RESUMO
Hepatic steatosis and oxidative stress are considered to be the sequential steps in the development of non-alcoholic fatty liver disease (NAFLD). We previously found that catalpol, an iridoid glucoside extracted from the root of Romania glutinosa L, protected against diabetes-induced hepatic oxidative stress. Here, we found that the increased expression of p66shc was observed in NAFLD models and catalpol could inhibit p66shc expression to ameliorate NAFLD effectively. However, the underlying mechanisms remained unknown. The aim of the present study was to investigate the p66shc-targeting miRNAs in regulating oxidative stress and hepatic steatosis, also the mechanisms of catalpol inhibiting NAFLD. We found that the effects of catalpol inhibiting hepatic oxidative stress and steasis are dependent on inhibiting P66Shc expression. In addition, miR-96-5p was able to suppress p66shc/cytochrome C cascade via targeting p66shc mRNA 3'UTR, and catalpol could lead to suppression of NAFLD via upregulating miR-96-5p level. Thus, catalpol was effective in ameliorating NAFLD, and miR-96-5p/p66shc/cytochrome C cascade might be a potential target.
Assuntos
Glucosídeos Iridoides/farmacologia , Fígado/efeitos dos fármacos , MicroRNAs/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/genética , Estresse Oxidativo/efeitos dos fármacos , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/efeitos dos fármacos , Animais , Citocromos c , Dieta Ocidental , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/genética , Receptores de LDL/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/genética , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismoRESUMO
C-peptide exerts protective effects against diabetic complications; however, its role in inhibiting hyperglycemic memory (HGM) has not been elucidated. We investigated the beneficial effect of C-peptide on HGM-induced vascular damage in vitro and in vivo using human umbilical vein endothelial cells and diabetic mice. HGM induced apoptosis by persistent generation of intracellular ROS and sustained formation of ONOO(-) and nitrotyrosine. These HGM-induced intracellular events were normalized by treatment with C-peptide, but not insulin, in endothelial cells. C-peptide also inhibited persistent upregulation of p53 and activation of mitochondrial adaptor p66(shc) after glucose normalization. Further, C-peptide replacement therapy prevented persistent generation of ROS and ONOO(-) in the aorta of diabetic mice whose glucose levels were normalized by the administration of insulin. C-peptide, but not insulin, also prevented HGM-induced endothelial apoptosis in the murine diabetic aorta. This study highlights a promising role for C-peptide in preventing HGM-induced intracellular events and diabetic vascular damage.
