Insights into the regulatory role of RNA methylation modifications in glioma.

Epitranscriptomic abnormalities, which are highly prevalent in primary central nervous system malignancies, have been identified as crucial contributors to the development and progression of gliomas. RNA epitranscriptomic modifications, particularly the reversible modification methylation, have been observed throughout the RNA cycle. Epitranscriptomic modifications, which regulate RNA transcription and translation, have profound biological implications. These modifications are associated with the development of several cancer types. Notably, three main protein types-writers, erasers, and readers, in conjunction with other related proteins, mediate these epitranscriptomic changes. This review primarily focuses on the role of recently identified RNA methylation modifications in gliomas, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), and N1-methyladenosine (m1A). We delved into their corresponding writers, erasers, readers, and related binding proteins to propose new approaches and prognostic indicators for patients with glioma.

Genome-Wide 5-Formylcytosine Redistribution in KCl-Stimulated Mouse Primary Cortical Neurons is Associated with Neuronal Activity.

An abundant accumulation of DNA demethylation intermediates has been identified in mammalian neurons. While the roles of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in neuronal function have been extensively studied, little is known about 5-formylcytosine (5fC) in neurons. Therefore, this study was to investigate the genome-wide distribution and potential functions of 5fC in neurons. In an in vitro culture model of mouse primary cortical neurons, we observed a dynamic increase in the total 5fC level in the neuronal genome after potassium chloride (KCl) stimulation. Subsequently, we employed chemical-labeling-enabled C-to-T conversion sequencing (CLEVER-seq) to examine the 5fC distribution at a single-base resolution. Bioinformatic analysis revealed that 5fC was enriched in promoter regions, and gene ontology (GO) analysis indicated that the differential formylation positions (DFP) were correlated with neuronal activities. Additionally, integration with previously published nascent RNA-seq data revealed a positive correlation between gene formylation and mRNA expression levels. As well, 6 neuro-activity-related genes with a positive correlation were validated. Furthermore, we observed higher chromatin accessibility and RNA pol II binding signals near the 5fC sites through multiomics analysis. Motif analysis identified potential reader proteins for 5fC. In conclusion, our work provides a valuable resource for studying the dynamic changes and functional roles of 5fC in activated mammalian neurons.

The role of the gut microbiome and its metabolites in cerebrovascular diseases.

The gut microbiome is critically involved in maintaining normal physiological function in the host. Recent studies have revealed that alterations in the gut microbiome contribute to the development and progression of cerebrovascular disease via the microbiota-gut-brain axis (MGBA). As a broad communication network in the human body, MGBA has been demonstrated to have significant interactions with various factors, such as brain structure and function, nervous system diseases, etc. It is also believed that the species and composition of gut microbiota and its metabolites are intrinsically linked to vascular inflammation and immune responses. In fact, in fecal microbiota transplantation (FMT) research, specific gut microbiota and downstream-related metabolites have been proven to not only participate in various physiological processes of human body, but also affect the occurrence and development of cerebrovascular diseases directly or indirectly through systemic inflammatory immune response. Due to the high mortality and disability rate of cerebrovascular diseases, new treatments to improve intestinal dysbacteriosis have gradually attracted widespread attention to better ameliorate the poor prognosis of cerebrovascular diseases in a non-invasive way. This review summarizes the latest advances in the gut microbiome and cerebrovascular disease research and reveals the profound impact of gut microbiota dysbiosis and its metabolites on cerebrovascular diseases. At the same time, we elucidated molecular mechanisms whereby gut microbial metabolites regulate the expression of specific interleukins in inflammatory immune responses. Moreover, we further discuss the feasibility of novel therapeutic strategies targeting the gut microbiota to improve the outcome of patients with cerebrovascular diseases. Finally, we provide new insights for standardized diagnosis and treatment of cerebrovascular diseases.

Novel tumor necrosis factor-related long non-coding RNAs signature for risk stratification and prognosis in glioblastoma.

Background: Tumor necrosis factor (TNF) is an inflammatory cytokine that can coordinate tissue homeostasis by co-regulating the production of cytokines, cell survival, or death. It widely expresses in various tumor tissues and correlates with the malignant clinical features of patients. As an important inflammatory factor, the role of TNFα is involved in all steps of tumorigenesis and development, including cell transformation, survival, proliferation, invasion and metastasis. Recent research has showed that long non-coding RNAs (lncRNAs), defined as RNA transcripts >200 nucleotides that do not encode a protein, influence numerous cellular processes. However, little is known about the genomic profile of TNF pathway related-lncRNAs in GBM. This study investigated the molecular mechanism of TNF related-lncRNAs and their immune characteristics in glioblastoma multiforme (GBM) patients. Methods: To identify TNF associations in GBM patients, we performed bioinformatics analysis of public databases - The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). The ConsensusClusterPlus, CIBERSORT, Estimate, GSVA and TIDE and first-order bias correlation and so on approaches were conducted to comprehensively characterize and compare differences among TNF-related subtypes. Results: Based on the comprehensive analysis of TNF-related lncRNAs expression profiles, we constructed six TNF-related lncRNAs (C1RL-AS1, LINC00968, MIR155HG, CPB2-AS1, LINC00906, and WDR11-AS1) risk signature to determine the role of TNF-related lncRNAs in GBM. This signature could divide GBM patients into subtypes with distinct clinical and immune characteristics and prognoses. We identified three molecular subtypes (C1, C2, and C3), with C2 showing the best prognosis; otherwise, C3 showing the worst prognosis. Moreover, we assessed the prognostic value, immune infiltration, immune checkpoints, chemokines cytokines and enrichment analysis of this signature in GBM. The TNF-related lncRNA signature was tightly associated with the regulation of tumor immune therapy and could serve as an independent prognostic biomarker in GBM. Conclusion: This analysis provides a comprehensive understanding of the role of TNF-related characters, which may improve the clinical outcome of GBM patients.

Application of nanomaterials in diagnosis and treatment of glioblastoma.

Diagnosing and treating glioblastoma patients is currently hindered by several obstacles, such as tumor heterogeneity, the blood-brain barrier, tumor complexity, drug efflux pumps, and tumor immune escape mechanisms. Combining multiple methods can increase benefits against these challenges. For example, nanomaterials can improve the curative effect of glioblastoma treatments, and the synergistic combination of different drugs can markedly reduce their side effects. In this review, we discuss the progression and main issues regarding glioblastoma diagnosis and treatment, the classification of nanomaterials, and the delivery mechanisms of nanomedicines. We also examine tumor targeting and promising nano-diagnosis or treatment principles based on nanomedicine. We also summarize the progress made on the advanced application of combined nanomaterial-based diagnosis and treatment tools and discuss their clinical prospects. This review aims to provide a better understanding of nano-drug combinations, nano-diagnosis, and treatment options for glioblastoma, as well as insights for developing new tools.

LncRNA Taurine Up-Regulated 1 plays a proapoptotic role by regulating nuclear-cytoplasmic shuttle of HuR under the condition of neuronal ischemia.

The study aimed to identify TUG1 as an essential regulator of apoptosis in HT22 (mouse hippocampal neuronal cells) by direct interaction with the RNA-binding protein HuR. In order to study the role of TUG1 in the context of ischemia, we used mouse hippocampal neuronal cells treated with oxyglucose deprivation to establish an in-vitro ischemia model. A bioinformatic analysis and formaldehyde RNA immunoprecipitation (fRIP) were used to investigate the biological functions. A Western blot assay and reverse transcription polymerase chain reaction were used to explore the expression of the molecules involved. A cell proliferation and cytotoxicity assay was performed to detect neuronal apoptosis. TUG1 exhibits a localization-specific expression pattern in HT22 cells under OGD treatment. The bioinformatics analysis showed a strong correlation between the TUG1 and HuR as predicted, and this interaction was subsequently confirmed by fRIP-qPCR. We found that HuR was translocated from the nucleus to the cytoplasm after ischemia treatment and subsequently targeted and stabilized COX-2 mRNA, which led to elevated COX-2 mRNA levels and apoptosis of the HT22 cells. Furthermore, nuclear-specific disruption of TUG1 prevented the translocation of HuR to the cytoplasm and decreased COX-2 mRNA expression, resulting in increased cell viability and partially reversed apoptosis. In conclusion, it was demonstrated that TUG1 accelerates the process of apoptosis by promoting the transfer of HuR to the cytoplasm and stabilizing COX-2 mRNA. These results provide useful information concerning a therapeutic target for ischemic stroke.

The role of RNA modification in the generation of acquired drug resistance in glioma.

Glioma is the most common malignant tumor in the central nervous system. The clinical treatment strategy is mainly surgery combined with concurrent temozolomide chemotherapy, but patients can develop drug resistance during treatment, which severely limits its therapeutic efficacy. Epigenetic regulation at the RNA level is plastic and adaptable, and it can induce a variety of tumor responses to drugs. The regulators of RNA modification include methyltransferases, demethylases, and methylation binding proteins; these are also considered to play an important role in the development, prognosis, and therapeutic response of gliomas, which provides a basis for finding new targets of epigenetic drugs and resetting the sensitivity of tumor cells to temozolomide. This review discusses the relationship between the development of adaptive drug resistance and RNA modification in glioma and summarizes the progress of several major RNA modification strategies in this field, especially RNA m6A modification, m5C modification, and adenosine-to-inosine editing.

Matrix Metalloproteinase 11 is a Potential Biomarker in Bladder Cancer Diagnosis and Prognosis.

PURPOSE: Bladder cancer is one of the leading causes of cancer death all over the world, and half of patients are diagnosed at advanced stages with poor therapeutic response. Thus, developing new biomarkers for bladder cancer diagnosis and prognosis is urgently needed. MATERIALS AND METHODS: Bioinformatic and gene ontology (GO) analysis were employed to screen highly upregulated and secretory tumor markers in the TCGA BLCA cohort. IHC in tissue microarray and ELISA in cancer cell culture medium were used to validate the expression of putative biomarkers in bladder cancer. Bisulfite sequencing was used to detect DNA methylation status in the promoter of putative genes. RESULTS: In this study, MMP11 is first identified as one of the most differentially expressed genes (DEGs) in bladder cancer by meta-analysis in a TCGA bladder cancer cohort. The strong upregulation of MMP11 is confirmed at protein levels in both bladder cancer patients and cell lines. Mechanistic studies reveal that MMP11 promoter hypomethylation, but not genomic amplification or mutation, accounts for its enhanced expression in bladder cancer both in vitro and in vivo. Moreover, clinicopathological analysis indicates that MMP11 upregulation is associated with the tumor progression and poor survival in bladder cancer patients. DISCUSSION: These findings suggest that MMP11, as a secretory protein, is a promising biomarker for diagnosis and prognosis in bladder cancer.

To construct a ceRNA regulatory network as prognostic biomarkers for bladder cancer.

Emerging evidence demonstrates that competing endogenous RNA (ceRNA) hypothesis has played a role in molecular biological mechanisms of cancer occurrence and development. But the effect of ceRNA network in bladder cancer (BC), especially lncRNA-miRNA-mRNA regulatory network of BC, was not completely expounded. By means of The Cancer Genome Atlas (TCGA) database, we compared the expression of RNA sequencing (RNA-Seq) data between 19 normal bladder tissue and 414 primary bladder tumours. Then, weighted gene co-expression network analysis (WGCNA) was conducted to analyse the correlation between two sets of genes with traits. Interactions between miRNAs, lncRNAs and target mRNAs were predicted by MiRcode, miRDB, starBase, miRTarBase and TargetScan. Next, by univariate Cox regression and LASSO regression analysis, the 86 mRNAs obtained by prediction were used to construct a prognostic model which contained 4 mRNAs (ACTC1 + FAM129A + OSBPL10 + EPHA2). Then, by the 4 mRNAs in the prognostic model, a ceRNA regulatory network with 48 lncRNAs, 14 miRNAs and 4 mRNAs was constructed. To sum up, the ceRNA network can further explore gene regulation and predict the prognosis of BC patients.

CDCA8 expression and its clinical relevance in patients with bladder cancer.

Cell division cycle associated 8 (CDCA8) overexpression is detected in various malignant tumors and closely associated with tumor growth. However, the correlations of CDCA8 expression with clinicopathological factors and prognosis of bladder cancer (BC) remain unclear. The purpose of this study was to identify the expression of CDCA8 and its clinical relevance in BC patients.GEO datasets were employed to obtain CDCA8 expression data and its clinical information in BC samples. Real-time PCR (RT-PCR) was performed to detect the expression of CDCA8 in BC and the adjacent normal tissues. Nonpaired t test was used to statistically analyze the difference between the 2 groups. Cox univariable and multivariable analyses of overall survival (OS) and cancer specific survival (CSS) among BC patients were performed. Biological processes or signaling pathways that might mediate the activity of CDCA8 in BC were analyzed.CDCA8 levels were significantly higher in BC (8.870 ±â€Š0.08281 vs 7.472 ±â€Š0.07035, P < .0001). CDCA8 expression was significantly associated with tumor progression (P = .001), T stage (P < .0001), N stage (P = .013), and grade (P < .0001). Higher expression of CDCA8 predicted poor cancer-specific survival (P < .0001, HR = 0.2752, 95% CI:0.1364-0.5554) and overall survival (P < .0001, HR = 0.4270, 95% CI: 0.2630-0.6930) in patients with BC. Cox univariable and multivariable analyses showed that intravesical therapy, N stage and progression were the independent influence factors of overall survival among bladder cancer patients, CDCA8 expression, tumor grade and progression were the independent influence factors of cancer specific survival among bladder cancer patients. The results of GSEA indicated that CDCA8-regulated gene sets associated with spermatogenesis, G2M checkpoint, E2F targets, Myc targets, mTORC1 signaling, mitotic spindle angiogenesis, PI3K/AKT/mTOR signaling, cholesterol homeostasis and glycolysis. Finally, RT-PCR results confirmed that CDCA8 expression was upregulated in BC (P = .0039).CDCA8 is overexpressed in BC and its high levels are correlated with poor clinicopathological features of BC patients. Therefore, CDCA8 may act as a novel prognostic marker and therapeutical target in the diagnosis and treatment of patients with BC.