treatment, although expected and desired, has in fact not been achieved so far, and physicians must consider not only the glycemic efficacy of the agent but also all the other potential benefits, balanced by the possible adverse effects. Compounds modulating multiple signaling pathways are a promising approach to manage this multifactorial disorder, with the primary objective of maintaining the therapeutic efficacy observed in several clinical studies, alongside reducing adverse effects, the main reason for the discontinuation of developments, to levels that enable a favorable risk-benefit balance.
Polo-like kinase 1 inhibitors in refractory colorectal cancer: deciphering the myth of synthetic lethality
(AME Publishing Company, 2024-08-25) Rojas, Mariam; Gonzalez, Laura; Cascante i Serratosa, Marta; Maurel Santasusana, Joan
Metastatic colorectal cancer (mCRC) remains a highly lethal disease because resistance to chemotherapy and targeted agents—including anti-VEGF and anti-EGFR therapies—emerges rapidly and universally. In RAS‑mutant mCRC, second-line treatment with FOLFIRI plus bevacizumab achieves modest clinical benefit, underscoring the need to understand mechanisms of resistance and develop rational combination strategies. Recent evidence implicates oxidative phosphorylation (OXPHOS), antioxidant programs such as the pentose phosphate pathway (PPP), and polo-like kinase 1 (PLK1)–dependent cell‑cycle regulation as key determinants of therapeutic refractoriness. In a recent phase Ib study, onvansertib, a PLK1 inhibitor, combined with FOLFIRI and bevacizumab produced a notable 44% response rate and a median progression-free survival of 12.6 months in RAS‑mutant tumors, suggesting a subset of patients may derive meaningful benefit. Integrating these clinical findings with current metabolic and genomic insights, we highlight how OXPHOS‑driven tumors activate antioxidant networks, sustain chromosome instability, and remodel nutrient usage—features that may blunt synthetic lethality and foster resistance to DNA‑damaging agents, PARP inhibitors, and PLK1 inhibition. We also discuss how altered DNA‑repair reliance (HR, NHEJ, and MMEJ), lactate‑supported mitochondrial metabolism, ENPP1‑mediated immunosuppression, and MYC activation converge to shape chemoresistance and impaired immune responses in microsatellite‑stable colorectal cancer. A more precise therapeutic approach may require selecting patients with combined OXPHOS and PPP activation and leveraging rational combinations involving PLK1, PARP, or ENPP1 inhibitors together with immune checkpoint blockade. Such strategies could enhance the efficacy of ongoing clinical trials and refine future treatment paradigms for heavily pretreated colorectal cancer.
Metabolic plasticity drives specific mechanisms of chemotherapy and targeted therapy resistance in metastatic colorectal cancer
(Open Exploration, 2025-09-23) Rojas, Mariam; Manzi, Malena; Madurga Díez, Sergio; García Velásquez, Fernando Enrique; Romero, Maira Alejandra; Marín Martínez, Silvia; Cascante i Serratosa, Marta; Maurel Santasusana, Joan
Microsatellite-stable metastatic colorectal cancer (MSS mCRC) is currently treated with chemotherapy and targeted agents based on RAS and BRAF mutational status. Although these therapies offer initial benefit, most patients rapidly develop resistance, with fewer than 20% remaining progression-free at two years. This review aims to synthesize emerging evidence on the metabolic mechanisms driving treatment resistance in MSS mCRC, with a particular focus on the immune-metabolic signature (IMMETCOLS) classification. We conducted a comprehensive review of preclinical models, transcriptomic datasets, and clinical trial results addressing metabolic adaptations to chemotherapy and targeted therapies in MSS mCRC. The IMMETCOLS framework defines three metabolic subtypes—IMC1, IMC2, and IMC3—each associated with distinct resistance mechanisms. IMC1 exhibits glycolysis and transforming growth factor-β (TGF-β)-dependent signaling enriched in inflammatory fibroblasts, conferring resistance to chemotherapy. IMC2 relies on oxidative phosphorylation and glutamine metabolism, supporting antioxidant defenses and resistance to both cytotoxic agents and anti-EGFR therapies. IMC3 demonstrates lactate-fueled respiration and pentose phosphate pathway activation, contributing to redox balance, DNA repair, and resistance to targeted therapies such as anti-BRAF or KRAS inhibitors. All subtypes display metabolic plasticity under therapeutic pressure. Emerging clinical data support tailoring targeted therapy combinations based on IMMETCOLS subtype, particularly in BRAF- and HER2-positive populations. Understanding subtype-specific metabolic rewiring in MSS mCRC offers novel opportunities to overcome drug resistance. Targeting the metabolic vulnerabilities defined by the IMMETCOLS signature may improve response durability and inform precision treatment strategies.
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.
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.
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.
Lithium response in bipolar disorder: Epigenome-wide DNA methylation signatures and epigenetic aging
(Elsevier B.V., 2024-04-25) Zafrilla-López, Marina ; Acosta-Díez, Miriam; Mitjans Niubó, Marina; Giménez Palomo, Anna; Saiz, Pilar A.; Barrot i Feixat, Carme; Jiménez Martínez, Ester; Papiol, Sergi; Ruiz, Victoria; Gavín, Patrícia; García-Portilla González, María Paz, 1962-; González-Blanco, Leticia; Bobes García, Julio; Schulze, Thomas G.; Vieta i Pascual, Eduard, 1963-; Benabarre, Antonio; Arias Sampériz, Bárbara
Lithium (Li) is the first-line treatment for bipolar disorder (BD) even though only 30 % of BD patients are considered excellent responders. The mechanisms by which Li exerts its action are not clearly understood, but it has been suggested that specific epigenetic mechanisms, such as methylation processes, may play a role. In this regard, DNA methylation patterns can be used to estimate epigenetic age (EpiAge), which is accelerated in BD patients and reversed by Li treatment. Our first aim was to compare the DNA methylation profile in peripheral blood between BD patients categorized as excellent responders to Li (Ex-Rp) and non-responders (N-Rp). Secondly, EpiAge was estimated to detect differential age acceleration between the two groups. A total of 130 differentially methylated positions (DMPs) and 16 differentially methylated regions (DMRs) between Ex-Rp (n = 26) and N-Rp (n = 37) were identified (FDR adjusted p-value < 0.05). We found 122 genes mapping the DMPs and DMRs, nine of which (HOXB6, HOXB3, HOXB-AS3, TENM2, CACNA1B, ANK3, EEF2K, CYP1A1, and SORCS2) had previously been linked to Li response. We found genes related to the GSK3β pathway to be highly represented. Using FUMA, we found enrichment in Gene Ontology Cell Component for the synapse. Gene network analysis highlighted functions related to the cell cycle, nervous system development and function, and gene expression. No significant differences in age acceleration were found between Ex-Rp and N-Rp for any of the epigenetic clocks analysed. Our findings indicate that a specific methylation pattern could determine the response to Li in BD patients. We also found that a significant portion of the differentially methylated genes are closely associated with the GSK3β pathway, reinforcing the role of this system in Li response. Future longitudinal studies with larger samples will help to elucidate the epigenetic mechanisms underlying Li response.
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.

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