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Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation
(Springer Verlag, 2024-07-06) Hernández-Hernández, Irene; Rosa, Juan V. de la; Martín-Rodríguez, Patricia; Díaz-Sarmiento, Mercedes; Recio, Carlota; Guerra, Borja; Fernández-Pérez, Leandro; León Moreno, Theresa Elizabeth; Torres, Rosa; Font Díaz, Joan; Roig, Angela; Mora, Fernando de; Boscá, Lisardo; Díaz, Mario; Valledor Fernández, Annabel; Castrillo, Antonio; Tabraue, Carlos
Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRβ, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRβ as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases.
Liver X receptors and inflammatory-induced C/EBPβ selectively cooperate to control CD38 transcription
(Karger, 2024-12-19) Glaría Percaz, Estibaliz; Rodríguez Martínez, Pol; Font Díaz, Joan; Rosa, Juan Vladimir de la; Castrillo, Antonio; Crawshaw, Dylan J.; Vidal Taboada, José Manuel; Saura Martí, Josep; Matalonga, Jonathan; Nunes Chini, Eduardo; Caelles Franch, Carme; Valledor Fernández, Annabel
Introduction: Macrophages abundantly express liver X receptors (LXRs), which are ligand-dependent transcription factors and sensors of several cholesterol metabolites. In response to agonists, LXRs promote the expression of key lipid homeostasis regulators. Cross talk between LXRs and inflammatory signals exists in a cell type- and gene-specific manner. A common feature in the macrophage response to inflammatory mediators is the induction of CCAAT/enhancer-binding protein beta (C/EBPβ), a master transcriptional regulator and lineage-determining transcription factor in monocytes/macrophages. Methods: Quantitative real-time PCR in control and C/EBPβ-deficient macrophages was used to explore the role of C/EBPβ in the cross talk between inflammatory mediators and the macrophage response to pharmacological LXR activation. The functional interaction between C/EBPβ and LXRs on selected genomic regions was further characterized by chromatin-immunoprecipitation (ChIP) and gene reporter studies. Results: Whereas inflammatory signaling repressed several LXR-regulated genes involved in lipid metabolism, these effects were conserved after deletion of C/EBPβ. In contrast, inflammatory mediators and LXRs synergistically induced the expression of the multifunctional protein CD38 in a C/EBPβ-dependent manner. C/EBPβ and LXRs bound to several regions with enhancer activity upstream and within the mouse Cd38 gene and their functional cooperation in macrophages required intact binding sites for LXR and C/EBPβ. Conclusion: This study reveals positive cross talk between C/EBPβ and LXRs during the macrophage inflammatory response, which selectively impacts CD38 expression.
LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based Parkinson’s disease model
(Springer Science and Business Media LLC, 2025-08-12) Blasco Agell, Lucas; Pons Espinal, Meritxell; Testa, Veronica; Roch, Gerard; Montero-Muñoz, Jara; Fernández Carasa, Irene; Baruffi, Valentina; Gonzalez-Sepulveda, Marta; Richaud-Patin, Yvonne; Jimenez, Senda; Cuadros, Thais; Cladera-Sastre, Joana M.; Compte, Joan; Manglano-Artuñedo, Zoe; Ventura, Salvador; Juan, Manel; Tolosa, Eduardo; Raya Chamorro, Ángel; Vila, Miquel; Consiglio, Antonella
Parkinson's disease (PD) is a progressive, incurable neurodegenerative disorder characterized by the loss of neuromelanin (NM)-containing dopamine neurons (DAn) in the substantia nigra of the midbrain. Non-neuronal cells are increasingly recognized as contributors to PD. We generated human microglia-like cells (hMG) from induced pluripotent stem cells (iPSC) derived from patients with LRRK2 PD-causing mutations, gene-corrected isogenic controls, and healthy donors. While neither genotype induced neurodegeneration in healthy DAn, LRRK2 hMG become hyperreactive to LPS stimulation, exhibiting increased cytokine expression, reactive oxygen species, and phagocytosis. When exposed to NM-containing particles, but not alpha-synuclein fibrils, LRRK2 hMG trigger DAn degeneration, in a process that is prevented by pre-treatment with the immunomodulatory drug ivermectin. Finally, post-mortem analysis of midbrain tissue of LRRK2-PD patients show increased microglia activation around NM-containing neurons, confirming our in vitro findings. Overall, our work highlights NM-activated microglia's role in PD progression, and provides a model for testing therapeutic targets.
A Nanoencapsulated Ir(III)-Phthalocyanine Conjugate as a Promising Photodynamic Therapy Anticancer Agent
(American Chemical Society, 2024-07-23) Bonelli Blasco, Joaquin Daniel; Ortega-Forte, Enrique; Vigueras, Gloria; Follana-Berná, Jorge; Ashoo, Pezhman; Abad-Montero, Diego; Isidro, Neus; López-Corrales, Marta; Hernández, Adrián; Ortiz, Javier; Izquierdo-García, Eduardo; Bosch, Manel; Rocas, Josep; Sastre-Santos, Ángela; Ruiz, José; Marchán Sancho, Vicente
Despite the potential of photodynamic therapy (PDT) in cancer treatment, the development of efficient and photostable photosensitizing molecules that operate at long wavelengths of light has become a major hurdle. Here, we report for the first time an Ir(III)-phthalocyanine conjugate (Ir-ZnPc) as a novel photosensitizer for high-efficiency synergistic PDT treatment that takes advantage of the longwavelength excitation and near infrared (NIR) emission of the phthalocyanine scaffold and the known photostability and high phototoxicity of cyclometalated Ir(III) complexes. In order to increase water solubility and cell membrane permeability, the conjugate and parent zinc phthalocyanine (ZnPc) were encapsulated in amphoteric redox-responsive polyurethane-polyurea hybrid nanocapsules (Ir-ZnPc-NCs and ZnPc-NCs, respectively). Photobiological evaluations revealed that the encapsulated Ir-ZnPc conjugate achieved high photocytotoxicity in both normoxic and hypoxic conditions under 630 nm light irradiation, which can be attributed to dual Type I and Type II reactive oxygen species (ROS) photogeneration. Interestingly, PDT treatments with Ir-ZnPc-NCs and ZnPc-NCs significantly inhibited the growth of three-dimensional (3D) multicellular tumor spheroids. Overall, the nanoencapsulation of Zn phthalocyanines conjugated to cyclometalated Ir(III) complexes provides a new strategy for obtaining photostable and biocompatible red-light-activated nano-PDT agents with efficient performance under challenging hypoxic environments, thus offering new therapeutic opportunities for cancer treatment.
Sequential activation of transcription factors promotes liver regeneration through specific and developmental enhancers
(Elsevier, 2025-07-09) Llorens-Giralt, Palmira; Ruiz Romero, Marina; Nurtdinov, Ramil; Herranz Itúrbide, Macarena; Vicent, Guillermo Pablo; Serras Rigalt, Florenci; Fabregat Romero, Isabel; Corominas, Montserrat (Corominas Guiu)
The mammalian liver exhibits remarkable regenerative capabilities after injury or resection. Central to this process is the precise modulation of gene expression, driven by changes in chromatin structure and the temporal activation of distal regulatory elements. In this study, we integrated chromatin accessibility and transcriptomic data after partial hepatectomy in mice. We show that the expression of crucial regeneration genes is orchestrated by a diverse array of cis-regulatory elements, including regeneration-specific enhancers and enhancers repurposed from various developmental stages. These enhancers collaborate to activate the transcriptional programs required for hepatocyte priming and proliferation, with their activity initially regulated by the activator protein-1 (AP-1) complex and ATF3, and subsequently by nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) during proliferation. Our results also indicate that hepatic regeneration involves the repression of enhancers regulating liver-specific metabolic functions, particularly those involved in lipid metabolism. This study provides a genome-wide atlas of enhancer-gene interactions, offering new insights into the regulatory mechanisms underlying liver regeneration.
Lifetime suicidal thoughts, attempts, and lethality of attempts as major outcome domains of psychotic disorders: a 21-year prospective cohort study after a first-episode psychosis
(Cambridge University Press (CUP), 2025-03-04) Peralta, Víctor; Moreno-Izco, Lucía; García de Jalón, Elena; Sánchez Torres, Ana M.; Peralta, David; Janda, Lucía; Cuesta, Manuel J.; SEGPEPs group; Ansorena, Xabier; Ballesteros, Alejandro; Chato, Julen; Fañanás Saura, Lourdes; Gil-Berrozpe, Gustavo; Giné-Servé, Eloi; Lorente, Ruth; Papiol, Sergi; Ribeiro, María; Rosado, Esther; Rosero, Ángela
Background: Suicidal thoughts and behaviors (STBs) are a major concern in people with psychotic disorders. There is a need to examine their prevalence over long-term follow-up after first-episode psychosis (FEP) and determine their early predictors. Methods: Of 510 participants with FEP evaluated on 26 risk factors for later outcomes, 260 were reassessed after 21 years of follow-up for lifetime ratings of most severe suicidal ideation, number of suicide attempts, and lethality of the most severe attempt. Risk factors and STB outcomes were modeled using hierarchical linear regression analysis. Results: Over the 21-year follow-up period, 62.7% of participants experienced suicidal thoughts, 40.8% attempted suicide, and 18 died of suicide (3.5% case fatality and 20.6% proportionate mortality). Suicidal ideation was independently predicted by parental socioeconomic status, familial load of major depression, neurodevelopmental delay, poor adolescence social networks, and suicidal thoughts/behavior at FEP. The number of suicide attempts was independently predicted by years of follow-up, familial load of major depression, obstetric complications, childhood adversity, and suicidal thoughts/behavior at FEP. Lethality was independently predicted by familial load of major depression, obstetric complications, neurodevelopmental delay, and poor adolescence social networks. The proportion of variance in suicidal ideation, attempts, and lethality explained by the independent predictors was 29.3%, 21.2%, and 18.1%, respectively. Conclusions: STBs are highly prevalent in psychotic disorders and leads to substantial morbidity and mortality. They were predicted by a number of early risk factors, whose clinical recognition should contribute to improved prediction and prevention in people with psychotic disorders.
Decreased brain serotonin in rbfox1 mutant zebrafish and partial reversion of behavioural alterations by the SSRI fluoxetine
(MDPI, 2024-02-16) Adel, Maja R.; Antón Galindo, Ester; Gago-Garcia, Edurne; Arias-Dimas, Ángela; Arenas Solà, Concepción; Artuch, Rafael; Cormand Rifà, Bru; Fernàndez Castillo, Noèlia
RBFOX1 functions as a master regulator of thousands of genes, exerting a pleiotropic effect on numerous neurodevelopmental and psychiatric disorders. A potential mechanism by which RBFOX1 may impact these disorders is through its modulation of serotonergic neurotransmission, a common target for pharmacological intervention in psychiatric conditions linked to RBFOX1. However, the precise effects of RBFOX1 on the serotonergic system remain largely unexplored. Here we show that homozygous rbfox1sa15940 zebrafish, which express a shorter, aberrant rbfox1 mRNA, have significantly reduced serotonin levels in telencephalon and diencephalon. We observed that the acute administration of fluoxetine partially reverses the associated behavioural alterations. The hyperactive phenotype and altered shoaling behaviour of the rbfox1sa15940/sa15940 zebrafish could be reversed with acute fluoxetine exposure in the Open Field and the Shoaling test, respectively. However, in the other paradigms, hyperactivity was not diminished, suggesting a distinct intrinsic motivation for locomotion in the different paradigms. Acute fluoxetine exposure did not reverse the alterations observed in the aggression and social novelty tests, suggesting the involvement of other neurological mechanisms in these behaviours. These findings underscore the importance of investigating the intricate working mechanisms of RBFOX1 in neurodevelopmental and psychiatric disorders to gain a better understanding of the associated disorders along with their pharmacological treatment.
In search of radical transformations from metal enolates. Direct reactions of N‑acyl-1,3-oxazolidin-2-ones with TEMPO catalyzed by copper(II) acetate
(American Chemical Society, 2025-05-27) Balaguer Garcia, Eduard; Pérez-Palau, Marina; Bello Quiñones, Cristina; Costa, Ana Maria; Romea, Pedro; Urpí Tubella, Fèlix
The direct reactions of a diverse range of N-acyl-1,3-oxazolidin-2-ones with TEMPO, catalyzed by copper(II) acetate and 4,7-dimethyl-1,10-phenanthroline without the need for any base, are herein described. These reactions afford the corresponding aminoxylated derivatives with high chemoselectivity and complete regioselectivity, achieving excellent yields under mild conditions. Further treatment of the resulting imides enables access to a variety of formally protected hydroxy compounds, which can be regarded as valuable synthetic intermediates. The efficient formal synthesis of isoproterenol highlights the potential of this methodology and sets the stage for further advancements in the catalytic chemistry of metal enolates.
Reactive oxygen species activate the Drosophila TNF receptor Wengen for damage-induced regeneration
(EMBO Press, 2024-09-02) Esteban-Collado, José; Fernández Mañas, Mar; Fernández Moreno, Manuel; Maeso, Ignacio; Corominas, Montserrat (Corominas Guiu); Serras Rigalt, Florenci
Tumor necrosis factor receptors (TNFRs) control pleiotropic pro-inflammatory functions that range from apoptosis to cell survival. The ability to trigger a particular function will depend on the upstream cues, association with regulatory complexes, and downstream pathways. In Drosophila melanogaster, two TNFRs have been identified, Wengen (Wgn) and Grindelwald (Grnd). Although several reports associate these receptors with JNK-dependent apoptosis, it has recently been found that Wgn activates a variety of other functions. We demonstrate that Wgn is required for survival by protecting cells from apoptosis. This is mediated by dTRAF1 and results in the activation of p38 MAP kinase. Remarkably, Wgn is required for apoptosis-induced regeneration and is activated by the reactive oxygen species (ROS) produced following apoptosis. This ROS activation is exclusive for Wgn, but not for Grnd, and can occur after knocking down Eiger/TNFα. The extracellular cysteine-rich domain of Grnd is much more divergent than that of Wgn, which is more similar to TNFRs from other animals, including humans. Our results show a novel TNFR function that responds to stressors by ensuring p38-dependent regeneration.
Estimation of the critical micelle concentration of sodium taurocholate inintestine-relevant conditions using complimentary techniques
(Elsevier B.V., 2025-05-13) Amézqueta, Susana; Casdanova, Unai; Fuguet i Jordà, Elisabet; Ràfols Llach, Clara
Bile salts such as sodium taurocholate (NaTc) play an important role in drugs’ bioavailability due to their capacityto form micelles. These aggregates can host a wide range of drugs and enhance their solubility in biologicalfluids. The micellization process and the types of micelles formed not only depend on the surfactant, butalso on the environment (solvent, temperature, presence of other compounds, etc.). Therefore, when solubilityassays are performed it is key to ensure that micelles are present. In this work, the critical micelle concentration(CMC) of NaTc has been evaluated using three different techniques (conductometry, fluorescence and calorimetry)in water and in different biorelevant conditions (intestinal biorelevant aqueous buffers, FaSSIF-v2 andFeSSIF-v2). While conductometry is not adequate for CMC determination of bile salts, fluorescence and calorimetryoffer complementary information. CMC experiments have shown that ion strength and the presence ofmixed micelles (formed by NaTc, phosphatidylcholine and lipids) favor the micellization process and wouldimpact on the drugs bioavailability.
Influence of Ionization and the Addition of Cyclodextrins andHydrophilic Excipients on the Solubility of Benzthiazide,Isoxicam, and Piroxicam
(MDPI, 2025-04-25) Lucero Borja, Diego Sebastián; Ruiz, Rebeca; Fuguet i Jordà, Elisabet; Ràfols Llach, Clara
Background: The bioavailability of a drug depends, among other parameters,on solubility. One of the strategies used to enhance the solubility of sparingly solubledrugs is the use of excipients. Excipients can interact with the drug by increasing its solubilityand/or stabilizing supersaturated solutions. Some of the most common excipientsare cyclodextrins and hydrophilic polymers. Objectives: The effect of two cyclodextrins(captisol and cavasol) and three hydrophilic polymers (klucel, kollidon and plasdoneS630) on the solubility of three ionizable drugs (benzthiazide, isoxicam, and piroxicam) isevaluated at biorelevant pH values, using two complementary techniques. Methods: Thesolubility enhancement was evaluated by the comparison of the solubility with and withoutthe presence of excipients through the shake-flask and CheqSol methodology. Results:Captisol and cavasol slightly increase the concentration of the neutral species of the drugsin the solution before precipitation begins, although they do not enhance the supersaturationduration nor the thermodynamic solubility of the drugs. The increase in solubilityin the presence of cyclodextrins is mainly caused by the ionization state of the drug. Hydrophilicpolymers not only improve thermodynamic solubility but also the extent andthe duration of the supersaturation. Some metastable forms are observed for benzthiazideand isoxicam in the presence of kollidon and plasdone S630. Conclusions: The shake-flaskmethod enabled the evaluation of thermodynamic solubility both in the absence and presenceof excipients. Meanwhile, the CheqSol method provided insights into the presenceof supersaturated solutions. Different behavior is observed depending on the nature ofthe excipient.
New Visible-Light-Sensitive Dicyanocoumarin- andCOUPY-Based Caging Groups with ImprovedPhotolytic Efficiency
(MDPI, 2025-05-14) López-Corrales, Marta; Marchán Sancho, Vicente
Photolabile protecting groups (PPGs), also known as caging groups, are valuable tools in photopharmacology. They enable precise control over the release of bioactive compounds from the corresponding caged compounds at a precisely controlled time and place using light of specific wavelengths. This study introduces a novel approach to fine-tuning the photophysical and photochemical properties of visible-light-sensitive dicyanocoumarin- and COUPY-based caging groups by incorporating a phenyl group in a position adjacent to the photolabile bond. Our photoactivation studies with visible light demonstrated that this structural modification slightly improved the photolytic efficiency of both dicyanocoumarin- and COUPY-caged model compounds compared to their methylsubstituted or unsubstituted counterparts. Furthermore, COUPY PPGs were efficiently photoactivated with red light (620 nm) and successfully used to cage two antitumor drugs, chlorambucil and 4-phenylbutyric acid. These findings highlight the potential of phenylcontaining caging groups based on dicyanocoumarin and COUPY scaffolds as versatile platforms for developing new light-activated tools for photopharmacology applications.
Exploring the Phototherapeutic Applications of Mitochondria-Targeted COUPY Photocages of Antitumor Drugs
(American Chemical Society, 2025-04-28) López-Corrales, Marta; Izquierdo-García, Eduardo; Bosch Marimon, Manel; Das, Tapas; Llebaria Soldevila, Amadeu; Josa-Culleré, Laia; Marchán Sancho, Vicente
Photocleavable protecting groups hold great promise in photopharmacology to control the release of bioactive molecules from their caged precursors within specific subcellular compartments. Herein, we describe a series of photocages based on a COUPY scaffold, incorporating chlorambucil (CLB) and 4-phenylbutyric acid (4-PBA) as bioactive payloads that can be efficiently activated with visible light. Confocal microscopy confirmed the preferential accumulation of CLB and 4-PBA N-hexyl COUPY photocages in the mitochondria, which exhibited aremarkable phototoxicity against cancer cells upon green-yellow light irradiation, with IC50 values in the nanomolar range. This effect was attributed to a synergistic mechanism involving the photorelease of the bioactive payloads and the intrinsic photogeneration of Type I and Type II ROS by the COUPY scaffold within mitochondria. Thus, COUPY-caged derivatives of CLB and 4-PBA underscore the potential of COUPY-caging groups as a versatile platform to develop innovative light-activated agents operating simultaneously through photodynamic therapy and photoactivated chemotherapy.
Cell death in regeneration and cell turnover: lessons from planarians and Drosophila
(Elsevier, 2025-05) Adell i Creixell, Teresa; Cebrià Sánchez, Francesc; Abril Ferrando, Josep Francesc, 1970-; Araújo, Sofia J.; Corominas, Montserrat (Corominas Guiu); Morey i Ramonell, Marta; Serras Rigalt, Florenci; González Estévez, Cristina
Programmed cell death plays a crucial role during tissue turnover in all animal species, and it is also essential during regeneration, serving as a key signalling mechanism to promote tissue repair and regrowth. In freshwater planarians, remarkable regenerative abilities are supported by neoblasts, a population of adult stem cells, which enable high somatic cell turnover. Cell death in planarians occurs continuously during regeneration and adult homeostasis, underscoring its critical role in tissue remodeling and repair. However, the exact mechanisms regulating cell death in these organisms remain elusive. In contrast, Drosophila melanogaster serves as a powerful model for studying programmed cell death in development, metamorphosis, and adult tissue maintenance, leveraging advanced genetic tools and visualization techniques. In Drosophila, cell death sculpts tissues, eliminates larval structures during metamorphosis, and supports homeostasis in adulthood. Despite limited regenerative capacity compared to planarians, Drosophila provides unique insights into cell death's regulatory mechanisms. Comparative analysis of these two systems highlights both conserved and divergent roles of programmed cell death in tissue renewal and regeneration. This review synthesizes the latest knowledge of programmed cell death in planarians and Drosophila, aiming to illuminate shared principles and system-specific adaptations, with relevance to tissue repair across biological systems.
Characterization of biosurfactants' micelles formation using flu-orescence measurements: sodium taurocholate as case of study
(IAPC Publishing, 2024-07-16) Amézqueta, Susana; Fuguet i Jordà, Elisabet; Cabañas, Rubén; Ràfols Llach, Clara
Background and purpose:The evaluation of micellization parameters of surfactants that aggregate gradually, such as bile salts, is not trivial. In this work,different probes and data treatment models are tested to set up ananalytical method based on fluorescence measurements to determinethe critical micelle concentration (CMC) and micellization range (C) of biosurfactants. Sodium taurocholate (NaTc)is used as example.Experimental approach: The fluorescence intensity of five fluorophores has been monitored upon the addition of a concentrated NaTcsolution in two different media: wateranda biorelevant buffer(maleic buffer pH 6.5, I = 120 mM). Four differentdata treatment methodshave been tested.Key results;The micellization processcan be evaluated satisfactorily using fluorescent probes such as propranolol and tetracaine, and also monitoring directly the intrinsic fluorescence of NaTc. However, the results obtained with nonpolar probes(pyrene andnaphthalene)aremore complex to evaluate due to the presence of confluent processes.Although the four models testedfor the data treatmentare commonly used for this purpose, Carpena’s method is the most appropriate as it provides the most accurate CMC and ΔCvalues. The micellization process isfaster in a biorelevant buffer than in water.Conclusion:The study of the micellization of bile salts is not an evident process. After the selection of adequate probes and data treatment methods, the CMC values for NaTC in water and maleic buffer reveal that the biorelevant conditions favour micellization, which in turn may allow faster solubilization of ingested compounds.
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.
Total Synthesis of the Myrioneuron Alkaloid (–)-Schoberine B and Its Enantiomer (+)-Schoberine B
(Wiley-VCH, 2023) Calbó Zabala, Arnau; Griera Farres, Rosa; Bosch, Jordi; Amat Tusón, Mercedes
A dynamic kinetic asymmetric transformation, involving the generation of four stereogenic centers with a well-defined configuration, occurs in the cyclocondensation of diastereomeric mixtures of 2-oxocyclohexanepropionic acid racemates with (1S,2R)-cis-aminoindanol: two major tetracyclic lactams, that differ in the configuration of the four stereocenters on the decahydroquinoline moiety were obtained. From the above lactams, the removal of the chiral auxiliary, the introduction of a 2-piperidone ring, and the closure of the diazine ring complete the first enantioselective total synthesis of the Myrioneuron alkaloid (–)-schoberine B and its enantiomer (+)-schoberine B.
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.
Actin-Interacting Amphidinolides: Syntheses and Mechanisms of Action of Amphidinolides X, J and K
(MDPI, 2023-07-06) Costa i Arnau, Anna M.
Amphidinolides are a family of more than forty macrolides of varying sizes and complex structures isolated from dinoflagellates of the genus Amphidinium. Although all of them display potent-to-moderate cytotoxicity, their full bioactivity profile and mode of action have not been fully investigated. Access to enough material is needed for these studies, but samples of these compounds are limited due to the minute amounts that can only be obtained by either large-scale cultivation of the organism that produces them or by total synthesis. Of all the amphidinolides known to date, only the targets of five of them (B1, H1, J, K, and X) have been examined and all have been found to interact with actin, a crucial cytoskeletal protein. This paper reviews what is currently known about actin-interacting amphidinolides, with a focus on the research of our group. Amphidinolides J and X are F-actin destabilizers, whereas Amphidinolides H1 and K stabilize actin filaments, likely via different mechanisms. More precise details of the interaction between amphidinolides and actin are missing.

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