No abstract

During metabolic reprogramming, glioma cells and their initiating cells efficiently utilized carbohydrates, lipids and amino acids in the hypoxic lesions, which not only ensured sufficient energy for rapid growth and improved the migration to normal brain tissues, but also altered the role of immune cells in tumor microenvironment. Glioma cells secreted interferential metabolites or depriving nutrients to injure the tumor recognition, phagocytosis and lysis of glioma-associated microglia/macrophages (GAMs), cytotoxic T lymphocytes, natural killer cells and dendritic cells, promoted the expansion and infiltration of immunosuppressive regulatory T cells and myeloid-derived suppressor cells, and conferred immune silencing phenotypes on GAMs and dendritic cells. The overexpressed metabolic enzymes also increased the secretion of chemokines to attract neutrophils, regulatory T cells, GAMs, and dendritic cells, while weakening the recruitment of cytotoxic T lymphocytes and natural killer cells, which activated anti-inflammatory and tolerant mechanisms and hindered anti-tumor responses. Therefore, brain-targeted metabolic therapy may improve glioma immunity. This review will clarify the metabolic properties of glioma cells and their interactions with tumor microenvironment immunity, and discuss the application strategies of metabolic therapy in glioma immune silence and escape.

Background Atherosclerosis (AS), which characterized with the accumulation of lipids on the vessel wall, is the pathological basis of many cardiovascular diseases (CVD) and seriously threatens human health. Resveratrol (RES) has been reported to be benefit for AS treatment. This research aimed to observe the effects of RES on AS induced by high-fat diet (HFD) and LPS in ApoE−/− mice and investigate the underlying mechanism. Methods ApoE−/− mice were fed with HFD companied with LPS to induce AS and RES was administrated for 20 weeks. Splenic CD4+ T cells were cultured and treated with anti-CD3/CD28 together with LPS, and RES was added. Serum lipids and the atherosclerotic areas of aortas were detected. The activation of CD4+ T cells were investigated both in vivo and in vitro and the expression of DNA methyltransferases (Dnmt) in CD4+ T cells were measured. Results In vivo, administration of RES prevented HFD and LPS induced dysfunction of serum lipids including TC (total cholesterol), TG (triglyceride), LDL-C (low density lipoprotein cholesterol) and HDL-C (high density lipoprotein cholesterol), ameliorated the thickened coronary artery wall and decreased the areas of atherosclerotic lesion on aortas. Besides, RES decreased the number of CD4+ T cells in peripheral blood, decreased the expression of CD25 and CD44, but not affected the expression of L-selectin (CD62L). In vitro, RES decreased the expression of Ki67, CD25 and CD44 in CD4+ T cells. Moreover, RES increased the secretion of IL-2, IL-10 and TGF-β1, decreased IL-6. In addition, RES decreased both the mRNA and protein level of Dnmt1 and Dnmt3b in CD4+ T cells. Conclusion These results indicated that RES ameliorated AS induced by HFD companied with LPS in ApoE−/− mice, inhibited the proliferation and activation of CD4+ T cells and regulated the expression of Dnmt1 and Dnmt3b.

Fms-like tyrosine kinase 3 (FLT3) is an important member of the class III receptor tyrosine kinase (RTK) family, which is involved in the proliferation of hematopoietic cells and lymphocytes. In recent years, increasing evidence have demonstrated that the activation and mutation of FLT3 is closely implicated in the occurrence and development of acute myeloid leukemia (AML). The exploration of small-molecule inhibitors targeting FLT3 has aroused wide interest of pharmaceutical chemists and is expected to bring new hope for AML therapy. In this review, we specifically highlighted FLT3 mediated JAK/STAT, RAS/MAPK, and PI3K/AKT/mTOR signaling. The structural properties and biological activities of representative FLT3 inhibitors reported from 2014 to the present were also summarized. In addition, the major challenges in the current advance of novel FLT3 inhibitors were further analyzed, with the aim to guide future drug discovery.

No abstract