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Articles publicats en revistes (Institut de Biomedicina (IBUB))

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    Atomically-dispersed transition metal electrocatalysts supported on lignin-derived carbons for cathodic hydrogen peroxide synthesis using a gas-diffusion electrode
    (Elsevier B.V., 2026-05-14) Zuccante, G.; Escaja Sánchez, Nuria; Sirés Sadornil, Ignacio; Muhyuddin, Mohsin; Santoro, Carlo
    Hydrogen peroxide (H2O2) is nowadays a commodity chemical, with a particularly relevant application in wastewater treatment. However, its industrial production is energy demanding, highly polluting and potentially dangerous. Lately, oxygen reduction reaction (ORR) conducted on a gas-diffusion electrode (GDE) has been explored to deploy a more sustainable synthesis route. In this work, a set of lignin-derived carbons, either metal-free or loaded with atomically dispersed transition metals (Fe, Co and Ni), was successfully synthesized for the electrogeneration of H2O2. For some electrocatalysts, the rotating ring-disk electrode (RRDE) analysis showed a peroxide selectivity () over 90% and a number of transferred electrons of ∼2. Accordingly, the type of metal and the carbon porosity had a major influence on the performance of GDEs during bulk electrolysis. In galvanostatic assays conducted in 0.05 M Na2SO4 medium at pH 5.9 and 10 mA cm−2, the carbon obtained from direct lignin pyrolysis at 400 °C outperformed a commercial GDE, showing the highest H2O2 yield (13.8 mM after 360 min), with a maximum current efficiency of 85% and relatively low energy consumption (∼ 8 ). Such optimum performance is related to its optimal porosity and hydrophobicity. Moreover, upon functionalization with Fe, an effective electro-Fenton (EF) catalyst was obtained, allowing a 97% removal of the drug lisinopril using only 0.1 g L−1 of suspended catalyst. This work demonstrates the possibility of producing cost-effective electrocatalysts from waste for H2O2 production and wastewater treatment.
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    Extracellular Vesicles from Escherichia coli Strains of the Gut Microbiota Trigger Hepatic Antioxidant and Anti-Lipogenic Effects via the Gut-Liver Axis in Healthy Neonatal Rats
    (MDPI, 2025-09-25) Martínez-Ruiz, Sergio; Badía Palacín, Josefa; Baldomà Llavinés, Laura
    Background: The gut-liver axis is essential for maintaining liver physiology, with the gut microbiota playing a central role in this bidirectional communication. Recent studies have identified microbiota-derived extracellular vesicles (EVs) as key mediators of inter-organ signaling. This study explored the impact of EVs from two beneficial Escherichia coli strains, the probiotic EcN and the commensal EcoR12, on hepatic metabolism and oxidative stress in healthy neonatal rats. Methods: EVs were administered orally during the first 16 days of life, and blood and liver samples were collected on days 8 and 16. Results: The results demonstrated that EVs significantly reduced intestinal permeability, as evidenced by decreased plasma zonulin levels. In the liver, EVs enhanced redox homeostasis by downregulating CYP2E1 and upregulating key antioxidant genes (SOD1, CAT, GPX). Furthermore, the treatment shifted liver metabolism toward an anti-lipogenic profile by inducing fatty acid oxidation genes (PPARA, CPT1A) and suppressing genes involved in de novo lipogenesis (SREBP1C, ACC1, FASN, CNR1). Importantly, markers of hepatic inflammation remained unchanged, indicating the safety of the intervention. In vitro experiments using human HepG2 cells supported these findings, further validating the antioxidant and metabolic effects of the EVs. Conclusions: Our results underscore the role of microbiota-derived EVs as important mediators of hepatic metabolic programming in healthy individuals via the gut-l
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    Effects of Acute Severe Hypobaric Hypoxia on Gut-Muscle Axis in Rats
    (Springer Verlag, 2026-07-17) Santocildes Martinez, Garoa; Lorenzo, Karenia; Magalhães, José; Amézqueta Pérez, Susana; Pagés, Teresa; Torres Simón, Josep Lluís; Viscor Carrasco, Ginés; Ramos Romero, Sara; Torrella Guio, Joan Ramon
    Acute exposure to high-altitude hypobaric hypoxia (HH) disrupts physiological homeostasis. While gastrointestinal and neurological disturbances are its main manifestations, muscle function is also affected. However, its short-term effects on the gut–muscle axis remain poorly understood. The present study investigated the impact of a 4-hour exposure to simulated altitude (5,000 m) on intestinal morphology, gut microbiota composition, short-chain fatty acid (SCFA) levels, and skeletal muscle mitochondrial function in male Sprague-Dawley rats. Despite the severity of the hypoxic stimulus, biometric and hematological parameters remained largely unchanged, suggesting preserved systemic stability. Histological analysis revealed a significant reduction in intestinal crypt depth, indicating early structural alterations, while villus morphology and goblet cell counts remained unchanged. Microbiota profiling showed a decrease in Enterobacteriales abundance, while other bacterial groups and SCFA concentrations remained stable, pointing to limited microbial shifts under acute conditions. In skeletal muscle, reactive oxygen species (ROS) production increased under complex I-supported respiration while mitochondrial respiration was maintained across all respiratory states. This suggests a qualitative shift in redox balance. Collectively, these findings indicate that acute HH triggers early localized responses in intestinal and muscular tissues without inducing widespread systemic disruption, highlighting the resilience of the gut–muscle axis to short-term hypoxic stress. Longer or repeated exposures may be required to elicit broader physiological adaptations. This study contributes to understanding the early effects of altitude-related hypoxia and underscore the importance of exposure duration in shaping host responses.
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    New UB006 derivatives with a higher solubility and cytotoxic activity in ovarian cancer cells
    (MDPI, 2025-01-31) Reina del Pozo, Manuel; Ariza Piquer, Xavier; Serra i Cucurull, Dolors; García Gómez, Jordi; Herrero Rodríguez, Laura
    Background/Objectives: The compound (±)-UB006 ((4SR,5SR)-4 (hydroxymethyl)- 3-methylene-5-octyldihydrofuran-2(3H)-one) is a promising anti-cancer molecule. The enantiomer (–)-UB006 displays a potent cytotoxic effect in several tumor cell lines, particularly the ovarian cancer OVCAR-3 cell line, with a 40-fold increase in potency compared with the fatty acid synthase (FAS) inhibitor C75. Furthermore, in vivo, (–)-UB006 reduced the tumor burden in neuroblastoma xenografts. This effect was attributed to FAS inhibition and upregulation of apoptotic markers. However, CoA adducts of UB006 presented low solubility. Methods: We synthesized several (±)-UB006 derivatives by elongating the carbon chain of the primary alcohol and/or by adding hydroxyl groups with the aim of finding more potent and soluble anti-cancer compounds. Results: Our results showed a decrease in cytotoxicity when the carbon chain was elongated by more than two carbons. However, ethyl or propyl polyhydroxylated four-branched compounds showed an increased or maintained potency and solubility. The most promising compound was (±)-UB035 (IC50: 2.1 ± 0.2 µM), with a 2.5-fold increase in cytotoxicity in the OVCAR-3 cell line and a >4-fold increase in solubility (>2 mM) compared with (±)-UB006.
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    Association analysis between polygenic risk scores and traits: practical guidelines and tutorial with an illustrative data set of schizophrenia
    (Frontiers Media, 2025-08-21) Irigoien, Itziar; Mas-Bermejo, Patricia; Papiol, Sergi; Barrantes Vidal, Neus; Rosa de la Cruz, Araceli; Arenas Solà, Concepción
    Most methodological Polygenic Risk Score (PRS)-related papers explain the laborious process of computing the PRS in great depth. Afterwards, as a last step, it is generally described that to test a possible association between a PRS and a trait of interest, an analysis through regression models (linear or logistic, depending on data type) should be carried out adjusting for covariates (e.g., sex, age, clinical information, or genetic ancestry-based Principal Components). When covariates are included, measurements such as the increment on the variance explained by the addition of the PRS to the model or the significance of the PRS term are usually reported. However, the association study between PRSs and a trait is a complex concern that requires proper modeling and analysis, since interactions and validation conditions represent crucial aspects. Even though excellent papers explain how to use and interpret the results obtained with such regression models, sometimes important information from the previously calculated PRS may be lost, partly due to the automation of analyses. With this guide, we intend to fill a gap in association studies between PRSs and a trait and to facilitate the analysis, obtaining statistically correct results. It contains a motivating real data case analyzed exhaustively to illustrate how to face a real analysis. Besides, it is accompanied by four examples, called Working Examples, which present different situations the researcher may encounter along with the R code for analyzing all these data sets and the corresponding application of the steps in this guide.
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    Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models
    (Elsevier Masson SAS, 2022-11-21) Staderini, Matteo; Vanni, Silvia; Colini Baldeschi, Arianna; Giachin, Gabriele; Zattoni, Marco; Celauro, Luigi; Ferracin, Chiara; Bistaffa, Edoardo; Moda, Fabio; Pérez, Daniel I.; Martínez, Ana; Martín, M. Antonia; Martín Cámara, Olmo; Cores, Ángel; Bianchini, Giulia; Kammerer, Robert; Menéndez, J. Carlos; Legname, Giuseppe; Bolognesi, Maria Laura
    Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four-step route, and a representative member was confirmed to have native fluorescence, including a band in the near-infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cell lines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrPC levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain-independent anti-prion compounds.
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    Validity and reliability of tools to measure ultraprocessed food intake under the NOVA system: A systematic review
    (Elsevier B.V., 2026-05) Cavero Redondo, Ivan; Saz Lara, Alicia; Bouzas, Cristina; Saz Lara, Andrea del; Chiva Blanch, Gemma; Konieczna, Jadwiga; Picó, Catalina; Fernández Aranda, Fernando; Moreno-Aliaga, María J.; Daimiel, Lidia; Martínez, J. Alfredo; Salas Salvadó, Jordi; Portillo, María P.; Toledo Atucha, Estefanía; Giralt i Oms, Marta; Corella Piquer, Dolores; Moreno-Indias, Isabel; López de Las Hazas, María-Carmen; Dávalos, Alberto
    Background: Ultraprocessed foods (UPFs) contribute substantially to global energy intake and are consistently linked to adverse health outcomes. However, accurately assessing UPF intake remains challenging due to reliance on self-reported data and retrospective processing classification, with performance highly dependent on reference method quality. Objectives: To evaluate the validity, reliability, agreement, and risk of bias of instruments used to quantify UPF intake according to the NOVA classification and to examine the agreement between food processing classification systems. Methods: We conducted a 2020 PRISMA–compliant systematic review of PubMed/MEDLINE, Scopus, and Web of Science from inception to 12 January, 2026, without language restrictions. Two reviewers (IC-R and AS-L) independently screened studies, extracted data, and assessed methodological quality via the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) risk of bias checklist. The evidence was synthesized narratively and through structured visual summaries of test–retest reliability (intraclass correlation coefficients), relative (criterion/convergent) validity against dietary reference methods, classification agreement (Cohen’s κ and prevalence-adjusted bias-adjusted κ), and internal consistency (Cronbach’s α or McDonald’s ω). Results: Thirty studies were included: 19 evaluated basic dietary intake instruments (NOVA-oriented food frequency questionnaires, short screening tools, or UPF scores), 4 examined biomarker-based or indirect tools, and 7 assessed contextual or auxiliary instruments. The test–retest reliability of the dietary intake instruments was generally moderate-to-high (intraclass correlation coefficients ≈ 0.46–0.94). Relative validity against dietary reference methods was modest to moderate (correlations typically r ≈ 0.47–0.72), and agreement between processing classification systems ranged from fair-to-substantial (Cohen’s κ and prevalence-adjusted bias-adjusted κ ≈ 0.36–0.84). The contextual and auxiliary instruments showed high internal consistency (Cronbach’s α/McDonald’s ω ≥0.74). Fifteen studies were rated as having a low risk of bias, and 15 were rated as unclear. Conclusions: Instruments assessing NOVA-defined UPF intake demonstrate acceptable reproducibility but variable, reference-dependent validity and system-specific classification uncertainty. Future research should prioritize higher-quality reference methods, transparent coding rules, calibration strategies, and routine evaluation of measurement error and responsiveness.
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    The Antiobesity Effects of Rosehip (Rosa canina) Flesh by Antagonizing the PPAR Gamma Activity in High-Fat Diet-Fed Mice
    (Wiley-VCH, 2024-02-08) Sanz Lamora, Héctor; Nicola Llorente, Mariano; Torres-Oteros, Daniel; Pérez-Martí, A.; Aghziel, Inass; Lozano Castellón, Julián; Vallverdú i Queralt, Anna; Canudas Puig, Sílvia; Marrero González, Pedro F.; Haro Bautista, Diego; Relat Pardo, Joana
    Scope: The rosehip (Rosa canina) is a perennial shrub with a reddish pseudofruit that has demonstrated antidiabetic, antiatherosclerotic, and antiobesogenic effects in rodent models but there is low information about the molecular mechanisms underlying these effects on the onset and progression of diet-induced obesity. Methods and results: Four-week-old C57BL/6J male mice are subjected to a high-fat diet (HFD)-supplemented or not with R. canina flesh for 18 weeks. The results indicated that the R. canina flesh exerts a preventive effect on HFD-induced obesity with a significant reduction in body-weight gain and an improvement of hyperglycemia and insulin resistance caused by a HFD. At the tissue level, subcutaneous white adipose tissue exhibits a higher number of smaller adipocytes, with decreased lipogenesis. On its side, the liver shows a significant decrease in lipid droplet content and in the expression of genes related to lipogenesis, fatty acid oxidation, and glucose metabolism. Finally, the data suggest that most of these effects agree with the presence of a putative Perosxisome proliferator-activated receptor gamma (PPAR ) antagonist in the R. canina flesh. Conclusions: R. canina flesh dietary supplementation slows down the steatotic effect of a HFD at least in part through the regulation of the transcriptional activity of PPAR .
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    GADD45A: With or without you
    (Wiley, 2024-07-01) Palomer Tarridas, Francesc Xavier; Salvador, Jesús M.; Griñán Ferré, Christian; Barroso Fernández, Emma; Pallàs i Llibería, Mercè, 1964-; Vázquez Carrera, Manuel
    The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non-genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well-known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP-activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune-related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.
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    Is Helicobacter pylori a new kid on the block?
    (Elsevier España, 2024-02-23) Vázquez Carrera, Manuel
    It is well known that traditional risk factors for atherosclerosis, such as age, smoking, diabetes mellitus, dyslipidemia, hypertension, and chronic inflammation, only account for approximately 50% of the incidence of atherosclerosis.1 Therefore, identifying new risks factors that contribute to atherosclerosis development may help to better recognize people with a high cardiovascular risk in the early stages of the disease.
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    The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance
    (John Wiley & Sons, 2024-11-05) Medaglia, Stefano; Reig-Palou, Jaume; Bellés, Ariadna; Moreno-Ruiz, Nerea; Rodríguez, Jairo; Armengol, Xavier; Aróstegui Gorospe, Juan Ignacio; Armengol, Lluís; Guillén, Juan José; Laayouni, Hafid; Casals López, Ferran
    Functional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics. In this study, we evaluated the efficacy of genetic screening technologies in accurately predicting pathogenic variants and their corresponding disease prevalence in a cohort of over 6000 healthy individuals involved in assisted reproduction programs. Using data from 305 genes associated with recessive disorders, we determined the frequency of carriers of pathogenic variants and VOUS in our dataset and compared the predicted prevalence based on this information with reported population prevalence data. The higher predicted prevalence in some disorders when considering VOUS suggests a mostly benign effect.
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    NRN1 epistasis with BDNF and CACNA1C: mediation effects on symptom severity through neuroanatomical changes in schizophrenia
    (Springer Verlag, 2024-05-09) Almodóvar Payá, Carmen; Guardiola Ripoll, Maria; Giralt López, Maria; Oscoz Irurozqui, Maitane; Canales Rodríguez, Erick Jorge; Madre, Mercè; Soler-Vidal, Joan; Ramiro, Núria; Callado, Luis F.; Arias Sampériz, Bárbara; Gallego González, Carmen; Pomarol-Clotet, Edith; Fatjó-Vilas Mestre, Mar
    The expression of Neuritin-1 (NRN1), a neurotrophic factor crucial for neurodevelopment and synaptic plasticity, is enhanced by the Brain Derived Neurotrophic Factor (BDNF). Although the receptor of NRN1 remains unclear, it is suggested that NRN1’s activation of the insulin receptor (IR) pathway promotes the transcription of the calcium voltage-gated channel subunit alpha1 C (CACNA1C). These three genes have been independently associated with schizophrenia (SZ) risk, symptomatology, and brain differences. However, research on how they synergistically modulate these phenotypes is scarce. We aimed to study whether the genetic epistasis between these genes affects the risk and clinical presentation of the disorder via its effect on brain structure. First, we tested the epistatic effect of NRN1 and BDNF or CACNA1C on (i) the risk for SZ, (ii) clinical symptoms severity and functionality (onset, PANSS, CGI and GAF), and (iii) brain cortical structure (thickness, surface area and volume measures estimated using FreeSurfer) in a sample of 86 SZ patients and 89 healthy subjects. Second, we explored whether those brain clusters influenced by epistatic effects mediate the clinical profiles. Although we did not find a direct epistatic impact on the risk, our data unveiled significant effects on the disorder’s clinical presentation. Specifically, the NRN1-rs10484320 x BDNF-rs6265 interplay influenced PANSS general psychopathology, and the NRN1-rs4960155 x CACNA1C-rs1006737 interaction affected GAF scores. Moreover, several interactions between NRN1 SNPs and BDNF-rs6265 significantly influenced the surface area and cortical volume of the frontal, parietal, and temporal brain regions within patients. The NRN1-rs10484320 x BDNF-rs6265 epistasis in the left lateral orbitofrontal cortex fully mediated the effect on PANSS general psychopathology. Our study not only adds clinical significance to the well-described molecular relationship between NRN1 and BDNF but also underscores the utility of deconstructing SZ into biologically validated brain-imaging markers to explore their mediation role in the path from genetics to complex clinical manifestation.
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    Assessing Viral Pollution in Seawater, Using Passive Samplers, Quantitative PCR and Target Enrichment Sequencing
    (Springer Science + Business Media, 2026-01-16) Estarlich-Landajo, Ignasi; Tarradas-Alemany, Maria; Martínez-Puchol, Sandra; Mejías-Molina, Cristina; Verdaguer, Júlia; Bofill Mas, Silvia; Rusiñol Arantegui, Marta
    Detecting pathogenic viruses in seawater presents significant challenges due to their typically low concentrations and the transient nature of contamination events. To address these challenges, this study evaluates passive sampling (PS) as a semiquantitative methodology for viral surveillance in seawater, focusing on human adenovirus (HAdV), norovirus GI (NoVGI) and GII (NoVGII). To optimize the approach, nylon and nitrocellulose membranes were compared, with nylon demonstrating greater consistency and reliability. In Barcelona, across 14 sampling events, 6 of them during combined sewer overflow (CSO) events, PS (n = 51) was assessed against grab sampling (n = 21) coupled with ultrafiltration (UF). Using PS, HAdV, NoVGI, and NoVGII were detected in 100%, 62.5%, and 75% of non-CSO events, respectively, outperforming UF, which detected these viruses in only 37.5%, 25%, and 37.5% of the same events. PS was applied during CSO events at both the CSO discharge point and at a nearby bathing site. As expected, the sampler deployed at the discharge point detected higher viral loads of HAdV, NoVGI, and NoVGII. However, viral genomes were also detected at the bathing site. Target enrichment sequencing of seawater vertebrate-infecting viruses conducted on PS samples, identified vertebrate viral pathogens, including members of the Circoviridae, Parvoviridae and Picornaviridae families, showcasing the extensive viral diversity in seawater due to fecal contamination. This study emphasizes the risk of viral exposure when seawater is impacted by CSO and the potential of PS as a robust tool for seawater viral surveillance, offering enhanced sensitivity and utility for quality management and public health risk assessment.
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    Metabolic Singularities in Microsatellite-Stable Colorectal Cancer: Identifying Key Players in Immunosuppression to Improve the Immunotherapy Response.
    (MDPI, 2025-02-02) Gorría, Teresa; Sierra-Boada, Marina; Rojas, Mariam; Figueras, Carolina; Marín Martínez, Silvia; Madurga Díez, Sergio; Cascante i Serratosa, Marta; Maurel Santasusana, Joan
    Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of patients. In this review, we focus on metabolic singularities-at the transcriptomic (either bulk or single cell), proteomic, and post-translational modification levels-that induce immunosuppression in cancer and specifically in MSS CRC. First, we evaluate the current efficacy of ICIs in limited and metastatic disease in MSS CRC. Second, we discuss the latest findings on the potential biomarkers for evaluating ICI efficacy in MSS CRC using strict REMARK criteria. Third, we review the current evidence on metabolic patterns in CRC tumors and immune cell metabolism to advance our understanding of metabolic crosstalk and to pave the way for the development of combination strategies to enhance ICI efficacy.
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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.
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    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
    Author approved manuscript attached
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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.
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    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.
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    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.
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    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.