The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling.

Glioma is the most prevalent brain tumor, presenting with limited treatment options, while patients with malignant glioma and glioblastoma (GBM) have poor prognoses. The physical obstacle to drug delivery imposed by the blood‒brain barrier (BBB) and glioma stem cells (GSCs), which are widely recognized as crucial elements contributing to the unsatisfactory clinical outcomes. In this study, we found a small molecule, gambogic amide (GA-amide), exhibited the ability to effectively penetrate the blood-brain barrier (BBB) and displayed a notable enrichment within the tumor region. Moreover, GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models, encompassing transgenic and primary patient-derived xenograft (PDX) models. We further performed a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen to determine the druggable target of GA-amide. By the combination of the cellular thermal shift assay (CETSA), the drug affinity responsive target stability (DARTS) approach, molecular docking simulation and surface plasmon resonance (SPR) analysis, WD repeat domain 1 (WDR1) was identified as the direct binding target of GA-amide. Through direct interaction with WDR1, GA-amide promoted the formation of a complex involving WDR1, MYH9 and Cofilin, which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells (PDCs) and induce PDC apoptosis via the mitochondrial apoptotic pathway. In conclusion, our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.

Production and Stabilization of Specific Upregulated Long Noncoding RNA HOXD-AS2 in Glioblastomas Are Mediated by TFE3 and miR-661, Respectively.

Differential expression of long noncoding RNAs (lncRNA) plays a key role in the development of gliomas. Because gliomas are the most common primary central nervous system tumor and glioblastomas have poor prognosis, it is urgent to develop new diagnostic methods. We have previously reported that lncRNA HOXD-AS2, which is specifically up-regulated in gliomas, can activate cell cycle and promote the development of gliomas. It is expected to be a new marker for molecular diagnosis of gliomas, but little is known about HOXD-AS2. Here, we demonstrate that TFE3 and miR-661 maintain the high expression level of HOXD-AS2 by regulating its production and degradation. We found that TFE3 acted as a transcription factor binding to the HOXD-AS2 promoter region and raised H3K27ac to activate HOXD-AS2. As the cytoplasmic-located lncRNA, HOXD-AS2 could be degraded by miR-661. This process was inhibited in gliomas due to the low expression of miR-661. Our study explains why HOXD-AS2 was specifically up-regulated in gliomas, helps to understand the molecular characteristics of gliomas, and provids insights for the search for specific markers in gliomas.

Deferoxamine ameliorates adipocyte dysfunction by modulating iron metabolism in ob/ob mice.

OBJECTIVE: The mechanisms underlying obesity and anti-obesity processes have garnered remarkable attention as potential therapeutic targets for obesity-associated metabolic syndromes. Our prior work has shown the healing efficacy of iron reduction therapies for hepatic steatosis in a rodent model of diabetes and obesity. In this study, we investigated how iron depletion by deferoxamine (DFO) affected adipocyte dysfunction in the epididymal adipose tissues of ob/ob mice. METHODS: Male ob/ob mice were assigned to either a vehicle-treated or DFO-treated group. DFO (100 mg/kg body weight) was injected intraperitoneally for 15 days. RESULTS: We confirmed that iron deposits were statistically increased in the epididymal fat pad of 26-week-old ob/ob mice compared with wild-type (WT) mice. DFO significantly improved vital parameters of adipose tissue biology by reducing reactive oxygen species and inflammatory marker (TNFα, IL-2, IL-6, and Hepcidin) secretion, by increasing the levels of antioxidant enzymes, hypoxia-inducible factor-1α (HIF-1α) and HIF-1α-targeted proteins, and by altering adipocytic iron-, glucose- and lipid-associated metabolism proteins. Meanwhile, hypertrophic adipocytes were decreased in size, and insulin signaling pathway-related proteins were also activated after 15 days of DFO treatment. CONCLUSIONS: These findings suggest that dysfunctional iron homeostasis contributes to the pathophysiology of obesity and insulin resistance in adipose tissues of ob/ob mice. Further investigation is required to develop safe iron chelators as effective treatment strategies against obesity, with potential for rapid clinical application.