RESUMEN
Acrylic copolymers are useful in medical therapeutics. As in dental implants or intraocular lenses, acrylics are present in many medical devices or drug adjuvants. Industrial using of acrylics is still important in painting or textile manufacturing. Scientific research background has proved that acrylic suffer for depolymerized and cross-linking mechanisms under heating and photo-oxidative conditions. Those aging processes could lead to release of unreacted monomers and degradation products. We developed a new RP-HPLC method with good resolution, recovery, linearity, detection and quantification limits that is efficient for acrylic monomers quantification in in vitro and in vivo saline solution matrices. This method allows the detection of copolymer and medical devices degradation products too. Both the limit of quantification and the limit of detection for monomers and degradation products are above cytotoxic concentrations for human epithelial cells. Those biological results confirm the interest of the method for dosage of unreacted acrylics after polymerization and for the research of degradation products in body fluids as aqueous humor.
Asunto(s)
Ácidos Acíclicos/análisis , Resinas Acrílicas/análisis , Materiales Biocompatibles/análisis , Ácidos Acíclicos/toxicidad , Resinas Acrílicas/toxicidad , Materiales Biocompatibles/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Calefacción , Humanos , Oxidación-Reducción , Prótesis e ImplantesRESUMEN
Several physiological processes in the CNS are regulated by the endocannabinoid system (ECS). Cannabinoid receptors (CBr) and CBr agonists have been involved in the modulation of the N-methyl-D-aspartate receptor (NMDAr) activation. Glutaric (GA), 3-hydroxyglutaric (3-OHGA), methylmalonic (MMA) and propionic (PA) acids are endogenous metabolites produced and accumulated in the brain of children affected by severe organic acidemias (OAs) with neurodegeneration. Oxidative stress and excitotoxicity have been involved in the toxic pattern exerted by these organic acids. Studying the early pattern of toxicity exerted by these metabolites is crucial to explain the extent of damage that they can produce in the brain. Herein, we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) on early markers of GA-, 3-OHGA-, MMA- and PA-induced toxicity in brain synaptosomes from adult (90-day-old) and adolescent (30-day-old) rats. As pre-treatment, WIN exerted protective effects on the GA- and MMA-induced mitochondrial dysfunction, and prevented the reactive oxygen species (ROS) formation and lipid peroxidation induced by all metabolites. Our findings support a protective and modulatory role of cannabinoids in the early toxic events elicited by toxic metabolites involved in OAs.
Asunto(s)
Ácidos Acíclicos/metabolismo , Ácidos Acíclicos/toxicidad , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Benzoxazinas/farmacología , Encefalopatías Metabólicas/metabolismo , Encéfalo/metabolismo , Agonistas de Receptores de Cannabinoides/farmacología , Glutaril-CoA Deshidrogenasa/deficiencia , Morfolinas/farmacología , Naftalenos/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Glutaratos/metabolismo , Glutaratos/toxicidad , Glutaril-CoA Deshidrogenasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ácido Metilmalónico/metabolismo , Ácido Metilmalónico/toxicidad , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Propionatos/metabolismo , Propionatos/toxicidad , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
The objectives of this study were to determine the structural characteristics of perfluoroalkyl acids (PFAAs) that confer estrogen-like activity in vivo using juvenile rainbow trout (Oncorhynchus mykiss) as an animal model and to determine whether these chemicals interact directly with the estrogen receptor (ER) using in vitro and in silico species comparison approaches. Perfluorooctanoic (PFOA), perfluorononanoic (PFNA), perfluorodecanoic (PFDA), and perfluoroundecanoic (PFUnDA) acids were all potent inducers of the estrogen-responsive biomarker protein vitellogenin (Vtg) in vivo, although at fairly high dietary exposures. A structure-activity relationship for PFAAs was observed, where eight to ten fluorinated carbons and a carboxylic acid end group were optimal for maximal Vtg induction. These in vivo findings were corroborated by in vitro mechanistic assays for trout and human ER. All PFAAs tested weakly bound to trout liver ER with half maximal inhibitory concentration (IC(50)) values of 15.2-289 µM. Additionally, PFOA, PFNA, PFDA, PFUnDA, and perlfuorooctane sulfonate (PFOS) significantly enhanced human ERα-dependent transcriptional activation at concentrations ranging from 10-1000 nM. Finally, we employed an in silico computational model based upon the crystal structure for the human ERα ligand-binding domain complexed with E2 to structurally investigate binding of these putative ligands to human, mouse, and trout ERα. PFOA, PFNA, PFDA, and PFOS all efficiently docked with ERα from different species and formed a hydrogen bond at residue Arg394/398/407 (human/mouse/trout) in a manner similar to the environmental estrogens bisphenol A and nonylphenol. Overall, these data support the contention that several PFAAs are weak environmental xenoestrogens of potential concern.