RESUMEN
BACKGROUND: Duodenal-jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction. Increasing evidence has demonstrated that brain insulin signaling plays an important role in the pathophysiology of type 2 diabetes. This study explores whether the antidiabetic effect of DJB is involved in brain insulin signaling activation and brain glucose utilization. METHODS: A diabetic rat model was established by high-fat and high-glucose diet. DJB or sham surgery was performed in diabetic rats. 18F-FDG PET scanning was used to detect glucose uptake in different organs, particularly in the brain. The levels of glucose transporters, glucose utilization-related proteins (HK1 and PFK2), insulin, and insulin signaling pathway-related proteins (InsR, IRS1/2, PI3K, and p-Akt) in the brain tissues were evaluated and analyzed. RESULTS: The results showed that DJB significantly improved basal glycemic parameters and reversed the decreasing glucose uptake in the brains of type 2 diabetic rats. DJB significantly increased not only the expression levels of brain insulin, IRS1/2, PI3K, and p-Akt but also the levels of the glucose utilization enzymes HK1 and PFK2 in the brain. CONCLUSION: These results indicate that enhanced brain insulin signaling transduction and brain glucose utilization play important roles in the antidiabetic effect of DJB.
Asunto(s)
Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Duodeno/cirugía , Derivación Gástrica/métodos , Glucosa/metabolismo , Insulina/metabolismo , Yeyuno/cirugía , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/cirugía , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Duodeno/patología , Resistencia a la Insulina/fisiología , Yeyuno/patología , Hígado/metabolismo , Masculino , Ratas , Ratas Wistar , Transducción de Señal/fisiología , Resultado del Tratamiento , Pérdida de PesoRESUMEN
BACKGROUND: The tumor-targeting ability and pH-sensitive properties of intelligent drug delivery systems are crucial for effective drug delivery and anti-tumor therapy. METHODS: In this study, sHA-DOX/HA-GA mixed micelles were designed with the following properties: sulfated hyaluronic acid (sHA) was synthesized to block cell migration by inhibiting HAase; sHA-DOX conjugates were synthesized via pH-sensitive hydrazone bond to realize DOX-sensitive release. The introduction of HA-GA conjugate could improve active-targeting ability and cellular uptake. RESULTS: The results showed that the mixed micelles possessed a nearly spherical shape, nanoscale particle size (217.70±0.89 nm), narrow size distribution (PDI=0.07±0.04), negative zeta potential (-31.87±0.61 mV) and pH-dependent DOX release. In addition, the sHA-DOX/HA-GA micelles exhibited concentration-dependent cytotoxicities against liver carcinoma cells (HepG2) and HeLa cells, and were shown to be effectively taken up by HepG2 cells by confocal microscopy analysis. Furthermore, the in vivo anti-tumor study showed that mixed micelles had a superior anti-tumor effect compared to that of free DOX. Further evidence obtained from the hematoxylin-eosin staining and immunohistochemistry analysis also demonstrated that sHA-DOX/HA-GA exhibited stronger tumor inhibition and lower systemic toxicity than free DOX. CONCLUSION: The sHA-DOX/HA-GA mixed micelles could be a potential drug delivery system for anti-hepatoma therapy.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Ácido Hialurónico/química , Neoplasias Hepáticas/tratamiento farmacológico , Hígado/patología , Micelas , Sulfatos/química , Carcinoma Hepatocelular/patología , Movimiento Celular/efectos de los fármacos , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Endocitosis , Células HeLa , Células Hep G2 , Humanos , Concentración de Iones de Hidrógeno , Hígado/efectos de los fármacos , Neoplasias Hepáticas/patología , Tamaño de la Partícula , Polímeros/química , Distribución Tisular/efectos de los fármacosRESUMEN
BACKGROUND: Recent efforts have been focused on combining two or more therapeutic approaches with different mechanisms to enhance antitumor therapy. Moreover, nanosize drug-delivery systems for codelivering two drugs with proapoptotic and antiangiogenic activities have exhibited great potential in efficient treatment of cancers. METHODS: Glycyrrhetinic acid (GA)-modified liposomes (GA LPs) for liver-targeted codelivery of curcumin (Cur) and combretastatin A4 phosphate (CA4P) were prepared and characterized. In vitro cellular uptake, cytotoxicity, cell migration, in vivo biodistribution, antitumor activity, and histopathological studies were performed. RESULTS: Compared with unmodified LPs (Cur-CA4P LPs), Cur-CA4P/GA LPs were taken up effectively by human hepatocellular carcinoma cells (BEL-7402) and showed higher cytotoxicity than free drugs. In vivo real-time near-infrared fluorescence-imaging results indicated that GA-targeted LPs increased accumulation in the tumor region. Moreover, Cur-CA4P/GA LPs showed stronger inhibition of tumor proliferation than Cur, Cur + CA4P, and Cur-CA4P LPs in vivo antitumor studies, which was also verified by H&E staining. CONCLUSION: GA-modified LPs can serve as a promising nanocarrier for liver-targeted co-delivery of antitumor drugs against hepatocellular carcinoma.