RESUMEN
Modulation of major histocompatibility complex (MHC) expression using drugs has been proposed to control immunity. Phytochemical investigations on Garcinia species have allowed the isolation of bioactive compounds such as polycyclic polyprenylated acylphloroglucinols (PPAPs). PPAPs such as guttiferone J (1), display anti-inflammatory and immunoregulatory activities while garcinol (4) is a histone acetyltransferases (HAT) p300 inhibitor. This study reports on the isolation, identification and biological characterization of two other PPAPs, i.e., xanthochymol (2) and guttiferone F (3) from Garcinia bancana, sharing structural analogy with guttiferone J (1) and garcinol (4). We show that PPAPs 1-4 efficiently downregulated the expression of several MHC molecules (HLA-class I, -class II, MICA/B and HLA-E) at the surface of human primary endothelial cells upon inflammation. Mechanistically, PPAPs 1-4 reduce MHC proteins by decreasing the expression and phosphorylation of the transcription factor STAT1 involved in MHC upregulation mediated by IFN-γ. Loss of STAT1 activity results from inhibition of HAT CBP/p300 activity reflected by a hypoacetylation state. The binding interactions to p300 were confirmed through molecular docking. Loss of STAT1 impairs the expression of CIITA and GATA2 but also TAP1 and Tapasin required for peptide loading and transport of MHC. Overall, we identified new PPAPs issued from Garcinia bancana with potential immunoregulatory properties.
Asunto(s)
Garcinia/química , Floroglucinol/análogos & derivados , Floroglucinol/farmacología , Compuestos Policíclicos/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia B, Miembro 2/metabolismo , Acilación , Benzofenonas/química , Benzofenonas/aislamiento & purificación , Benzofenonas/farmacología , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Factor de Transcripción GATA2/metabolismo , Humanos , Interferón gamma/metabolismo , Complejo Mayor de Histocompatibilidad/efectos de los fármacos , Complejo Mayor de Histocompatibilidad/genética , Proteínas de Transporte de Membrana/metabolismo , Simulación del Acoplamiento Molecular , Proteínas Nucleares/metabolismo , Floroglucinol/química , Floroglucinol/aislamiento & purificación , Compuestos Policíclicos/química , Compuestos Policíclicos/aislamiento & purificación , Prenilación , Cultivo Primario de Células , Factor de Transcripción STAT1/metabolismo , Terpenos/química , Terpenos/farmacología , Transactivadores/metabolismo , Factores de Transcripción p300-CBP/antagonistas & inhibidores , Factores de Transcripción p300-CBP/químicaRESUMEN
Usually isolated from Garcinia (Clusiaceae) or Hypericum (Hypericaceae) species, some Polycyclic Polyprenylated AcylPhloroglucinols (PPAPs) have been recently reported as potential research tools for immunotherapy. Aiming at exploring the chemodiversity of PPAPs amongst Garcinia genus, a dereplication process suitable for such natural compounds has been developed. Although less sensitive than mass spectrometry, NMR spectroscopy is perfectly reproducible and allows stereoisomers distinction, justifying the development of 13C-NMR strategies. Dereplication requires the use of databases (DBs). To define if predicted DBs were accurate enough as dereplication tools, experimental and predicted δC of natural products usually isolated from Clusiaceae were compared. The ACD/Labs commercial software allowed to predict 73% of δC in a 1.25â¯ppm range around the experimental values. Consequently, with these parameters, the major PPAPs from a Garcinia bancana extract were successfully identified using a predicted DB.