RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease that may progress to nonalcoholic steatohepatitis (NASH), hepatic tissue fibrosis, liver cirrhosis, and hepatocellular carcinoma. In this study, we investigated the effects of Pien Tze Huang (PTH), a well-known traditional Chinese herbal formula with liver protective effect, in methionine-choline deficient diet (MCD)- and high-fat diet (HFD)-induced NASH mouse models. Our results showed that PTH could exert hepatoprotective effects by improving liver weight and steatosis and reducing the fibrosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST) in both animal models. The effects of PTH was accompanied with the reduction of infiltrated macrophages, the inhibition of the expression of cytokines, and the induction of adiponectin expression. Mechanistically, we found that PTH could inhibit the activation of proinflammatory transcription factor nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor of κBα (IκBα). These results demonstrate that PTH can improve NAFLD largely due to its suppression of the NF-κB inflammatory pathway.
Asunto(s)
Medicamentos Herbarios Chinos , Enfermedad del Hígado Graso no Alcohólico , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Fibrosis , Hígado , Cirrosis Hepática/metabolismo , Metionina/farmacología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Nur77, an orphan member of the nuclear receptor superfamily, plays an important role in the regulation of inflammatory processes. Our previous work found that celastrol, a pentacyclic triterpene, bound to Nur77 to inhibit inflammation in a Nur77-dependent manner. Celastrol binding to Nur77 promotes Nur77 translocation from nucleus to cytoplasm, resulting in clearance of inflamed mitochondria and then alleviation of inflammation. Here, we report the design, synthesis, SAR study and biological evaluation of a series of celastrol analogs. A total of 24 celastrol derivatives were made. Compound 3a with a Kd of 0.87⯵M was found to be less toxic than celastrol and could be a hit molecule for further optimization.
Asunto(s)
Antiinflamatorios/farmacología , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/antagonistas & inhibidores , Triterpenos/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Antiinflamatorios/toxicidad , Sitios de Unión , Diseño de Fármacos , Células Hep G2 , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/química , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Triterpenos Pentacíclicos , Unión Proteica/efectos de los fármacos , Proteína Sequestosoma-1/metabolismo , Relación Estructura-Actividad , Factor 2 Asociado a Receptor de TNF/metabolismo , Triterpenos/síntesis química , Triterpenos/metabolismo , Triterpenos/toxicidad , Pez CebraRESUMEN
Celastrol is one of the most studied natural products. Our studies show for the first time that celastrol can bind to its target protein via specific noncovalent interactions that position celastrol next to the thiol group of the reactive cysteine for reversible covalent bond formation. Such specific noncovalent interactions confer celastrol binding specificity and demonstrate the feasibility of improving the efficacy and selectivity of celastrol for therapeutic applications.