Farmacologia, Toxicologia i Química Terapèutica

PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells

2025-11-19T10:50:21Z

PPARβ/δ attenuates hepatic fibrosis by reducing SMAD3 phosphorylation and p300 levels via AMPK in hepatic stellate cells 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.

Impact of a high-fat diet on spatial learning and memory: the role of sex, APOE genotype, and postnatal chlorpyrifos exposure.

2025-11-19T10:49:25Z

Impact of a high-fat diet on spatial learning and memory: the role of sex, APOE genotype, and postnatal chlorpyrifos exposure. Guardia Escoté, Laia; Biosca Brull, Judit; Blanco, Jordi; Cabré, Maria; Basaure, Pia; Pérez Fernández, Cristian; Sánchez Santed, Fernando; Domingo, José L.; Colomina, Maria Teresa Environmental factors, such as exposure to neurotoxicants and diet, play a critical role in shaping cognitive

function, particularly in genetically susceptible individuals. Chlorpyrifos (CPF), an organophosphate pesticide,

and high-fat diets (HFD) have been independently associated with cognitive impairment, yet their combined

effects remain poorly understood. Apolipoprotein E (APOE) genotype influences vulnerability to cognitive

decline, with the ε4 allele being a major risk factor for neurodegenerative diseases. This study assessed the

interplay between APOE genotype, sex, early-life CPF exposure, and HFD on spatial learning and memory. Male

and female C57BL/6, apoE3- and apoE4-targeted replacement (TR) mice were orally exposed to CPF during

postnatal days 10–15 and subsequently subjected to a HFD for 8 weeks. At the end of the HFD challenge, body

weight gain was calculated, and spatial learning and memory assessed using the Morris Water Maze test. Results

indicate that HFD-driven weight gain was influenced by sex and APOE genotype. All groups acquired the spatial

learning task, but postnatal CPF exposure affected performance in certain groups. Retention was more variable in

females, suggesting increased susceptibility to environmental exposures. Notably, apoE4-TR females showed

improved memory retention following either CPF exposure or HFD, whereas apoE4-TR males exhibited impaired

long-term memory after HFD exposure. These findings highlight the complex interactions between genetic and

environmental factors. Understanding these dynamics is essential for developing targeted nutritional and public

health strategies to mitigate cognitive decline. Importantly, dietary recommendations should not be generalized

but tailored to individual profiles to optimize cognitive health and disease prevention.<

Synthesis of the ABC Core of Daphniphyllum Alkaloids with a [5-6-7] Azatricyclic Scaffold via Ring Expansion of Azabicyclic and Azatricyclic Building Blocks

2025-11-19T10:49:25Z

Synthesis of the ABC Core of Daphniphyllum Alkaloids with a [5-6-7] Azatricyclic Scaffold via Ring Expansion of Azabicyclic and Azatricyclic Building Blocks 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.

A review of vancomycin, gentamicin and amikacin population pharmacokientic models in neonates and infants.

2025-11-19T10:49:19Z

A review of vancomycin, gentamicin and amikacin population pharmacokientic models in neonates and infants. 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.