Background Glioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood–brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment. Methods Betulinic acid NPs (BA NPs) were synthesized by the standard emulsion approach and characterized by electron microscopy and dynamic light scattering analysis. The resulting NPs were characterized for their anti-tumor effects by cell viability assay, EdU-DNA synthesis assay, cell cycle assay, mitochondrial membrane potential, and PI-FITC apoptosis assay. Further mechanistic studies were carried out through Western Blot and immunostaining analyses. Finally, we evaluated BA NPs in vivo for their pharmacokinetics and antitumor effects in intracranial xenograft GBM mouse models. Results BA NPs were successfully prepared and formed into rod shape. BA NPs could significantly suppress glioma cell proliferation, induce apoptosis, and arrest the cell cycle in the G0/G1 phase in vitro. Furthermore, BA NPs downregulated the Akt/NFκB-p65 signaling pathway in a concentration dependent manner. We found that the observed anti-tumor effect of BA NPs was dependent on the function of CB1/CB2 receptors. Moreover, in the intracranial GBM xenograft mouse models, BA NPs could effectively cross the BBB and greatly prolong the survival time of the mice. Conclusions We successfully synthesized BA NPs, which could cross the BBB and demonstrated a strong anti-tumor effect. Therefore, BA NPs may potentially be used for effective treatment of GBM. Graphical Abstract

Lower-grade glioma (LGG) is a common malignant primary tumour in the central nervous system, and most patients eventually develop highly aggressive gliomas despite comprehensive traditional treatment. Tumour molecular subtypes and prognostic biomarkers play a crucial role in LGG diagnosis and treatment. Therefore, the identification of novel biomarkers in LGG patients is crucial for predicting the prognosis of glioma. Immunogenic cell death (ICD) is defined as regulated cell death that is sufficient to activate the adaptive immune response of immunocompetent hosts. The combination of ICD and immunotherapy might exert a greater and more persistent antitumour effect in gliomas. In our study, we explored the expression, function, and genetic alterations of 34 ICD-related genes. Using 12 ICD-related genes, including IL17RA, IL1R1, EIF2AK3, CD4, PRF1, CXCR3, CD8A, BAX, PDIA3, CASP8, MYD88, and CASP1, we constructed and validated an ICD-related risk signature via least absolute shrinkage and selection operator (LASSO) Cox regression analysis. All the information was obtained from public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and the Chinese Glioma Genome Atlas (CGGA) databases. Our results revealed that ICD-high risk groups have a poor prognosis and might be more sensitive to immune checkpoint blockade (ICB) immunotherapy. In addition, ICD-high risk groups were associated with 1p19q noncodeletion, higher WHO grade, wild type IDH, and an immunosuppressive tumour microenvironment. We verified the prognostic value of 12 ICD-related genes in TCGA and CGGA databases. Immunohistochemistry was performed to verify the expression of several ICD-related genes at the protein level. Our study provides a novel and comprehensive perspective to elucidate the underlying mechanisms of LGG prognosis and direction for future individualized cancer immunotherapy.

WHO 2/3 glioma is a common intracranial tumor that seriously affects the quality of life and survival time of patients. Previous studies have shown that the tricarboxylic acid (TCA) cycle is closely related to the occurrence and development of glioma, while recent studies have shown that cuproptosis, a novel programmed death pathway, is closely related to the inhibition of the TCA cycle. In our study, eight of ten cuproptosis-related genes (CRGs) were found to be differentially expressed between normal and WHO 2/3 glioma tissues. Through the LASSO algorithm, the cuproptosis-associated risk signatures (CARSs) were constructed, which can effectively predict the prognosis of WHO 2/3 glioma patients and are closely related to clinicopathological features. We analyzed the relationship between risk score and immune cell infiltration through Xcell, ssGSEA, TIMER database, and immune checkpoint molecules. In addition, the relationship between risk score and chemotherapeutic drug sensitivity was also investigated. The prognosis-related independent risk factors FDX1 and CDKN2A identified from CARSs are considered potential prognostic biomarkers for WHO 2/3 glioma. The clinical prognosis model based on cuproptosis is expected to provide an effective reference for the diagnosis and treatment of clinical WHO 2/3 glioma patients.

Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.

Herein, we employ a partial phase conversion strategy to transform cobalt/nickel carbonate hydroxide (CoxNiyCH) nanosheet arrays in Fe-containing KOH electrolyte. The optimized sample exhibits a remarkable electrocatalytic activity (η50 =...