Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

URI permanent per a aquesta col·leccióhttps://hdl.handle.net/2445/20403

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GADD45A: With or without you
(Wiley, 2024-07-01) Palomer Tarridas, Francesc Xavier; Salvador, Jesús M.; Griñán Ferré, Christian; Barroso Fernández, Emma; Pallàs i Llibería, Mercè, 1964-; Vázquez Carrera, Manuel
The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non-genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well-known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP-activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune-related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.
G9a an Epigenetic Therapeutic Strategy for Neurodegenerative Conditions: From Target Discovery to Clinical Trials
(Wiley, 2025-01-06) Bellver Sanchis, Aina; Ribalta Vilella, Marta; Irisarri, Alba; Gehlot, Pinky; Choudhary, Bhanwar Singh; Jana, Abhisek; Vyas, Vivek Kumar; Banerjee, Deb Ranjan; Pallàs i Llibería, Mercè, 1964-; Guerrero López, Ana; Griñán Ferré, Christian
This review provides a comprehensive overview of the role of G9a/EHMT2, focusing on its structure and exploring the impact of its pharmacological and/or gene inhibition in various neurological diseases. In addition, we delve into the advancements in the design and synthesis of G9a/EHMT2 inhibitors, which hold promise not only as a treatment for neurodegeneration diseases but also for other conditions, such as cancer and malaria. Besides, we presented the discovery of dual therapeutic approaches based on G9a inhibition and different epigenetic enzymes like histone deacetylases, DNA methyltransferases, and other lysine methyltransferases. Hence, findings offer valuable insights into developing novel and promising therapeutic strategies targeting G9a/EHMT2 for managing these neurological conditions.
Structure-Activity Relationship of Synthetic Cathinones: An Updated Review
(American Chemical Society, 2024-09-13) Nadal-Gratacós, Núria; Pazos, Martalu D.; Pubill Sánchez, David; Camarasa García, Jordi; Escubedo Rafa, Elena; Berzosa, Xavier; López Arnau, Raúl
The escalating prevalence of new psychoactive substances (NPSs) poses a significant public health challenge, evidenced by the vast chemical diversity, with over 500 substances reported annually to the United Nations Office on Drugs and Crime-Early Warning Advisory (UNODC-EWA) in the past five years. Among NPSs, synthetic cathinones are gaining a lot of popularity among users. Notably, synthetic cathinones accounted for approximately 50% of the total quantity of NPSs reported as seized by EU Member States in 2021. Preliminary data from UNODC indicates that a total of 209 synthetic cathinones have been reported to date. As their popularity grows, studying the structure–activity relationship (SAR) of synthetic cathinones is essential. SAR studies elucidate how structural features impact biological effects, aiding in toxicity prediction, regulatory compliance, and forensic identification. Additionally, SAR studies play a pivotal role in guiding drug policies, aiding authorities in categorizing and regulating newly emerging synthetic cathinones, mitigate public health risks and offer valuable insights into potential therapeutic applications. Thus, our Review consolidates recent findings on the effects of different substitutions in the chemical scaffold of synthetic cathinones on their mechanism of action as well as pharmacological and toxicological effects of synthetic cathinones, thus enhancing understanding of the SAR of synthetic cathinones’ pharmacology and potential implications.
Effective oral countermeasures against ionizing radiation-induced damagewithout hindering cancer radiotherapy
(Elsevier Masson SAS, 2026-04-06) López-Blanch, Rafael; Oriol-Caballo, María; Salvador-Palmer, Rosario; Moreno-Murciano, Paz; Benlloch, María; Villaescusa, Juan I.; Montoro, Alegría; Prohens López, Rafael; Albertí, Joan; Estrela, José M.; Obrador, Elena
High-dose ionizing radiation induces severe multi-organ injury, yet no broadly effective, orally available countermeasure has been validated. Here we describe a fully oral, multi-component formulation comprising bioavailable polyphenol derivatives (pterostilbene cocrystals and silybin-phosphatidylcholine), the NAD⁺ precursor nicotinamide riboside, and captopril, an angiotensin-converting enzyme inhibitor with established radiomitigative activity that synergizes with the polyphenols. This combination provides robust systemic radioprotection, enabling long-term survival in 90% of mice exposed to a lethal (LD50/30) dose of X-rays. Mechanistically, the formulation mitigates hematopoietic, intestinal, and neuromotor injury while enhancing DNA repair, suppressing oxidative stress, preserving NAD⁺ homeostasis, and activating autophagy. In intestinal epithelial cells, it markedly reduces radiation-induced apoptosis, inflammatory signaling, and mitochondrial dysfunction through coordinated modulation of Nrf2, NF-κB, and sirtuin-regulated stress responses. Critically, normal tissue protection does not compromise tumor control. In triple-negative breast cancer models, irradiation-induced tumor regression is preserved, whereas in glioblastoma (a typically radioresistant malignancy) tumor radiosensitivity is significantly enhanced via sustained oxidative stress, reduced PARP1 expression, and inhibition of HIF-1α and VEGF signaling. Collectively, these findings define an orally deployable, mechanistically integrated strategy that protects normal tissues while preserving or augmenting tumor radiosensitivity, supporting its translational potential as a practical and effective countermeasure against ionizing radiation exposure.
Is Helicobacter pylori a new kid on the block?
(Elsevier España, 2024-02-23) Vázquez Carrera, Manuel
It is well known that traditional risk factors for atherosclerosis, such as age, smoking, diabetes mellitus, dyslipidemia, hypertension, and chronic inflammation, only account for approximately 50% of the incidence of atherosclerosis.1 Therefore, identifying new risks factors that contribute to atherosclerosis development may help to better recognize people with a high cardiovascular risk in the early stages of the disease.
Advancing personalized medicine in neurodegenerative diseases: The role of epigenetics and pharmacoepigenomics in pharmacotherapy
(Elsevier B.V., 2024-06-02) Griñán Ferré, Christian; Bellver Sanchis, Aina; Guerrero López, Ana; Pallàs i Llibería, Mercè, 1964-
About 80 % of brain disorders have a genetic basis. The pathogenesis of most neurodegenerative diseases is associated with a myriad of genetic defects, epigenetic alterations (DNA methylation, histone/chromatin remodeling, miRNA dysregulation), and environmental factors. The emergence of new sequencing technologies and tools to study the epigenome has led to identifying predictive biomarkers for earlier diagnosis, opening up the possibility of prophylactical interventions. As a result, advances in pharmacogenetics and pharmacoepigenomics now allow for personalized treatments based on the profile of each patient and the specific genetic and epigenetic mechanisms involved. This Review highlights the complexity of neurodegenerative diseases and the variability in patient responses to pharmacotherapy, emphasizing the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of drugs used to treat those conditions. We specifically discuss the potential modulatory effect of several genetic polymorphisms associated with an increased risk of developing different neurodegenerative diseases. We explore genetic and genomic technologies and the potential of analyzing individual-specific drug metabolism to predict and influence drug response and associated clinical outcomes. We also provide insights into the mechanism of action of the drugs under investigation and their potential impact on disease-modifying pathways. Finally, the Review underscores the great potential of this field to enhance the effectiveness and safety of drug treatments through personalized medicine.
Ring-closing metathesis studies in the context of the formal synthesis of themarine macrolide (–)-callyspongiolide
(Michigan Publishing, 2025-09-11) Urbina, Andrea; Calbó Zabala, Arnau; Llor Brunés, Núria; Bosch Mestres, Jordi; Amat Tusón, Mercedes
Attempts to synthesize the natural product macrolide polyketide (–)-callyspongiolide have drawn great interestbecause of its potent cytotoxic activity. Its total synthesis has proven to be difficult, however, due to itschallenging structure. The influence of the configuration of a homoallylic stereocenter on the closure of a 14-membered macrocyclic carbonate by ring-closing metathesis (RCM) from two epimeric dienes is described. Theresults offer some insights into the structural features which contribute to hampering the closure of themacrocyclic core of the macrolide polyketide. A formal synthesis of the marine macrolide (–)-callyspongiolide isalso reported using a RCM approach (C10-C11 bond formed) from analogous dienes bearing an α,β-unsaturatedester instead of a carbonate
Visualizing nanostructures in supramolecular hydrogels: a correlative study using confocal and cryogenic scanning electron microscopy
(Beilstein Institute, 2025-12-01) Smith, Shaun S.; Malagreca, Ferdinando; Hicks, Jacqueline M.; Mantovani, Giuseppe; Amabilino, David B.; Parmenter, Christopher; Pérez García, M. Lluïsa (Maria Lluïsa)
Solvated supramolecular hydrogels present unique challenges in nanoscale morphological characterization because of their fragilefibrous nature and low concentration of the solid component. In this study, imidazolium-based hydrogels containing either diketopyrrolopyrrole(DPP) or zinc(II) phthalocyanine (ZnPc) fluorophores were imaged using confocal laser scanning microscopy(CLSM) of fully solvated gels and cryogenic scanning electron microscopy (cryo-SEM) was used to observe the correspondingxerogels. The DPP@Gel systems exhibit strong fluorescence and are effectively imaged using CLSM, with fibre morphologies thatclosely correlate with those seen with cryo-SEM. In contrast, the analogous imidazolium gel system containing a sulfonated zincphthalocyanine (ZnPc@Gel) yields poor CLSM images because of the relatively weak emission and sample disruption duringcompression, whereas cryo-SEM enables clear visualization of the native fibrous network. These results demonstrate the complementarynature of CLSM and cryo-SEM and highlight the value of cryo-SEM as a very useful tool for imaging soft nanomaterialswith low fluorescence or limited optical contrast.
Liposomal formulations for waterproofing mucosal membranes
(Elsevier B.V., 2025-08-01) Coderch Negra, Ma. Luisa; Ricci, Lucia; Martí, Meritxell; Bagherpour, Saman; Pérez García, M. Lluïsa (Maria Lluïsa); Alonso, Cristina
Liposome formulations consisting of lipids contained in the stratum corneum have been recently demonstrated todecrease the permeability of mucosae. The permeability barrier of the mucosa is dependent on the presence ofspecific lipids. The main objective of this work is to reinforce the barrier effect of the oral mucosa with liposomalformulations to decrease permeation. Due to the high similarity in composition and structure between lanolinand human stratum corneum lipids, liposomes were formed with lipids contained in the stratum corneum withtwo kinds of ceramide or with lanolin. Transmembrane water loss of the two formulations was assessed,obtaining an important diminution for both liposomal formulations. Caffeine, lidocaine, ketoprofen and ivermectinand a virus model were tested on mucosa and on modified mucosa to evaluate the liposomal efficacy.A somewhat consistent permeation pattern was obtained for the different membranes: caffeine > lidocaine >ketoprofen > ivermectin. For all drugs and for the virus model, the most effective formulation was the liposomalformulation, consisting of lipids found in the horny layer of the skin. The effect of the lanolin on the transmembranewater loss is not reflected on the drug permeation. Therefore, it is demonstrated the main role ofceramides in the barrier function for drugs and a virus model. Strengthening the barrier function of the mucosapromotes the prevention or reduction of the permeation of different actives, which could be to extrapolate toharmful actives like viruses, pollutants, toxins, contaminants, etc.
Unveiling the supramolecular features of Oxyma-T: crystal structures, salt formation, and computational investigation of noncovalent interactions
(Elsevier B.V., 2026-03-05) Jemai, Mahdi; Barbas Cañero, Rafael; Barceló-Oliver, Miquel; Marouani, Houda; Frontera, Antonio; Prohens López, Rafael
The single-crystal structures of Oxyma-T, the recent member of the Oxyma racemization-suppressor family for peptide synthesis, have been synthesized and structurally characterized by single-crystal X-ray diffraction (SCXRD). The crystalline materials include the anhydrous form of Oxyma-T, as well as two salts incorporating ammonium and pyridinium as hydrogen-bond donors. The electron-rich framework of Oxyma-T offers multiple sites for hydrogen bonding, giving rise to characteristic supramolecular motifs such as R (6) in the salts, and S(5) and S(6) ring motifs in the anhydrous form. In addition to these hydrogen-bonding networks, lone pair⋅⋅⋅ 1 π (n→ π (5) and R 1 *) interactions are revealed in the anhydrous structure, with energy estimated at –6.4 kcal/mol, acting cooperatively with conventional hydrogen bonds to stabilize the packing. Complementary density functional theory (DFT) calculations, including molecular electrostatic potential (MEP) surface mapping, QTAIM, and NCI plot analyses, further dissect the interplay of noncovalent interactions governing the stability and organization of these new Oxyma-T materials.
Soluble epoxide hydrolase inhibition improves Alzheimer’s disease hallmarks: correlation with peripheral inflammation and gut microbiota modulation
(International Society on Aging and Disease (ISOAD), 2026-01-26) Jarne Ferrer, Júlia; Griñán Ferré, Christian; Jora, Beatrice Elena; Codony Gisbert, Sandra; Miró Martí, Ma. Lluïsa; Rosell Cardona, Cristina; Miñana i Galbis, David; Pérez Bosque, Anna; Vázquez Cruz, Santiago; Pallàs i Llibería, Mercè, 1964-
Targeting brain inflammation has been proposed as a promising therapeutic strategy to cope with neurodegenerative diseases. Interestingly, accumulating data suggest that the gut microbiota partially exerts its neurodegenerative effects by exacerbating neuroinflammation through increased pathogenic or unhealthy genera that releases different types of cytokines in the periphery. Recently, soluble epoxide hydrolase enzyme (sEH) emerged as a new pharmacological approach for treating Alzheimer’s Disease. Treatment with a sEH inhibitor (UB-BJ-02) modified the gut microbiota in the 5xFAD mouse model, increasing health-promoting genera such as Lactobacillus and Limosilactobacillus. By contrast, pro-inflammatory genera (e.g., Bacteroides) were decreased. UB-BJ-02 treatment enhanced the production of anti-inflammatory peripheral mediators in the colon and spleen, such as Il-10. 5xFAD mice treated with UB-BJ-02 showed improved short- and long-term memory and spatial memory compared to 5xFAD control. Furthermore, we found a reduction in neuroinflammatory markers evaluated by immunohistochemical assays, such as GFAP and IBA-1, and gene expression, such as Il-1β, Tnf-a, Il-6, and Trem2, in the brain of 5xFAD-treated mice and a significant decrease in the number of Aβ plaques. T Treatment decreased DRP1 protein levels while increasing OPA1 levels, resulting in improved mitochondrial function corroborated by the elevation of Pgc1-α. Interestingly, a correlation between UB-BJ-02 brain effects and microbiota changes were demonstrated. To validate this correlation, we fed CL4176 AD transgenic strain, with Limosilactobacillus reuteri and Bacteroides rodentium. Consequently, we observed that changes in feeding modified the number of Aβ plaques and neuroinflammatory markers in C. elegans. Therefore, the present study suggested that sEH inhibition with UB-BJ-02 promoted neuroprotective effects, modulating gut microbiota and modifying peripheral and brain pro-inflammatory markers.
Seeking new polymorphs in pharmaceutical cocrystals: focus on furosemide–ethenzamide
(Royal Society of Chemistry, 2026) Muñoz-Hernández, Estephany; Alarcón-Payer, Carolina; Frontera, Antonio; Prohens López, Rafael; Barbas Cañero, Rafael; Acebedo-Martínez, Francisco Javier; Domínguez-Martín, Alicia; Choquesillo-Lazarte, Duane
Polymorphism remains a critical challenge in the pharmaceutical industry due to its profound impact on the physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs). While pharmaceutical multicomponent materials (PMMs) such as cocrystals were initially believed to mitigate polymorphic risks through stabilization via non-covalent interactions, while modulating the properties of different APIs, recent studies have revealed a growing number of polymorphic PMMs, highlighting the need for targeted screening and structural understanding of these materials. In this work, we report the discovery and selective synthesis of a novel polymorph of the furosemide–ethenzamide (FUR–ETZ) cocrystal through kinetic crystallization via fast solvent evaporation. Solid-state characterization confirmed the formation of a polymorph with morphotropic packing relative to the known form, despite maintaining similar molecular conformation and hydrogen bonding motifs. Crystal structure analysis revealed that formII exhibits a lateral layer shift and increased surface polarity, resulting in enhanced aqueous solubility and a slightly higher melting point. In contrast, formI was shown to be thermodynamically more stable, both in dry and aqueous environments, as supported by lattice energy calculations and competitive slurry experiments. These findings underscore the relevance of polymorph screening in PMMs and demonstrate how subtle variations in crystal packing can critically influence the stability and performance of pharmaceutical cocrystals.
A serendipitous synthesis of N,N′‑Diethyloxamide: crystallographic and computational analysis of its solid‑state structure‑Diethyloxamide: crystallogra
(Springer Verlag, 2025-10-17) Marouani, Houda; Jemai, Mahdi; Barceló-Oliver, Miquel; Frontera, Antonio; Prohens López, Rafael
A combined crystallographic/computational analysis focused on the supramolecular features of the crystal structure of N,N′-diethyloxamide (NNDO) is discussed in this work. The studied compound was obtained unexpectedly during the synthesis of a series of salts of cyclic oximes derivatives. In the solid state NNDO is stabilized essentially through a strong N–H···O hydrogen bond but Hirshfeld surface analysis and Density Functional Theory (DFT) calculations were carried out to evalu-ate the strength of the predominant hydrogen bonds observed in the X-ray structure, as well as the secondary C–H···O and C–H···N contacts established between the ethyl groups and the perpendicular dioxamide group. These interactions were further investigated using a combination of Quantum Theory of Atoms in Molecules (QTAIM), Non-Covalent Interaction Plot (NCIplot) and natural bond orbital (NBO) analysis computational tools, and were rationalized using Molecular Elec-trostatic Potential (MEP) surface, electron localization function (ELF), localized orbital locator (LOL) and Fukui function calculations. The insights gathered in this study enrich the understanding of the factors governing crystal packing in amides and related compounds.
A DSC study of the non-isothermal cold crystallization and relaxation effects in ubiquinone and ubiquinol
(Royal Society of Chemistry, 2025-08-04) Barbas Cañero, Rafael; Sande, Dafne de; Bofill, Lídia; Prohens López, Rafael
Cold crystallization effects, the kinetics-dependent crystallization behaviour of amorphous ubiquinone and ubiquinol produced in a series of quenching from-the-melt experiments, have been extensively studied through the combination of differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) techniques under a big diversity of experimental conditions, which has allowed the exploration of their poorly understood polymorphic landscapes. The investigation revealed the existence of a non-previously described polymorph together with a rich set of kinetically dependent transformations, which were observed for the first time by thermal analysis conducted at different heating rates in both oxidized and reduced solid forms of Coenzyme Q10.
Deciphering supramolecular synthons in OXYMA-B salts: Crystallographic characterization and theoretical evaluation of hydrogen bond networks
(Elsevier B.V., 2026-02-15) Jemai, Mahdi; Barbas Cañero, Rafael; Barceló-Oliver, Miquel; Marouani, Houda; Albericio Palomera, Fernando; Frontera, Antonio; Prohens López, Rafael
Four new crystal structures of OXYMA-B in its anionic form have been synthesized and structurally characterized via single-crystal X-ray diffraction. The new salts incorporate protonated amine-based cations including 1-phenylpiperazine (1PP), 1,4-dioxa-8-azaspiro[4.5]decane (DASD), ethylenediamine (ETDA), and pyrrolidine (Pyr), which function as efficient hydrogen bond (H-bond) donors. The electron-rich nature of the OXYMA-B anion provides multiple sites for H-bond acceptance, leading to diverse supramolecular synthons including (5),(6), (8) and(12). The theoretical component of this study is based on density functional theory (DFT) calculations to dissect and characterize the individual H-bonded synthons using the quantum theory of atoms in molecules (QTAIM) framework. Additionally, interaction energies of discrete H-bonds have been quantified to rationalize their strength and directional preferences, showing that directional NH···O bonds contribute the most to the stability of the assemblies, with ancillary contacts playing a secondary but supportive role. The total interaction energies range from –34.0 to –50.0 kcal/mol, underscoring the critical role of hydrogen bonding in dictating the supramolecular architectures. This combined experimental–computational approach sheds light on the structural determinants driving supramolecular organization in OXYMA-B-based salts and highlights their potential for crystal engineering applications.
New and promising type of leukotriene B4 (LTB4) antagonists based on the 1,4-benzodioxine structure
(Elsevier Masson SAS, 2023-04-06) Bouissane, Latifa; Khouili, Mostafa; Coudert, Gérard; Pujol Dilmé, M. Dolors; Guillaumet, Gérald
New leukotriene B4 (LTB4) antagonists have been synthesized that can be considered as potential anti-inflammatory drugs. Structures containing the dioxygenated nucleus of 1,4-benzodioxine constitute a potential group of leukotriene B4 (LTB4) antagonists. The objective of this study was to access efficient and selective LTB4 antagonists as a way to elucidate the role of LTB4 in inflammatory processes and therefore allow the development of new types of structures based on 1,4-benzodioxine. Forty-one new 1,4-benzodioxine molecules substituted at different positions of the heterocyclic nucleus were synthesized to determine the minimum structural requirements by studying structure-activity relationships. Eighteen of them were tested in vitro and in vivo for their anti-inflammatory activity related to the antagonist character of LTB4. Pharmacological tests have shown satisfactory in vitro activity for compounds 24b, 24c and 24e with IC50's of 288, 439, 477 nM respectively. The results of the in vivo tests, carried out with the compound that presented greater activity in the in vitro tests 24b, have shown significant anti-inflammatory properties.
SnCl2-catalyzed Kabachnik-Fields of alfa-aminophosphonates with potent antioxidant activity
(Royal Society of Chemistry, 2025-12-12) Hibot, Achraf; Hamri, Salha; Hafid, Abderrafia; Khouili, Mostafa; Pujol, Maria Dolors
A novel and efficient method for synthesizing a-aminophosphonates was developed through a Kabachnik–Fields multicomponent reaction using 6-aminocoumarin or 6-aminobenzodioxane, benzaldehyde, triethylphosphite, and a catalytic amount of SnCl2 in ethanol. The resulting 25 compounds 1a–l (71–92%) and 6a–m (45–96%) were obtained in moderate to excellent yields. Antioxidant activity, assessed via the FRAP andCUPRAC assays, the results demonstrated that several of these compounds exhibit comparable or evensuperior reducing power to ascorbic acid, particularly at low concentrations. These findings underscorethe potential of these a-aminophosphonates as promising antioxidant agents for future applications.ADME analysis predicts good oral bioavailability, limited brain and skin penetration, and potential CYP450inhibition.
The effect of aerobic and resistance training in patientswith type 2 diabetes on vitamin D(DIAVITEX): a study protocol
(Frontiers Media, 2026-01-05) Guerra Balic, Miriam; Montané Mogas, Joel; Dardashtipour, Elnaz; Canivell Fusté, Silvia; Azarbayjani, Mohammad Ali; Fuente Vidal, Andrea; Surroca, Aina; Gascón Lecha, M. Pilar; Mestres Miralles, Concepción; Antón, Alicia; Peña-Mateo, Maria José; Carrillo-Alvarez, Elena; Canudas Teixidó, Anna-Maria
Introduction: Aerobic and resistance training can effectively improve clinicalmanagement in people with type 2 diabetes (T2D). Low vitamin D (VitD) levels areassociated with T2D risk and metabolic disturbances, and may help reduce thisrisk, particularly in individuals with low VitD levels. In this line, many individualswith T2D, who may also be older adults or have osteoporosis, regularly includeVitD treatment in their healthcare routines. Although the impact of exercisehas been extensively studied, its effect on diabetic patients taking VitD remainslimited. The aim of this study is to investigate the effect of aerobic and resistancetraining on clinical parameters in patients with T2D already taking VitD.Methods: The DIAVITEX study is a randomized controlled superiority trial, withfour parallel arms, including 80 individuals with T2D. Patients will be selectedat the Primary Care Centers and stratified according to their pre-existingVitD treatment. Participants will subsequently be randomized to the exerciseintervention or control as follows: Group 1, Exercise + VitD users (n = 20);Group 2, Exercise + VitD non-users (n = 20); Group 3, VitD only (no exercise)(n = 20); and Group 4, Control (No VitD & No Exercise) (n = 20). In this study,a sarcoplasm-stimulating training program will be carried out online, threesessions per week for a total of 16 weeks. Before and after the physical activitysubjects will perform fitness and blood tests. Nutritional education programswill be provided to normalize their diets for study consistency. The primaryendpoint of the trial is the change in HOMA-IR index from baseline to week 16.Secondary endpoints include changes in HbA1c, lipid profile, body composition,and inflammatory biomarkers.Discussion: Expected improvements in insulin resistance, glycated hemoglobin,lipid profile, and inflammatory markers are anticipated following a 16-weekregimen of exercise in patients with T2D on VitD.Clinical trial registration: The study was registered on September 21, 2024,with the identifier number NCT06081387, https://clinicaltrials.gov/study/NCT06081387.
Telmisartan Reverses Hepatic Steatosis via PCK1 Upregulation: A Novel PPAR-independent Mechanism in Experimental Models of MASLD
(Elsevier B.V., 2025-07-15) Bentanachs Raset, Roger; Ramírez-Carrasco, Patricia; Braster, Bianca; Emmanouilidou, Anastasia; Mujica, Endrina; Rodrigo Calvo, María Teresa; Rodríguez, Carla; Roglans i Ribas, Núria; den Hoed, Marcel; Laguna Egea, Juan Carlos; Alegret i Jordà, Marta
Drug combination and repurposing are potential therapeutic strategies for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we have demonstrated that, in rats, both pemafibrate and telmisartan reverse hepatic steatosis induced by a high-fat, high-fructose diet. Pemafibrate attenuated liver steatosis via a PPARα-mediated increase in fatty acid catabolism, while the antisteatotic response to telmisartan did not rely on PPAR modulation. Our results in rats and in a zebrafish larva model of liver lipid accumulation suggest that part of telmisartan's antisteatotic effects are driven through the blockade of the angiotensin II type 1 receptor, along with a reduction in the expression of several lipogenic genes, which also contributes to some extent. Telmisartan's response is mediated by the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) expression. Liver metabolomic analysis revealed that by increasing PCK1, telmisartan diverted the metabolic flux of fructose from lipid towards glucose synthesis, which was subsequently fueled to the polyol pathway, thereby preserving glucose homeostasis. Moreover, telmisartan increased the hepatic levels of spermine and spermidine, which may counteract the putative detrimental effects caused by the accumulation of metabolites of the polyol route. Targeting different intrahepatic pathways, both PPAR-dependent and independent, the combination of pemafibrate and telmisartan, each at half the individual dose, was equally effective as the full dose of either drug alone to reduce liver lipid accumulation in the rat model. Our findings support the repurposing potential of these drugs, with the additional advantage of addressing both hepatic and cardiometabolic MASLD-associated complications.
Walnut-enriched diet increases the association of LDL from hypercholestero lemic men with human HepG2 cells
(American Society for Biochemistry and Molecular Biology, 2001) Muñoz, Sonia; Merlos Roca, Manuel; Zambón, Daniel; Rodríguez, Carmen; Sabaté, Joan; Ros Rahola, Emilio; Laguna Egea, Juan Carlos
In a randomized, cross-over feeding trial involving 10 men with polygenic hypercholesterolemia, a control, Mediterranean-type cholesterol-lowering diet, and a diet of similar composition in which walnuts replaced approximately 35% of energy from unsaturated fat, were given for 6 weeks each. Compared with the control diet, the walnut diet reduced serum total and LDL cholesterol by 4.2% (P = 0.176), and 6.0% (P = 0.087), respectively. No changes were observed in HDL cholesterol, triglycerides, and apolipoprotein A-I levels or in the relative proportion of protein, triglycerides, phospholipids, and cholesteryl esters in LDL particles. The apolipoprotein B level declined in parallel with LDL cholesterol (6.0% reduction). Whole LDL, particularly the triglyceride fraction, was enriched in polyunsaturated fatty acids from walnuts (linoleic and alpha-linolenic acids). In comparison with LDL obtained during the control diet, LDL obtained during the walnut diet showed a 50% increase in association rates to the LDL receptor in human hepatoma HepG2 cells. LDL uptake by HepG2 cells was correlated with alpha-linolenic acid content of the triglyceride plus cholesteryl ester fractions of LDL particles (r(2) = 0.42, P < 0.05). Changes in the quantity and quality of LDL lipid fatty acids after a walnut-enriched diet facilitate receptor-mediated LDL clearance and may contribute to the cholesterol-lowering effect of walnut consumption.

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