RESUMEN
BACKGROUND: Our previous study revealed that microRNA-125a-5p plays a crucial role in regulating hepatic glycolipid metabolism by targeting STAT3 in type 2 diabetes mellitus (T2DM). Dioscin, a major active ingredient in Dioscoreae nipponicae rhizomes, displays various pharmacological activities, but its role in T2DM has not been reported. PURPOSE: The aim of this study was to investigate the effect of dioscin on T2DM and elucidate its potential mechanism. METHODS: The effect of dioscin on glycolipid metabolic disorder in insulin-induced HepG2 cells, palmitic acid-induced AML12 cells, high-fat diet- and streptozotocin- induced T2DM rats, and spontaneous T2DM KK-Ay mice were evaluated. Then, the possible mechanisms of dioscin were comprehensively evaluated. RESULTS: Dioscin markedly alleviated the dysregulation of glycolipid metabolism in T2DM by reducing hyperglycemia and hyperlipidemia, improving insulin resistance, increasing hepatic glycogen content, and attenuating lipid accumulation. When the mechanism was investigated, dioscin was found to markedly elevate miR-125a-5p level and decrease STAT3 expression. Consequently, dioscin increased phosphorylation levels of STAT3, PI3K, AKT, GSK-3ß, and FoxO1 and decreased gene levels of PEPCK, G6Pase, SREBP-1c, FAS, ACC, and SCD1, leading to an increase in glycogen synthesis and a decrease in gluconeogenesis and lipogenesis. The effects of dioscin on regulating miR-125a-5p/STAT3 pathway were verified by miR-125a-5p overexpression and STAT3 overexpression. CONCLUSIONS: Dioscin showed potent anti-T2DM activity by improving the inhibitory effect of miR-125a-5p on STAT3 signaling to alleviate glycolipid metabolic disorder of T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diosgenina/análogos & derivados , Glucolípidos/metabolismo , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa/efectos adversos , Diosgenina/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Gluconeogénesis/efectos de los fármacos , Células Hep G2 , Humanos , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Lipogénesis/efectos de los fármacos , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , MicroARNs/genética , Ratas Wistar , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
Berberine and evodiamine, two kinds of alkaloids, have been reported to show many activities. In the present paper, inhibitory activities of the two compounds and their mixtures on human hepatocellular carcinoma SMMC-7721 cells were investigated, and the inhibitory rates, apoptosis, cell cycle distribution and tumor necrosis factor-alpha (TNF-alpha) were all tested and described. The results indicate that the mixtures of the two compounds showed the highest inhibition effect (50.00%) as compared with berberine and evodiamine used individually (20.24% and 16.33%, respectively) over 48 h. Through fluorescence microscope and flow cytometry (FCM) analysis, the cell apoptosis and cell cycle distribution of SMMC-7721 induced by the synergy of the two compounds was made evident. Furthermore, the TNF-alpha value in the mixture treated group was much higher (p<0.05) than in the other two groups. Thus, the combined use of berberine and evodiamine could significantly enhance the apoptosis of SMMC-7721 cells, which will be useful to further anti-cancer therapy and research.