Inhibition of glioblastoma progression by Urolithin A in vitro and in vivo by regulating Sirt1-FOXO1 axis via ERK/AKT signaling pathways.

Glioblastoma (GBM) is the most universal and devastating primary intracranial neoplasm in the central nervous system. Urolithin A (UA) possesses many pharmacological and biological activities, but its function in GBM is not clear. CCK-8 and colony formation test were used to measure the anti-proliferative potency of UA against GBM cells. Flow cytometry was applied to evaluate cell cycle arrest and apoptosis of U251 and U118 MG cells upon UA incubation. Quantitative real-time PCR and western blotting were conducted to test the regulatory effect of UA on the expression of Sirt1 and FOXO1. Immunodeficient mice were implanted with GBM cells for in vivo validation of the anti-cancer effect of UA. We found UA repressed the proliferation, migration and invasion of glioblastoma cells, while also inhibiting the induction of colony formation ability and epithelial to mesenchymal transition (EMT) in a time- or dose-dependent manner. The does-dependent relationship of UA inducing the cell cycle arrest and apoptosis of glioblastoma cells was identified. Furthermore, UA could enhance the expression levels of Sirt1 and FOXO1 and the knockdown of Sirt1 blocked the inhibitory effects of UA on the proliferation and migration of glioblastoma cells and correspondingly modified the expression level of FOXO1. Overexpression of Sirt1 restored the despaired inhibitory effect of UA induced by Sirt1 knockout on the proliferation and migration of glioblastoma cells. In animal experiments, UA decreased the tumor size and weight of glioblastoma in xenograft nude mice and promoted the expression of Sirt1 and FOXO1 in transplanted tumors. Our findings presented in this study indicate that UA exerts a repressive effect on glioblastoma cells in vivo and in vitro by regulating the Sirt1-FOXO1 axis via the ERK and AKT pathways, indicating that UA is a new novel therapeutic candidate for the treatment of glioblastoma.

Exposure to chronic constant light impairs spatial memory and influences long-term depression in rats.

Exposure to chronic constant light (CCL) influences circadian rhythms and evokes stress. Since hippocampus is sensitive to stress, which facilitates long-term depression (LTD) in the hippocampal CA1 area, we examined whether CCL exposure influenced hippocampus-dependent spatial memory and synaptic plasticity in Wistar rats. Here we report that CCL exposure (3 weeks) disrupted 24-h cycle of locomotion activity in open field test. These rats showed shorter escape latency during initial phase of spatial learning but impaired hippocampus-dependent spatial memory without affecting the visual platform learning task in Morris water maze (MWM) compared with control rats. This effect may be due to stress adaptation as reflected by reduced thigmotaxis and anxiety-like behaviors in CCL rats. Moreover, in CA1 area of the hippocampal slices, CCL rats failed to show LTD by low frequency stimulation (LFS, 900 pulses, 1 Hz), while showed decreased short-term depression compared with control rats indicating the induction of LTD was influenced by CCL exposure. Furthermore, additional acute stress enabled LFS to induce LTD in control rats but not in CCL rats. Thus, these results suggested that CCL exposure impaired spatial memory and influenced hippocampal LTD, which may be due to stress adaptation.