Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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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.
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.
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.
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.
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.
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.
Current efficacy of immune checkpoint inhibitors in microsatellite unstable colorectal cancer and potential biomarkers
(Open Exploration, 2025-02-18) Rojas, Mariam; Rodrigo, Clara; Moreno, Reinaldo; Cascante i Serratosa, Marta; Maurel Santasusana, Joan
Microsatellite unstable (MSI) colorectal cancer (CRC) tumors have a high mutational load (particularly frame-shift mutations) that creates numerous neoantigens that are presented to major histocompatibility complex molecules and recognized by T cells. Consequently, MSI tumors have a higher presence of tumor-infiltrating lymphocytes than mismatch repair-proficient tumors. Colorectal cancer patients with MSI constitute a rare group of immune checkpoint inhibitor (ICI)-responsive patients. Nonetheless, complete radiological responders comprise between 3% and 16% of MSI advanced CRC patients, which compares poorly with the 45% to 87% rate of pathological complete response in early MSI CRC patients treated with ICIs. In this review, we address the efficacy of current ICIs and the biological differences between early and advanced MSI CRC to potentially increase the efficacy of ICIs in both settings.
Success and Limitations of Current Force Fields for the Description of RNA–Ligand Complexes
(American Chemical Society, 2025-10-31) Fernández Migens, Paula; Serrano Chacón, Israel; Orozco López, Modesto; Battistini, Federica
We present a systematic assessment of the last generation of RNA force fields to reproduce the structures and dynamics of ligand−RNA complexes. Our comprehensive analysis helped not only to define the more reliable force field to represent complex structures but also suggests details that can be improved and provide a critical analysis of the quality of experimental structures in complex systems that are expected to be very flexible and environment dependent.
Using control bias to identify initial targets for bioproduction improvement
(Elsevier B.V., 2025-11-25) Binns, Michael; Atauri Carulla, Ramón de; Cascante i Serratosa, Marta; Theodoropoulos, Constantinos
Sensitivity analysis of bioprocess metabolic reaction networks analysis allows the prediction of system parameters such as those associated with the enzyme activity of certain reaction steps which significantly affect the overall production. However, uncertainties in kinetic rate expressions and in the resulting steady-state flux distributions limit the accuracy of these predictions. Starting from minimal information (reaction stoichiometry, and external fluxes in/out of the system and potentially identification of steps at equilibrium) a new preliminary method is proposed using sampling of elasticities and metabolic fluxes to calculate the control bias. The calculated control bias identifies steps which are likely to have positive control, negative control or negligible/uncertain control. This is intended to give initial guidance before further detailed investigation is carried out, identifying targets for any organism to enhance production of valuable chemicals. As a case study, this methodology is applied to succinic acid bioproduction using Actinobacillus succinogenes and analysis successfully reveals the reaction steps having the greatest positive and negative influence on biosuccinic acid production.
Circulating metabolic markers after surgery identify patients at risk for severe postoperative complications: a prospective cohort study in colorectal cancer
(Elsevier, 2024-03-01) Montcusí, Blanca; Pera Román, Miguel; Madrid Gambín, Francisco Javier; Pozo Mendoza, Óscar J., 1975-; Marco Colás, Santiago; Marín Martínez, Silvia; Mayol, Xavier; Pascual Damieta, Marta; Alonso-Gonçalves, Sandra; Silvia Salvans Ruiz; Jiménez-Toscano, Marta; Cascante i Serratosa, Marta
Background: Early detection of postoperative complications after colorectal cancer (CRC) surgery is associated with improved outcomes. The aim was to investigate early metabolomics signatures capable to detect patients at risk for severe postoperative complications after CRC surgery. Materials and methods: Prospective cohort study of patients undergoing CRC surgery from 2015 to 2018. Plasma samples were collected before and after surgery, and analyzed by mass spectrometry obtaining 188 metabolites and 21 ratios. Postoperative complications were registered with Clavien–Dindo Classification and Comprehensive Complication Index. Results: One hundred forty-six patients were included. Surgery substantially modified metabolome and metabolic changes after surgery were quantitatively associated with the severity of postoperative complications. The strongest positive relationship with both Clavien–Dindo and Comprehensive Complication Index (β=4.09 and 63.05, P<0.001) corresponded to kynurenine/tryptophan, against an inverse relationship with lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs). Patients with LPC18:2/PCa36:2 below the cut-off 0.084 µM/µM resulted in a sevenfold higher risk of major complications (OR=7.38, 95% CI: 2.82–21.25, P<0.001), while kynurenine/tryptophan above 0.067 µM/µM a ninefold (OR=9.35, 95% CI: 3.03–32.66, P<0.001). Hexadecanoylcarnitine below 0.093 µM displayed a 12-fold higher risk of anastomotic leakage-related complications (OR=11.99, 95% CI: 2.62–80.79, P=0.004). Conclusion: Surgery-induced phospholipids and amino acid dysregulation is associated with the severity of postoperative complications after CRC surgery, including anastomotic leakage-related outcomes. The authors provide quantitative insight on metabolic markers, measuring vulnerability to postoperative morbidity that might help guide early decision-making and improve surgical outcomes.
Transcriptomic profiling of endothelial progenitor cells in post-COVID-19 patients: Insights at 3- and 6-month post-infection
(Elsevier, 2025-11-21) Poyatos Dorado, Paula; Gratacòs-Aurich, Miquel; Aguilar, Daniel; Luque, Neus; Bonnin Vilaplana, Marc; Eizaguirre, Saioa; Cascante i Serratosa, Marta; Orriols Martínez, Ramon; Tura-Ceide, Olga
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused significant global morbidity since 2019. Long COVID, characterized by persistent symptoms after acute infection, may involve endothelial injury. We analyzed endothelial colony-forming cells (ECFCs) from post-COVID-19 patients at 3- and 6-month post-infection, comparing them with healthy controls and stratifying by prior pulmonary embolism (PE). Transcriptomic profiling identified differentially expressed genes (DEGs) associated with endothelial homeostasis, inflammation, oxidative stress, and thrombosis. Post-COVID ECFCs showed downregulation of NOS3, KLF2, ANGPT1, PIK3R3, GBX2, GDF6, SMAD6, SRC, and TGFB1, and upregulation of CASP1, CXCL5, IL12A, SOD2, TIMP3, and TLR2. Minimal differences were observed between 3 and 6-month samples. PE patients showed downregulation of thrombosis-related genes such as PTGS2 and ACKR3. These findings indicate sustained endothelial dysfunction and inflammation up to 6 months post-infection, highlighting the importance of long-term monitoring and potential therapeutic strategies to support vascular health in post-COVID-19 patients.
Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain
(Nature Publishing Group, 2015-04-14) Volkow, Nora D., 1956-; Wang, Gene-Jack; Logan, Jean; Alexoff, David; Fowler, Joanna S.; Thanos, Panayotis K.; Wong, Christopher T.; Casadó, Vicent; Ferré, Sergi; Tomasi, Dardo
Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [11C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.
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.

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