Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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Cannabidiol as a multifaceted therapeutic agent: mitigating Alzheimer's disease pathology and enhancing cognitive function
(BioMed Central, 2025-12-01) Raïch, Iu; Lillo, Jaume; Rebassa, Joan-Biel; Griñán Ferré, Christian; Bellver Sanchis, Aina; Reyes Resina, Irene; Franco Fernández, Rafael; Pallàs i Llibería, Mercè, 1964-; Navarro Brugal, Gemma
Background Cannabidiol (CBD), the second most abundant phytocannabinoid in Cannabis sativa, has garnered significant interest due to its non-psychoactive nature and diverse receptor interactions. Methods This study employs in vitro and in vivo methodologies to validate CBD's potential as a treatment for Alzheimer's disease (AD) by addressing key hallmarks of the condition and promoting neuroprotective effects on spatial memory. Results Our findings demonstrate CBD's ability to decrease pTau and Aβ aggregation and to mitigate their axonal transport between cortical and hippocampal neurons. Moreover, CBD treatment was shown to reduce neuroinflammation, as CBD was able to skew microglia towards a neuroprotective M2 phenotype while attenuating proinflammatory cytokine release in the 5xFAD AD mouse model. Notably, daily CBD injections (10 mg/Kg) for 28 days in 5xFAD mice resulted in significant improvements in both short- and long-term spatial memory. The study also reveals CBD's capacity to partially revert neurite formation loss induced by Aβ, Tau, and pTau proteins, suggesting a potential role in promoting neuronal plasticity. Additionally, CBD treatment led to a reduction in reactive oxygen species (ROS) formation and increased neuronal viability in the presence of AD-associated protein aggregates. Conclusions These multifaceted effects of CBD, ranging from molecular-level modulation to behavioral improvements, underscore its potential as a comprehensive therapeutic approach for AD. The findings not only support CBD's neuroprotective properties but also highlight its ability to target multiple pathological processes simultaneously, offering a promising avenue for future AD treatment strategies.
The conserved lysine residue in transmembrane helix 5 is pivotal for the cytoplasmic gating of the L- amino acid transporters
(Oxford University Press, 2025-01-01) Llorca, Oscar; Orozco López, Modesto; Cordes, Thorben; Palacín Prieto, Manuel; Fort, Joana; Nicolàs Aragó, Adrià; Maggi, Luca; Martinez-Molledo, Maria; Kapiki, Despoina; González Novoa, Paula; Gómez Gejo, Patricia; Zijlstra, Niels; Bodoy i Salvans, Susanna; Pardon, Els; Steyaert, Jan
L-Amino acid transporters (LATs) play a key role in a wide range of physiological processes. Defects in LATs can lead to neurological disorders and aminoacidurias, while the overexpression of these transporters is related to cancer. BasC is a bacterial LAT transporter with an APC fold. In this study, to monitor the cytoplasmic motion of BasC, we developed a single-molecule Förster resonance energy transfer assay that can characterize the conformational states of the intracellular gate in solution at room temperature. Based on combined biochemical and biophysical data and molecular dynamics simulations, we propose a model in which the conserved lysine residue in TM5 supports TM1a to explore both open and closed states within the cytoplasmic gate under apo conditions. This equilibrium can be altered by substrates, mutation of conserved lysine 154 in TM5, or a transport-blocking nanobody interacting with TM1a. Overall, these findings provide insights into the transport mechanism of BasC and highlight the significance of the lysine residue in TM5 in the cytoplasmic gating of LATs.
Acyl CoA-binding protein in brown adipose tissue acts as a negative regulator of adaptive thermogenesis.
(Elsevier GmbH, 2025) Blasco Roset, Albert; Villarroya i Gombau, Francesc; Quesada López, Tania Paloma; Mestres Arenas, Alberto; Villarroya i Terrade, Joan; Godoy‑Nieto, Francisco Javier; Cereijo Téllez, Rubén; Rupérez, Celia; Neess, Ditte; Færgeman, Nils J.; Giralt i Oms, Marta; Planavila Porta, Ana
Objective Defective activity of brown adipose tissue (BAT) is linked to obesity and cardiometabolic diseases. While much is known regarding the biological signals that trigger BAT thermogenesis, relatively little is known about the repressors that may impair BAT function in physiological and pathological settings. Acyl CoA-binding protein (ACBP; also known as diazepam binding inhibitor, DBI) has intracellular functions related to lipid metabolism and can be secreted to act as a circulating regulatory factor that affects multiple organs. Our objective was to determine the role of ACBP in BAT function. Methods Experimental models based on the targeted inactivation of the Acbp gene in brown adipocytes, both in vitro and in vivo, as well as brown adipocytes treated with recombinant ACBP, were developed and analyzed for transcriptomic and metabolic changes. Results ACBP expression and release in BAT are suppressed by noradrenergic cAMP-dependent signals that stimulate thermogenesis. This regulation occurs through gene expression modulation and autophagy-related processes. Mice with targeted ablation of Acbp in brown adipocytes exhibit enhanced BAT thermogenic activity and protection against high-fat diet-induced obesity and glucose intolerance; this is associated with BAT transcriptome changes, including upregulation of BAT thermogenesis-related genes. Treatment of brown adipocytes with exogenous ACBP suppresses oxidative activity, lipolysis, and thermogenesis-related gene expression. ACBP treatment inhibits the noradrenergic-induced phosphorylation of p38 MAP-kinase and CREB, which are major intracellular mediators of brown adipocyte thermogenesis. Conclusions The ACBP system acts as a crucial auto regulatory repressor of BAT thermogenesis that responds reciprocally to the noradrenergic induction of BAT activity.
Immune–Metabolic Profiling Reveals Functional Heterogeneity Within Colorectal Cancer Consensus Molecular Subtypes
(MDPI, 2026-07-10) Madurga Díez, Sergio; López Blanco, David; Foguet, Carles; Lahoz, Sara; Oliveres, Helena; Moreno, Reinaldo; Gorría, Teresa; Pedrosa Eguílez, Leire; Marín Martínez, Silvia; Rojas, Mariam; Camps, Jordi; Mas i Pujadas, Francesc; Maurel Santasusana, Joan; Cascante i Serratosa, Marta
The Consensus Molecular Subtype (CMS) classification provides a widely used transcrip- tomic framework for colorectal cancer (CRC) stratification with clear prognostic and thera- peutic relevance. However, it does not fully capture the immune–metabolic heterogeneity underlying tumor–microenvironment interactions within each subtype. Here, we integrate a validated immune–metabolic gene signature as a functional layer to refine CMS classifica- tion and systematically characterize diversity across CMS1-4 tumors. Using transcriptomic data from 2918 CRC samples across three independent cohorts (GSE1, TCGA, and GSE2), we show that CMSs display robust yet distinct immune–metabolic distributions across datasets. CMS4 tumors exhibit glycolytic, stromal-dependent, and immunosuppressive pro- files, whereas CMS2 and CMS3 are enriched in oxidative and metabolically flexible states. Importantly, CMS1 tumors segregate into two major immune–metabolic profiles, revealing marked heterogeneity within this immune-activated subtype. These patterns are preserved in metastatic samples, supporting their stability across disease stages. Overall, integrating immune–metabolic profiling into CMSs reveals previously unrecognized functional het- erogeneity and provides a refined framework to interpret tumor–microenvironment states. This approach facilitates the identification of context-specific metabolic vulnerabilities with potential clinical relevance.
Glycogen drives the sensory activation of POMC neurons
(Nature Publishing Group, 2026-05-27) Gómez-Valadés, Alicia G.; Meseguer, David; Varela, Luis; Lienhard, Gabriele; Fernández, Uxía; Vidal Itriago, Andrés; Toledo Soler, Miriam; Eyre, Elena; Laudo, Berta; Díaz Castro, Francisco; Pozo, Macarena; Boutagouga Boudjadja, Mehdi; Fos Domènech, Júlia; García Ramón, Pau; Ferreira, Mariana; Altirriba Gutiérrez, Jordi; Beiroa, Daniel; Chen, Bandy; Rodríguez Díaz, Amanda; Milà Guasch, Maria; Chivite, Íñigo; Obri, Arnaud; Ramírez, Sara; Haddad Tovolli, Roberta; Tahiri, Iasim; Gentry, Matthew S.; Agostino, Giuseppe D'; Nogueiras, Rubén; Renier, Nicolas; Horvath, Tamas L.; Guinovart, Joan J. (Joan Josep), 1947-2025; Duran Castells, Jordi; Schneeberger, Marc; Claret i Carles, Marc
Hypothalamic POMC neurons modulate systemic energy balance and glucose homeostasis by sensing nutritional state signals. In addition to this classic regulatory mode, these neurons are also activated by the sensory perception of food. Here, we report that food-related sensory cues engage glycogen metabolism in POMC neurons. Genetic depletion of glycogen through various approaches renders POMC neurons unresponsive to food-associated sensory stimuli. This defective perception of food is linked to alterations in consummatory behaviour, hepatic adaptations and cephalic insulin release associated with a prediabetic phenotype that progresses into overweight and overt diabetes with a high-calorie diet or ageing. Collectively, our results posit glycogen as a decisive fuel resource for meeting the rapid and demanding energy requirements linked with sensory activation. Furthermore, our data delineate the biological function of food perception and provide support for the physiological relevance of neuronal glycogen.
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.
Allosterism in the adenosine A2A and cannabinoid CB2 heteromer
(Blackwell, 2024-07-23) Llinàs del Torrent, Clàudia; Raïch, Iu; González, Andrea; Lillo, Jaume; Casajuana-Martin, Nil; Franco Fernández, Rafael; Pardo, Leonardo; Navarro Brugal, Gemma
Background and Purpose Allosterism is a regulatory mechanism for GPCRs that can be attained by ligand-binding or protein–protein interactions with another GPCR. We have studied the influence of the dimer interface on the allosteric properties of the A2A receptor and CB2 receptor heteromer. Experimental Approach We have evaluated cAMP production, phosphorylation of signal-regulated kinases (pERK1/2), label-free dynamic mass redistribution, β-arrestin 2 recruitment and bimolecular fluorescence complementation assays in the absence and presence of synthetic peptides that disrupt the formation of the heteromer. Molecular dynamic simulations provided converging evidence that the heteromeric interface influences the allosteric properties of the A2AR–CB2R heteromer. Key Results Apo A2AR blocks agonist-induced signalling of CB2R. The disruptive peptides, with the amino acid sequence of transmembrane (TM) 6 of A2AR or CB2R, facilitate CB2R activation, suggesting that A2AR allosterically prevents the outward movement of TM 6 of CB2R for G protein binding. Significantly, binding of the selective antagonist SCH 58261 to A2AR also facilitated agonist-induced activation of CB2R.
Cannabidiol releases CB1R from A2AR repression in ischemic stroke.
(Elsevier, 2025-10) Raïch, Iu; Lillo, Jaume; Rebassa, Joan-Biel; Rivas-Santiesteban, Rafael; Santandreu, Montserrat; Reyes Resina, Irene; Martínez-Orgado, José; Navarro Brugal, Gemma
Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, adenosine A2AR and cannabinoid CB1R receptors included. These two receptors may interact to form heteromers (A2AR-CB1R Hets) that are also a target of CBD. Thus, we aimed to assess whether the expression and function of A2AR–CB1R-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen deprived (GOD) neurons and microglial cells. Results indicated that the formation of A2AR-CB1R heteromers increased A2AR affinity for its selective agonist CGS21680. Moreover, resonance energy transfer assays showed that CBD and cannabigerol (CBG) affected the structure of the heteromer. Regarding functionallity, CBD partially bloked A2AR induced signalling in transfected HEK-293 T cells, while it recovered CB1R signalling in glucose/oxygen-deprived neurons and microglial cells. The expression of A2AR-CB1R Hets increased in GOD neurons and microglial cells. This increase was counteracted with a pre-treatment with CBD and CBG. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of A2AR-CB1R Hets. In conclusion, CBD effects in the hypoxia of the neonate can be mediated by A2AR-CB1R complex. CBD partially blocks A2AR signalling while potentiates the neuroprotective effect of CB1R in hypoxic-ischemic conditions.
Equibiaxial Stretching Device for High Magnification Live-Cell Confocal Fluorescence Microscopy
(JoVE, 2025-06-13) Le Roux, Anabel-Lise; Venturini, Valeria; Gómez González, Manuel; Beedle, Amy E. M.; Quiroga, Xarxa; Menino, Xavier; Trepat Guixer, Xavier; Roca-Cusachs Soulere, Pere
Cells are continuously exposed to mechanical forces in physiological and pathological situations, including a variety of tensile and compressive stresses. There is very active research exploring how cells and tissues respond and adapt to such stresses and how these responses integrate with mechanochemical signaling. This has generated a need for sophisticated tools compatible with standard cell culture protocols and microscopy methods, reproducing physiological stresses in in-vitro studies. This study presents the design, function, and characterization of a stretching device compatible with high-resolution optical and fluorescence microscopy. Numerous stretching devices, either pneumatic- or motor-based, have been developed and used in the field. We present one of these systems in detail, including design guidelines, a variety of applications, and all the tools to fabricate a similar setup. The system is based on a deformable polydimethylsiloxane (PDMS) membrane, stretched equibiaxially upon vacuum application, rendering a homogeneous, reproducible, and controlled sample strain. It provides a variety of tensile stresses, from punctual and immediate stretch to repeated stretch-release cycles of controlled amplitude and frequency. Substrate coating with adhesion proteins allows seeding cells bearing fluorescent reporters in the stretching device and performing live-imaging of these cells upon stretch using high magnification fluorescence microscopes. Compressive stresses can also be applied by letting the sample adapt to stretch and subsequently releasing it or by seeding the sample on a pre-stretched substrate before stretch release. Additional topographical patterning of the PDMS substrate enables imaging of the same sample in different microscopy modes (such as fluorescence and electron microscopy). Polyacrylamide gels can also be attached to the PDMS membrane, resulting in the stretching of cells seeded on substrates of different stiffnesses. Overall, by applying controlled tensile stresses on live samples, this stretching device, coupled with high-quality fluorescence microscopy, can address a large variety of questions in mechanobiology.
Oleuropein Aglycone, an Olive Polyphenol, Influences Alpha-Synuclein Aggregation and Exerts Neuroprotective Effects in Different Parkinson's Disease Models.
(Humana Press, 2025-12-01)
Α-synuclein aggregation is the pathological feature of several neurodegenerative disorders, including Parkinson's disease. The aggregates can diffuse within brain areas, and their toxicity has been proven in both cellular and animal models. Given that, recent therapeutic strategies have been focusing on the identification of compounds able to promote the degradation of aggregates or, at least, to prevent the aggregation process. In this field, the use of natural-derived polyphenols has been proposed as a potential tool against α-synuclein pathology. On these bases, we tested the neuroprotective potential of oleuropein aglycone, an olive polyphenol, in two cellular and C. elegans-based models of Parkinson's disease. The compound was effective in reducing the burden of early-aggregates pathology upon α-synuclein overexpression in neuroblastoma cells, as well as neutralizing both the extent and the toxicity of administered preformed fibrils. In addition, oleuropein aglycone administration was beneficial for healthspan and lifespan in animals overexpressing α-synuclein, improved motor defects, recovered dopaminergic neuronal loss, and reduced the extent of α-synuclein pathology. Finally, through molecular modelling simulations, we propose a model for the α-synuclein and oleuropein aglycone interaction, predicting a dynamic that involves early α-synuclein oligomers. Overall, our results support the neuroprotective potential of oleuropein aglycone against α-synuclein aggregation and toxicity and shed light into the molecular features of these mechanisms, suggesting that further studies should be performed to gain insight about the neuroprotective actions of this polyphenol in humans.
Novel protocol for metabolomics data normalization and biomarker discovery in human tears.
(Walter de Gruyter, 2025-03-28) Serrano-Marín, Joan; Bernal Casas, David; Marín Martínez, Silvia; Iglesias, Arnau; Lillo, Jaume; Garrigós, Claudia; Capó, Toni; Reyes Resina, Irene; Alkozi, Hanan Awad; Cascante i Serratosa, Marta; Franco Fernández, Rafael; Sánchez-Navés, Juan
Objectives: Human tear analysis holds promise for biomarker discovery, but its clinical utility is hindered by the lack of standardized reference values, limiting interindividual comparisons. This study aimed at developing a protocol for normalizing metabolomic data from human tears, enhancing its potential for biomarker identification. Methods: Tear metabolomic profiling was conducted on 103 donors (64 females, 39 males, aged 18-82 years) without ocular pathology, using the AbsoluteIDQ™ p180 Kit for targeted metabolomics. A predictive normalization model incorporating age, sex, and fasting time was developed to correct for interindividual variability. Key metabolites from six compound families (amino acids, biogenic amines, acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins) were identified as normalization references. The approach was validated using Linear Discriminant Analysis (LDA) to test its ability to classify donor sex based on metabolite concentrations. Results: Metabolite concentrations exhibited significant interindividual variability. The normalization model, which predicted metabolite concentrations based on a reference "concomitant" metabolite from each compound family, successfully reduced this variability. Using the ratio of observed-to-predicted concentrations, the model enabled robust comparisons across individuals. LDA classification of donor sex using acylcarnitine C4 achieved 78 % accuracy, correctly identifying 92 % of female donors. This approach outperformed traditional statistical and machine learning methods (Lasso logistic regression and Random Forest classification) in sex discrimination based on tear metabolomics. Conclusions: This novel normalization protocol significantly improves the reliability of tear metabolomics by enabling standardized interindividual comparisons. The approach facilitates biomarker discovery by mitigating variability in metabolite concentrations and may be extended to other biological fluids, enhancing its applicability in precision medicine.
The multimerization pathway of the glucocorticoid receptor
(Oxford University Press, 2025-10-21)
The glucocorticoid receptor (GR) is a leading drug target due to its antiinflammatory and immunosuppressive roles. The functional oligomeric conformation of full-length GR (FL-GR), which is key for its biological activity, remains disputed. Here we present a new crystal structure of agonist-bound GR ligand-binding domain (GR-LBD) comprising eight copies of a noncanonical dimer. We verified the biological relevance of this dimer for receptor multimerization in wild-type and selected FL-GR mutants using molecular dynamics and crosslinking-mass spectrometry together with fluorescence microscopy and transcriptomic analysis in living cells. Self-association of this GR-LBD basic dimer in two mutually exclusive assemblies reveals clues for FL-GR multimerization and activity in cells. We propose a model for the structure of multidomain GR based on our new data and suggest a detailed oligomerization pathway. This model reconciles all currently available structural and functional information and provides a more comprehensive understanding of the rare disorder, generalized glucocorticoid resistance.
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.
Synthesis and biological evaluation of novel carnosic acid derivatives with anticancer activity
(Royal Society of Chemistry, 2025-10-06) S. P. Moura, Sara P.; Cascante i Serratosa, Marta; Rufino, Ismael; Guedes, Rita C.; Marín Martínez, Silvia; Salvador, Jorge A. R.
Novel derivatives of carnosic acid 1 with ester or carbamate groups at C-20 and derivatives with these functional groups combined with benzylic modifications (C-7) were synthesized and evaluated in a colorectal cancer cell line (HCT116). Compound 8, which featured a butyl ester at C-20 and a carbonyl group at C-7, and compound 17, which featured a 2-methylpropyl carbamate at C-20, achieved the best results in HCT116 cells. Compounds 8 and 17 also demonstrated better ability to inhibit the growth of other cancer cell lines than CA 1. In general, the best results were achieved with compound 17, which exhibited higher potency against SW480 cells (IC50 = 6.3 μM). This compound also showed selectivity for cancer cells compared to normal cells. Compound 17 was subjected to additional studies to elucidate the mechanism responsible for its antiproliferative activity in SW480 cells. At 24 h, compound 17 arrested the cell cycle at the G0/G1 phase by decreasing the CDK4/CDK6 levels. It also reduced ROS levels by increasing the expression of SOD2/MnSOD. However, at 48 h, compound 17 induced cell cycle arrest in the S phase and increased ROS levels. At 72 h, compound 17 elevated the ROS levels without inducing cell cycle arrest. Additionally, molecular docking studies showed that compound 17 establishes several interactions with the amino acids of the CDK6 active site. In conclusion, compound 17 is a promising candidate for the development of novel anticancer drugs.
Subcutaneous and visceral adipose tissue lipidome in children reveals novel lipid species involved in obesity
(Springer Verlag, 2026) Cereijo Téllez, Rubén; Herrero Rodríguez, Laura; Barbas, Coral; Sánchez-Infantes, David; Soria-Gondek, Andrea; Gonzalez-Riano, C.; Fernández-García, Pablo; Requena, B.; González, Lorena; Reyes, Majorie; Murillo, M.; Valls, A.; Real, N.; Villarroya i Gombau, Francesc; Corrales, Patricia
Overweight impacts over 390 million children and adolescents worldwide, of whom around 160 million are living with obesity. Adipose tissue biology in pediatric obesity is still relatively unknown. Adaptations to obesity including fat mobilization and remodeling are being investigated. The objective was to examine the lipidomic profile of subcutaneous and visceral adipose tissue (sWAT and vWAT, respectively) in children with obesity compared to those with normal weight, in order to identify novel lipid species modulated by obesity. Thirty pediatric patients with and without obesity were prospectively recruited at a referral single center and clinical data were reported. sWAT and vWAT samples were obtained for lipidomic analysis. Novel lipid species, including ether-linked triglycerides, ether-linked phosphatidylethanolamine, and oxidized triglycerides, were identified as altered in the sWAT from children with obesity compared with normal-weight children. These species are involved in beige adipose tissue development, energy metabolism, mitochondrial function, and oxidative stress. Compared with normal-weight children, the vWAT lipidome from children with obesity showed significant changes in some glycerophosphocholines, ceramides, and diglycerides, with accumulation of lipid species involved in inflammation, insulin resistance, and cardiovascular risk. The observed lipid correlations between vWAT and sWAT highlighted systemic dysregulation of lipid storage in childhood obesity, identifying both shared and depot-specific mechanisms of lipid handling. Our study reveals several critical lipid species that are modulated across both WAT depots, with notable implications for oxidative stress, lipid storage, and adipose tissue dysfunction. Key Points • The adipose lipidome of children with obesity showed specific alterations. • Lipid correlations revealed shared and depot-specific lipid handling mechanisms. • The altered lipid species had an impact on oxidative stress and insulin resistance.
Molecular dynamics modelling of the interaction of a synthetic zinc-finger miniprotein with DNA
(Royal Society of Chemistry, 2023) Rodriguez, Jessica; Battistini, Federica; Learte-Aymamí, Soraya; Orozco López, Modesto; Mascareñas, José L.
We report the modelling of the DNA complex of an artificial miniprotein composed of two zinc finger modules and an AT-hook linking peptide. The computational study provides for the first time a structural view of these types of complexes, dissecting interactions that are key to modulate their stability. The relevance of these interactions was validated experimentally. These results confirm the potential of this type of computational approach for studying peptide–DNA complexes and suggest that they could be very useful for the rational design of non-natural, DNA binding miniproteins.
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.

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