Epitranscriptomic modifications in mesenchymal stem cell differentiation: advances, mechanistic insights, and beyond.

Glioblastoma multiforme (GBM) is the most common and invasive primary central nervous system tumor in humans, accounting for approximately 45–50% of all primary brain tumors. How to conduct early diagnosis, targeted intervention, and prognostic evaluation of GBM, in order to improve the survival rate of glioblastoma patients, has always been an urgent clinical problem to be solved. Therefore, a deeper understanding of the molecular mechanisms underlying the occurrence and development of GBM is also needed. Like many other cancers, NF-κB signaling plays a crucial role in tumor growth and therapeutic resistance in GBM. However, the molecular mechanism underlying the high activity of NF-κB in GBM remains to be elucidated. This review aims to identify and summarize the NF-κB signaling involved in the recent pathogenesis of GBM, as well as basic therapy for GBM via NF-κB signaling.

/pdf/the-recent-research-progress-of-nf-kb-signaling-on-the-1nfy1434.pdf

The Recent Research Progress of NF-κB Signaling on the Proliferation, Migration, Invasion, Immune Escape and Drug Resistance of Glioblastoma

This scoping review examines the use of CRISPR/Cas9 gene editing in glioblastoma (GBM), a predominant and aggressive brain tumor. Categorizing gene targets into distinct groups, this review explores their roles in cell cycle regulation, microenvironmental dynamics, interphase processes, and therapy resistance reduction. The complexity of CRISPR-Cas9 applications in GBM research is highlighted, providing unique insights into apoptosis, cell proliferation, and immune responses within the tumor microenvironment. The studies challenge conventional perspectives on specific genes, emphasizing the potential therapeutic implications of manipulating key molecular players in cell cycle dynamics. Exploring CRISPR/Cas9 gene therapy in GBMs yields significant insights into the regulation of cellular processes, spanning cell interphase, renewal, and migration. Researchers, by precisely targeting specific genes, uncover the molecular orchestration governing cell proliferation, growth, and differentiation during critical phases of the cell cycle. The findings underscore the potential of CRISPR/Cas9 technology in unraveling the complex dynamics of the GBM microenvironment, offering promising avenues for targeted therapies to curb GBM growth. This review also outlines studies addressing therapy resistance in GBM, employing CRISPR/Cas9 to target genes associated with chemotherapy resistance, showcasing its transformative potential in effective GBM treatments.

CRISPR/Cas9-Mediated Gene Therapy for Glioblastoma: A Scoping Review

Ischemic stroke (IS) is one of the principal causes of disability and death worldwide. Berberine (BBR), derived from the traditional Chinese herbal medicine Huang Lian, has been reported to inhibit the progression of stroke, but the specific mechanism whereby BBR modulates the progression of ischemic stroke remains unclear. N6-methyladenosine (m6A) modification is the most typical epigenetic modification of mRNA post-transcriptional modifications, among which METTL3 is the most common methylation transferase. During the study, the middle cerebral artery occlusion/reperfusion (MCAO/R) was established in mice, and the mice primary astrocytes and neurons induced by oxygen-glucose deprivation/reoxygenation (OGD/R) was simulated in vitro. Level of LncNEAT1, miR-377-3p was detected via RT-qPCR. The levels of Nampt and METTL3 were measured by Western blot. CCK8 and LDH assay was performed to detect cell viability. Here, we found that berberine alleviates MCAO/R-induced ischemic injury and up-regulates the expression of Nampt in astrocytes, miR-377-3p inhibits the expression of Nampt in astrocytes after OGD/R, thus promoting neuronal injury. NEAT1 binds to miR-377-3p in OGD/R astrocytes and plays a neuronal protective role as a ceRNA. METTL3 can enhance NEAT1 stability in OGD/R astrocytes by modulating m6A modification of NEAT1. Taken together, our results demonstrate that berberine exerts neuroprotective effects via the m6A methyltransferase METTL3, which regulates the NEAT1/miR-377-3p/Nampt axis in mouse astrocytes to ameliorate cerebral ischemia/reperfusion (I/R) injury.

METTL3-dependent N6-methyladenosine modification is involved in berberine-mediated neuroprotection in ischemic stroke by enhancing the stability of NEAT1 in astrocytes.

Brain tumors are common malignancies with high mortality and morbidity in which glioblastoma (GB) is a grade IV astrocytoma with heterogeneous nature. The conventional therapeutics for the GB mainly include surgery and chemotherapy, however their efficacy has been compromised due to the aggressiveness of tumor cells. The dysregulation of cell death mechanisms, especially autophagy has been reported as a factor causing difficulties in cancer therapy. As a mechanism contributing to cell homeostasis, the autophagy process is hijacked by tumor cells for the purpose of aggravating cancer progression and drug resistance. The autophagy function is context-dependent and its role can be lethal or protective in cancer. The aim of the current paper is to highlight the role of autophagy in the regulation of GB progression. The cytotoxic function of autophagy can promote apoptosis and ferroptosis in GB cells and vice versa. Autophagy dysregulation can cause drug resistance and radioresistance in GB. Moreover, stemness can be regulated by autophagy and overall growth as well as metastasis are affected by autophagy. The various interventions including administration of synthetic/natural products and nanoplatforms can target autophagy. Therefore, autophagy can act as a promising target in GB therapy. 

Autophagy machinery in glioblastoma: The prospect of cell death crosstalk and drug resistance with bioinformatics analysis.

Epidermal growth factor receptor variant III (EGFRvIII) is a mutant isoform of EGFR with a deletion of exons 2-7 making it insensitive to EGF stimulation and downstream signal constitutive activation. However, the mechanism underlying the stability of EGFRvIII remains unclear. Based on CRISPR-Cas9 library screening, we found that mucin1 (MUC1) is essential for EGFRvIII glioma cell survival and temozolomide (TMZ) resistance. We revealed that MUC1-C was upregulated in EGFRvIII-positive cells, where it enhanced the stability of EGFRvIII. Knockdown of MUC1-C increased the colocalization of EGFRvIII and lysosomes. Upregulation of MUC1 occurred in an NF-κB dependent manner, and inhibition of the NF-κB pathway could interrupt the EGFRvIII-MUC1 feedback loop by inhibiting MUC1-C. In a previous report, we identified AC1Q3QWB (AQB), a small molecule that could inhibit the phosphorylation of NF-κB. By screening the structural analogs of AQB, we obtained EPIC-1027, which could inhibit the NF-κB pathway more effectively. EPIC-1027 disrupted the EGFRvIII-MUC1-C positive feedback loop in vitro and in vivo, inhibited glioma progression, and promoted sensitization to TMZ. In conclusion, we revealed the pivotal role of MUC1-C in stabilizing EGFRvIII in glioblastoma (GBM) and identified a small molecule, EPIC-1027, with great potential in GBM treatment. 

MUC1 promotes glioblastoma progression and TMZ resistance by stabilizing EGFRvIII.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomal KLF4 Alleviated Ischemic Stroke Through Inhibiting N6-Methyladenosine Modification Level of Drp1 by Targeting lncRNA-ZFAS1

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MUC1 promotes glioblastoma progression and TMZ resistance by stabilizing EGFRvIII.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomal KLF4 Alleviated Ischemic Stroke Through Inhibiting N6-Methyladenosine Modification Level of Drp1 by Targeting lncRNA-ZFAS1