Implantation of hydrogel-liposome nanoplatform inhibits glioblastoma relapse by inducing ferroptosis.

Glioblastoma is acknowledged as the most aggressive cerebral tumor in adults. However, the efficacy of current standard therapy is seriously undermined by drug resistance and suppressive immune microenvironment. Ferroptosis is a recently discovered form of iron-dependent cell death that may have excellent prospect as chemosensitizer. The utilization of ferropotosis inducer Erastin could significantly mediate chemotherapy sensitization of Temozolomide and exert anti-tumor effects in glioblastoma. In this study, a combination of hydrogel-liposome nanoplatform encapsulated with Temozolomide and ferroptosis inducer Erastin was constructed. The αvß3 integrin-binding peptide cyclic RGD was utilized to modify codelivery system to achieve glioblastoma targeting strategy. As biocompatible drug reservoirs, cross-linked GelMA (gelatin methacrylamide) hydrogel and cRGD-coated liposome realized the sustained release of internal contents. In the modified intracranial tumor resection model, GelMA-liposome system achieved slow release of Temozolomide and Erastin in situ for more than 14 d. The results indicated that nanoplatform (T+E@LPs-cRGD+GelMA) improved glioblastoma sensitivity to chemotherapeutic temozolomide and exerted satisfactory anti-tumor effects. It was demonstrated that the induction of ferroptosis could be utilized as a therapeutic strategy to overcome drug resistance. Furthermore, transcriptome sequencing was conducted to reveal the underlying mechanism that the nanoplatform (T+E@LPs-cRGD+GelMA) implicated in. It is suggested that GelMA-liposome system participated in the immune response and immunomodulation of glioblastoma via interferon/PD-L1 pathway. Collectively, this study proposed a potential combinatory therapeutic strategy for glioblastoma treatment.

Biomimetic nanoparticles in ischemic stroke therapy.

Abstract: Ischemic stroke is one of the most severe neurological disorders with limited therapeutic strategies. The utilization of nanoparticle drug delivery systems is a burgeoning field and has been widely investigated. Among these, biomimetic drug delivery systems composed of biogenic membrane components and synthetic nanoparticles have been extensively highlighted in recent years. Biomimetic membrane camouflage presents an effective strategy to prolong circulation, reduce immunogenicity and enhance targeting. For one thing, biomimetic nanoparticles reserve the physical and chemical properties of intrinsic nanoparticle. For another, the biological functions of original source cells are completely inherited. Compared to conventional surface modification methods, this approach is more convenient and biocompatible. In this review, membrane-based nanoparticles derived from different donor cells were exemplified. The prospect of future biomimetic nanoparticles in ischemic stroke therapy was discussed.

N6-Methyladenosine-modified lncRNA LINREP promotes Glioblastoma progression by recruiting the PTBP1/HuR complex.

Glioblastoma multiforme (GBM) is acknowledged as the most aggressive primary brain tumor in adults. It is typically characterized by the high heterogeneity which corresponds to extensive genetic mutations and complex alternative splicing (AS) profiles. Known as a major repressive splicing factor in AS, polypyrimidine tract-binding protein 1 (PTBP1) is involved in the exon skipping events of multiple precursor mRNAs (pre-mRNAs) in GBM. However, precise mechanisms that modulate the expression and activity of PTBP1 remain to be elucidated. In present study, we provided evidences for the role of a long intergenic noncoding RNA (LINREP) implicated in the regulation of PTBP1-induced AS. LINREP interacted with PTBP1 and human antigen R (HuR, ELAVL1) protein complex and protected PTBP1 from the ubiquitin-proteasome degradation. Consequently, a broad spectrum of PTBP1-induced spliced variants was generated by exon skipping, especially for the skipping of reticulon 4 (RTN4) exon 3. Interestingly, LINREP also promoted the dissociation of nuclear UPF1 from PTBP1, which increased the binding of PTBP1 to RTN4 transcripts, thus enhancing the skipping of RTN4 exon 3 to some extent. Besides, HuR recruitment was essential for the stabilization of LINREP via a manner dependent on N6-methyladenosine (m6A) formation and identification. Taken together, our results demonstrated the functional significance of LINREP in human GBM for its dual regulation of PTBP1-induced AS and its m6A modification modality, implicating that HuR/LINREP/PTBP1 axis might serve as a potential therapeutic target for GBM.

Mechanisms of long non-coding RNAs in biological phenotypes and ferroptosis of glioma.

Glioma, one of the most common malignant tumors in the nervous system, is characterized by limited treatment, high mortality and poor prognosis. Numerous studies have shown that lncRNAs play an important role in the onset and progression of glioma by acting on various classical signaling pathways of tumors through signaling, trapping, guiding, scaffolding and other functions. LncRNAs contribute to the malignant progression of glioma via proliferation, apoptosis, epithelial-mesenchymal transformation, chemotherapy resistance, ferroptosis and other biological traits. In this paper, relevant lncRNA signaling pathways involved in glioma progression were systematically evaluated, with emphasis placed on the specific molecular mechanism of lncRNAs in the process of ferroptosis, in order to provide a theoretical basis for the application of lncRNAs in the anticancer treatment of glioma.

Comprehensive Analysis of the Prognostic Value and Immune Infiltration of Butyrophilin Subfamily 2/3 (BTN2/3) Members in Pan-Glioma.

The BTN2/3 subfamilies are overexpressed in many cancers, including pan-glioma (low- and high-grade gliomas). However, the expression and prognosis of BTN2/3 subfamilies and tumor-infiltrating lymphocytes in pan-glioma remain unknown. In the present study, we systematically explored and validated the expression and prognostic value of BTN2/3 subfamily members in pan-glioma [The Cancer Genome Atlas-glioblastoma and low-grade glioma (TCGA-GBMLGG) merge cohort] using multiple public databases. We used clinical specimens for high-throughput verification and cell lines for qRT-PCR verification, which confirmed the expression profiles of BTN2/3 subfamilies. In addition, the function of the BTN2/3 subfamily members and the correlations between BTN2/3 subfamily expression and pan-glioma immune infiltration levels were investigated. We found that BTN2/3 subfamily members were rarely mutated. BTN2/3 subfamilies were overexpressed in pan-glioma; high expression of BTN2/3 subfamily members was correlated with poor prognosis. In addition, BTN2/3 subfamilies might positively regulate proliferation, and the overexpression of BTN2/3 subfamilies influenced cell cycle, differentiation, and glioma stemness. In terms of immune infiltrating levels, BTN2/3 subfamily expression was positively associated with CD4+ T-cell, B-cell, neutrophil, macrophage, and dendritic cell infiltrating levels. These findings suggest that BTN2/3 subfamily expression is correlated with prognosis and immune infiltration levels in glioma. Therefore, the BTN2/3 subfamilies can be used as biomarkers for pan-glioma and prognostic biomarkers for determining the prognosis and immune infiltration levels in pan-glioma.

Nanoscale Drug Delivery Systems in Glioblastoma.

Glioblastoma is the most aggressive cerebral tumor in adults. However, the current pharmaceuticals in GBM treatment are mainly restricted to few chemotherapeutic drugs and have limited efficacy. Therefore, various nanoscale biomaterials that possess distinct structure and unique property were constructed as vehicles to precisely deliver molecules with potential therapeutic effect. In this review, nanoparticle drug delivery systems including CNTs, GBNs, C-dots, MOFs, Liposomes, MSNs, GNPs, PMs, Dendrimers and Nanogel were exemplified. The advantages and disadvantages of these nanoparticles in GBM treatment were illustrated.

Immune-Related Gene SERPINE1 Is a Novel Biomarker for Diffuse Lower-Grade Gliomas via Large-Scale Analysis.

BACKGROUND: Glioma is one of the highly fatal primary tumors in the central nervous system. As a major component of tumor microenvironment (TME), immune cell has been proved to play a critical role in the progression and prognosis of the diffuse lower-grade gliomas (LGGs). This study aims to screen the key immune-related factors of LGGs by investigating the TCGA database. METHODS: The RNA-sequencing data of 508 LGG patients were downloaded in the TCGA database. ESTIMATE algorithm was utilized to calculate the stromal, immune, and ESTIMATE scores, based on which, the differentially expressed genes (DEGs) were analyzed by using "limma" package. Cox regression analysis and the cytoHubba plugin of Cytoscape software were subsequently applied to screen the survival-related genes and hub genes, the intersection of which led to the identification of SERPINE1 that played key roles in the LGGs. The expression patterns, clinical features, and regulatory mechanisms of SERPINE1 in the LGGs were further analyzed by data mining of the TCGA database. What's more, the above analyses of SERPINE1 were further validated in the LGG cohort from the CGGA database. RESULT: We found that stromal and immune cell infiltrations were strongly related to the prognosis and malignancy of the LGGs. A total of 54 survival-related genes and 46 hub genes were screened out in the DEGs, within which SERPINE1 was identified to be significantly overexpressed in the LGG samples compared with the normal tissues. Moreover, the upregulation of SERPINE1 was more pronounced in the gliomas of WHO grade III and IDH wild type, and its expression was correlated with poor prognosis in the LGG patients. The independent prognostic value of SERPINE1 in the LGG patients was also confirmed by Cox regression analysis. In terms of the functions of SERPINE1, the results of enrichment analysis indicated that SERPINE1 was mainly enriched in the immune-related biological processes and signaling pathways. Furthermore, it was closely associated with infiltrations of immune cells in the LGG microenvironment and acted synergistically with PD1, PD-L1, PD-L2. CONCLUSION: These findings proved that SERPINE1 could serve as a prognostic biomarker and potential immunotherapy target of LGGs.

Oxiracetam Mediates Neuroprotection Through the Regulation of Microglia Under Hypoxia-Ischemia Neonatal Brain Injury in Mice.

In neonatal hypoxic-ischemic brain damage (HIBD), in addition to damage caused by hypoxia and ischemia, over-activation of inflammation leads to further deterioration of the condition, thus greatly shortening the optimal treatment time window. Ischemic penumbra, the edematous area encompassing the infarct core, is characterized by typical activation of microglia and overt inflammation, and prone to incorporate into the infarct core gradually after ischemia onset. If treated in time, the cells located in the penumbra can survive, thereby impeding the expansion of the infarction. We demonstrated for the first time that in the acute phase of HIBD in neonatal mice, treatment of Oxiracetam (ORC) significantly curtailed the size of ischemic penumbra together with drastic reduction of infarction. By staining various cellular markers, we found that the penumbra was defined and concentrated with activated microglia. We also analyzed transmission electron microscopy and Luminex assay results to elucidate the mechanisms involved. We further confirmed that ORC switched polarization of microglia from the inflammatory towards the alternatively activated phenotype, thus promoting microglia from being neurotoxic into neuroprotective. Meanwhile, ORC decreased proliferation of microglia; however, their functions of phagocytosis and autophagy were otherwise enhanced. Last, we clarified that ORC promoted autophagy through the AMPK/mTOR pathway, which further induced the transition of the inflammatory to the alternatively activated phenotype in microglia. The pro-inflammatory factors secretion was inhibited as well, thereby reducing the progression of the infarction. Taken together, it is concluded that Oxiracetam reduced the expansion of ischemic infarction in part via regulating the interplay between microglia activation and autophagy, which would delay the progression of HIBD and effectively prolong the time window for the clinical treatment of HIBD.

Molecular and Clinical Characterization of a Novel Prognostic and Immunologic Biomarker FAM111A in Diffuse Lower-Grade Glioma.

BACKGROUND: Family with sequence similarity 111 member A (FAM111A), as a replication factor required for proliferating cell nuclear antigen (PCNA) loading, has been demonstrated a possible association with carcinogenesis. However, the role of FAM111A in lower-grade glioma (LGG) remains unclear. We aim at investigating the expression and function of FAM111A in lower-grade glioma at the molecular and clinical levels. METHODS: In total, 711 lower-grade glioma samples were analyzed in our research, including 182 RNA-seq data from the Chinese Glioma Genome Atlas (CGGA) dataset and 529 RNA-seq data from The cancer Genome Atlas (TCGA) dataset. R language and the GraphPad software were used for the majority of statistical analysis and graphical work. RESULTS: FAM111A expression was overexpressed in WHO grade III and IDH-wildtype lower-grade glioma. FAM111A was significantly downregulated in the IDHmut-Codel molecular subtype. Univariate and multivariate Cox analysis demonstrated that FAM111A was an independent prognostic factor in LGG patients. Functional characterization of FAM111A revealed that it was associated with inflammatory response and immune response to tumor cells. FAM111A could also act as an indicator of the stromal and immune population, especially for monocytic lineage, myeloid dendritic cells and fibroblasts. It was positively correlated with macrophages, especially the M2 macrophage cells. Furthermore, FAM111A revealed predictive value for the immune subtypes and immune checkpoint blockade therapy. CONCLUSION: FAM111A expression was closely related to the malignant phenotype, molecular pathology and immune response of lower-grade glioma. It might be a promising target for LGG immunotherapeutic strategies.