The progression and recurrence are the fatal prognostic factors in glioma patients. However, the therapeutic role and potential mechanism of TRAF7 in glioma patients remain largely unknown.

TRAF7 RNA-seq was analysed with the TCGA and CGGA databases between glioma tissues and normal brain tissues. The expression of TRAF7, cellular senescence and cell cycle arrest pathways in glioma tissues and cell lines was detected by real-time quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The interaction between TRAF7 and KLF4 was determined by Co-immunoprecipitation (Co-IP) assays. The functions of TRAF7 combined with lomustine in glioma were assessed by both in vitro, in vivo and patient-derived primary and recurrent glioma stem cell (GSC) assays.

High TRAF7 expression is closely associated with a higher recurrence rate and poorer overall survival (OS). In vitro, TRAF7 knockdown significantly inhibits glioma cell proliferation, invasion, and migration. RNA-seq analysis revealed that TRAF7 inhibition activates pathways related to cellular senescence and cell cycle arrest. In both in vitro and patient-derived GSC assays, the combination of sh-TRAF7 and lomustine enhanced therapeutic efficacy by inducing senescence and G0/G1 cell cycle arrest, surpassing the effects of lomustine or TRAF7 inhibition alone. Mechanistically, TRAF7 interacts with KLF4, and a rescue assay demonstrated that KLF4 overexpression could reverse the effects of TRAF7 depletion on proliferation and cellular senescence. In vivo, TRAF7 knockdown combined with lomustine treatment effectively suppressed glioma growth.

TRAF7 could be used as a predictive biomarker and the potential therapeutic target among National Comprehensive Cancer Network (NCCN) treatment guidelines in the progression and recurrence of glioma. Lomustine, regulating cellular senescence and cell cycle could be the priority choice in glioma patients with high-level TRAF7 expression.

Chemotherapy and radiotherapy are widely used in clinical practice across the globe as cancer treatments. Intrinsic or acquired chemoresistance poses a significant problem for medical practitioners and researchers, causing tumor recurrence and metastasis. The most dangerous kind of malignant brain tumor is called glioblastoma multiforme (GBM) that often recurs following surgery. The most often used medication for treating GBM is temozolomide chemotherapy; however, most patients eventually become resistant. Researchers are studying preclinical models that accurately reflect human disease and can be used to speed up drug development to overcome chemoresistance in GBM. Non-coding RNAs (ncRNAs) have been shown to be substantial in regulating tumor development and facilitating treatment resistance in several cancers, such as GBM. In this work, we mentioned the mechanisms of how different ncRNAs (microRNAs, long non-coding RNAs, circular RNAs) can regulate temozolomide chemosensitivity in GBM. We also address the role of these ncRNAs encapsulated inside secreted exosomes.

This study aims to assess the prognostic value of Cyclin-dependent kinases 6 (CDK6) expression levels and establish a machine learning-based radiomics model for predicting the expression levels of CDK6 in high-grade gliomas (HGG).

Clinical parameters and genomic data were extracted from 310 HGG patients in the Cancer Genome Atlas (TCGA) database and 27 patients in the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database. Univariate and multivariate Cox regression, as well as Kaplan-Meier analysis, were performed for prognosis analysis. The correlation between immune cell Infiltration with CDK6 was assessed using spearman correlation analysis. Radiomic features were extracted from contrast-enhanced magnetic resonance imaging (CE-MRI) in the Cancer Imaging Archive (TCIA) database (n = 82) and REMBRANDT database (n = 27). Logistic regression (LR) and support vector machine (SVM) were employed to establish the radiomics model for predicting CDK6 expression. Receiver operating characteristic curve (ROC), calibration curve, and decision curve analysis (DCA) were utilized to assess the predictive performance of the radiomics model. Generate radiomic scores (RS) based on the LR model. An RS-based nomogram was constructed to predict the prognosis of HGG.

CDK6 was significantly overexpressed in HGG tissues and was related to lower overall survival. A significant elevation in infiltrating M0 macrophages was observed in the CDK6 high group (P < 0.001). The LR radiomics model for the prediction of CDK6 expression levels (AUC=0.810 in the training cohort, AUC = 0.784 after cross-validation, AUC=0.750 in the testing cohort) was established utilizing three radiomic features. The predictive efficiencies of the RS-based nomogram, as measured by AUC, were 0.769 for 1-year, 0.815 for 3-year, and 0.780 for 5-year, respectively.

The expression level of CDK6 can impact the prognosis of patients with HGG. The expression level of HGG can be noninvasively prognosticated utilizing a radiomics model.

Glioma is a highly lethal brain cancer in humans. Despite advancements in treatment, the prognosis for patients remains unfavorable. Epigenetic factors, along with their interactions and non-coding RNAs (ncRNAs), are crucial in glioma cells' development and aggressive characteristics. MicroRNAs (miRNAs) are a class of small non-coding RNAs (ncRNAs) that modulate the expression of various genes by binding to target mRNA molecules. They play a critical role in regulating essential biological mechanisms such as cell proliferation and differentiation, cell cycle, and apoptosis. MiR-146a/miR-146b is a significant and prevalent miRNA whose expression alterations are linked to various pathological changes in cancer cells, as well as the modulation of several cellular signaling pathways, including NF-κB, TGF-β, PI3K/Akt, and Notch-1. Scientists may identify novel targets in clinical settings by studying the complicated link between Mir-146a/mir-146b, drug resistance, molecular pathways, and pharmacological intervention in gliomas. Additionally, its interactions with other ncRNAs, such as circular RNA and long non-coding RNA, contribute to the pathogenesis of glioma. As well as miR-146 holds potential as both a diagnostic and therapeutic biomarker for patients with this condition. In the current review, we investigate the significance of miRNAs in the context of glioma, with a particular focus on the critical role of Mir-146a/mir-146b in glioma tumors. Additionally, we examined the clinical relevance of this miRNA, highlighting its potential implications for diagnosis and treatment.

Tumor resistance poses a significant challenge to effective cancer treatment, making it imperative to explore new therapeutic strategies. Recent studies have highlighted the profound involvement of immune cells in the development of tumor resistance. Within the tumor microenvironment, macrophages undergo polarization into the M2 phenotype, thus promoting the emergence of drug-resistant tumors. Neutrophils contribute to tumor resistance by forming extracellular traps. While T cells and natural killer (NK) cells exert their impact through direct cytotoxicity against tumor cells. Additionally, dendritic cells (DCs) have been implicated in preventing tumor drug resistance by stimulating T cell activation. In this review, we provide a comprehensive summary of the current knowledge regarding immune cell-mediated modulation of tumor resistance at the molecular level, with a particular focus on macrophages, neutrophils, DCs, T cells, and NK cells. The targeting of immune cell modulation exhibits considerable potential for addressing drug resistance, and an in-depth understanding of the molecular interactions between immune cells and tumor cells holds promise for the development of innovative therapies. Furthermore, we explore the clinical implications of these immune cells in the treatment of drug-resistant tumors. This review emphasizes the exploration of novel approaches that harness the functional capabilities of immune cells to effectively overcome drug-resistant tumors.

The CDK4/CDK6 inhibitor palbociclib has shown the encouraging promise in the treatment of glioma. Here, we elucidated how palbociclib exerts suppressive functions in the M2 polarization of glioma-related microglia and the progression of glioma. Xenograft experiments were used to evaluate the function in vivo. The mRNA levels of transcription factor 12 (TCF12) and VSIG4 were detected by RT-qPCR, and their protein levels were assessed by immunoblotting. Cell migration was tested by wound-healing assay. Cell cycle distribution and M1/M2 microglia phenotype analysis were performed by flow cytometry. The levels of IFN-γ, TNF-α, IL-6，and TGF-β were measured by ELISA. The TCF12/VSIG4 association was verified by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. In U251 and LN229 glioma cells, TCF12 and VSIG4 were overexpressed, and palbociclib reduced their expression levels. TCF12 upregulation enhanced the proliferation and migration of glioma cells and the M2 polarization of glioma-associated microglia in vitro as well as the tumorigenicity of U251 glioma cells in vivo, which could be reversed by palbociclib. Mechanistically, TCF12 could enhance VSIG4 transcription and expression by binding to the VSIG4 promoter. TCF12 deficiency led to repression in glioma cell proliferation and migration as well as microglia M2 polarization, which could be abolished by increased VSIG4 expression. Our study reveals the novel TCF12/VSIG4 axis responsible for the efficacy of palbociclib in combating glioma, offering a rationale for the application of palbociclib in glioma treatment.

Glioblastoma (GBM) is an aggressive nervous system tumor with a poor prognosis. Although, surgery, radiation therapy, and chemotherapy are the current standard protocol for GBM patients, there is still a poor prognosis in these patients. Temozolomide (TMZ) as a first-line therapeutic agent in GBM can easily cross from the blood-brain barrier to inhibit tumor cell proliferation. However, there is a high rate of TMZ resistance in GBM patients. Since, there are limited therapeutic choices for GBM patients who develop TMZ resistance; it is required to clarify the molecular mechanisms of chemo resistance to introduce the novel therapeutic targets. MicroRNAs (miRNAs) regulate chemo resistance through regulation of drug metabolism, absorption, DNA repair, apoptosis, and cell cycle. In the present review we discussed the role of miRNAs in TMZ response of GBM cells. It has been reported that miRNAs mainly induced TMZ sensitivity by regulation of signaling pathways and autophagy in GBM cells. Therefore, miRNAs can be used as the reliable diagnostic/prognostic markers in GBM patients. They can also be used as the therapeutic targets to improve the TMZ response in GBM cells.

Immunological processes, such as inflammation, can both cause tumor suppression and cancer progression. Moreover, deregulated levels of long non-coding RNA (lncRNA) expression in the brain may cause inflammation and lead to the growth of tumors. Like other biological processes, the immune system's role in cancer is complicated, varies, and can help or hurt the cancer's maintenance. According to research, inflammation and brain cancer are correlated via several signaling pathways. A variety of lncRNAs have recently been revealed to influence cancer by modulating inflammatory pathways. As a result, lncRNAs have the potential to influence carcinogenesis, tumor formation, or tumor suppression via an increase or decrease in inflammation functions. Although the study and targeting of lncRNAs have made great progress in the treatment of cancer, there are definitely limitations and challenges. Using new technologies like nanocarriers and cell-penetrating peptides (CPPs) to target treatments without hurting healthy body tissues has shown to be very effective. In this review article, we have collected significantly related lncRNAs and their inhibitory or stimulating roles in inflammation and brain cancer for the first time. However, there are limitations, such as side effects and damage to normal tissues. With the advancement of new targeting technologies, these lncRNAs may be candidates for the specific targeting therapy of brain cancers by limiting inflammation or stimulating the immune system against them in the future.

Temozolomide (TMZ), a DNA alkylating agent, has become the primary treatment for glioma, the most common malignancy of the central nervous system. Although TMZ-containing regimens produce significant clinical response rates, some patients inevitably suffer from inferior treatment outcomes or disease relapse, likely because of poor chemosensitivity of glioma cells due to a robust DNA damage response (DDR). GINS2, a subunit of DNA helicase, contributes to maintaining genomic stability and is highly expressed in various cancers, promoting their development. Here, we report that GINS2 was upregulated in TMZ-treated glioma cells and co-localized with γH2AX, indicating its participation in TMZ-induced DDR. Furthermore, GINS2 regulated the malignant phenotype and TMZ sensitivity of glioma cells, mostly by promoting DNA damage repair by affecting the mRNA stability of early growth response factor 1 (EGR1), which in turn regulates the transcription of epithelial cell-transforming sequence 2 (ECT2). We constructed a GINS2-EGR1-ECT2 prognostic model, which accurately predicted patient survival. Further, we screened Palbociclib/BIX-02189 which dampens GINS2 expression and synergistically inhibits glioma cell proliferation with TMZ. These findings delineate a novel mechanism by which GINS2 regulates the TMZ sensitivity of glioma cells and propose a promising combination therapy to treat glioma.

Glioblastoma (GBM) is an aggressive malignancy of the central nervous system (CNS) that remains incurable despite the multitude of improvements in cancer therapeutics. The conventional chemo and radiotherapy post-surgery have only been able to improve the prognosis slightly; however, the development of resistance and/or tumor recurrence is almost inevitable. There is a pressing need for adjuvant molecular therapies that can successfully and efficiently block tumor progression. During the last few decades, non-coding RNAs (ncRNAs) have emerged as key players in regulating various hallmarks of cancer including that of GBM. The levels of many ncRNAs are dysregulated in cancer, and ectopic modulation of their levels by delivering antagonists or overexpression constructs could serve as an attractive option for cancer therapy. The therapeutic potential of several types of ncRNAs, including miRNAs, lncRNAs, and circRNAs, has been validated in both in vitro and in vivo models of GBM. However, the delivery of these RNA-based therapeutics is highly challenging, especially to the tumors of the brain as the blood-brain barrier (BBB) poses as a major obstacle, among others. Also, since RNA is extremely fragile in nature, careful considerations must be met while designing a delivery agent. In this review we have shed light on how ncRNA therapy can overcome the limitations of its predecessor conventional therapy with an emphasis on smart nanomaterials that can aide in the safe and targeted delivery of nucleic acids to treat GBM. Additionally, critical gaps that currently exist for successful transition from viral to non-viral vector delivery systems have been identified. Finally, we have provided a perspective on the future directions, potential pathways, and target areas for achieving rapid clinical translation of, RNA-based macromolecular therapy to advance the effective treatment of GBM and other related diseases.

Brain tumors are a diverse collection of neoplasms affecting the brain with a high prevalence rate in people of all ages around the globe. In this pathological context, glioblastoma, a form of glioma that belongs to the IV-grade astrocytoma group, is the most common and most aggressive form of the primary brain tumors. Indeed, despite the best treatments available including surgery, radiotherapy or a pharmacological approach with Temozolomide, glioblastoma patients' mortality is still high, within a few months of diagnosis. Therefore, to increase the chances of these patients surviving, it is critical to keep finding novel treatment opportunities. In the past, efforts to treat glioblastoma have mostly concentrated on customized treatment plans that target specific mutations such as epidermal growth factor receptor (EGFR) mutations, Neurotrophic Tyrosine Receptor Kinase (NTRK) fusions, or multiple receptors using multi-kinase inhibitors like Sunitinib and Regorafenib, with varying degrees of success. Here, we focused on the receptor tyrosine kinase AXL that has been identified as a mediator for tumor progression and therapy resistance in various cancer types, including squamous cell tumors, small cell lung cancer, and breast cancer. Activated AXL leads to a significant increase in tumor proliferation, tumor cell migration, and angiogenesis in different in vitro and in vivo models of cancer since this receptor regulates interplay with apoptotic, angiogenic and inflammatory pathways. Based on these premises, in this review we mainly focused on the role of AXL in the course of glioblastoma, considering its primary biological mechanisms and as a possible target for the application of the most recent treatments.

The polarization of glioma-associated microglia/macrophages (GAMs) affects the growth and infiltration of glioma. Astragali Radix (AR) and Solanum nigrum L. (SN) are traditional antitumor combinations in Chinese herbal medicine, but their roles and mechanisms against glioma are not yet clear.

The effects of AR and SN compound (ARSN) on the polarization of GAMs and glioma cells in vitro and in vivo were studied, providing new ideas for the treatment of glioma.

The UPLC-QTOF-MS method was used to examine the quality of ARSN extracts. The effects of ARSN on proliferation, migration and apoptosis of C6 cells were investigated using CCK-8 assay, colony-forming assay, wound healing assay and flow cytometry. The impact of ARSN on the polarization of GAMs was verified by PCR, ELISA, and flow cytometry. In addition, a rat glioma model was established to assess the effects of ARSN on glioma growth, infiltration, and polarization of GAMs.

In vitro experiments, ARSN can effectively inhibit the proliferation and migration of C6 cells and promote apoptosis. In the rat orthotopic tumor model, ARSN also effectively inhibited tumor growth and infiltration. The SN part of ARSN has strong cytotoxicity. Meanwhile the AR part can effectively inhibit the M2 polarization of GAMs and chemokine production induced by tumor, promote the M1 phenotype of GAMs, and regulate the tumor immune microenvironment to indirectly kill glioma.

ARSN inhibited glioma growth both in vitro and in vivo. SN takes effect through direct cytotoxicity, while AR works by regulating GAMs polarization. ARSN extracts can be used as a potential agent for glioma treatment.

The roles of cyclin-dependent kinase 6 (CDK6) in various cancers, including small cell lung carcinoma (SCLC), remain unclear. Here, 111,54 multi-center samples were investigated to determine the expression, clinical significance, and underlying mechanisms of CDK6 in 34 cancers. The area under the curve (AUC), Cox regression analysis, and the Kaplan-Meier curves were used to explore the clinical value of CDK6 in cancers. Gene set enrichment analysis and correlation analysis were performed to detect potential CDK6 mechanisms. CDK6 expression was essential in 24 cancer cell types. Abnormal CDK6 expression was observed in 14 cancer types (e.g., downregulated in breast invasive carcinoma; p < 0.05). CDK6 allowed six cancers to be distinguished from their controls (AUC > 0.750). CDK6 expression was a prognosis marker for 13 cancers (e.g., adrenocortical carcinoma; p < 0.05). CDK6 was correlated with several immune-related signaling pathways and the infiltration levels of certain immune cells (e.g., CD8+ T cells; p < 0.05). Downregulated CDK6 mRNA and protein levels were observed in SCLC (p < 0.05, SMD = - 0.90). CDK6 allowed the identification of SCLC status (AUC = 0.91) and predicted a favorable prognosis for SCLC patients (p < 0.05). CDK6 may be a novel biomarker for the prediction and prognosis of several cancers, including SCLC.

Gliomas are the most common and deadly types of brain tumors, known for their extensive genetic and epigenetic variability, which poses considerable challenges for pharmacological treatment. Glioma heterogeneity is also related to their intricate and dynamic tumor microenvironment (TME), which comprises a diverse array of cell types, including immune cells, vascular cells, glial cells, and neural precursors, collectively influencing tumor behavior and progression. A pivotal aspect of this intercellular communication relies on the exchange of extracellular vesicles (EVs), which contain and transfer complex molecular cargoes typical of their cells of origin, such as proteins, lipids, carbohydrates, metabolites, and non-coding RNAs (ncRNAs), that encompass microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Glioma cells actively release EVs loaded with specific ncRNAs that can target genes and other ncRNAs in recipient cells residing within the TME. Among these recipient cells, prominent players include tumor-associated macrophages and microglia (TAMs), non-neoplastic astrocytes and endothelial cells. The intricate interplay between EVs derived from glioma cells and these recipient cells significantly contributes to the establishment of a tumor-permissive microenvironment, promoting tumor cell proliferation, migration, angiogenesis, and invasion, by targeting various downstream pathways. This review critically examines the current understanding of the intricate interplay between glioma, exosomal ncRNAs, and various components of the glioma TME. By shedding light on the roles of ncRNAs in mediating intercellular communication, this review underscores their significance in orchestrating TME transformation and highlights their potential as novel therapeutic targets for effectively tackling glioma progression.

As the most common and aggressive type of primary brain tumor in adults, glioblastoma is estimated to end over 10,000 lives each year in the United States alone. Stand treatment for glioblastoma, including surgery followed by radiotherapy and chemotherapy (i.e., Temozolomide), has been largely unchanged since early 2000. Cancer immunotherapy has significantly shifted the paradigm of cancer management in the past decade with various degrees of success in treating many hematopoietic cancers and some solid tumors, such as melanoma and non-small cell lung cancer (NSCLC). However, little progress has been made in the field of neuro-oncology, especially in the application of immunotherapy to glioblastoma treatment. In this review, we attempted to summarize the common drug resistance mechanisms in glioblastoma from Temozolomide to immunotherapy. Our intent is not to repeat the well-known difficulty in the area of neuro-oncology, such as the blood-brain barrier, but to provide some fresh insights into the molecular mechanisms responsible for resistance by summarizing some of the most recent literature. Through this review, we also hope to share some new ideas for improving the immunotherapy outcome of glioblastoma treatment.

Long noncoding RNAs (lncRNAs) play a crucial regulatory role in the development and progression of multiple cancers. However, the potential mechanism by which lncRNAs affect the recurrence and metastasis of ovarian cancer remains unclear. In the current study, the lncRNA LOC646029 was markedly downregulated in metastatic ovarian tumors compared with primary tumors. Gain- and loss-of-function assays demonstrated that LOC646029 inhibits the proliferation, invasiveness, and metastasis of ovarian cancer cells in vivo and in vitro. Moreover, the downregulation of LOC646029 in metastatic ovarian tumors was strongly correlated with poor prognosis. Mechanistically, LOC646029 served as a miR-627-3p sponge to promote the expression of Sprouty-related EVH1 domain-containing protein 1, which is necessary for suppressing tumor metastasis and inhibiting KRAS signaling. Collectively, our results demonstrated that LOC646029 is involved in the progression and metastasis of ovarian cancer, which may be a potential prognostic biomarker.

Gallbladder cancer (GBC) is a major malignant carcinoma of the biliary tract with extremely poor prognosis. Currently, there is no useful therapy strategies for GBC treatment, indicating the unmet mechanism researches for GBC. In this study, our data showed that SNHG15 expression significantly up-regulated and its high expression associated with poor overall survival of patients suffer from GBC. Functional experiments showed that SNHG15 depletion delayed the proliferation and enhanced the apoptosis of GBC tumor cells under the nutrition stress condition, which further confirmed in the subcutaneous xenograft model and liver metastasis model. Mechanistically, SNHG15 could interact with AMPK and facilitate the phosphorylation of AMPK to Tuberous sclerosis complex TSC2, resulting in mTOR suppression and autophagy enhancement, and finally, conferring the GBC cell sustain proliferation under nutrition stress. Taken together, our findings revealed that SNHG15 promotes GBC tumor progression by enhancing the autophagy under poor nutrition tumor microenvironment, which could be a promising targets for GBC.

Lower-grade glioma (LGG) is a primary intracranial tumor that carry a high risk of malignant transformation and limited therapeutic options. Emerging evidence indicates that the tumor microenvironment (TME) is a superior predictor for tumor progression and therapy response. PLEKHA4 has been demonstrated to be a biomarker for LGG that correlate with immune infiltration. However, the fundamental mechanism by which PLEKHA4 contributes to LGG is still poorly understood.

Multiple bioinformatic tools, including Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA2), Shiny Methylation Analysis Resource Tool (SMART), etc., were incorporated to analyze the PLEKHA4. ESTIMATE, ssGSEA, CIBERSORT, TIDE and CellMiner algorithms were employed to determine the association of PLEKHA4 with TME, immunotherapy response and drug sensitivities. Immunohistochemistry (IHC)-based tissue microarrays and M2 macrophage infiltration assay were conducted to verify their associations.

PLEKHA4 expression was found to be dramatically upregulated and strongly associated with unfavorable overall survival (OS) and disease-specific survival (DSS) in LGG patients, as well as their poor clinicopathological characteristics. Cox regression analysis identified that PLEKHA4 was an independent prognostic factor. Methylation analysis revealed that DNA methylation correlates with PLEKHA4 expression and indicates a better outcome in LGG. Moreover, PLEKHA4 was remarkably correlated with immune responses and TME remodeling, as evidenced by its positive correlation with particular immune marker subsets and the putative infiltration of immune cells. Surprisingly, the proportion of M2 macrophages in TME was strikingly higher than others, inferring that PLEKHA4 may regulate the infiltration and polarization of M2 macrophages. Evidence provided by IHC-based tissue microarrays and M2 macrophage infiltration assay further validated our findings. Moreover, PLEKHA4 expression was found to be significantly correlated with chemokines, interleukins, and their receptors, further supporting the critical role of PLEKHA4 in reshaping the TME. Additionally, we found that PLEKHA4 expression was closely associated with drug sensitivities and immunotherapy responses, indicating that PLEKHA4 expression also had potential clinical significance in guiding immunotherapy and chemotherapy in LGG.

PLEKHA4 plays a pivotal role in reshaping the TME of LGG patients, and may serve as a potential predictor for LGG prognosis and therapy.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by complex pathophysiological features. Amyloid plaques resulting from extracellular amyloid deposition and neurofibrillary tangles formed by intracellular hyperphosphorylated tau accumulation serve as primary neuropathological criteria for AD diagnosis. The activation of microglia has been closely associated with these pathological manifestations. Non-coding RNA (ncRNA), a versatile molecule involved in various cellular functions such as genetic information storage and transport, as well as catalysis of biochemical reactions, plays a crucial role in microglial activation. This review aims to investigate the regulatory role of ncRNAs in protein expression by directly targeting genes, proteins, and interactions. Furthermore, it explores the ability of ncRNAs to modulate inflammatory pathways, influence the expression of inflammatory factors, and regulate microglia activation, all of which contribute to neuroinflammation and AD. However, there are still significant controversies surrounding microglial activation and polarization. The categorization into M1 and M2 phenotypes may oversimplify the intricate and multifaceted regulatory processes in microglial response to neuroinflammation. Limited research has been conducted on the role of ncRNAs in regulating microglial activation and inducing distinct polarization states in the context of neuroinflammation. Moreover, the regulatory mechanisms through which ncRNAs govern microglial function continue to be refined. The current understanding of ncRNA regulatory pathways involved in microglial activation remains incomplete and may be influenced by spatial, temporal, and tissue-specific factors. Therefore, further in-depth investigations are warranted. In conclusion, there are ongoing debates and uncertainties regarding the activation and polarization of microglial cells, particularly concerning the categorization into M1 and M2 phenotypes. The study of ncRNA regulation in microglial activation and polarization, as well as its mechanisms, is still in its early stages and requires further investigation. However, this review offers new insights and opportunities for therapeutic approaches in AD. The development of ncRNA-based drugs may hold promise as a new direction in AD treatment.

Brain tumors, which are highly malignant, pose a significant threat to health and often result in substantial rates of mortality and morbidity worldwide. The brain cancer therapy has been challenging due to obstacles such as the BBB, which hinders effective delivery of therapeutic agents. Additionally, the emergence of drug resistance further complicates the management of brain tumors. TMZ is utilized in brain cancer removal, but resistance is a drawback. ncRNAs are implicated in various diseases, and their involvement in the cancer is particularly noteworthy. The focus of the current manuscript is to explore the involvement of ncRNAs in controlling drug resistance, specifically in the context of resistance to the chemotherapy drug TMZ. The review emphasizes the function of ncRNAs, particularly miRNAs, in modulating the growth and invasion of brain tumors, which significantly influences their response to TMZ treatment. Through their interactions with various molecular pathways, miRNAs are modulators of TMZ response. Similarly, lncRNAs also associate with molecular pathways and miRNAs, affecting the efficacy of TMZ chemotherapy. Given their functional properties, lncRNAs can either induce or suppress TMZ resistance in brain tumors. Furthermore, circRNAs, which are cancer controllers, regulate miRNAs by acting as sponges, thereby impacting the response to TMZ chemotherapy. The review explores the correlation between ncRNAs and TMZ chemotherapy, shedding light on the underlying molecular pathways involved in this process.

Glioma is the most common and malignant tumor of the central nervous system. Glioblastoma (GBM) is the most aggressive glioma, with a poor prognosis and no effective treatment because of its high invasiveness, metabolic rate, and heterogeneity. The tumor microenvironment (TME) contains many tumor-associated macrophages (TAMs), which play a critical role in tumor proliferation, invasion, metastasis, and angiogenesis and indirectly promote an immunosuppressive microenvironment. TAM is divided into tumor-suppressive M1-like (classic activation of macrophages) and tumor-supportive M2-like (alternatively activated macrophages) polarized cells. TAMs exhibit an M1-like phenotype in the initial stages of tumor progression, and along with the promotion of lysing tumors and the functions of T cells and NK cells, tumor growth is suppressed, and they rapidly transform into M2-like polarized macrophages, which promote tumor progression. In this review, we discuss the mechanism by which M1- and M2-polarized macrophages promote or inhibit the growth of glioblastoma and indicate the future directions for treatment.

Gliomas are highly malignant tumors accounting for the majority of brain neoplasms. They are characterized by nuclear atypia, high mitotic rate and cellular polymorphism that often contributes to aggressiveness and resistance to standard therapy. They often associate with challenging treatment approaches and poor outcomes. New treatment strategies or regimens to improve the efficacy of glioma treatment require a deeper understanding of glioma occurrence and development as well as elucidation of their molecular biological characteristics. Recent studies have revealed RNA modifications as a key regulatory mechanism involved in tumorigenesis, tumor progression, immune regulation, and response to therapy. The present review discusses research advances on several RNA modifications involved in glioma progression and tumor microenvironment (TME) immunoregulation as well as in the development of adaptive drug resistance, summarizing current progress on major RNA modification targeting strategies.

The invasive nature of glioblastoma is problematic in a radical surgery approach and can be responsible for tumor recurrence. In order to create new therapeutic strategies, it is imperative to have a better understanding of the mechanisms behind tumor growth and invasion. The continuous cross-talk between glioma stem cells (GSCs) and the tumor microenvironment (TME) contributes to disease progression, which renders research in this field difficult and challenging. The main aim of the review was to assess the different possible mechanisms that could explain resistance to treatment promoted by TME and GSCs in glioblastoma, including the role of M2 macrophages, micro RNAs (miRNAs), and long non-coding RNAs (lncRNAs) from exosomes from the TME. A systematic review of the literature on the role of the TME in developing and promoting radioresistance and chemoresistance of GBM was performed according to PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) guidelines. A dedicated literature review search was also performed on the immunotherapeutic agents against the immune TME. We identified 367 papers using the reported keywords. The final qualitative analysis was conducted on 25 studies. A growing amount of evidence in the current literature supports the role of M2 macrophages and non-coding RNAs in promoting the mechanisms of chemo and radioresistance. A better insight into how GBM cells interact with TME is an essential step towards comprehending the mechanisms that give rise to resistance to standard treatment, which can help to pave the way for the development of novel therapeutic strategies for GBM patients.

Cyclin-dependent kinases (CDKs) regulate cell division at multiple levels. Aberrant proliferation induced by abnormal cell cycle is a hallmark of cancer. Over the past few decades, several drugs that inhibit CDK activity have been created to stop the development of cancer cells. The third generation of selective CDK4/6 inhibition has proceeded into clinical trials for a range of cancers and is quickly becoming the backbone of contemporary cancer therapy. Non-coding RNAs, or ncRNAs, do not encode proteins. Many studies have demonstrated the involvement of ncRNAs in the regulation of the cell cycle and their abnormal expression in cancer. By interacting with important cell cycle regulators, preclinical studies have demonstrated that ncRNAs may decrease or increase the treatment outcome of CDK4/6 inhibition. As a result, cell cycle-associated ncRNAs may act as predictors of CDK4/6 inhibition efficacy and perhaps present novel candidates for tumor therapy and diagnosis.

N6-methyladenosine (m6A)-related lncRNAs could be involved in the development of multiple tumors with an unknown role in lung adenocarcinoma (LUAD). Hence, gene expression data and clinical data of LUAD patients were acquired from The Cancer Genome Atlas Database. The prognostic m6A-related lncRNAs were identified through differential lncRNA expression analysis and Spearman's correlation analysis. The least absolute shrinkage and selection operator regression was used to establish the prognostic risk model, so as to evaluate and validate the predictive performance with survival analysis and receiver operating characteristic curve analysis. The expression of immune checkpoints, immune cell infiltration and drug sensitivity of patients in different risk groups were analyzed separately. A total of 19 prognostic m6A-related lncRNAs were identified to set up the prognostic risk model. The patients were divided into high- and low-risk groups based on the median value of the risk scores. Compared with the patients in the low-risk group, the prognosis of the patients in the high-risk group was relatively worse. The receiver operating characteristic curves indicated that this model had excellent sensitivity and specificity. Multivariate Cox regression analysis demonstrated that the risk score could be supposed as an independent prognostic risk factor. We highlighted that the risk scores were correlated with immune cell infiltration and drug sensitivity for constructing a prognostic risk model in LUAD patients based on m6A-related lncRNAs.

The unique intracranial tumor microenvironment (TME) contributes to the immunotherapy failure for glioblastoma (GBM), thus new functional protein targets are urgently needed. Alternative splicing is a widespread regulatory mechanism by which individual gene can express variant proteins with distinct functions. Moreover, proteins located in the cell plasma membrane facilitate targeted therapies. This study sought to obtain functional membrane protein isoforms from GBM TME.

With combined single-cell RNA-seq and bulk RNA-seq analyses, novel candidate membrane proteins generated by prognostic splicing events were screened within GBM TME. The short isoform of MS4A7 (MS4A7-s) was selected for evaluation by RT-PCR and western blotting in clinical specimens. Its clinical relevance was evaluated in a GBM patient cohort. The function of MS4A7-s was identified by in vitro and in vivo experiments. MS4A7-s overexpression introduced transcriptome changes were analyzed to explore the potential molecular mechanism.

The main expression product, isoform MS4A7-s, generated by exon skipping, is an M2-specific plasma membrane protein playing a pro-oncogenic role in GBM TME. Higher expression of MS4A7-s correlates with poor prognosis in a GBM cohort. In vitro cell co-culture experiments, intracranial co-injection tumorigenesis assay, and RNA-seq suggest MS4A7-s promotes activation of glioma-associated macrophages' (GAMs) PI3K/AKT/GSK3β pathway, leading to M2 polarization, and drives malignant progression of GBM.

MS4A7-s, a novel splicing isoform of MS4A7 located on the surface of GAMs in GBM TME, is a predictor of patient outcome, which contributes to M2 polarization and the malignant phenotype of GBM. Targeting MS4A7-s may constitute a promising treatment for GBM.

Pyroptosis, also known as inflammatory necrosis, is a programmed cell death that manifests itself as a continuous swelling of cells until the cell membrane breaks, leading to the liberation of cellular contents, which triggers an intense inflammatory response. Pyroptosis might be a panacea for a variety of cancers, which include immunotherapy and chemotherapy-insensitive tumors such as glioma. Several findings have observed that long non-coding RNAs (lncRNAs) modulate the bio-behavior of tumor cells by binding to RNA, DNA and protein. Nevertheless, there are few studies reporting the effect of lncRNAs in pyroptosis processes in glioma.

The principal goal of this study was to identify pyroptosis-related lncRNAs (PRLs) utilizing bioinformatic algorithm and to apply PCR techniques for validation in human glioma tissues. The second goal was to establish a prognostic model for predicting the overall survival patients with glioma. Predict algorithm was used to construct prognosis model with good diagnostic precision for potential clinical translation.

Noticeably, molecular subtypes categorized by the PRLs were not distinct from any previously published subtypes of glioma. The immune and mutation landscapes were obviously different from previous subtypes of glioma. Analysis of the sensitivity (IC50) of patients to 30 chemotherapeutic agents identified 22 agents as potential therapeutic agents for patients with low riskscores.

We established an exact prognostic model according to the expression profile of PRLs, which may facilitate the assessment of patient prognosis and treatment patterns and could be further applied to clinical.

Microglia polarization and microglia-mediated inflammation play a crucial role in the development of ischaemic brain injury. Electroacupuncture (EA) has the function of anti-inflammatory, which has been thoroughly validated and utilized to treat ischemic brain damage. The fundamental mechanism by which EA alleviates ischemic brain damage by decreasing microglia polarization and microglia-mediated inflammation, however, remains unknown. In the current study, the activation of microglia and inflammatory cytokines was analyzed to confirm the anti-inflammatory function of EA in middle cerebral artery occlusion (MCAO) rats. Whole-transcriptome sequencing was used to examine the differentially expressed lncRNAs in the control, MCAO, and MCAO +EA groups. Our findings demonstrated that EA treatment reduced microglia activation and inflammatory cytokine production. In addition, there are 44 lncRNAs were found significantly different in three groups, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the predicted targets of these lncRNAs suggested that the Hippo pathway may contribute to the development of ischaemic brain injury and to the anti-inflammatory function of EA. Moreover, our data showed that lncRNA TCONS_00022826 (Lnc826) was upregulated in MCAO group, whereas blocked by EA treatment. Furthermore, in vitro OGD cell model data showed that Lnc826 promoted M1 polarization of microglia by regulating the Hippo pathway. Our data suggested that regulating microglia polarization via Lnc826-mediated hippo pathway is a possible mechanism of the EA treatment on ischemic brain injury.

Glioblastoma (GBM) is the most aggressive and invasive primary brain tumor. Current therapies are not curative, and patients' outcomes remain poor with an overall survival of 20.9 months after surgery. The typical growing pattern of GBM develops by infiltrating the surrounding apparent normal brain tissue within which the recurrence is expected to appear in the majority of cases. Thus, in the last decades, an increased interest has developed to investigate the cellular and molecular interactions between GBM and the peritumoral brain zone (PBZ) bordering the tumor tissue. The aim of this review is to provide up-to-date knowledge about the oncogenic properties of the PBZ to highlight possible druggable targets for more effective treatment of GBM by limiting the formation of recurrence, which is almost inevitable in the majority of patients. Starting from the description of the cellular components, passing through the illustration of the molecular profiles, we finally focused on more clinical aspects, represented by imaging and radiological details. The complete picture that emerges from this review could provide new input for future investigations aimed at identifying new effective strategies to eradicate this still incurable tumor.

To investigate the immune cell infiltration status in glioblastoma multiforme (GBM) and construct a novel prognostic risk model that can predict patients' prognosis.

The Cancer Genome Atlas (TCGA) database was used to obtain RNA-sequence information and relevant clinical data. We performed Pearson correlation, univariate Cox regression to screen m6A-related prognostic lncRNA. GMB patients' samples were separated into different clusters through the ConsensusClusterPlus package. The risk score model was established through LASSO regression analysis. Besides, KEGG pathway enrichment analysis was implemented. CIBERSORT algorithm was used to analyze the difference of 22 types of immune cell infiltration in different cluster of GBM patient. Cox regression analyses were used to verify the independence of the model and correlation analysis was performed to demonstrate the link between our model and clinical characteristics of GBM patients. Experiments were used to validate the differential expression of the model lncRNA in patients with different prognosis.

17 lncRNA related to prognosis were screened from 1021 m6A-related lncRNAs. Further, four m6A-related lncRNAs that were significantly correlated with GBM prognosis were selected to establish our prognostic risk model, which had excellent accuracy and can independently predict the prognosis of GBM patients. The infiltration fractions of T regulatory cells, T cells CD4 memory activated and neutrophils were positively associated with risk score, which suggested a significant relationship between the model and tumor immune microenvironment.

The m6A-related RNA risk model offered potential for identifying biomarkers of therapy and predicting prognosis of GBM patients.

Brain tumors are one of the most mortal cancers, leading to many deaths among kids and adults. Surgery, chemotherapy, and radiotherapy are available options for brain tumor treatment. However, these methods are not able to eradicate cancer cells. The blood-brain barrier (BBB) is one of the most important barriers to treat brain tumors that prevents adequate drug delivery to brain tissue. The connection between different brain parts is heterogeneous and causes many challenges in treatment. Mesenchymal stem cells (MSCs) migrate to brain tumor cells and have anti-tumor effects by delivering cytotoxic compounds. They contain very high regenerative properties, as well as support the immune system. MSCs-based therapy involves cell replacement and releases various vesicles, including exosomes. Exosomes receive more attention due to their excellent stability, less immunogenicity and toxicity compare to cells. Exosomes derived from MSCs can develop a powerful therapeutic strategy for different diseases and be a hopeful candidate for cell-based and cell-free regenerative medicine. These nanoparticles contain nucleic acid, proteins, lipids, microRNAs, and other biologically active substances. Many studies show that each microRNA can prevent angiogenesis, migration, and metastasis in glioblastoma. These exosomes can-act as a suitable nanoparticle carrier for therapeutic applications of brain tumors by passing through the BBB. In this review, we discuss potential applications of MSC and their produced exosomes in the treatment of brain tumors.

Melanoma is one of the most lethal tumors with highly aggressive and metastatic properties. Although immunotherapy and targeted therapy have certain therapeutic effects in melanoma, a significant proportion of patients still have drug resistance after treatment. Recent studies have shown that long noncoding RNAs (lncRNAs) are widely recognized as regulatory factors in cancer. They can regulate numerous cellular processes, including cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) progression and the immune microenvironment. The role of lncRNAs in malignant tumors has received much attention, whereas the relationship between lncRNAs and melanoma requires further investigation. Our review summarizes tumor suppressive and oncogenic lncRNAs closely related to the occurrence and development of melanoma. We summarize the role of lncRNAs in the immune microenvironment, immunotherapy and targeted therapy to provide new targets and therapeutic methods for clinical treatment.

Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially in the context of therapeutic considerations. New ideas have emerged regarding the role of microglia and, more recently, blood-derived brain macrophages in glioblastoma (GBM) progression. We are now beginning to understand the mechanisms that allow malignant glioma cells to weaken microglia and brain macrophage defence mechanisms. Surface molecules and cytokines have a prominent role in microglia/macrophage-glioma cell interactions, and we discuss them in detail. The involvement of exosomes and microRNAs forms another focus of this review. In addition, certain microglia and glioma cell pathways deserve special attention. These "synergistic" (we suggest calling them "Janus") pathways are active in both glioma cells and microglia/macrophages where they act in concert supporting malignant glioma progression. Examples include CCN4 (WISP1)/Integrin α6β1/Akt and CHI3L1/PI3K/Akt/mTOR. They represent attractive therapeutic targets.

Temozolomide (TMZ) is the recommended drug for glioblastoma (GBM) treatment, but its clinical effect is restricted due to drug resistance. This research studies the effects of long non-coding RNA (lncRNA) ZBED3-AS1 and its related molecules on acquired TMZ resistance in glioblastoma (GBM). ZBED3-AS1 was identified to be downregulated in TMZ-resistant GBM cells by analyzing GSE113510 and GSE100736 datasets. ZBED3-AS1 downregulation was detected in TMZ-resistant GBM tissues and cell lines (U251/TMZ and U87/TMZ). ZBED3-AS1 knockdown promoted, whereas its overexpression suppressed TMZ resistance, viability and mobility, and glycolytic activity of TMZ-resistant cells. ZBED3-AS1 bound to Spi-1 proto-oncogene (SPI1) but did not affect its expression. Instead, it blocked SPI1-mediated transcriptional activation of thrombomodulin (THBD). SPI1 and THBD increased TMZ resistance and glycolysis in TMZ-resistant cells. Either ZBED3-AS1 overexpression or SPI1 knockdown in U87/TMZ cells blocked the growth of orthotopic and subcutaneous xenograft tumors in nude mice. In conclusion, this study demonstrates that ZBED3-AS1 downregulation and THBD activation is linked to increased TMZ resistance and glycolysis in GBM cells.

With a reported rise in global air pollution, more than 50% of the population remains exposed to toxic air pollutants in the form of particulate matters (PMs). PMs, from various sources and of varying sizes, have a significant impact on health as long-time exposure to them has seen a correlation with various health hazards and have also been determined to be carcinogenic. In addition to disrupting known cellular pathways, PMs have also been associated with lncRNA dysregulation-a factor that increases predisposition towards the onset or progression of cancer. lncRNA dysregulation is further seen to mediate glioblastoma multiforme (GBM) progression. The vast array of information regarding cancer types including GBM and its various precursors can easily be obtained via innovative in silico approaches in the form of databases such as GEO and TCGA; however, a need to obtain selective and specific information correlating anthropogenic factors and disease progression-in the case of GBM-can serve as a critical tool to filter down and target specific PMs and lncRNAs responsible for regulating key cancer hallmarks in glioblastoma. The current review article proposes an in silico approach in the form of a database that reviews current updates on correlation of PMs with lncRNA dysregulation leading to GBM progression.

Epigenetic factors are critical regulators of biological and pathological mechanisms and they could interact with different molecular pathways. Targeting epigenetic factors has been an idea approach in disease therapy, especially cancer. Accumulating evidence has highlighted function of long non-coding RNAs (lncRNAs) as epigenetic factors in cancer initiation and development and has focused on their association with downstream targets. microRNAs (miRNAs) are the most well-known targets of lncRNAs and present review focuses on lncRNA-miRNA axis in malignancy and therapy resistance of tumors. LncRNA-miRNA regulates cell death mechanisms such as apoptosis and autophagy in cancers. This axis affects tumor metastasis via regulating EMT and MMPs. Besides, lncRNA-miRNA axis determines sensitivity of tumor cells to chemotherapy, radiotherapy and immunotherapy. Based on the studies, lncRNAs can be affected by drugs and genetic tools in cancer therapy and this may affect expression level of miRNAs as their downstream targets, leading to cancer suppression/progression. LncRNAs have both tumor-promoting and tumor-suppressor functions in cancer and this unique function of lncRNAs has complicated their implication in tumor therapy. LncRNA-miRNA axis can also affect other signaling networks in cancer such as PI3K/Akt, STAT3, Wnt/β-catenin and EZH2 among others. Notably, lncRNA/miRNA axis can be considered as a signature for diagnosis and prognosis in cancers.

For decades, research in cancer biology has been focused on the protein-coding fraction of the human genome. However, with the discovery of non-coding RNAs (ncRNAs), it has become known that these entities not only function in numerous fundamental life processes such as growth, differentiation, and development, but also play critical roles in a wide spectrum of human diseases, including cancer. Dysregulated ncRNA expression is found to affect cancer initiation, progression, and therapy resistance, through transcriptional, post-transcriptional, or epigenetic processes in the cell. In this review, we focus on the recent development and advances in ncRNA biology that are pertinent to their role in glioma tumorigenesis and therapy response. Gliomas are common, and are the most aggressive type of primary tumors, which account for ~30% of central nervous system (CNS) tumors. Of these, glioblastoma (GBM), which are grade IV tumors, are the most lethal brain tumors. Only 5% of GBM patients survive beyond five years upon diagnosis. Hence, a deeper understanding of the cellular non-coding transcriptome might help identify biomarkers and therapeutic agents for a better treatment of glioma. Here, we delve into the functional roles of microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) in glioma tumorigenesis, discuss the function of their extracellular counterparts, and highlight their potential as biomarkers and therapeutic agents in glioma.