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

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

Estadístiques

Examinar

Mostrant 1 - 20 de 565

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.
Developmental neurotoxicity evaluation of di(2-ethylhexyl) phthalate (DEHP) and three alternative plasticizers in human neurospheres
(Elsevier Ltd., 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.
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.
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.
Towards a glutathione-cleavable azobenzene linker for antibody–drug conjugates
(Royal Society of Chemistry, 2025-10-28) Kapun, Mia; Patel, Roshan; Park, Mahri; Pérez Areales, Francisco Javier; Kostadinova, Kristina A.; Wharton, Thomas; Carroll, Jason S.; Spring, David R.
Herein we describe the development of a novel azobenzene-containing glutathione-cleavable linker for use in antibody–drug conjugates (ADCs). This linker demonstrated efficient payload release under elevated glutathione levels while maintaining stability in human plasma. An anti-HER2 ADC incorporating this linker exhibited potent in vitro cytotoxicity and selective activity towards HER2-positive cell lines.
Next-Generation MDMA Analogue SDMA: Pharmacological and Metabolic Insights
(American Chemical Society, 2025-12-02) Kastner, Nina; Nadal-Gratacós, Núria; Shacham, Sharon; Cuccurazzu, Bruna; Halberstadt, Adam L.; McCorvy, John D.; Stockner, Thomas; Meyer, Markus R.; López Arnau, Raúl; Grill, Matthias; Sitte, Harald H.; Hemmer, Selina; Alves da Silva, Leticia; McKee, John L.; Hell, Tamara; Cicalese, Giulia; Holy, Marion; Kooti, Fatemeh; Jäntsch, Kathrin; Baron, Roland
3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, shows promise in treating depression and post-traumatic stress disorder (PTSD), resulting in breakthrough status. However, concerns regarding MDMA's abuse potential and cytotoxicity have sparked interest in developing safer analogues with similar therapeutic benefits. This study investigated the pharmacological properties of MDMA analogues in which the 1,3-benzodioxole group is replaced by a 1,3-benzoxathiole, termed SDA and SDMA, compared to MDA and MDMA through in silico, in vitro, and in vivo assays. In vitro experiments using human embryonic kidney (HEK293) cells examined the interactions with monoamine transporters. SDA and SDMA showed similar profiles to MDMA at the serotonin transporter (SERT), while both inhibited dopamine (DAT) and norepinephrine (NET) transporters more potently, in line with in silico molecular docking fitness scores of binding. SDA and SDMA also showed increased potency in evoking efflux through SERT and DAT acting as partial releasers. SDA and SDMA exhibited a similar interaction profile with 5-HT₂ receptors compared with their respective analogues. Metabolism studies revealed faster clearance rates for SDA and SDMA, in contrast to MDA and MDMA, which exhibited only weak degradation. In contrast to MDMA's rewarding effects, SDMA did not induce significant effects in mice, while SDA only produced a significant preference for the drug-paired compartment at the lowest dose tested. Moreover, while SDMA shares similar locomotor and hyperthermic profiles as MDMA in mice, SDA induced increased hyperlocomotion and more sustained hyperthermia. In conclusion, these findings suggest that SDMA, with enhanced metabolic profiles and reduced abuse potential, is a promising candidate for further studies.
Neuroprotective effects of N-acetylcysteine-amide (AD4) in a Survival Mouse Model of Paraoxon Intoxication: Targeting Oxidative Stress, Neuroinflammation and Memory Impairments.
(MDPI, 2025-12-06) Urquizu, Edurne; Cuiller, Marine; Papadopoulou, Georgia; Pubill Sánchez, David; Raldúa, Demetrio; Camarasa García, Jordi; Escubedo Rafa, Elena; López-Arnau, Raúl
Neurotoxicity induced by organophosphorus (OP) compounds such as paraoxon (POX)
leads to severe brain damage and cognitive impairments. Although current treatments
alleviate acute cholinergic symptoms, they fail to address secondary neurotoxicity. This
study investigated the therapeutic potential of N-acetylcysteine-amide (AD4), a blood–
brain-barrier permeable antioxidant, in a survival mouse model of acute POX intoxication.
Male Swiss CD-1 mice received POX (4 mg/kg) followed by standard emergency therapy
(atropine, pralidoxime and diazepam). AD4 (150 mg/kg) was administered 2 and 6 h
post-exposure. AD4 treatment effectively prevented oxidative stress by reducing lipid
peroxidation and restoring the expression in hippocampus (HP) and/or prefrontal cortex
(PFC) of key antioxidant enzymes such as glutathione peroxidase-1 (GPx-1) and catalase
(CAT) suppressed by POX acute exposure. Moreover, AD4 attenuated neuroinflammation
in specific hippocampal subregions, as evidenced by reduced Glial Fibrillary Acidic Protein
(GFAP) and Ionized Calcium Binding Adaptor Molecule 1 (Iba-1) immunoreactivity. Im-
portantly, AD4 also rescued recognition memory deficits, as assessed by the Novel Object
Recognition Test (NORT). In summary, these findings demonstrate that AD4 mitigates
oxidative stress, neuroinflammation, and cognitive dysfunction following acute POX in-
toxication, supporting its potential as an adjuvant therapy for mitigating the secondary
neurotoxicity derived from organophosphorus poisoning.
3,4-Methylenedioxymethamphetamine, synthetic cathinones and psychedelics: From recreational to novel psychotherapeutic drugs
(Frontiers Media, 2022-10-03) López Arnau, Raúl; Camarasa García, Jordi; Carbó Banús, Marcel·lí; Nadal-Gratacós, Núria; Puigseslloses, Pol; Espinosa-Velasco, María; Urquizu, Edurne; Escubedo Rafa, Elena; Pubill Sánchez, David
The utility of classical drugs used to treat psychiatric disorders (e.g.,antidepressants, anxiolytics) is often limited by issues of lack of efficacy, delayed onset of action or side effects. Psychoactive substances have a long history of being used as tools to alter consciousness and as a gateway to approach the unknown and the divinities. These substances were initially obtained from plants and animals and more recently by chemical synthesis, and its consumption evolved toward a more recreational use, leading to drug abuse-related disorders, trafficking, and subsequent banning by the authorities. However, these substances, by modulation of certain neurochemical pathways, have been proven to have a beneficial effect on some psychiatric disorders. This evidence obtained under medically controlled conditions and often associated with psychotherapy, makes these substances an alternative to conventional medicines, to which in many cases the patient does not respond properly. Such disorders include post-traumatic stress disease and treatment-resistant depression, for which classical drugs such as MDMA, ketamine, psilocybin and LSD, among others, have already been clinically tested, reporting successful outcomes. The irruption of new psychoactive substances (NPS), especially during the last decade and despite their recreational and illicit uses, has enlarged the library of substances with potential utility on these disorders. In fact, many of them were synthetized with therapeutic purposes and were withdrawn for concrete reasons (e.g., adverse effects, improper pharmacological profile). In this review we focus on the basis, existing evidence and possible use of synthetic cathinones and psychedelics (specially tryptamines) for the treatment of mental illnesses and the properties that should be found in NPS to obtain new therapeutic compounds.
Mg/Fe-LDH: An efficient promoter for the synthesis of tetrahydrospiro[pyrazole-4,5′-pyrazolo[3,4-b]pyridine] derivatives
(Elsevier, 2024-03-10) Hibot, Achraf; Fadili, Hicham; Hafid, Abderrafia; Lebreton, Jacques; Pujol, Maria Dolors; Khouili, Mostafa
The synthesis of tetrahydrospiro[pyrazole-4,5'-pyrazolo[3,4-b]pyridine] derivativesusing Mg/Fe-LDH as a heterogeneous catalyst was reported. This methodology usedfor the condensation of pyrazolones with aldehydes in a basic medium and with thepresence of the Mg/Al-LDH catalyst presents many benefits, such as the fact of using areusable and low-cost catalyst, environmentally friendly conditions, time short reactiontimes and excellent yields. It has been verified and confirmed that the catalyst isrelatively stable and allows its reuse without additional treatment. Condensation hasbeen carried out with different aldehydes and bis-pyrazolone derivatives have beenobtained with yields ranging from 71 to 91% of purified product. The stereo impedanceof the adduct formed prevents subsequent condensation.
JNK signaling and its impact on neural cell maturation and differentiation
(Elsevier, 2024-05-25) Castro-Torres, Rubén Darío; Olloquequi, Jordi; Parcerisas, Antoni; Ureña, Jesús; Ettcheto Arriola, Miren; Beas Zárate, Carlos; Camins Espuny, Antoni; Verdaguer, Ester; Auladell i Costa, M. Carme
C-Jun-N-terminal-kinases (JNKs), members of the mitogen-activated-protein-kinase family, are significantly linked with neurological and neurodegenerative pathologies and cancer progression. However, JNKs serve key roles under physiological conditions, particularly within the central-nervous-system (CNS), where they are critical in governing neural proliferation and differentiation during both embryogenesis and adult stages. These processes control the development of CNS, avoiding neurodevelopment disorders. JNK are key to maintain the proper activity of neural-stem-cells (NSC) and neural-progenitors (NPC) that exist in adults, which keep the convenient brain plasticity and homeostasis. This review underscores how the interaction of JNK with upstream and downstream molecules acts as a regulatory mechanism to manage the self-renewal capacity and differentiation of NSC/NPC during CNS development and in adult neurogenic niches. Evidence suggests that JNK is reliant on non-canonical Wnt components, Fbw7-ubiquitin-ligase, and WDR62-scaffold-protein, regulating substrates such as transcription factors and cytoskeletal proteins. Therefore, understanding which pathways and molecules interact with JNK will bring knowledge on how JNK activation orchestrates neuronal processes that occur in CNS development and brain disorders.
A polycyclic scaffold identified by structure-based drug design effectively inhibits the human P2X7 receptor
(Nature Publishing Group, 2025-09-15) Kim, Yong-Chul; Müller, Christa E.; Kolocouris, Antonios; Vázquez Cruz, Santiago; Mansoor, Steven E; Oken, Adam C.; Turcu, Andreea L.; Tzortzini, Eva; Georgiou, Kyriakos; Nagel, Jessica; Westermann, Franka G.; Barniol-Xicota, Marta; Seidler, Jonas; Kim, Ga-Ram; Lee, So-Deok; Nicke, Annette
TheP2X7receptorisanATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Understanding species-specific pharmacological effects of existing antagonists has been challenging, in part due to the dearth of molecular information on receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the fulllength wild-type human P2X7 receptor in apo closed and ATP-bound open state conformationsanddrawcomparisonswithstructuresofotherorthologs. Wealso report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, termed UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with subnanomolar potency and high selectivity, revealing its significant therapeutic potential.
A review of vancomycin, gentamicin and amikacin population pharmacokientic models in neonates and infants.
(Springer Nature Switzerland, 2025-01-15) Albanell Fernández, Marta; Bastida Fernández, Carla; Rodríguez Reyes, Montse; Soy Muner, Dolors
Abstract Population pharmacokinetic (popPK) models are an essential tool when implementing therapeutic drug monitoring (TDM) and to overcome dosing challenges in neonates in clinical practice. Since vancomycin, gentamicin, and amikacin are among the most prescribed antibiotics for the neonatal population, we aimed to characterize the popPK models of these antibiotics and the covariates that may influence the pharmacokinetic parameters in neonates and infants with no previous pathologies. We searched the PubMed, Embase, Web of Science, and Scopus databases and the bibliographies of relevant articles from inception to the beginning of February 2024. The search identified 2064 articles, of which 68 met the inclusion criteria (34 for vancomycin, 21 for gentamicin, 13 for amikacin). A one-compartment popPK model was more frequently used to describe the pharmacokinetics of the three antibiotics (91.2% vancomycin, 76.9% gentamicin, 57.1% amikacin). Pharmacokinetic parameter (mean ± standard deviation) values calculated for a “typical” neonate weighing 3 kg were as follows: clearance (CL) 0.34 ± 0.80 L/h for vancomycin, 0.27 ± 0.49 L/h for gentamicin, and 0.19 ± 0.07 L/h for amikacin; volume of distribution (V d): 1.75 ± 0.65 L for vancomycin, 1.54 ± 0.53 L for gentamicin, and 1.67 ± 0.27 L for amikacin for one compartment models. Total body weight, postmenstrual age, and serum creatinine were common predictors (covariates) for describing the variability in CL, whereas only total body weight predominated for V d. A single universal popPK model for each of the antibiotics reviewed cannot be implemented in the neonatal population because of the significant variability between them. Body weight, renal function, and postmenstrual age are important predictors of CL in the three antibiotics, and total body weight for V d. TDM represents an essential tool in this population, not only to avoid toxicity but to attain the desired pharmacokinetic/pharmacodynamic index. The characteristics of the neonatal population, coupled with the lack of prospective studies and external validation of most models, indicate a need to continue investigating the pharmacokinetics of these antibiotics in neonates.
PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells
(Elsevier Masson SAS, 2024-10-01) Zhang, Meijian; Barroso Fernández, Emma; Peña, Lucía; Rada, Patricia; Valverde, Ángela M.; Wahli, Walter; Palomer Tarridas, Francesc Xavier; Vázquez Carrera, Manuel
The role of peroxisome proliferator-activated receptor (PPAR)β/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARβ/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-β (TGF-β). The PPARβ/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard-/- mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARβ/δ activation abrogated TGF-β1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-β1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARβ/δ agonist reduces TGF-β1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.
Assessment of Endocrine-Disrupting Properties in Cosmetic Ingredients: Focus on UV Filters and Alternative Testing Methods
(MDPI, 2025-08-16) Maddaleno Jiménez, Adriana Solange; Guardia Escoté, Laia; Teixidó Condomines, Elisabet; Vinardell Martínez-Hidalgo, Ma. Pilar; Mitjans Arnal, Montserrat
Endocrine-disrupting chemicals are substances capable of interfering with hormonal systems, potentially leading to adverse developmental, reproductive, neurological, and immune effects in both humans and wildlife. Various experimental models are currently available to assess the endocrine-disrupting potential of substances. However, in the context of cosmetic ingredients, the ban on animal testing for safety and efficacy evaluations in Europe and other regions necessitates the use of in vitro or in silico approaches. Concerns have been raised regarding the possible endocrine-disrupting properties of certain cosmetic compounds, prompting the development of a priority substance list that includes several ultraviolet (UV) filters. This review provides a comprehensive overview of the main methodologies employed to evaluate endocrine-disrupting effects, with a particular focus on different endocrine organs. It also compiles and analyzes literature data related to commonly used UV filters such as benzophenones, avobenzone, homosalate, octocrylene, octinoxate, and 4-methylbenzylidene camphor. A major limitation identified is the lack of validated in vitro methods for assessing disruptions in specific endocrine organs, such as the thyroid and pancreas. This gap hinders accurate interpretation of experimental results and highlights the urgent need for further research to clarify the safety profiles of UV filters and other cosmetic ingredients.
Novel molecular mechanism driving neuroprotection after soluble epoxide hydrolase inhibition: Insights for Alzheimer's disease therapeutics
(John Wiley & Sons, 2023-12-31) Griñán Ferré, Christian; Jarne Ferrer, Júlia; Bellver Sanchis, Aina; Codony Gisbert, Sandra; Puigoriol Illamola, Maria Dolors; Sanfeliu, Coral; Oh, Yumin; Lee, Seulki; Vázquez Cruz, Santiago; Pallàs i Llibería, Mercè, 1964-
Background Neuroinflammation is widely recognized as a significant hallmark of Alzheimer's disease (AD). To combat neuroinflammation, the inhibition of the soluble epoxide hydrolase (sEH) enzyme has been demonstrated crucial. Importantly, sEH inhibition could be related to other neuroprotective pathways described in AD. Aims The aim of the study was to unveil new molecular pathways driving neuroprotection through sEH, we used an optimized, potent, and selective sEH inhibitor (sEHi, UB-SCG-51). Materials and Methods UB-SCG-51 was tested in neuroblastoma cell line, SH-SY5Y, in primary mouse and human astrocytes cultures challenged with proinflammatory insults and in microglia cultures treated with amyloid oligomers, as well as in mice AD model (5XFAD). Results UB-SCG-51 (10 and 30 μM) prevented neurotoxic reactive-astrocyte conversion in primary mouse astrocytes challenged with TNF-α, IL-1α, and C1q (T/I/C) combination for 24 h. Moreover, in microglial cultures, sEHi reduced inflammation and glial activity. In addition, UB-SCG-51 rescued 5XFAD cognitive impairment, reducing the number of Amyloid-β plaques and Tau hyperphosphorylation accompanied by a reduction in neuroinflammation and apoptotic markers. Notably, a transcriptional profile analysis revealed a new pathway modulated by sEHi treatment. Specifically, the eIF2α/CHOP pathway, which promoted the endoplasmic reticulum response, was increased in the 5XFAD-treated group. These findings were confirmed in human primary astrocytes by combining sEHi and eIF2α inhibitor (eIF2αi) treatment. Besides, combining both treatments resulted in increased in C3 gene expression after T/I/C compared with the group treated with sEHi alone in cultures. Discussion Therefore, sEHi rescued cognitive impairment and neurodegeneration in AD mice model, based on the reduction of inflammation and eIF2α/CHOP signaling pathway. Conclusions In whole, our results support the concept that targeting neuroinflammation through sEH inhibition is a promising therapeutic strategy to fight against Alzheimer's disease with additive and/or synergistic activities targeting neuroinflammation and cell stress.
Synthesis of the ABC Core of Daphniphyllum Alkaloids with a [5-6-7] Azatricyclic Scaffold via Ring Expansion of Azabicyclic and Azatricyclic Building Blocks
(American Chemical Society, 2024-07-19) Marquès, Clàudia; González-Lizana, David; Diaba, Faïza; Bonjoch i Sesé, Jose
The [5–6–7] azatricyclic ABC core, found in several Daphniphyllum alkaloids, has been synthesized through a novel route involving ring expansion of a perhydroindolone to afford the AC ring system and a radical B ring closure as key steps. The level of functionalization of the reported octahydro-1,7-ethanocyclohepta[b]pyrroles suggests that they can serve as valuable building blocks in this alkaloid field. Also reported is the first synthesis of homomorphans by the ring enlargement of 2-azabicyclo[3.3.1]nonanes.

Examinar

Enviaments recents