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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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 fragile
fibrous 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 corresponding
xerogels. The DPP@Gel systems exhibit strong fluorescence and are effectively imaged using CLSM, with fibre morphologies that
closely correlate with those seen with cryo-SEM. In contrast, the analogous imidazolium gel system containing a sulfonated zinc
phthalocyanine (ZnPc@Gel) yields poor CLSM images because of the relatively weak emission and sample disruption during
compression, whereas cryo-SEM enables clear visualization of the native fibrous network. These results demonstrate the complementary
nature of CLSM and cryo-SEM and highlight the value of cryo-SEM as a very useful tool for imaging soft nanomaterials
with low fluorescence or limited optical contrast.
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 interest
because of its potent cytotoxic activity. Its total synthesis has proven to be difficult, however, due to its
challenging 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. The
results offer some insights into the structural features which contribute to hampering the closure of the
macrocyclic core of the macrolide polyketide. A formal synthesis of the marine macrolide (–)-callyspongiolide is
also reported using a RCM approach (C10-C11 bond formed) from analogous dienes bearing an α,β-unsaturated
ester instead of a carbonate
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 to
decrease the permeability of mucosae. The permeability barrier of the mucosa is dependent on the presence of
specific lipids. The main objective of this work is to reinforce the barrier effect of the oral mucosa with liposomal
formulations to decrease permeation. Due to the high similarity in composition and structure between lanolin
and human stratum corneum lipids, liposomes were formed with lipids contained in the stratum corneum with
two 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 ivermectin
and 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 liposomal
formulation, consisting of lipids found in the horny layer of the skin. The effect of the lanolin on the transmembrane
water loss is not reflected on the drug permeation. Therefore, it is demonstrated the main role of
ceramides in the barrier function for drugs and a virus model. Strengthening the barrier function of the mucosa
promotes the prevention or reduction of the permeation of different actives, which could be to extrapolate to
harmful 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, 2025-10-04) 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, Maite; 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.
“Synthetic Map”: A Graphic Organizer Inspired by Artificial Neural Network Paradigms for Learning Organic Synthesis.
(Division of Chemical Education of the American Chemical Society., 2024-09-09) Luque Corredera, Carlos; Bartolomé, Elena; Bradshaw, Ben
Organic Chemistry is widely recognized as a challenging subject, with the design of syntheses and retrosyntheses identified as particularly difficult tasks. Inspired by the success of artificial neural networks in machine learning, we propose a framework that leverages similar principles to enhance the teaching and learning of organic synthesis. In this paper, we introduce a novel teaching tool, the “Synthetic Map”, that attempts to visually recreate an expert’s mental map and conceptual understanding of organic synthesis built over years of experience. The educational benefits of the Synthetic Map were evaluated through its implementation in an Organic Chemistry course of a Pharmacy degree over two years. The new tool promoted students’ learning by providing a mental organizer fostering a deeper understanding of the subject and empowering students to design and execute effective synthetic strategies.
Sex Differences Affect the NRF2 Signaling Pathway in the Early Phase of Liver Steatosis: A High-Fat-Diet-Fed Rat Model Supplemented with Liquid Fructose
(MDPI, 2024-08-01) Di Veroli, Benedetta; Bentanachs Raset, Roger; Roglans i Ribas, Núria; Alegret i Jordà, Marta; Giona, Letizia; Profumo, Elisabetta; Berry, Alessandra; Saso, Luciano; Laguna Egea, Juan Carlos; Buttari, Brigitta
Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis. The KEAP1/NRF2 signaling pathway, autophagy process (LC3B and LAMP2), and endoplasmic reticulum stress response (XBP1) were analyzed in liver homogenates in male and female rats that were fed a 12-week HFHFr diet. In females, the HFHFr diet resulted in the initial activation of the KEAP1/NRF2 pathway, which was not followed by the modulation of downstream molecular targets; this was possibly due to the increase in KEAP1 levels preventing the nuclear translocation of NRF2 despite its cytosolic increase. Interestingly, while in both sexes the HFHFr diet resulted in an increase in the levels of LC3BII/LC3BI, a marker of autophagosome formation, only males showed a significant upregulation of LAMP2 and XBP1s; this did not occur in females, suggesting impaired autophagic flux in this sex. Overall, our results suggest that males are characterized by a greater ability to cope with an HFHFr metabolic stimulus mainly through an autophagic-mediated proteostatic process while in females, this is impaired. This might depend at least in part upon the fine modulation of the cytoprotective and antioxidant KEAP1/NRF2 pathway resulting in sex differences in the occurrence and severity of MASLD. These results should be considered to design effective therapeutics for MASLD.
Developmental neurotoxicity evaluation of di(2-ethylhexyl) phthalate (DEHP) and three alternative plasticizers in human neurospheres
(Elsevier , 2026-01-07) Illa Armengol, Míriam; Seeger, Brettina; Klose, Jördis; Kühne, Britta Anna; Muñoz-Torrero López-Ibarra, Diego; Koch, Katharina; Fritsche, Ellen; Barenys Espadaler, Marta
Plasticizers like di-(2-ethylhexyl) phthalate (DEHP) are commonly used in medical devices to enhance plastic flexibility. DEHP is classified as a CMR1b substance due to its adverse effects on reproduction and fertility, and it has been linked to neurodevelopmental disorders such as ADHD, autism spectrum disorder, and learning disabilities. While DEHP is scheduled for phase-out by 2030, data on the developmental neurotoxicity (DNT) of alternative plasticizers remain scarce. We evaluated the DNT potential of DEHP and three alternative plasticizers: di-(2-ethylhexyl) terephthalate (DEHT), di-(2-ethylhexyl) adipate (DEHA), and tris-(2-ethylhexyl) trimellitate (TOTM), aiming to identify safer substitutes, particularly for neonates in neonatal intensive care units (NICUs). The human Neurosphere Assay was used to assess plasticizer effects on seven key neurodevelopmental processes: neural progenitor cell (NPC) proliferation, migration of radial glia, neurons, and oligodendrocytes, neurite outgrowth, and differentiation of neurons and oligodendrocytes. Concentration-response analyses provided benchmark concentrations (BMCs) and lowest observed adverse effect concentrations (LOAECs). Gene expression profiling provided mechanistic insights, and toxicity was ranked using the most sensitive endpoint (MSE) and ToxPi Tool. DEHP and TOTM showed the highest DNT potential, with NPC proliferation as the MSE. DEHT impacted oligodendrocyte differentiation, while no BMC was determined for DEHA within the tested concentrations. Considering an exposure scenario in NICUs, the estimated neonatal DEHP plasma levels exceeded the LOAEC for NPC proliferation, raising concerns for DNT. Overall, DEHA emerged as the least hazardous alternative for neurodevelopment, highlighting the value of combined human-relevant in vitro phenomics and human biomonitoring for DNT hazard evaluation.
First-Generation Synthetic Cathinones Produce Arrhythmia in Zebrafish Eleutheroembryos: A New Approach Methodology for New Psychoactive Substances Cardiotoxicity Evaluation
(MDPI, 2023-09-08) Teixidó Condomines, Elisabet; Riera-Colomer, Clara; Raldúa, Demetrio; Pubill Sánchez, David; Escubedo Rafa, Elena; Barenys Espadaler, Marta; López Arnau, Raúl
The increasing number of new psychoactive substances (NPS) entering the illicit drug market, especially synthetic cathinones, as well as the risk of cardiovascular complications, is intensifying the need to quickly assess their cardiotoxic potential. The present study aims to evaluate the cardiovascular toxicity and lethality induced by first-generation synthetic cathinones (mephedrone, methylone, and MDPV) and more classical psychostimulants (cocaine and MDMA) in zebrafish embryos using a new approach methodology (NAM). Zebrafish embryos at 4 dpf were exposed to the test drugs for 24 h to identify drug lethality. Drug-induced effects on ventricular and atrial heart rate after 2 h exposure were evaluated, and video recordings were properly analyzed. All illicit drugs displayed similar 24 h LC₅₀ values. Our results indicate that all drugs are able to induce bradycardia, arrhythmia, and atrial-ventricular block (AV block), signs of QT interval prolongation. However, only MDPV induced a different rhythmicity change depending on the chamber and was the most potent bradycardia and AV block-inducing drug compared to the other tested compounds. In summary, our results strongly suggest that the NAM presented in this study can be used for screening NPS for their cardiotoxic effect and especially for their ability to prolong the QT intervals.
A gram-scale route to phlegmarine alkaloids: rapid total synthesis of (-)-cermizine B
(Royal Society of Chemistry, 2014-04-03) Bradshaw, Ben; Luque Corredera, Carlos; Bonjoch i Sesé, Josep
The synthesis of the Lycopodium alkaloid ( )-cermizine B (1), which establishes its absolute configuration, is achieved by combining asymmetric organocatalysis and an uninterrupted eight-step reaction sequence, followed by a final reduction step. This ''pot-economy'' strategy provides access to the cis-phlegmarine stereo parent embedded in 1 for the first time, rapidly and on a gram-scale.
cis-Decahydroquinolines via asymmetric organocatalysis:application to the total synthesis of lycoposerramine Z
(American Chemical Society, 2012-12-27) Bradshaw, Ben; Luque Corredera, Carlos; Bonjoch i Sesé, Josep
Aquest article és el primer que es va obtenir en el context de la tesi doctoral. Es va publicar a finals de 2012 - principis de 2013. Es descriu
el primer dels resultats que es varen obtenir, i que va ser la clau per la obtenció dels articles posteriors (anys 2013 i 2014). Descriu, en
concret, el descobriment d'una nova reacció en síntesis química, que inclou 3 reaccions en un sol pas sintètic, en un procediment anomenat
"one-pot procedure". Aquesta reacció permet accedir, de forma directa i selectiva, a una estructura mare (o building block) que és un
heterocicle anomenat "decahidroquinolina", que a la seva vegada, és un intermedi avançat per la síntesis total d'una família d'alcaloides
anomenada flegmarina. A més, aquest procediment permet la obtenció d'un compost bi-cíclic (com ho és la decahidroquinolina) desde
material comercial i acíclic. El procés, te una selectivitat i una puressa superiors al 99% (amb traces d'altres compostos anàlegs), i per tant,
suposa un mètode molt eficient per accedir a aquesta familia d'estructures naturals.

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