BackgroundSesquiterpene lactones are plant-derived, natural, bioactive molecules often used against inflammatory diseases in traditional Chinese medicines. Recently, sesquiterpene lactones have been reported to exhibit potent anticancer activity. In the present study, we have investigated the anticancer activity of Brevilin A, a sesquiterpene lactone component of Centipeda minima, against U87 glioblastoma cells.Materials and methodsThe cell proliferation was determined by MTT assay. Cell morphological changes were observed by phase-contrast microscopy. Flow cytometry was used to measure apoptosis. Glutathione (GSH), ROS generation, and mitochondrial membrane potential were measured using commercially available kits. The expression of proteins was measured by Western blotting analysis.ResultsBrevilin A inhibited the proliferation of, and induced severe morphological changes and apoptotic cell death in, U87 glioblastoma cells in a dose-dependent manner. Further mechanistic study revealed that Brevilin A induces oxidative stress, as evident from ROS generation, GSH depletion, and increased phosphorylation of stress-activated proteins p38 and JNK. Furthermore, Brevilin A bcl-xl/bak ratio, decreased mitochondrial membrane potential and induced cytochrome c release from mitochondria into cytosol in a dose-dependent manner. Finally, Brevilin A decreased the expression of Xiap and increased the expression of cleaved forms of caspase-9 and -3 and PARP in a dose-dependent manner.ConclusionCollective findings demonstrated that Brevilin A is a potent, anticancer, bioactive molecule and it effectively induces apoptosis in U87 glioblastoma cells, which is associated with induction of oxidative stress and mitochondrial dysfunction.
Aquaporin-9 (AQP9) is an aquaglyceroporin strongly expressed in the basolateral membrane of hepatocytes facing the sinusoids. AQP9 is permeable to hydrogen peroxide (H 2 O 2 ) and glycerol as well as to water. Here, we report impaired liver regeneration in AQP9 −/− mice which involves altered steady-state H 2 O 2 concentration and glucose metabolism in hepatocytes. AQP9 −/− mice showed remarkably delayed liver regeneration and increased mortality following 70% or 90% partial hepatectomy. Compared to AQP9 +/+ littermates, AQP9 −/− mice showed significantly greater hepatic H 2 O 2 concentration and more severe liver injury. Fluorescence measurements indicated impaired H 2 O 2 transport across plasma membrane of primary cultured hepatocytes from AQP9 −/− mice, supporting the hypothesis that AQP9 deficiency results in H 2 O 2 accumulation and oxidative injury in regenerating liver because of reduced export of intracellular H 2 O 2 from hepatocytes. The H 2 O 2 overload in AQP9 −/− hepatocytes reduced PI3K-Akt and insulin signaling, inhibited autophagy and promoted apoptosis, resulting in impaired proliferation and increased cell death. In addition, hepatocytes from AQP9 −/− mice had low liver glycerol and high blood glycerol levels, suggesting decreased glycerol uptake and gluconeogenesis in AQP9 −/− hepatocytes. Adeno-associated virus (AAV)-mediated expression of hepatic expression of aquaglyceroporins AQP9 and AQP3 in AQP9 −/− mice, but not water-selective channel AQP4, fully rescued the impaired liver regeneration phenotype as well as the oxidative injury and abnormal glucose metabolism. Our data revealed a pivotal role of AQP9 in liver regeneration by regulating hepatocyte H 2 O 2 homeostasis and glucose metabolism, suggesting AQP9 as a novel target to enhance liver regeneration following injury, surgical resection or transplantation.
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