Parkinson’s disease is a progressive neurodegenerative disease characterized by degeneration of dopaminergic neurons in the substantia nigra, reduced striatal dopamine levels, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Delicaflavone, a natural biflavonoid, possesses antioxidant, anti-inflammatory, and neuroprotective effects; however, its neuroprotective potential against rotenone-induced Parkinson’s disease warrants exploration. To induce Parkinson’s disease in rats, 0.5 mg/kg of rotenone was administered subcutaneously for 28 days, and delicaflavone was administered orally at different doses (10, 20, and 40 mg/kg). In addition to behavioral tests, neurochemical parameters, oxidative stress, mitochondrial function, inflammatory cytokines, and apoptosis were assessed. Delicaflavone treatment increased square-crossed activity and rotarod performance and reduced catalepsy time. It was also found to positively affect neurochemical parameters, activate antioxidant enzymes, and support neuronal survival by inhibiting apoptosis. In addition to suppressing inflammatory parameters, it reduced pro-inflammatory cytokines and increased anti-inflammatory cytokines. Delicaflavone ameliorates rotenone-induced Parkinson's disease in rats via alteration of Nrf2/HO-1, NF-κB mediated inflammatory pathway and PI3K/Akt/mTOR survival signaling pathway.

Neuroinflammation and macrophage polarization play important roles in secondary injury and functional recovery after spinal cord injury (SCI). GP130, the common signal-transducing receptor subunit of the IL-6 cytokine family, is closely associated with JAK/STAT3-mediated inflammatory signaling. However, its role in macrophage polarization after SCI remains unclear. This study investigated whether GP130 inhibition regulates macrophage polarization and improves functional recovery after SCI. A rat model of T10 spinal cord compression injury was established using a standardized microvascular clip compression method. The GP130 inhibitor SC144 was administered after SCI. Functional recovery was evaluated using BBB scoring and inclined plane tests. Histopathological, ultrastructural, immunofluorescence, flow cytometry, qRT-PCR, western blotting, ELISA, and single-cell RNA sequencing analyses were performed to evaluate tissue injury, inflammatory signaling, and macrophage polarization. Primary bone marrow-derived macrophages were further used to assess the direct effects of GP130 knockdown or pharmacological inhibition on macrophage phenotype in vitro. SCI induced severe locomotor impairment, tissue disruption, ultrastructural damage, and activation of GP130-related inflammatory signaling. SC144 treatment improved functional recovery, reduced inflammatory cytokine expression, and attenuated downstream STAT3 activation. Single-cell RNA sequencing revealed a prominent monocyte/macrophage-related myeloid-cell response after SCI and transcriptional heterogeneity within the myeloid compartment. Immunofluorescence and flow cytometry showed that GP130 inhibition reduced M1-like marker expression and promoted M2-like marker expression in vivo. In primary macrophages, GP130-siRNA and SC144 similarly suppressed M1-like pro-inflammatory marker expression and enhanced M2-like reparative marker expression. GP130 inhibition modulates macrophage polarization and promotes functional recovery after T10 spinal cord compression injury. These findings suggest that GP130-related inflammatory signaling may be a potential therapeutic target for regulating macrophage-mediated neuroinflammation after SCI.

5-Fluorouracil (5-FU) is a primary chemotherapeutic agent for gastrointestinal cancers, known to improve survival but also cause significant intestinal damage, affecting patient quality of life. This study investigated the IL-23-IL-22 axis’s role in moderating 5-FU-induced intestinal damage. We analyzed paracancerous tissue damage in colon cancer patients with different Tumor Regression Grade (TRG) and found a direct correlation between TRG and tissue damage severity, indicating that higher chemotherapy effectiveness is linked to increased tissue damage. In a 5-FU-treated mouse model, we observed severe intestinal damage and a reduction in proliferative cells. Transcriptome sequencing and immunofluorescence revealed that myeloid cells in damaged tissues produced IL-23, which activated ILC3s to secrete IL-22, promoting tissue repair and homeostasis. IL-22 supplementation in deficient mice significantly mitigated damage, underscoring the IL-22/IL-23 axis’s potential as a therapeutic target to reduce chemotherapy-induced damage and enhance recovery. This research advances understanding of the biochemical responses to chemotherapy and suggests new avenues for developing therapies to maintain intestinal integrity during cancer treatment.

Glioma is highly prone to recurrence post-surgery, and effective postoperative adjuvant therapeutic agents are lacking. Developing drugs that can efficiently cross the blood-brain barrier and target postoperative glioma is crucial for overcoming the challenges associated with the treatment of glioma. Nanomaterials modified with cell membranes have shown promise in crossing the blood-brain barrier for the treatment of glioma, but the origin of the cells as well as their heterogeneity are the current bottlenecks of this strategy. Previously, we demonstrated that immortalized mesenchymal stem cell membranes retain natural tumor-homing capability and offer a stable, scalable, and uniform source for sustained tumor targeting. Here, we proposed the use of immortalized mesenchymal stem cell plasma membranes with tumor-homing properties as carriers to develop biomimetic nanoparticles loaded with shCD73 and doxorubicin, named Lipo-PM@shCD73@DOX. By harnessing the tumor-homing factors, the developed biomimetic nanoparticles effectively crossed the blood-brain barrier and targeted postoperative residual glioma tissues to achieve postoperative gene therapy and chemotherapy for glioma. The present study demonstrates the therapeutic efficacy of biomimetic nanoparticles in delaying glioma progression by inhibiting cellular proliferation and inducing apoptosis. Additionally, we confirmed the in vitro and in vivo biosafety of biomimetic nanoparticles. In conclusion, this study overcame the problems of insufficient cell source and cellular heterogeneity in previous mimetic strategies and developed anti-glioma targeting drug biomimetic nanoparticles that efficiently cross the blood-brain barrier. It constitutes a novel anti-glioma adjuvant that enhances postoperative therapy and delays recurrence.

Alzheimer’s disease (AD) has a significant impact on an individual’s health and places a heavy burden on society. Studies have emphasized the importance of microglia in the progression and development of AD. Interferon responses and Interferon-stimulated genes (ISGs) significantly function in neuroinflammatory and neurodegenerative diseases involving AD. Therefore, further exploration of the relationship among microglia, ISGs, and neuroinflammation in AD is warranted. Microglia datasets from the GEO database were retrieved, along with additional microglia RNA-seq data from laboratory mice. Weighted Correlation Network Analysis was used on the training dataset to identify gene co-expression networks. Genes from the black module were intersected with interferon-stimulated genes, and differentially expressed genes (DEGs) were identified. Machine learning algorithms were applied to DEGs, and genes selected by both methods were identified as hub genes, with ROC curves used to evaluate their diagnostic accuracy. Gene Set Enrichment Analysis was performed to reveal functional pathways closely relating to hub genes. Microglia cells were transfected with siRNAs targeting Oas1g and STAT1. Total RNA from microglia cells and mouse brain tissues was extracted, reverse-transcribed, and analyzed via qRT-PCR. Proteins were extracted from cells, quantified, separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies. Microglia cells were fixed, permeabilized, blocked, and stained with antibodies for STAT1, then visualized and photographed. Bioinformatics and machine learning algorithms revealed that Oas1g was identified as a hub gene, with an AUC of 0.812. Enrichment Analysis revealed that Oas1g is closely associated with interferon-related pathways. Expression of Oas1g was validated in AD mouse models, where it was significantly upregulated after microglial activation. Knockdown experiments suggested siOas1g attenuated the effect of siSTAT1, and the expressions of STAT1 and p-STAT1 were elevated. siOas1g could reverse the effect of siSTAT1, indicating that Oas1g potentially regulates the ISGs through the STAT1 pathway. We demonstrated that Oas1g was identified as a hub ISG in AD and can downregulate the activation of IFN-β and STAT1, reducing the expression of ISGs in neuroinflammation. Oas1g might potentially be a beneficial candidate for both prevention and treatment of AD.

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.

JOURNAL/nrgr/04.03/01300535-202504000-00032/figure1/v/2024-07-06T104127Z/r/image-tiff Microglia, the primary immune cells within the brain, have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system, including Parkinson's disease. Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity, but also exhibit remarkable anti-inflammatory properties. However, the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood. In this study, we developed perfluoropentane-based oxygen-loaded nanodroplets (PFP-OLNDs) and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo, and suppressed microglial activation in a mouse model of Parkinson's disease. Microglial suppression led to a reduction in the inflammatory response, oxidative stress, and cell migration capacity in vitro. Consequently, the neurotoxic effects were mitigated, which alleviated neuronal degeneration. Additionally, ultrahigh-performance liquid chromatography-tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming. We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1α pathway. Collectively, our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

Invasion and migration are the key hallmarks of cancer, and aggressive growth is a major factor contributing to treatment failure and poor prognosis in glioblastoma. Protein arginine methyltransferase 6 (PRMT6), as an epigenetic regulator, has been confirmed to promote the malignant proliferation of glioblastoma cells in previous studies. However, the effects of PRMT6 on glioblastoma cell invasion and migration and its underlying mechanisms remain elusive. Here, we report that PRMT6 functions as a driver element for tumor cell invasion and migration in glioblastoma. Bioinformatics analysis and glioma sample detection results demonstrated that PRMT6 is highly expressed in mesenchymal subtype or invasive gliomas, and is significantly negatively correlated with their prognosis. Inhibition of PRMT6 (using PRMT6 shRNA or inhibitor EPZ020411) reduces glioblastoma cell invasion and migration in vitro, whereas overexpression of PRMT6 produces opposite effects. Then, we identified that PRMT6 maintains the protein stability of EZH2 by inhibiting the degradation of EZH2 protein, thereby mediating the invasion and migration of glioblastoma cells. Further mechanistic investigations found that PRMT6 inhibits the transcription of TRAF6 by activating the histone methylation mark (H3R2me2a), and reducing the interaction between TRAF6 and EZH2 to enhance the protein stability of EZH2 in glioblastoma cells. Xenograft tumor assay and HE staining results showed that the expression of PRMT6 could promote the invasion of glioblastoma cells in vivo, the immunohistochemical staining results of mouse brain tissue tumor sections also confirmed the regulatory relationship between PRMT6, TRAF6, and EZH2. Our findings illustrate that PRMT6 suppresses TRAF6 transcription via H3R2me2a to enhance the protein stability of EZH2 to facilitate glioblastoma cell invasion and migration. Blocking the PRMT6-TRAF6-EZH2 axis is a promising strategy for inhibiting glioblastoma cell invasion and migration.

Platelet-derived growth factor receptor β positive (PDGFRβ+) 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.

To investigate the correlation between neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in neurosurgery and their impact on the occurrence and prognosis of acute traumatic progressive hemorrhagic brain injury (PHI) among traumatic brain injury patients. A retrospective analysis encompassed 220 traumatic brain injury patients treated between 2019 and 2022. Patients were categorized into two groups: those experiencing progressive hemorrhagic brain injury (PHI) and those without PHI. The levels of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were examined within each group. Within the PHI cohort, patients were further stratified based on their Glasgow Outcome Scale (GOS) scores into good and poor prognosis groups, with corresponding observations of NLR and PLR levels. Logistic regression was used to identify factors influencing both the occurrence and poor prognosis of PHI. Additionally, Pearson’s linear analysis was utilized to investigate the correlation between serum NLR and PLR levels among PHI patients and the occurrence and prognosis of the disease. We found no statistically significant differences were observed between the PHI group and the non-PHI group in terms of gender, age, history of hypertension, smoking history, types of intracranial lesions, heart rate (HR), Injury Severity Score (ISS), Abbreviated Injury Scale (AIS), pupillary reflex status, mean arterial pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP) (P > 0.05). However, there were significant differences in GCS scores, PaO2, and Hb levels (P < 0.05). Furthermore, the non-PHI group had higher NLR and PLR than the PHI group (P < 0.05). Multiple Logistic regression analysis showed that neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) were independent risk factors for progressive hemorrhagic brain injury (PHI) in TBI patients (P < 0.05). Kendall analysis showed that there was a significant negative correlation between GOS score PHI (r=-0.458, P = 0.000). Additionally, Pearson linear correlation analysis showed a notable positive correlation between serum NLR and PLR levels in PHI patients and the occurrence of the disease (r = 0.377, P = 0.000). Evaluation based on the Glasgow Outcome Scale (GOS) score demonstrated no significant differences in gender, age, history of hypertension, smoking, types of intracranial lesions, heart rate (HR), Injury Severity Score (ISS), Abbreviated Injury Scale (AIS), pupillary reflex status, mean arterial pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP) between the good and poor prognosis groups but significant differences in GCS score, PaO2, and Hb levels (P < 0.05). In addition, the NLR and PLR of the poor prognosis group were higher than those of the good prognosis group (P < 0.05). Multiple Logistic regression analysis showed that NLR and PLR were independent risk factors for poor prognosis in PHI patients (P < 0.05). Pearson linear correlation analysis showed a statistically significant positive correlation between serum NLR and PLR levels in PHI patients and the likelihood of poor prognosis (r = 0.307, P = 0.000). Elevated NLR to PLR ratios in TBI patients significantly elevate the risk of PHI occurrence. Moreover, higher NLR to PLR ratios correlate with poorer prognostic outcomes among PHI patients.

The role of SLC3A2, a gene implicated in disulfidptosis, has not been characterized in gliomas. This study aims to clarify the prognostic value of SLC3A2 and its influence on glioma. We evaluated the expression of SLC3A2 and its prognostic importance in gliomas using publicly accessible databases and our clinical glioma samples and with reliance on Meta and Cox regression analysis approaches. Functional enrichment analyses were performed to explore SLC3A2's function. Immune infiltration was evaluated using CIBERSORT, ssGSEA, and single-cell sequencing data. Additionally, Tumor immune dysfunction and exclusion (TIDE) and epithelial-mesenchymal transition scores were determined. CCK8, colony formation, migration, and invasion assays were utilized in vitro, and an orthotopic glioma xenograft model was employed in vivo, to investigate the role of SLC3A2 in gliomas. Bioinformatics analyses indicated high SLC3A2 expression correlates with adverse clinicopathological features and poor patient prognosis. Upregulated SLC3A2 influenced the tumor microenvironment by altering immune cell infiltration, particularly of macrophages, and tumor migration and invasion. SLC3A2 expression positively correlated with immune therapy indicators, including immune checkpoints and TIDE. Elevated SLC3A2 was revealed as an independent risk element for poor glioma prognosis through Cox regression analyses. In vitro experiments showed that reduced SLC3A2 expression decreased cell proliferation, migration, and invasion. In vivo, knockdown of SLC3A2 led to a reduction in tumor volume and prolonged survival in tumor-bearing mice. Therefore, SLC3A2 is a prognostic biomarker and associated with immune infiltration in gliomas.

目的:探讨hsa_circ_0076931在胶质瘤中的表达及其潜在分子机制.方法:通过生物信息学分析,筛选出目的基因hsa_circ_0076931,在H4细胞系中过表达hsa_circ_0076931后进行转录组测序、生物信息学分析和验证.结果:基因本体(GO)和基因组百科全书(KEGG)结果显示:差异环状RNA(circRNAs)母基因及差异信使核糖核酸(mRNA)主要参与细胞周期、细胞分裂等生物学功能以及代谢、癌症相关和MAPK等信号通路.此外,与hsa_circ_0076931互相作用的基因主要参与细胞增殖、细胞凋亡和细胞迁移等生物功能以及MAPK、PI3K-Akt、Rapl等信号通路.hsa_circ_0076931可以下调靶基因hsa-miR-26a-5p、hsa-miR-181a-5p和hsa-miR-34a-5p表达,上调双特异性磷酸酶5(DUSP5)、血小板衍生生长因子受体(PDGFRB)和钙通道β3亚基(CACNB3)的表达,并抑制磷酸化ERK(p-ERK)蛋白的表达.结论:hsa_circ_0076931可能通过吸附hsa-miR-181a-5p结合上调DUSP5的表达,从而抑制MAPK信号通路参与胶质瘤的发生发展过程.

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.

Abstract Objective: This study aimed to delineate the features of cytokine-associated genes within glioma and formulate a corresponding prognostic model. Methods: We utilized mRNA expression and clinical data from glioma patients within TCGA and CGGA, along with mRNA expression data of normal brain tissue from GTEx. Cytokine-associated prognostic genes were identified through differential gene expression analysis, univariate Cox analysis, and LASSO regression, culminating in a risk score model. Subsequently, glioma patients were stratified into high and low-risk groups based on their risk scores. Kaplan-Meier survival and receiver operating characteristic curve analyses were conducted to assess the prognostic utility of the risk score model in TCGA and CGGA cohorts. We performed relevance analyses of risk score distributions across various subgroups defined by age, gender, WHO grade, IDH1 mutation status, MGMT promoter methylation status, and 1p/19q co-deletion status. Furthermore, we developed a column line plot model employing the risk scoring mechanism and validated its predictive accuracy in the TCGA and CGGA cohorts. Additionally, gene set enrichment analysis identified the predominant signaling pathways and pathological processes in the high-risk group. Lastly, we examined the tumor microenvironment, focusing on immune infiltration and immune checkpoint dynamics in relation to the risk score. Results: Integration of CGGA and GTEx data, comprising 325 glioma and 105 normal brain tissues, yielded 186 differentially expressed cytokine-related genes (DE-CRGS). KEGG analysis highlighted the cytokine-receptor interaction, JAK-STAT, and chemokine signaling pathways as most significant. Protein-protein interaction analysis segregated the 186 DE-CRGS into six modules, pinpointing core pathways such as HIF-1α, chemokine, p53, MAPK, JAK-STAT, and TNF signaling. Based on 186 DE-CRGS expression, the 325 CGGA glioma samples were bifurcated into clusters 1 and 2. Survival analysis indicated poorer prognosis for cluster 1, with CIBERSORT revealing higher quantities of M2 macrophages, activated mast cells, and centrocytes. Notably, cluster 1 correlated with individuals over 40, presenting wild-type IDH1, WHO grade IV, unmethylated MGMT promoters, and absence of 1p/19q co-deletions.We pinpointed prognostic features of three cytokine-associated genes (GPR17, CASP1, CYLD) and devised a risk score model. Elevated risk scores correlated with parameters such as age above 45, wild-type IDH1, WHO grade IV, unmethylated MGMT promoter, and absence of 1p/19q co-deletions. The model demonstrated proficiency in forecasting 1-, 3-, and 5-year overall survival rates for glioma patients in both TCGA and CGGA cohorts, as substantiated by ROC and KM analyses. The line plot model underscored its predictive potential for patient survival, with high-risk scores notably associated with increased expression of certain immune cells and checkpoints. Conclusions: We established a validated cytokine-associated gene risk scoring system, employing TCGA and CGGA data for enhanced prognosis and risk stratification. The constructed column chart model accurately predicts 1-year, 3-year, and 5-year survival, contributing to our understanding of glioma pathology. Additionally, analyses of tumor immune infiltration and immune checkpoints indicate cytokine involvement in aspects like tumorigenesis, progression, tumor microenvironment, and immune evasion, offering potential therapeutic avenues for glioma management.

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.

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.

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.

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.

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 (β= -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 (β= -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 (β= -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 (β=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.