RESUMEN
Emodin, a naturally occurring anthraquinone derivative isolated from Polygoni cuspidati radix, has several beneficial pharmacologic effects, which include anti-cancer, anti-diabetic, and anti-inflammatory activities. In this study, the authors examined the effect of emodin on the production of proinflammatory cytokines, such as, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, in mouse bone marrow-derived mast cells (BMMCs) stimulated with phorbol 12-myristate 13-acetate (PMA) plus the calcium ionophore A23187. To investigate the mechanism responsible for the regulation of pro-inflammatory cytokine production by emodin, the authors assessed its effects on the activations of transcriptional factor nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPKs). Emodin attenuated the nuclear translocation of (NF)-kappaB p65 and its DNA-binding activity by reducing the phosphorylation and degradation of IkappaBalpha and the phosphorylation of IkappaB kinase B (IKK). Furthermore, emodin dose-dependently attenuated the phosphorylations of MAPKs, such as, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAP kinase, and the stress-activated protein kinases (SAPK)/c-Jun-N-terminal kinase (JNK). Taken together, the findings of this study suggest that the anti-inflammatory effects of emodin on PMA plus A23187-stimulated BMMCs are mediated via the inhibition of NF-kappaB activation and of the MAPK pathway.
Asunto(s)
Animales , Ratones , Calcimicina , Calcio , Citocinas , Emodina , Quinasa I-kappa B , Interleucina-6 , Interleucinas , Mastocitos , Proteínas Quinasas Activadas por Mitógenos , FN-kappa B , Proteínas Quinasas p38 Activadas por Mitógenos , Fosforilación , Fosfotransferasas , Proteínas Quinasas , Factor de Necrosis Tumoral alfaRESUMEN
Glucagon-like peptide-1 (GLP-1) is a potent glucoincretin hormone and an important agent for the treatment of type 2 diabetes. Here we demonstrate that B-cell translocation gene 2 (BTG2) is a crucial regulator in GLP-1-induced insulin gene expression and insulin secretion via upregulation of pancreatic duodenal homeobox-1 (PDX-1) in pancreatic beta-cells. GLP-1 treatment significantly increased BTG2, PDX-1 and insulin gene expression in pancreatic beta-cells. Notably, adenovirus-mediated overexpression of BTG2 significantly elevated insulin secretion, as well as insulin and PDX-1 gene expression. Physical interaction studies showed that BTG2 is associated with increased PDX-1 occupancy on the insulin gene promoter via a direct interaction with PDX-1. Exendin-4 (Ex-4), a GLP-1 agonist, and GLP-1 in pancreatic beta-cells increased insulin secretion through the BTG2-PDX-1-insulin pathway, which was blocked by endogenous BTG2 knockdown using a BTG2 small interfering RNA knockdown system. Finally, we revealed that Ex-4 and GLP-1 significantly elevated insulin secretion via upregulation of the BTG2-PDX-1 axis in pancreatic islets, and this phenomenon was abolished by endogenous BTG2 knockdown. Collectively, our current study provides a novel molecular mechanism by which GLP-1 positively regulates insulin gene expression via BTG2, suggesting that BTG2 has a key function in insulin secretion in pancreatic beta-cells.
Asunto(s)
Animales , Humanos , Masculino , Ratones , Ratas , Regulación de la Expresión Génica/efectos de los fármacos , Péptido 1 Similar al Glucagón/farmacología , Proteínas de Homeodominio/genética , Proteínas Inmediatas-Precoces/genética , Insulina/genética , Células Secretoras de Insulina/efectos de los fármacos , Ratones Endogámicos C57BL , Péptidos/farmacología , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Transactivadores/genética , Proteínas Supresoras de Tumor/genética , Ponzoñas/farmacologíaRESUMEN
The antitumor effects of Phellinus linteus extract (Keumsa Linteusan) were investigated in a CT-26 cell-injected colon cancer mouse model. When administered orally (250~1,000 mg/kg body weight), Keumsa Linteusan significantly inhibited the growth of solid colon cancer. The highest dose was highly effective, reducing tumor formation by 26% compared with the control group. The anticomplementary activity of Keumsa Linteusan increased in a dose-dependent manner. Lysosomal enzyme activity of macrophages was increased by 2-fold (100 microg/ml) compared with the control group. Keumsa Linteusan can be regarded as a potent enhancer of the innate immune response, and can be considered as a very promising candidate for antitumor action.