RESUMEN
Nrf2 (nuclear factor erythroid 2-related factor-2) is a transcription factor that regulates oxidative/xenobiotic stress response and also suppress inflammation. Nrf2 signaling is associated with an increased susceptibility to various kinds of stress. Nrf2 has been shown as a promising therapeutic target in various human diseases including diabetes. Our earlier studies showed Pterostilbene (PTS) as a potent Nrf2 activator, and it protects the pancreatic ß-cells against oxidative stress. In this study, we investigated PTS confer protection against cytokine-induced ß-cell apoptosis and its role on insulin secretion in streptozotocin (STZ)-induced diabetic mice. The Nrf2 activation potential of PTS was assessed by dissociation of the Nrf2-Keap1 complex and by expression of ARE-driven downstream target genes in MIN6 cells. Further, the nuclear Nrf2 translocation and blockage of apoptotic signaling as demonstrated by the reduction of BAX/Bcl-2 ratio, Annexin-V positive cells and caspase-3 activity conferred the cyto-protection of PTS against cytokine-induced cellular damage. In addition, PTS treatment markedly improved glucose homeostasis and abated inflammatory response evidenced by the reduction of proinflammatory cytokines in diabetic mice. The inhibition of ß-cell apoptosis by PTS as assessed by BAX/Bcl-2 ratio and caspase-3 activity in the pancreas was associated with the activation of Nrf2 and the expression of its downstream target genes. PTS also inhibited the activation of iNOS and decreased nitric oxide (NO) formation in the pancreas of diabetic animals. The results obtained from both in vitro and in vivo experiments showed that PTS improves ß-cell function and survival against cytokine stress and also prevents STZ-induced diabetes.
Asunto(s)
Células Secretoras de Insulina/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal , Estilbenos/farmacología , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Glucemia/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Masculino , Ratones , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Nuclear factor erythroid 2-related factor (Nrf2), a key transcription factor triggers the expression of antioxidant and detoxification genes thereby providing cellular protective functions against oxidative stress-mediated disorders. Recent research has identified that pharmacological activation of Nrf2 also regulates the largest cluster of genes associated with lipid metabolism. With this background, this paper highlights the anti-hyperlipidemic and anti-peroxidative role of pterostilbene (PTS), an Nrf2 activator, in streptozotocin (STZ)-induced diabetic model. PTS administration to diabetic mice for 5 weeks significantly regulated blood glucose levels through the elevation of insulin secretion. The circulatory and liver lipid profiles of total cholesterol (TC), triglycerides (TG) and non-esterified fatty acids (NEFA) were maintained to normal levels upon PTS treatment. Moreover, PTS administration also normalized the circulatory levels of very low-, low- and high density lipoprotein cholesterols (VLDL-, LDL-, HDL-C) and also reduced lipid peroxidation in STZ-induced diabetic mice. In addition, Nrf2 and its downstream targets, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) enzyme activities and glutathione (GSH) levels were significantly elevated in liver tissues of diabetic mice upon PTS administration. Further, H&E staining of diabetic mouse liver showed collapse in hepatic microvesicles due to altered lipid metabolism. Both structural and functional alterations were attenuated by PTS indicating its role in diabetic dyslipidemia through Nrf2-mediated mechanism that could be considered as a promising therapeutic agent.