PRMT1 in human neoplasm: cancer biology and potential therapeutic target.

Protein arginine methyltransferase 1 (PRMT1), the predominant type I protein arginine methyltransferase, plays a crucial role in normal biological functions by catalyzing the methylation of arginine side chains, specifically monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), within proteins. Recent investigations have unveiled an association between dysregulated PRMT1 expression and the initiation and progression of tumors, significantly impacting patient prognosis, attributed to PRMT1's involvement in regulating various facets of tumor cell biology, including DNA damage repair, transcriptional and translational regulation, as well as signal transduction. In this review, we present an overview of recent advancements in PRMT1 research across different tumor types, with a specific focus on its contributions to tumor cell proliferation, metastasis, invasion, and drug resistance. Additionally, we expound on the dynamic functions of PRMT1 during distinct stages of cancer progression, elucidating its unique regulatory mechanisms within the same signaling pathway and distinguishing between its promotive and inhibitory effects. Importantly, we sought to provide a comprehensive summary and analysis of recent research progress on PRMT1 in tumors, contributing to a deeper understanding of its role in tumorigenesis, development, and potential treatment strategies.

Increased level of exosomal miR-20b-5p derived from hypothermia-treated microglia promotes neurite outgrowth and synapse recovery after traumatic brain injury.

Mild hypothermia has been proven to inhibit microglia activation after TBI. Exosomal microRNA derived from microglia played a critical role in promoting neurite outgrowth and synapse recovery. Here, we aimed to investigate the role of microRNAs in microglial exosomes after hypothermia treatment on neuronal regeneration after TBI. For in vitro study, stretch-injured neurons were co-cultured with microglial exosomes. For in vivo study, C57BL/6 mice were under controlled cortical impact and injected with microglial exosomes. The results showed that MG-LPS-EXOHT increased the number of dendrite branches and total length of dendrites both in vitro and in vivo, elevated the expression levels of PSD-95 and GluR1 in stretch-injured neurons, and increased spine density in the pericontusion region. Moreover, MG-LPS-EXOHT improved motor function and motor coordination. A high-throughput sequencing showed that miR-20b-5p was upregulated in MG-LPS-EXOHT. Elevating miR-20b-5p promoted neurite outgrowth and synapse recovery of injured neurons both in vitro and in vivo. Following mechanistic study demonstrated that miR-20b-5p might promote neurite outgrowth and synapse recovery by directly targeting PTEN and activating PI3K-AKT pathway. In conclusion, mild hypothermia could modify the microRNA prolife of exosomes derived from LPS activated BV2 cells. Furthermore, high level of microglial exosomal miR-20b-5p induced by mild hypothermia could transfer into injured neurons and promote neurite outgrowth and synapse recovery after TBI via activating the PI3K-AKT pathway by suppressing PTEN expression.

Elevated LILRB1 expression predicts poor prognosis and is associated with tumor immune infiltration in patients with glioma.

BACKGROUND: Leukocyte immunoglobulin-like receptor subfamily B1 (LILRB1) is regarded as an inhibitory molecule. However, the importance of LILRB1 expression in glioma has not yet been determined. This investigation examined the immunological signature, clinicopathological importance and prognostic value of LILRB1 expression in glioma. METHODS: We used data from the UCSC XENA database, the Cancer Genome Atlas (TCGA) database, the Chinese Glioma Genome Atlas (CGGA) database, the STRING database, the MEXPRESS database and our clinical glioma samples to perform bioinformatic analysis and used vitro experiments to examine the predictive value and potential biological roles of LILRB1 in glioma. RESULTS: Higher LILRB1 expression was considerably present in the higher WHO grade glioma group and was linked to a poorer prognosis in patients with glioma. Gene set enrichment analysis (GSEA) revealed that LILRB1 was positively correlated with the JAK/STAT signaling pathway. LILRB1 combined with tumor mutational burden (TMB) and microsatellite instability (MSI) may be a promising indicator for the effectiveness of immunotherapy in patients with glioma. Increased LILRB1 expression was positively linked with the hypomethylation, M2 macrophage infiltration, immune checkpoints (ICPs) and M2 macrophage makers. Univariate and multivariate Cox regression analyses determined that increased LILRB1 expression was a standalone causal factor for glioma. Vitro experiments determined that LILRB1 positively enhanced the proliferation, migration and invasion in glioma cells. MRI images demonstrated that higher LILRB1 expression was related with larger tumor volume in patients with glioma. CONCLUSION: Dysregulation of LILRB1 in glioma is correlated with immune infiltration and is a standalone causal factor for glioma.

Glucose-albumin ratio as new biomarker for predicting mortality after intracerebral hemorrhage.

OBJECTIVE: This study aims to evaluate the prognostic value of blood-based biomarkers and their combinations, in particular the glucose-albumin ratio (GAR), in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: A retrospective observational study on 2481 patients from one hospital was conducted and validated with 602 patients from another. We assessed 15 biomarkers and focused on GAR to elucidate its prognostic and predictive value for outcomes in both cohorts. The primary outcome was mortality at 90 days. RESULTS: The ratio of glucose-to-albumin, defined as GAR, was superior to other biomarkers for predicting mortality at 90 days in patients with ICH (AUC = 0.72). High GAR (using the best cutoff value of 0.19) was associated with increased mortality at 90 days (odds ratios of 1.90, 95% CI 1.54-2.34) and all-cause mortality in the first 3 years after admission (hazard ratio of 1.62, 95% CI 1.42-1.86). All aforementioned findings for GAR were successfully validated in an external independent cohort. CONCLUSIONS: GAR may be a valuable biomarker for predicting the mortality of patients with ICH.

Primary angioleiomyoma of right frontal cranial base with intracranial and extracranial communication.

INTRODUCTION: Primary intracranial angioleiomyoma (ALM) is quite rare and ALM of the adolescent is even rarer. To date, only three cases of adolescents have been reported. MATERIAL AND METHODS: We carefully introduced a new location of intracranial ALM in an adolescent. The clinical, pathological and imaging features of intracranial ALM were described in detail and published literature was reviewed. RESULTS: To our best knowledge, we presented the fourth primary intracranial ALM of adolescent and the first ALM of the right frontal cranial base with intracranial and extracranial communication. We not only summarize the generalities of ALM but also illustrate the difference between adult and adolescent ALM in the aspects of gender and age predominance, etiology, common location and pathologic subtype. CONCLUSIONS: We reported the first ALM of the right frontal cranial base with intracranial and extracranial communication of an adolescent with a good prognosis. We also summarize the generalities of ALM and illustrate the difference between adult and adolescent ALM. Future investigation of control study with large patient cohorts is needed for both adult and adolescent ALM to compare the difference between them.

Elevated TYROBP expression predicts poor prognosis and high tumor immune infiltration in patients with low-grade glioma.

BACKGROUND: Tyrosine protein tyrosine kinase binding protein (TYROBP) binds non-covalently to activated receptors on the surface of various immune cells, and mediates signal transduction and cellular activation. It is dysregulated in various malignancies, although little is known regarding its role in low-grade glioma. The aim of this study is to explore the clinicopathological significance, prognostic value and immune signature of TYROBP expression in low-grade glioma (LGG). METHODS: The differentially expressed genes (DEGs) between glioma samples and normal tissues were identified from two GEO microarray datasets using the limma package. The DEGs overlapping across both datasets were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. STRING database was used to establish the protein-protein interaction (PPI) of the DEGs. The PPI network was visualized by Cytoscape and cytoHubba, and the core module and hub genes were identified. The expression profile of TYROBP and patient survival were validated in the Oncomine, GEPIA2 and CGGA databases. The correlation between TYROBP expression and the clinicopathologic characteristics were evaluated. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were performed by R based on the LGG data from TCGA. The TIMER2.0 database was used to determine the correlation between TYROBP expression and tumor immune infiltrating cells in the LGG patients. Univariate and multivariate Cox regression analyses were performed to determine the prognostic impact of clinicopathological factors via TCGA database. RESULTS: Sixty-two overlapping DEGs were identified in the 2 datasets, and were mainly enriched in the response to wounding, focal adhesion, GTPase activity and Parkinson disease pathways. TYROBP was identified through the PPI network and cytoHubba. TYROBP expression levels were significantly higher in the LGG tissues compared to the normal tissues, and was associated with worse prognosis and poor clinicopathological parameters. In addition, GSEA showed that TYROBP was positively correlated to neutrophil chemotaxis, macrophage activation, chemokine signaling pathway, JAK-STAT signaling pathway, and negatively associated with gamma aminobutyric acid signaling pathway, neurotransmitter transport, neuroactive ligand receptor intersection etc. TIMER2.0 and ssGSEA showed that TYROBP expression was significantly associated with the infiltration of neutrophils, macrophages, myeloid dendritic cells and monocytes. The infiltration of the M2 phenotype macrophages, cancer-associated fibroblasts and myeloid dendritic cells correlated to worse prognosis in LGG patients. Finally, multivariate analysis showed that elevated TYROBP expression is an independent risk factor for LGG. CONCLUSION: TYROBP is dysregulated in LGG and correlates with immune infiltration. It is a potential therapeutic target and prognostic marker for LGG.

Clemastine promotes recovery of neural function and suppresses neuronal apoptosis by restoring balance of pro-inflammatory mediators in an experimental model of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) represents a common acute cerebrovascular event that imparts high rates of disability. The microglia-mediated inflammatory response is a critical factor in determining cerebral damage post-ICH. Clemastine (CLM) is a histamine receptor H1 (HRH1) antagonist that has been shown to modulate the inflammatory response. However, the effects of CLM on ICH and the underlying mechanism remain to be determined. This investigation reveals that CLM resulted in reduction of cerebral hematoma volume, decreased cerebral edema and lower rates of neuronal apoptosis as well as improved behavioral scores in an acute ICH murine model. CLM treatment was noted to decrease pro-inflammatory effectors and increased anti-inflammatory effectors post-ICH. In addition, CLM reduced the deleterious effects of activated microglia on neurons in a transwell co-culture system. Our findings show that CLM likely mediates its therapeutic effect through inhibition of microglia-induced inflammatory response and apoptosis, thereby enhancing restoration of neuronal function.

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma.

JNK activity has been implicated in the malignant proliferation, invasion and drug-resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c-Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel-like factor-5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated-SP1 and acetylated-KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant-negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c-Jun activities was involved in the tumor-growth inhibitory effects induced by LMK235 in U87-xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c-Jun signaling-mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c-Jun signaling in GCs.

Neuritin attenuates early brain injury in rats after experimental subarachnoid hemorrhage.

OBJECTIVES: Early brain injury (EBI) is central to the pathological progress of subarachnoid hemorrhage (SAH). In this study, we determined if neuritin protects the brain against EBI in rats and discussed the role of apoptosis pathway mediated by endoplasmic reticulum stress in this neuroprotective route. METHODS: A total of 96 male Sprague Dawley rats were divided into control, sham, SAH and SAH + neuritin groups. The rat SAH model was induced by injection 0.3 mL of nonheparinized arterial blood into the prechiasmatic cistern. Mortality assay, neurological scores, brain water content measurement, Evans blue dye assay, TUNEL stain assay and Western blot analysis were performed. RESULTS: Neuritin significantly improved the neurological scores, brain water content, blood-brain barrier (BBB) and apoptosis compared with the control and sham groups within 24 h after SAH. TUNEL staining assay results demonstrated that apoptosis was ameliorated, MMP-9 expression was reduced, whereas GRP78, CHOP, caspase-12 and ASK1 levels were markedly preserved after neuritin application. CONCLUSIONS: Our study demonstrated that neuritin plays a neuroprotective role on EBI after SAH by attenuating BBB disruption, brain edema and apoptosis.

Correlation between nitric oxide and early brain injury after subarachnoid hemorrhage.

BACKGROUND: Early brain injury (EBI) has recently been identified as the main factor of poor prognosis for subarachnoid hemorrhage (SAH), and apoptosis has an important function in EBI. Although nitric oxide (NO) and caspase-12, a specific molecule related to endoplasmic reticulum (ER) stress-induced apoptosis signaling pathways, are involved in brain injury after SAH, the relationship between NO and ER stress has not been reported yet. We examined the NO and caspase-12 contents and investigated the relationship between NO and ER stress-induced apoptosis. METHODS: Sprague-Dawley rats (n = 90), weighing 300 g to 350 g, were used for the SAH model. SAH was induced in rats by blood injection into the prechiasmatic cistern. NO, caspase-12, and apoptosis were measured by nitrate reductase method, real-time polymerase chain reaction, and terminal deoxynucleotidy1 transferase-mediated dUTP nick-end labeling staining, respectively, at different time points after SAH. Pearson correlation coefficients were used to examine correlation. RESULTS: NO level of cerebrospinal fluid significantly increased in the SAH group at 3, 24, 48, and 72 h compared with other groups. Caspase-12 also significantly increased at 1, 3, 6, 24, 48, and 72 h. Cell apoptosis significantly increased at 24, 48, and 72 h. A significant correlation between the number of apoptotic neurons and caspase-12 was found. NO was also correlated with caspase-12. CONCLUSIONS: Our results suggest that NO is involved in the pathophysiological events of EBI after SAH by increasing caspase-12, which results in neuronal apoptosis.

Microglia-mediated pericytes migration and fibroblast transition via S1P/S1P3/YAP signaling pathway after spinal cord injury.

Platelet-derived growth factor receptor ß positive (PDGFRß+) pericytes detach from the microvascular wall and migrate into the injury center following spinal cord injury (SCI), which has been widely regarded as the main source of fibrotic scar, but the mechanism of migration and fibroblast transition remains elusive. Here we show the associated spatiotemporal distribution between microglia and pericytes at three and seven days post-injury (dpi). The increased expression of Sphingosine kinase-1 (SPHK1) in microglia significantly raised the concentration of Sphingosine-1-phosphate (S1P) in the spinal cord, which promotes migration and fibroblast transition of pericyte. In vitro experiments, we found the elevated Sphingosine 1-phosphate receptor 3 (S1P3), the S1P/S1PR3 axis inhibited the phosphorylation of YAP and promoted its nuclear translocation, which contributed to the formation of alpha-smooth muscle actin (α-SMA) and collagen type I (COL1) protein, This process can be blocked by an S1P3 specific inhibitor TY52156 in vitro. The S1P/S1P3/YAP pathway might be a potential target for treatment in SCI.

Interfacial behaviour of short-chain fluorocarbon surfactants at the n-hexane/water interface: a molecular dynamics study.

The utilization of long-chain fluorocarbon surfactants is restricted due to environmental regulations, prompting a shift in the focus of research towards short-chain fluorocarbon surfactants. The present study employs molecular dynamics techniques to model the behaviour of potassium perfluorobutylsulfonate (PFBS) at the n-hexane/water interface, aiming to investigate the efficacy of short-chain fluorocarbon surfactants in enhancing oil recovery. The findings suggest that ionized PFBS- has the ability to autonomously migrate to the oil/water interface, forming a layered thin film, with the sulfonic acid group being submerged in water, while the fluorocarbon chain is oriented towards the oil phase. This phenomenon aligns with the fundamental concept of surfactants in reducing interfacial tension between oil and water. The spontaneous dispersion process is supported by changes in the number of water molecules surrounding each PFBS- anion, as is well indicated by the number density distribution within the simulation box. Based on the analysis conducted by IGMH (Independent Gradient Model based on Hirshfeld partition), it was determined that sulfonic acid molecules are capable of forming hydrogen bonds with water molecules, whereas the interaction between fluorocarbon chains and the oil phase is predominantly characterized by weak van der Waals interactions.

Association between 23 drugs and Parkinson's disease: A two-sample Mendelian randomization study.

BACKGROUND: Parkinson's disease (PD) is a common degenerative nervous system disease. At present, there are certain limitations in various treatment options aimed at preventing or delaying the progression of PD. Therefore, the exploration of new drugs for PD is beneficial. Mendelian randomization (MR) analysis can be used to explore the association between drugs and diseases. In this study, MR analysis was adopted to investigate the causal relationship between 23 drugs and PD. These drugs have been approved for the treatment of different diseases, such as salicylic acid and derivatives (collectively called salicylates, e.g., aspirin, used for fever and pain relief), antithrombotic agents (e.g., warfarin, aspirin, used for preventing thrombotic events). METHODS: The GWAS data for the 23 drugs were obtained from the UK Biobank (UKB) project, while the GWAS data for PD were sourced from FinnGen. Single-Nucleotide Polymorphisms (SNPs) were selected as instrumental variables (IVs). We first performed a series of quality control steps (including MR-PRESSO) to select the appropriate SNPs. Two-sample MR analysis was performed using five different methods, including inverse variance weighting (IVW) with random-effects model, weighted median, MR-Egger, simple model, and weighted model. At the same time, sensitivity analysis was carried out using the MR-Egger and Cochran's Q test to ensure the authenticity and reliability of the results. RESULTS: In MR-PRESSO, salicylates and antithrombotic agents showed statistically significant associations with PD, respectively. In the main MR analysis (IVW), there was a negative causal relationship between salicylates and PD (OR = 0.73, 95% CI = 0.54-0.98, p = .039). Similarly, there was a negative causal relationship between antithrombotic agents and PD (OR = 0.70, 95%CI = 0.52-0.96, p = .027). No statistically significant association was found between the remaining 21 drugs and PD. CONCLUSION: This MR study demonstrated that salicylates and antithrombotic agents can reduce the risk of PD, thus providing a novel avenue for future drug exploration in PD.

Mendelian Randomization Analyses Accounting for Causal Effect of COVID-19 on Brain Imaging-Derived Phenotypes.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has been a major challenge to global health and a financial burden. Little is known regarding the possible causal effects of COVID-19 on the macro- and micro-structures of the human brain. OBJECTIVE: To determine the causal links between susceptibility, hospitalization, and the severity of COVID-19 and brain imaging-derived phenotypes (IDPs). METHODS: Mendelian randomization (MR) analyses were performed to investigate the causal effect of three COVID-19 exposures (SARS-CoV-2 infection, hospitalized COVID-19, and critical COVID-19) on brain structure employing summary datasets of genome-wide association studies. RESULTS: In terms of cortical phenotypes, hospitalization due to COVID-19 was associated with a global decrease in the surface area (SA) of the cortex structure (ß= -624.77, 95% CI: -1227.88 to -21.66, p = 0.042). At the regional level, SARS-CoV-2 infection was found to have a nominally causal effect on the thickness (TH) of the postcentral region (ß= -0.004, 95% CI: -0.007 to -0.001, p = 0.01), as well as eight other IDPs. Hospitalized COVID-19 has a nominally causal relationship with TH of postcentral (ß= -0.004, 95% CI: -0.007 to -0.001, p = 0.01) and other 6 IDPs. The nominally causal effects of critical COVID-19 on TH of medial orbitofrontal (ß=0.004, 95% CI: 0.001to 0.007, p = 0.004) and other 7 IDPs were revealed. CONCLUSIONS: Our study provides compelling genetic evidence supporting causal relationships between three COVID-19 traits and brain IDPs. This discovery holds promise for enhancing predictions and interventions in brain imaging.

PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B.

PRMT6, a type I arginine methyltransferase, di-methylates the arginine residues of both histones and non-histones asymmetrically. Increasing evidence indicates that PRMT6 plays a tumor mediator involved in human malignancies. Here, we aim to uncover the essential role and underlying mechanisms of PRMT6 in promoting glioblastoma (GBM) proliferation. Investigation of PRMT6 expression in glioma tissues demonstrated that PRMT6 is overexpressed, and elevated expression of PRMT6 is negatively correlated with poor prognosis in glioma/GBM patients. Silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0/G1 phase, while overexpressing PRMT6 had opposite results. Further, we found that PRMT6 attenuates the protein stability of CDKN1B by promoting its degradation. Subsequent mechanistic investigations showed that PRMT6 maintains the transcription of CDC20 by activating histone methylation mark (H3R2me2a), and CDC20 interacts with and destabilizes CDKN1B. Rescue experimental results confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation via CDC20. We also verified that the PRMT6 inhibitor (EPZ020411) could attenuate the proliferative effect of GBM cells. Our findings illustrate that PRMT6, an epigenetic mediator, promotes CDC20 transcription via H3R2me2a to mediate the degradation of CDKN1B to facilitate GBM progression. Targeting PRMT6-CDC20-CDKN1B axis might be a promising therapeutic strategy for GBM.

Comprehensive analysis of the prognostic and immunological signature of eight Tripartitemotif (TRIM) family molecules in human gliomas.

BACKGROUND: TRIM family molecules have been identified as being involved in the tumor progression of various cancer types. Increasingly, experimental evidence indicates that some of TRIM family molecules are implicated in glioma tumorigenesis. However, the diverse genomic changes, prognostic values and immunological landscapes of TRIM family of molecules have yet to be fully determined in glioma. METHODS: In our study, employing the comprehensive bioinformatics tools, we evaluated the unique functions of 8 TRIM members including TRIM5/17/21/22/24/28/34/47 in gliomas. RESULTS: The expression levels of 7 TRIM members (TRIM5/21/22/24/28/34/47) were higher in glioma as well as its diverse cancer subtypes than in normal tissues, whereas the expression level of TRIM17 was the opposite, lower in the former than in the latter. In addition, survival analysis revealed that the high expression profiles of TRIM5/21/22/24/28/34/47 were associated with poor overall survival (OS), disease-specific survival (DSS) and progress-free interval (PFI) in glioma patients, whereas TRIM17 displayed adverse outcomes. Moreover, the 8 TRIM molecules expression as well as methylation profiles remarkably correlated with different WHO grades. And genetic alterations, including mutations and copy number alterations (CNAs), in the TRIM family were correlated with longer OS, DSS and progress-free survival (PFS) in glioma patients. Furthermore, through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results of these 8 molecules and their related genes, we found that these molecules may change the immune infiltration of the tumor microenvironment and regulate the expression of immune checkpoint molecules (ICMs), affecting the occurrence and development of gliomas. The correlation analyses between the 8 TRIM molecules and TMB (tumor mutational burden)/MSI (microsatellite instability)/ICMs discovered that as the expression level of TRIM5/21/22/24/28/34/47 increased, the TMB score also increased significantly, while TRIM17 showed an opposite outcome. Further, a 6-gene signature (TRIM 5/17/21/28/34/47) for predicting overall survival (OS) in gliomas was built by using the least absolute shrinkage and selection operator (LASSO) regression, and the survival and time-dependent ROC analyses all were found to perform well in testing and validation cohorts. Results of multivariate COX regression analysis showed that TRIM5/28 are both expected to become independent risk predictors to guide clinical treatment. CONCLUSION: In general, the results indicate that TRIM5/17/21/22/24/28/34/47 might exert a crucial influence on gliomas tumorigenesis and might be putative prognostic markers and therapeutic targets for glioma patients.

GPR37 expression as a prognostic marker in gliomas: a bioinformatics-based analysis.

BACKGROUND: Gliomas are the most frequently diagnosed primary brain tumors, and are associated with multiple molecular aberrations during their development and progression. GPR37 is an orphan G protein-coupled receptor (GPCR) that is implicated in different physiological pathways in the brain, and has been linked to various malignancies. The aim of this study was to explore the relationship between GPR37 gene expression and the clinicopathological factors, patient prognosis, tumor-infiltrating immune cell signature GSEA and methylation levels in glioma. METHODS: We explored the diagnostic value, clinical relevance, and molecular function of GPR37 in glioma using TCGA, STRING, cBioPortal, Tumor Immunity Estimation Resource (TIMER) database and MethSurv databases. Besides, the "ssGSEA" algorithm was conducted to estimate immune cells infiltration abundance, with 'ggplot2' package visualizing the results. Immunohistochemical staining of clinical samples were used to verify the speculations of bioinformatics analysis. RESULTS: GPR37 expression was significantly higher in the glioma tissues compared to the normal brain tissues, and was linked to poor prognosis. Functional annotation of GPR37 showed enrichment of ether lipid metabolism, fat digestion and absorption, and histidine metabolism. In addition, GSEA showed that GPR37 was positively correlated to the positive regulation of macrophage derived foam cell differentiation, negative regulation of T cell receptor signaling pathway, neuroactive ligand receptor interaction, calcium signaling pathway, and negatively associated with immunoglobulin complex, immunoglobulin complex circulating, ribosome and spliceosome mediated by circulating immunoglobulin etc. TIMER2.0 and ssGSEA showed that GPR37 expression was significantly associated with the infiltration of T cells, CD8 T cell, eosinophils, macrophages, neutrophils, NK CD56dim cells, NK cells, plasmacytoid DCs (pDCs), T helper cells and T effector memory (Tem) cells. In addition, high GPR37 expression was positively correlated with increased infiltration of M2 macrophages, which in turn was associated with poor prognosis. Furthermore, GPR37 was positively correlated with various immune checkpoints (ICPs). Finally, hypomethylation of the GPR37 promoter was associated with its high expression levels and poor prognosis in glioma. CONCLUSION: GPR37 had diagnostic and prognostic value in glioma. The possible biological mechanisms of GPR37 provide novel insights into the clinical diagnosis and treatment of glioma.

Possible Mechanisms Underlying the Effects of Glucagon-Like Peptide-1 Receptor Agonist on Cocaine Use Disorder.

Cocaine use disorder (CUD) is a major public health challenge with a high relapse rate and lack of effective pharmacotherapies; therefore, there is a substantial need to identify novel medications to treat this epidemic. Since the advent of glucagon-like peptide-1 (GLP-1) receptors (GLP-1Rs) agonists (GLP-1RAs), their potential has been extensively explored and expanded. In this review, we first summarized the biological effects of GLP-1, GLP-1Rs, and GLP-1RAs. Subsequently, the recent literature examining the behavioral effects and the possible pharmacological mechanisms of GLP-1RAs on CUD was reviewed. Increasing preclinical evidence suggests that GLP-1RAs are promising in regulating dopamine release, dopamine transporter (DAT) surface expression and function, mesolimbic reward system and GABAergic neurons, and maladaptive behaviors in animal models of self-administration and conditioned place preference. In addition, the emerging role of GLP-1RAs in inhibiting inflammatory cytokines was reported. These findings indicate that GLP-1RAs perform essential functions in the modulation of cocaine-seeking and cocaine-taking behaviors likely through multifaceted mechanisms. Although the current preclinical evidence provides convincing evidence to support GLP-1RA as a promising pharmacotherapy for CUD, other questions concerning clinical availability, impact and specific mechanisms remain to be addressed in further studies.

Neural stem cell­derived exosomes transfer miR­124­3p into cells to inhibit glioma growth by targeting FLOT2.

Currently, exosomes (EXOs) are being explored as novel drug delivery carriers with greater advantages, including crossing the blood­brain­barrier and loading drugs. The present study utilized EXOs derived from neural stem cells (NSCs) for the delivery of molecular drugs to treat gliomas. miR­124­3p was selected according to previous studies by the authors, and the effects of the delivery of miR­124­3p to glioma cells by NSC­EXOs in vitro and in vivo were evaluated. It was found that NSC­EXOs successfully delivered miR­124­3p into glioma cells, and NSC­EXOs loaded with miR­124­3p significantly inhibited glioma cell proliferation, invasion and migration. Furthermore, the delivery of miR­124­3p by NSC­EXOs suppressed flotillin 2 (FLOT2) expression by specifically binding to the 3' untranslated region of the FLOT2 gene in gliomas; subsequently, AKT1 was found to be associated with the EXO­miR­124­3p/FLOT2 pathway. Moreover, the therapeutic effects of the delivery of miR­124­3p by NSC­EXOs were confirmed in a mouse tumor xenograft model of glioma. Thus, bio­carrier NSC­EXOs loaded with miR­124­3p suppressed glioma growth via the EXO­miR­124­3p/FLOT2/AKT1 pathway. On the whole, the present study provides insight into stem cell­free molecular­targeted therapy based on bio­carrier NSC­EXOs and provides a potential strategy for the treatment of glioma.

3BDO inhibits the proliferation, epithelial-mesenchymal transition (EMT), and stemness via suppressing survivin in human glioblastoma cells.

Background: Glioblastoma (GBM) is a tumor of the central nervous system with an extremely poor prognosis. Stemness and EMT play important roles in GBM progression. 3-benzyl-5-((2-nitrophenoxy) methyl) dihydrofuran-2(3H)-one (3BDO), an autophagy inhibitor, has been reported to exert anti-cancer activities on lung carcinoma. However, the effects of 3BDO on GBM remain unknown. Therefore, the purpose of this study was to explore the effects of 3BDO on GBM and to investigate the underlying molecular mechanisms. Method: CCK-8 experiments and clone formation assays were conducted to determine the level of cell proliferation. Transwell assay was conducted to examine cell migration and invasion abilities. Western blotting and immunofluorescence staining were used to analyze protein expression levels. A xenograft mouse model was used to evaluate the effect of 3BDO in vivo. Results: We found that 3BDO inhibited U87 and U251 cell proliferation in a dose-dependent manner. Additionally, 3BDO decreased the degree of sphere formation and levels of stemness markers (sox2, nestin, and CD133) in GSCs. 3BDO also inhibited migration and invasion abilities and suppressed EMT markers (N-cadherin, vimentin, and snail) in GBM cells. Moreover, we found that 3BDO downregulated the expression of survivin in both GBM cells (U87, U251) and GSCs. Furthermore, overexpression of survivin decreased the therapeutic effect of 3BDO on EMT, invasion, migration, and proliferation of GBM cells, as well as decreased the stemness of GSCs. Finally, we demonstrated that 3BDO could inhibit tumor growth in a tumor xenograft mouse model constructed using U87 cells. Similar to the in vitro findings, 3BDO decreased the expression of survivin, EMT makers, and the degree of stemness in vivo. Conclusions: Our results demonstrate that 3BDO can repress GBM both in vitro and in vivo via downregulating survivin-mediated stemness and EMT.