The vast majority (>90%) of glioblastoma (GBM) patients belong to the isocitrate dehydrogenase 1 wild type (IDH1 WT ) group which exhibits a poor prognosis with a median survival of less than 15 months. This study demonstrated numerous immunosuppressive genes as well as β-catenin gene, pivotal for Wnt/βcatenin signaling, were upregulated in 206 IDH1 WT glioma patients using the Chinese Glioma Genome Atlas (CGGA) database. The increase in microglia with an immunosuppressive phenotype and the overexpression of β-catenin protein were further verified in IDH1 WT GBM patients and IDH1 WT GL261 glioma allografts. Subsequently, we found that IDH1 WT GL261 cell-derived conditioned medium activated Wnt/βcatenin signaling in primary microglia and triggered their transition to an immunosuppressive phenotype. Blocking Wnt/β-catenin signaling not only attenuated microglial polarization to the immunosuppressive subtype but also reactivated immune responses in IDH1 WT GBM allografts by simultaneously enhancing cytotoxic CD8 + T cell infiltration and downregulating regulatory T cells. Positron emission tomography imaging demonstrated enhanced proinflammatory activities in IDH1 WT GBM allografts after the blockade of Wnt signaling. Finally, gavage administration of a Wnt signaling inhibitor significantly restrained tumor proliferation and improved the survival of model mice bearing IDH1 WT GBM allografts. Depletion of CD8 + T cells remarkably abrogated the therapeutic efficacy induced by the Wnt signaling inhibitor. Overall, the present work indicates that the crosstalk between IDH1 WT glioma cells and immunosuppressive microglia is important in maintaining the immunosuppressive glioma microenvironment. Blocking Wnt/β-catenin signaling is a promising complement for IDH1 WT GBM treatment by improving the hostile immunosuppressive microenvironment.
ObjectiveExcessive carbohydrate intake is a high risk factor for increased morbidity of type 2 diabetes (T2D). A novel regimen for the dietary care of diabetes that consists of a highly active α-amylase inhibitor derived from white common bean extract (WCBE) and sufficient carbohydrates intake was applied to attenuate T2D and its complications. Furthermore, the role of gut microbiota in this remission was also investigated.MethodsWe conducted a 4-month randomized double-blinded placebo-controlled trial. During the intense intervention period, ninety subjects were randomly assigned to the control group (Group C) and WCBE group (Group W). Subjects in Group C were supplemented with 1.5 g of maltodextrin as a placebo. Subjects in Group W took 1.5 g of WCBE half an hour before a meal. Fifty-five participants continued the maintenance intervention receiving the previous dietary intervention whereas less frequent follow-up. The variation in biochemical, vasculopathy and neuropathy indicators and the structure of the fecal microbiota during the intervention was analyzed.ResultGlucose metabolism and diabetic complications showed superior remission in Group W with a 0.721 ± 0.742% decline of glycosylated hemoglobin after 4 months. The proportion of patients with diabetic peripheral neuropathy (Toronto Clinical Scoring System, TCSS ≥ 6) was significantly lower in Group W than in Group C. Both the left and right sural sensory nerve conduction velocity (SNCV-left sural and SNCV-right sural) slightly decreased in Group C and slightly increased in Group W. Additionally, the abundances of Bifidobacterium, Faecalibacterium and Anaerostipes were higher in Group W, and the abundances of Weissella, Klebsiella, Cronobacter and Enterobacteriaceae_unclassified were lower than those in Group C at month 2. At the end of month 4, Bifidobacterium remained more abundant in Group W.ConclusionTo our knowledge, this is the first report of improvement to diabetes complications by using a dietary supplement in such a short-term period. The enrichment of SCFA-producing bacteria might be responsible for the attenuation of T2D and its complications.Clinical trial registration numberhttp://www.chictr.org.cn/edit.aspx?pid=23309&htm=4, identifier ChiCTR-IOR-17013656
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