Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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Dysregulation of the FGF21-adiponectin axis in a large cohort of patients with severe obesity and liver disease
(MDPI, 2025-09-02) Castañé Vilafranca, Helena; Jiménez Franco, Andrea; Onoiu, Alina Iuliana; Cambra Cortés, Vicente; Hernández Aguilera, Anna; Parada Domíngues, David; Riu, Francisco; Zorzano Olarte, Antonio; Camps, Jordi; Joven, Jorge
We investigated the impact of liver damage on systemic inter-organ communication in an extensive observational case-control study of 923 patients with severe obesity and biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) undergoing bariatric surgery. Using a comprehensive panel of circulating organokines, including fibroblast growth factor (FGF) 19, FGF21, adiponectin, galectin-3, irisin, and leptin, along with choline metabolites, we characterized metabolic signaling patterns associated with liver disease severity. Compared to controls, patients with MASLD/MASH exhibited significantly lower levels of FGF19, choline, and trimethylamine, while FGF21, galectin-3, irisin, and leptin were elevated. Sex-specific alterations in leptin and adiponectin were observed in patients with severe obesity but not in controls. Network analysis revealed a complex and individualized interplay among organokines, shaped by age, sex, and anthropometric factors. Despite this complexity, a dysregulation of the FGF21-adiponectin axis was associated with more advanced liver involvement. The large cohort and comprehensive organokine profiling studied provide valuable insights into the role of the FGF21-adiponectin axis on systemic metabolic alterations in severe obesity and their potential clinical implications.
Identification of Neuritin 1 as a local metabolic regulator of brown adipose tissue
(Nature Publishing Group, 2025-09-04) Sánchez Feutrie, Manuela; Romero De Pablos, Montserrat; Veiga, Sonia Rosa Pereira da; Borràs Ferré, Núria; Berrow, Nick; Ràfols, Martina; Giménez, Noemí; Rodgers Furones, Andrea; Sabaté Pérez, Alba; Rodríguez Pérez, Ángela; Cataldo, Luis Rodrigo; Burghardt, Hans; Sebastián, David; Plana, Natàlia; Hernández, Vanessa; Alcaide, Laura Isabel; Reina, Óscar; Monte, M. Jesús; García Marin, José Juan; Palacín Prieto, Manuel; Burcelin, Remy; Antonson, Per; Gustafsson, Jan-Ake; Zorzano Olarte, Antonio
Brown adipose tissue (BAT) plays a key role in metabolic homeostasis through its thermogenic effects and the secretion of regulatory molecules. Here we report that RAP250 haploinsufficiency stimulates BAT in mice, thus contributing to a decrease in fat accumulation. Local in vivo AAV-mediated RAP250 silencing in BAT reduces body weight and fat mass and enhances glucose oxidation, thereby indicating that RAP250 participates in the regulation of BAT metabolic activity. Analysis of the mechanisms led to the finding that Neuritin 1 is produced and released by brown adipocytes, it plays a key metabolic role, and it participates in the enhanced BAT metabolic activity under RAP250 deficiency. Forced overexpression of Neuritin 1 in UCP1-expressing cells markedly decreases fat mass and body weight gain in mice and induces the expression of thermogenic genes in BAT. Neuritin 1-deficient brown adipocytes also shows a reduced β-adrenergic response. We demonstrate a metabolic role of BAT-derived Neuritin 1 acting through an autocrine/paracrine mechanism. Based on our results, Neuritin-1 emerges as a potential target for the treatment of metabolic disorders.
Systematic study of hybrid triplex topology and stability suggests a general triplex-mediated regulatory mechanism
(Oxford University Press, 2025-03-24) Genna, Vito; Portella, Guillem; Sala, Alba; Terrazas Martínez, Montserrat; Serrano Chacón, Israel; Gonzalez-Díaz, Joaquín; Villegas, Núria; Mateo, Lidia; Castellazzi, Chiara; Labrador, Mireia; Aviño, Anna; Hospital, Adam; Gandioso, Albert; Aloy, Patrick; Brun-Heath, Isabelle; Gonzalez, Camille; Eritja i Casadellà, Ramon; Orozco López, Modesto
By combining in silico, biophysical, and in vitro experiments, we decipher the topology, physical, and potential biological properties of hybrid-parallel nucleic acids triplexes, an elusive structure at the basis of life. We found that hybrid triplex topology follows a stability order: r(Py)-d(Pu)·r(Py) > r(Py)-d(Pu)·d(Py) > d(Py)-d(Pu)·d(Py) > d(Py)-d(Pu)·r(Py). The r(Py)-d(Pu)·d(Py) triplex is expected to be preferred in the cell as it avoids the need to open the duplex reducing the torsional stress required for triplex formation in the r(Py)-d(Pu)·r(Py) topology. Upon a massive collection of melting data, we have created the first predictor for hybrid triplex stability. Leveraging this predictor, we conducted a comprehensive scan to assess the likelihood of the human genome and transcriptome to engage in triplex formation. Our findings unveil a remarkable inclination—of both the human genome and transcriptome—to generate hybrid triplex formation, particularly within untranslated (UTRs) and regulatory regions, thereby corroborating the existence of a triplex-mediated regulatory mechanism. Furthermore, we found a correlation between nucleosome linkers and Triplex-forming sequence (TFS) which agree with a putative role of triplexes in arranging chromatin structure.
Flexibility in PAM recognition expands DNA targeting in xCas9
(eLife Sciences, 2025-02-10) Hossain, Kazi A.; Nierzwicki, Lukasz; Orozco López, Modesto; Czub, Jacek; Palermo, Giulia
xCas9 is an evolved variant of the CRISPR-Cas9 genome editing system, engineered to improve specificity and reduce undesired off-target effects. How xCas9 expands the DNA targeting capability of Cas9 by recognising a series of alternative protospacer adjacent motif (PAM) sequences while ignoring others is unknown. Here, we elucidate the molecular mechanism underlying xCas9’s expanded PAM recognition and provide critical insights for expanding DNA targeting. We demonstrate that while wild-type Cas9 enforces stringent guanine selection through the rigidity of its interacting arginine dyad, xCas9 introduces flexibility in R1335, enabling selective recognition of specific PAM sequences. This increased flexibility confers a pronounced entropic preference, which also improves recognition of the canonical TGG PAM. Furthermore, xCas9 enhances DNA binding to alternative PAM sequences during the early evolution cycles, while favouring binding to the canonical PAM in the final evolution cycle. This dual functionality highlights how xCas9 broadens PAM recognition and underscores the importance of fine-tuning the flexibility of the PAM-interacting cleft as a key strategy for expanding the DNA targeting potential of CRISPR-Cas systems. These findings deepen our understanding of DNA recognition in xCas9 and may apply to other CRISPR-Cas systems with similar PAM recognition requirements.
Gromologist: A GROMACS-oriented utility library for structure and topology manipulation
(Elsevier B.V., 2025-03-12) Wieczór, Miłosz; Czub, Jacek; Orozco López, Modesto
Despite the increasing automation of workflows for the preparation of systems for molecular dynamics simulations, the custom editing of molecular topologies to accommodate non-standard modifications remains a daunting task even for experienced users. To alleviate this issue, we created Gromologist, a utility library that provides the simulation community with a toolbox of primitive operations, as well as useful repetitive procedures identified during years of research. The library has been developed in response to users' feedback, and will continue to grow to include more use cases, thorough automatic testing and support for a broader spectrum of rare features. The program is available at gitlab.com/KomBioMol/gromologist and via Python's pip.
Una Escape-room para recordar la estructura de aminoácidos y proteínas en la asignatura de Bioquímica del grado de Química.
(Asociación de Químicos de Galicia, 2023-07-12) Centelles Serra, Josep Joan; Imperial Ródenas, Santiago; Moreno Guillén, Estefanía; Pérez Torras, Sandra; Atauri Carulla, Ramón de
La asignatura de Bioquímica del grado de Química de la Universidad de Barcelona se trasladó recientemente al séptimo semestre, aunque la Biología se sigue impartiendo en el primer semestre. A pesar de que los conocimientos de Química Orgánica sean superiores a cuando se impartía en el cuarto semestre, esta separación de 5 semestres entre la Biología y la Bioquímica puede implicar que los alumnos no recuerden la estructura de las biomoléculas aprendida en Biología. Por ello, nos planteamos preparar unos ejercicios como recordatorio o autoaprendizaje de las biomoléculas, que podrían ser útiles para los estudiantes de Química. Los juegos suelen ser muy apreciados por parte del alumnado y la población en general. Durante la pandemia preparamos diversos juegos para los alumnos, clasificados en las categorías: palabras carentes de sílabas o grupos de letras, anagramas y laberintos [1], palabras codificadas [2], palabras encadenadas, juegos del salto de caballo. A partir de estos juegos, y basándonos en una Escape-room desarrollada anteriormente por nuestro grupo de innovación docente (QuiMet) [3], realizamos una Escape-room dedicada a los aminoácidos y proteínas. Utilizando los cuestionarios de Google Drive, se presentan 10 secciones con preguntas dedicadas a la estructura de aminoácidos, estructura primaria, secundaria, supersecundaria, terciaria y cuaternaria de las proteínas, y dominios proteicos. En cada sección se realizaba una pregunta cerrada, cuya respuesta permitía superar la sección y pasar a la siguiente. Las preguntas se basaban en la resolución de un problema del que se solicitaba el resultado final, la visualización de un video donde se solicitaba el tiempo en el que aparecía un determinado aspecto comentado, así como de diversas palabras o frases obtenidas a partir de los juegos que habíamos preparado. Puesto que el grado de Química en la Universitat de Barcelona es un grado de doble semestralización, los cuestionarios fueron respondidos por los 39 alumnos matriculados en el semestre de otoño y están siendo respondidos ahora por los alumnos del semestre de primavera. Además, se presentaron al final del cuestionario varias preguntas para conocer la satisfacción de los alumnos, que consideraron muy positivamente esta forma de recordar la estructura, jugando al mismo tiempo.
The pseudotorsional space of RNA
(Cold Spring Harbor Laboratory Press, 2023-12-01) Grille, Leandro; Gallego Perez, Diego; Darré, Leonardo; da Rosa, Gabriela; Battistini, Federica; Orozco López, Modesto; Dans, Pablo D.
The characterization of the conformational landscape of the RNA backbone is rather complex due to the ability of RNA to assume a large variety of conformations. These backbone conformations can be depicted by pseudotorsional angles linking RNA backbone atoms, from which Ramachandran-like plots can be built. We explore here different definitions of these pseudotorsional angles, finding that the most accurate ones are the traditional η (eta) and θ (theta) angles, which represent the relative position of RNA backbone atoms P and C4′. We explore the distribution of η − θ in known experimental structures, comparing the pseudotorsional space generated with structures determined exclusively by one experimental technique. We found that the complete picture only appears when combining data from different sources. The maps provide a quite comprehensive representation of the RNA accessible space, which can be used in RNA-structural predictions. Finally, our results highlight that protein interactions lead to significant changes in the population of the η − θ space, pointing toward the role of induced-fit mechanisms in protein–RNA recognition.
Faced with a double challenge: obesity and climate change
(Sociedad Española para el Estudio de la Obesidad (SEEDO), 2024-06) Villarroya i Gombau, Francesc; Giralt i Oms, Marta
The current global obesity epidemic is occurring in parallel with global warming due to climate change. Epidemiological evidence suggests a role for increasing environmental temperatures in increasing rates of overweight and obesity. The suppression, caused by high temperatures, of the energy expenditure necessary for adaptive thermogenesis, may be a mechanism that explains the alteration in energy balance caused by global warming, which favors obesogenesis. Reciprocally, there are data indicating that high rates of obesity around the world are causing, directly and indirectly through increased food production and transportation, an increase in greenhouse gas emissions, thus contributing to global warming. The impact of global warming on obesity highlights the dangers of climate change and points to the need for greater action to slow the process to prevent its harmful effects on global health.
CGeNArate: a sequence-dependent coarse-grained model of DNA for accurate atomistic MD simulations of kb-long duplexes
(Oxford University Press, 2024-07-08) Farré Gil, David; Arcon, Juan Pablo; Laughton, Charles A.; Orozco López, Modesto
We present CGeNArate, a new model for molecular dynamics simulations of very long segments of B-DNA in the context of biotechnological or chromatin studies. The developed method uses a coarse-grained Hamiltonian with trajectories that are back-mapped to the atomistic resolution level with extreme accuracy by means of Machine Learning Approaches. The method is sequence-dependent and reproduces very well not only local, but also global physical properties of DNA. The efficiency of the method allows us to recover with a reduced computational effort high-quality atomic-resolution ensembles of segments containing many kilobases of DNA, entering into the gene range or even the entire DNA of certain cellular organelles.
The need to implement FAIR principles in biomolecular simulations
(Nature Publishing Group, 2025-04-02) Amaro, Rommie E.; Åqvist, Johan; Bahar, Ivet; Battistini, Federica; Bellaïche, Adam; Beltran, Daniel; Biggin, Philip C.; Bonomi, Massimiliano; Bowman, Gregory R.; Bryce, Richard A.; Bussi, Giovanni; Carloni, Paolo; Case, David A.; Cavalli, Andrea; Chang, Chia-En A.; Cheatham, Thomas E.; Cheung, Margaret S.; Chipot, Christophe; Chong, Lillian T.; Choudhary, Preeti; Cisneros, G. Andrés; Clementi, Cecilia; Collepardo Guevara, Rosana; Coveney, Peter; Covino, Roberto; Crawford, T. Daniel; Delemotte, Lucie; Essex, Jonathan W.; Fraternali, Franca; Gao, Jiali; Gelpí, Josep Lluís; Gervasio, Francesco Luigi; González Nilo, Fernando Danilo; Groot, Bert L. de; Grubmüller, Helmut; Guenza, Marina G.; Guzman, Horacio V.; Harris, Sarah; Head Gordon, Teresa; Hernandez, Rigoberto; Hospital, Adam; Huang, Niu; Huang, Xuhui; Hummer, Gerhard; Iglesias Fernández, Javier; Jensen, Jan H.; Jha, Shantenu; Jiao, Wanting; Jorgensen, William L.; Kamerlin, Shina Caroline Lynn; Khalid, Syma; Laughton, Charles A.; Levitt, Michael; Limongelli, Vittorio; Lindahl, Erik; Lindorff-Larsen, Kresten; Loverde, Sharon; Lundborg, Magnus; Luo, Yun Lyna; Luque Garriga, F. Xavier; Lynch, Charlotte I.; MacKerell, Alexander; Magistrato, Alessandra; Marrink, Siewert J.; Martin, Hugh; McCammon, J. Andrew; Merz, Kenneth; Moliner, Vicent; Mulholland, Adrian J.; Murad, Sohail; Naganathan, Athi N.; Nangia, Shikha; Noe, Frank; Noy Freixa, Agnès; Olah, Julianna; O’Mara, Megan L.; Ondrechen, Mary Jo; Onuchic, Jose N.; Onufriev, Alexey; Orozco López, Modesto; Osuna, Sílvia; Palermo, Giulia; Panchenko, Anna R.; Pantano, Sergio; Parish, Carol; Parrinello, Michele; Peraro, Matteo dal; Perez Acle, Tomas; Pérez, Alberto; Perilla, Juan R.; Pettitt, B. Montgomery; Pietropaolo, Adriana; Piquemal, Jean Philip; Poma, Adolfo B.; Praprotnik, Matej; Ramos, Maria João; Ren, Pengyu; Reuter, Nathalie; Roitberg, Adrian; Rosta, Edina; Rothlisberger, Ursula; Roux, Benoit; Rovira Virgili, Maria Del Carme; Sanbonmatsu, Karissa Y.; Schlick, Tamar; Shaytan, Alexey K.; Simmerling, Carlos; Smith, Jeremy C.; Sugita, Yuji; Świderek, Katarzyna; Taiji, Makoto; Tao, Peng; Tieleman, D. Peter; Tikhonova, Irina G.; Tirado Rives, Julian; Tuñón, Iñaki; van der Kamp, Marc W.; van der Spoel, David; Velankar, Sameer; Vivo, Marco de; Voth, Gregory A.; Wade, Rebecca; Warshel, Ariel; Welborn, Valerie Vaissier; Wetmore, Stacey D.; Wheeler, Travis J.; Wong, Chung F.; Yang, Lee Wei; Zacharias, Martin
In the Big Data era, a change of paradigm in the use of molecular dynamics is required. Trajectories should be stored under FAIR (findable, accessible, interoperable and reusable) requirements to favor its reuse by the community under an open science paradigm.
Novel Soluble Epoxide Hydrolase Inhibitor: Toward Regulatory Preclinical Studies
(2025-12-01) Jarne Ferrer, Júlia; Sánchez, Javier; Codony Gisbert, Sandra; Schneider, Marion; Müller, Christa E.; Sanfeliu i Pujol, Coral; Franco Fernández, Rafael; Vázquez Cruz, Santiago; Griñán Ferré, Christian; Pallàs i Llibería, Mercè, 1964-
Neuroinflammation is widely recognized as a key pathological hallmark of Alzheimer’s disease (AD). Recently, inhibiting soluble epoxide hydrolase (sEH) has emerged as a promising therapeutic strategy for AD. sEH plays a pivotal role in neuroinflammation by hydrolyzing epoxyeicosatrienoic acids (EETs), which have anti-inflammatory and neuroprotective properties, into pro-inflammatory dihydroepoxyeicosatrienoic acids (DHETs). Furthermore, the overexpression of the enzyme in the brains of AD patients and animal models of the disease highlights its relevance as a therapeutic target. Our previous studies, using the inhibitor UB-SCG-51 demonstrated that sEH inhibition regulates neuroinflammation and other mechanisms, such as the unfolded protein response pathway, while reducing autophagy, apoptosis, and neuronal death, thereby promoting neuroprotection. Building on these findings, we evaluated the arginine salt of the compound, designated UB-SCG-74, which offers improved oral absorption compared to that of UB-SCG-51 while retaining high permeability, potency, and selectivity. In experiments using 5XFAD mice, UB-SCG-74 treatment significantly improved cognition and synaptic plasticity, outperforming donepezil, a standard AD drug, and ibuprofen, an anti-inflammatory drug. Remarkably, these benefits persisted for 4 weeks after administration cessation, suggesting lasting therapeutic effects. Safety pharmacology studies showed no toxicity, supporting the advancement of UB-SCG-74 into preclinical regulatory evaluation. Our findings further indicate that sEH inhibition engages multiple neuroprotective pathways, potentially modifying both AD symptoms and disease progression, thus reinforcing its therapeutic potential.
Divergent effects of the antiretroviral drugs, dolutegravir, tenofovir alafenamide, and tenofovir disoproxil fumarate, on human adipocyte function
(Elsevier B.V., 2024-02-01) Quesada López, Tania Paloma; Cereijo Téllez, Rubén; Blasco Roset, Albert; Mestres Arenas, Alberto; Prieto, Patricia; Domingo i Pedrol, Joan Carles; Villarroya i Gombau, Francesc; Domingo, Pere (Domingo Pedrol); Giralt i Oms, Marta
Combined antiretroviral therapy (cART) has been associated with increased body weight accompanied by metabolic alterations in people living with human immunodeficiency virus (PLWH). To gain insight into the combined effects of cART components on adipocyte dysfunction, we assessed whether and how treatment of human adipocytes with dolutegravir (DTG) and the nucleotide-analog reverse-transcriptase inhibitors (NRTIs), tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF), alone and in combination, altered biological processes related to adipose tissue dysfunction. DTG, TAF, and TDF were applied to human Simpson-Golabi-Behmel syndrome (SGBS) adipose cells during differentiation (day 10) and ensuing differentiation (day 14). Expression of selected marker genes was determined by qPCR, the release of adipokines and inflammatory cytokines to the culture media was assessed, and cell respiration was measured. Adipogenesis was not altered by the combined treatment of human adipocytes. However, DTG at the highest dose repressed adipogenesis marker genes expression, and TAF and TDF appeared to mitigate this effect. DTG repressed the expression of adiponectin and the release of adiponectin and leptin in differentiating adipocytes, and these effects were mantained in combination with TAF and TDF. DTG plus TAF or TDF on human adipocytes enhanced inflammation and stress and increased the release of proinflammatory cytokines to the culture media. Together, our results show that combined therapy with these drugs can alter inflammation, cellular stress, and fibrosis in human adipocytes. These findings may improve our understanding and management of the effects of cART on body adiposity and metabolic dysregulation in PLWH.
Significant functional differences between dopamine D4 receptor polymorphic variants upon heteromerization with α1A adrenoreceptors
(Humana Press., 2023-11) Homar-Ruano, Patricia; Cai, Ning-Sheng; Casadó Anguera, Verònica; Casadó, Vicent; Ferré, Sergi; Moreno Guillén, Estefanía; Canela Campos, Enric I. (Enric Isidre), 1949-
The functional role of the dopamine D4 receptor (D4R) and its main polymorphic variants has become more evident with the demonstration of heteromers of D4R that control the function of frontal cortico-striatal neurons. Those include heteromers with the α2A adrenoceptor (α2AR) and with the D2R, localized in their cortical somato-dendritic region and striatal nerve terminals, respectively. By using biophysical and cell-signaling methods and heteromer-disrupting peptides in mammalian transfected cells and rat brain slice preparations, here we provide evidence for a new functionally relevant D4R heteromer, the α1AR-D4R heteromer, which is also preferentially localized in cortico-striatal glutamatergic terminals. Significant differences in allosteric modulations between heteromers of α1AR with the D4.4R and D4.7R polymorphic variants could be evidenced with the analysis of G protein-dependent and independent signaling. Similar negative allosteric modulations between α1AR and D4R ligands could be demonstrated for both α1AR-D4.4R and α1AR-D4.7R heteromers on G protein-independent signaling, but only for α1AR-D4.4R on G protein-dependent signaling. From these functional differences, it is proposed that the D4.4R variant provides a gain of function of the α1AR-mediated noradrenergic stimulatory control of cortico-striatal glutamatergic neurotransmission, which could result in a decrease in the vulnerability for impulse control-related neuropsychiatric disorders and increase in the vulnerability for posttraumatic stress disorder.
Parkin depletion prevents the age-related alterations in the FGF21 system and the decline in white adipose tissue thermogenic function in mice
(Springer Verlag, 2024-02) Delgado-Anglés, Alejandro; Blasco Roset, Albert; Godoy‑Nieto, Francisco Javier; Cairó, Montserrat; Villarroya i Gombau, Francesc; Giralt i Oms, Marta; Villarroya i Terrade, Joan
Parkin is an ubiquitin‐E3 ligase that is involved in cellular mitophagy and was recently shown to contribute to controlling adipose tissue thermogenic plasticity. We found that Parkin expression is induced in brown (BAT) and white (WAT) adipose tissues of aged mice. We determined the potential role of Parkin in the aging-associated decline in the thermogenic capacity of adipose tissues by analyzing subcutaneous WAT, interscapular BAT, and systemic metabolic and physiological parameters in young (5 month-old) and aged (16 month-old) mice with targeted invalidation of the Parkin (Park2) gene, and their wild-type littermates. Our data indicate that suppression of Parkin prevented adipose accretion, increased energy expenditure and improved the systemic metabolic derangements, such as insulin resistance, seen in aged mice. This was associated with maintenance of browning and reduction of the age-associated induction of inflammation in subcutaneous WAT. BAT in aged mice was much less affected by Parkin gene invalidation. Such protection was associated with a dramatic prevention of the age-associated induction of fibroblast growth factor-21 (FGF21) levels in aged Parkin-invalidated mice. This was associated with a parallel reduction in FGF21 gene expression in adipose tissues and liver in aged Parkin-invalidated mice. Additionally, Parkin invalidation prevented the protein down-regulation of β-Klotho (a key co-receptor mediating FGF21 responsiveness in tissues) in aged adipose tissues. We conclude that Parkin down-regulation leads to improved systemic metabolism in aged mice, in association with maintenance of adipose tissue browning and FGF21 system functionality.
Anabolic deficits and divergent unfolded protein response underlie skeletal and cardiac muscle growth impairments in the Yoshida hepatoma tumor model of cancer cachexia
(Wiley, 2024-09-18) Belcher, Daniel J.; Kim, Nina; Navarro-Llinas, Blanca; Möller, Maria; López-Soriano, Francisco J.; Busquets Rius, Sílvia; Nader, Gustavo A.
Cancer cachexia manifests as whole body wasting, however, the precise mechanisms governing the alterations in skeletal muscle and cardiac anabolism have yet to be fully elucidated. In this study, we explored changes in anabolic processes in both skeletal and cardiac muscles in the Yoshida AH-130 ascites hepatoma model of cancer cachexia. AH-130 tumor-bearing rats experienced significant losses in body weight, skeletal muscle, and heart mass. Skeletal and cardiac muscle loss was associated with decreased ribosomal (r)RNA, and hypophosphorylation of the eukaryotic factor 4E binding protein 1. Endoplasmic reticulum stress was evident by higher activating transcription factor mRNA in skeletal muscle and growth arrest and DNA damage-inducible protein (GADD)34 mRNA in both skeletal and cardiac muscles. Tumors provoked an increase in tissue expression of interferon-γ in the heart, while an increase in interleukin-1β mRNA was apparent in both skeletal and cardiac muscles. We conclude that compromised skeletal muscle and heart mass in the Yoshida AH-130 ascites hepatoma model involves a marked reduction translational capacity and efficiency. Furthermore, our observations suggest that endoplasmic reticulum stress and tissue production of pro-inflammatory factors may play a role in the development of skeletal and cardiac muscle wasting.
Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis
(BioMed Central, 2025-01-29) Giroud-Gernetant Deus, Judith; Sotillo, Fernando; Hernández, Gonzalo; Ruano, Irene; Sebastián, David; Fort, Joana; Sánchez, Mayka; Weiss, Günter; Prats, Neus; Zorzano Olarte, Antonio; Palacín Prieto, Manuel; Bodoy i Salvans, Susanna
Background: Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities. The specific cause of these hematopoietic defects-whether intrinsic to hematopoietic cells or driven by external factors-remains unclear. Given the limitations of current citrulline-based treatments and the unknown role of SLC7A7 in red blood cell production, there is an urgent need to investigate the pathways affected by SLC7A7 deficiency. Methods: We employed total inducible and cell type-specific Slc7a7 knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of Slc7a7 function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of Slc7a7 in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student's t test and ANOVA. Results: Whole-body Slc7a7 knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with Slc7a7 deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic Slc7a7 loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in Slc7a7-deficient mice, nor did the transplantation of Slc7a7-deficient cells induce defects in control recipients. Further investigation indicated that defective erythropoiesis is linked to impaired erythropoietin production in the kidney and subsequent iron overload. Conclusions: The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic Slc7a7 loss in hematopoietic cells but rather by impaired erythropoietin production in the kidney. This finding opens potential avenues for therapeutic strategies targeting erythropoietin production to address hematological abnormalities in humans with lysinuric protein intolerance. Keywords: Amino acids; Erythropoiesis; Kidney disease; Rare disease.
D816V KIT mutation induces mitochondrial morphologic and functional changes through BNIP3 downregulation in human myeloid cell lines ROSA and TF-1
(Elsevier B.V., 2025-05) Cisa-Wieczorek, Sabina; Hernández-Alvarez, María Isabel; Parreño, Matilde; Muñoz, Juan P.; Bussaglia, Elena; Carricondo, Maite; Ubeda, Jose; Dubreuil, Patrice; Zorzano Olarte, Antonio; Brenet, Fabienne; Nomdedéu, Josep
The KIT receptor is a transmembrane protein found on the surface of many different cell types. Mutant forms of KIT are drivers of myeloid neoplasms, including systemic mastocytosis. The KIT D816V mutation is the most common, leading to constitutive activation of the receptor and its downstream targets, and it is highly resistant to cKIT inhibitors. Metabolic rewiring is a common trait in cancer. We analyzed the metabolic profile induced by the KIT D816 mutation, measuring mitochondrial parameters in two myeloid cell lines. We found that the KIT D816V mutation causes 3 a significant increase in mitochondrial abundance and activity associated with superoxide production, which could promote DNA instability. Functional and morphological changes in mitochondria were associated with reduced levels of BNIP3 protein expression. We also detected low BNIP3 levels in clinical acute myeloid leukemia samples harboring D816V mutations. In addition, we have found a constitutive mTOR activation in mutated cells, a pathway that has been shown to regulate autophagy. Our data suggest that KIT D816V increases mitochondrial activity through BNIP3 down expression, which increases mitochondrial number through the autophagy pathway. Alterations in the cellular metabolism induced by the KIT D816V mutation could be therapeutically exploited.
The splicing factor SF3B1 is involved in brown adipocyte thermogenic activation
(Elsevier B.V., 2024-02) Castellá Giner, Moisés; Mestres Arenas, Alberto; Gavaldà i Navarro, Aleix; Blasco Roset, Albert; Quesada López, Tania Paloma; Romero-Carramiñana, Inés; Giralt i Oms, Marta; Villarroya i Gombau, Francesc; Cereijo Téllez, Rubén
The ability of alternative splicing mechanisms to control gene expression is increasingly being recognized as relevant for adipose tissue function. The expression of SF3B1, a key component of the SF3B complex directly involved in spliceosome formation, was previously reported to be significantly induced in brown adipose tissue under cold-induced thermogenic activation. Here, we identify that noradrenergic cAMP-mediated thermogenic stimulation increases SF3B1 expression in brown and beige adipocytes. We further show that pladienolide-B, a drug that binds SF3B1 to inhibit pre-mRNA splicing by targeting the SF3B complex, down-regulates key components of the thermogenic machinery (e.g., UCP1 gene expression), differentially alters the expression of alternative splicing-regulated transcripts encoding molecular actors involved in the oxidative metabolism of brown adipocytes (e.g., peroxisome proliferator-activated receptor-gamma co-activator-alpha [PGC-1α] and cytochrome oxidase subunit 7a genes), and impairs the respiratory activity of brown adipocytes. Similar alterations were found in brown adipocytes with siRNA-mediated knockdown of SF3B1 protein levels. Our findings collectively indicate that SF3B1 is a key factor in the appropriate thermogenic activation of differentiated brown adipocytes. This work exemplifies the importance of splicing processes in adaptive thermogenesis and suggests that pharmacological tools, such as pladienolide-B, may be used to modulate brown adipocyte thermogenic activity.
Metabolic interventions to enhance immunotherapy and targeted therapy efficacy in advanced colorectal cancer
(Elsevier, 2023-12) Oliveres, Helena; Cascante i Serratosa, Marta; Maurel Santasusana, Joan
Current standard-of-care for metastatic colorectal cancer patients includes chemotherapy and anti-angiogenic or anti-epidermal growth factor receptor for microsatellite stable tumors and pembrolizumab for microsatellite instable tumors. However, despite the available therapies, the prognosis remains poor. In recent years, new drugs combined with immune checkpoint inhibitors have been tested in microsatellite stable metastatic colorectal cancer patients, but the benefit was modest. Here, we review the metabolic interactions between the immune microenvironment and cancer cells. More specifically, we highlight potential correlatives of tumor immune and metabolic features with transcriptomic classifications such as the Consensus Molecular Subtype. Finally, we discuss the unmet need of immune-metabolic signatures and the value of a new signature (IMMETCOLS) for guiding new strategies in metastatic colorectal cancer. We conclude that the field is ready to propose customized strategies for modifying metabolism and improving immunotherapy and targeted therapy efficacy.
Control analysis in the identification of key enzymes driving metabolic adaptations: Towards drug target discovery
(Elsevier B.V., 2023-09) Atauri Carulla, Ramón de; Foguet, Carles; Cascante i Serratosa, Marta
Metabolic Control Analysis (MCA) marked a turning point in understanding the design principles of metabolic network control by establishing control coefficients as a means to quantify the degree of control that an enzyme exerts on flux or metabolite concentrations. MCA has demonstrated that control of metabolic pathways is distributed among many enzymes rather than depending on a single rate-limiting step. MCA also proved that this distribution depends not only on the stoichiometric structure of the network but also on other kinetic determinants, such as the degree of saturation of the enzyme active site, the distance to thermodynamic equilibrium, and metabolite feedback regulatory loops. Consequently, predicting the alterations that occur during metabolic adaptation in response to strong changes involving a redistribution in such control distribution can be challenging. Here, using the framework provided by MCA, we illustrate how control distribution in a metabolic pathway/network depends on enzyme kinetic determinants and to what extent the redistribution of control affects our predictions on candidate enzymes suitable as targets for small molecule inhibition in the drug discovery process. Our results uncover that kinetic determinants can lead to unexpected control distribution and outcomes that cannot be predicted solely from stoichiometric determinants. We also unveil that the inference of key enzyme-drivers of an observed metabolic adaptation can be dramatically improved using mean control coefficients and ruling out those enzyme activities that are associated with low control coefficients. As the use of constraint-based stoichiometric genome-scale metabolic models (GSMMs) becomes increasingly prevalent for identifying genes/enzymes that could be potential drug targets, we anticipate that incorporating kinetic determinants and ruling out enzymes with low control coefficients into GSMM workflows will facilitate more accurate predictions and reveal novel therapeutic targets.

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