Background:The intricate molecular pathways involved in gliomas, coupled with the shift toward more personalized treatment approaches, necessitate the identification of novel and dependable molecular targets. Cholesterol metabolism is a key player in modulating metabolic alterations in glioma cells and shaping the tumor immune microenvironment. Consequently, thoroughly examining messenger RNAs (mRNAs) within this pathway has emerged as a novel avenue for investigating the prognostic markers and immunotherapeutic targets for glioma, which also constitutes the objective of the present study. Methods:Transcriptomic profiles with matched clinical annotations were retrieved from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts, while additional single-cell expression data were accessed through the Gene Expression Omnibus (GEO) repository. Candidate cholesterol metabolism-related genes (CMRGs) were collected based on prior literature and curated databases. Prognostic genes were identified using stepwise Cox regression combined with least absolute shrinkage and selection operator (LASSO) regularization. On this basis, we formulated a multi-gene risk score to stratify patient survival. The score was incorporated with clinical covariates into a prognostic nomogram, and functional enrichment analyses were applied to characterize the associated molecular pathways. We further examined immune microenvironment differences, predicted potential response to immune checkpoint therapy, and estimated chemotherapeutic sensitivity. Finally, expression patterns of the selected genes were validated experimentally. Results:After stepwise selection, five mRNAs with prognostic value were incorporated into a survival risk score. In the independent validation cohort, this signature achieved favorable discrimination of overall survival (OS), with area under the curve (AUC) values of 0.893, 0.804, and 0.749 for 1-, 3-, and 5-year survival, respectively. Comparisons of immune infiltration, functional activity, ESTIMATE-derived scores, Tumor Immune Dysfunction and Exclusion (TIDE) prediction, and tumor mutation burden between risk groups confirmed the biological relevance of the model. Experimental assays further supported the predicted expression patterns and were consistent with our initial expectations. Conclusions:We established a cholesterol metabolism-associated mRNA signature to stratify glioma patients, and its predictive performance was confirmed in independent datasets and complementary analyses. This framework provides a practical tool for survival estimation and may contribute to optimizing immunotherapy decision-making in glioma management.

Neuroinflammation is a major determinant of secondary injury after intracerebral hemorrhage (ICH), but the microglial states that drive this process and their upstream regulators remain incompletely resolved. We integrated public single-cell RNA sequencing and bulk RNA sequencing datasets with experimental validation to define inflammatory microglial programs after ICH. Re-clustering of microglia identified an acute MG3 subpopulation enriched for cytokine, NF-κB, and TNF signaling pathways. Integrative analysis with weighted gene co-expression network analysis prioritized thrombospondin-1 (THBS1) as a candidate regulator of this state. In perihematomal tissue, THBS1 increased prominently at day 3 after ICH and localized predominantly to microglia. In oxyhemoglobin-stimulated BV2 cells, Thbs1 knockdown reduced iNOS/CD16/32-associated inflammatory features and the release of TNF-α, IL-6, and IL-1β, while increasing CD206 expression. In CX3CR1Cre/ERT2 mice, microglia-targeted Thbs1 knockdown decreased perihematomal TNF-α, IL-6, and IL-1β levels, attenuated neuronal injury, and improved long-term neurological recovery. Direct RNA sequencing and MeRIP-qPCR further showed dynamic changes in m6A enrichment on Thbs1 transcripts after ICH, supporting an association between RNA methylation and temporal Thbs1 regulation. Together, these data identify a THBS1-high inflammatory microglial state in experimental ICH and support THBS1 as a candidate mediator of inflammatory secondary injury after experimental ICH.

BACKGROUND: This study aimed to investigate the role of miR-218-5p and CKLF-like marvel transmembrane domain-containing 3 (CMTM3) and the interaction between them in glioma. METHODS: The presence of CMTM3 in glioma cells and tissues was detected using immunohistochemical analysis, quantitative reverse transcription polymerase chain reaction, and western blotting. Public databases were used to examine the relationship between CMTM3 expression and patient survival. Transwell assay was performed to evaluate the invasive potential of glioma cells with downregulated CMTM3. Luciferase reporter assay was performed to validate the role of miR-218-5p in regulating CMTM3 expression. Intracranial xenograft models were established to investigate the role of CMTM3 in glioma in vivo. RESULTS: CMTM3 was upregulated in glioma cells and tissues. Higher CMTM3 expression was significantly associated with shorter overall survival and more advanced clinicopathological characteristics in patients with glioma. Functional assays demonstrated that downregulation of CMTM3 potently suppressed the proliferative and invasive abilities of glioma cells in vitro and reduced tumor growth by approximately 66% in an intracranial xenograft model. Transfection with a miR-218-5p mimic suppressed CMTM3 expression by approximately 68% at the mRNA level and 70% at the protein level in glioma cell lines, indicating that CMTM3 was directly regulated by miR-218-5p. Additionally, the miR-218-5p mimic significantly inhibited the proliferative and invasive abilities of glioma cells. CONCLUSION: MiR-218-5p regulates the oncogenic role of CMTM3 in glioma. Therefore, targeting the miR-218-5p/CMTM3 axis is a promising therapeutic strategy for glioma.

Background Adenylosuccinate (ADSL) lyase, a critical enzyme involved in purine metabolism, has been implicated in tumorigenesis, however, its comprehensive role across cancers and underlying mechanisms in glioma remain incompletely elucidated. Methods We performed pan-cancer analyses using datasets from The Cancer Genome Atlas, Genotype-Tissue Expression and Human Protein Atlas to evaluate ADSL expression, diagnostic and prognostic significance, genetic alterations, and correlations with tumor immunity. In vitro functional assays and in vivo xenograft mouse experiments were conducted to validate ADSL’s functions. Furthermore, molecular docking, molecular dynamics simulations and cellular thermal shift assays were applied to identify and validate potential ADSL inhibitors. Results ADSL is upregulated in a majority of cancers and correlates with unfavorable prognosis in 13 distinct malignancies, with an area under the curve exceeding 0.9 in glioblastoma. ADSL mutations and copy number alterations are prevalent in endometrial cancer and melanoma. Functional enrichment showed ADSL involvement in purine metabolism, cell cycle, and DNA repair. ADSL expression correlates with immune cell infiltration, immune checkpoint molecules, tumor mutational burden, and microsatellite instability across various cancers. In glioma, ADSL forms a lncRNA-miRNA-ADSL regulatory network. Knockdown of ADSL results in the inhibition of in vitro glioma cell proliferation, migration and invasion, suppression of in vivo tumor growth. GANT-58 was identified as a potential ADSL inhibitor with stable binding affinity and validated by cellular thermal shift assays. Conclusion ADSL functions as a prognostic biomarker and represents a therapeutic target in various cancers, with particular significance in glioma, by regulating purine metabolism, tumor immunity, and epithelial-mesenchymal transition. GANT-58 shows a promising potential for ADSL-targeted therapy.

Glioblastoma, characterized by rapid proliferation and invasiveness, is largely resistant to current treatment modalities. A major obstacle is the blood-brain barrier (BBB), which restricts the delivery of therapeutic agents as well as the infiltration of effective immune cells into glioblastoma. In this study, we developed an injectable oxidized high-amylose starch hydrogel (OHASM) to serve as a biomaterial scaffold for the delivery of macrophages and macrophage-polarizing drugs, aiming to bypass the BBB and enhance glioblastoma treatment. The in vitro and in vivo experiments confirmed the efficacy of the hydrogel in loading and delivering macrophages and polarizing drugs against glioblastoma. Additionally, the hydrogel's interconnected porous structure was conducive to cellular growth and activity, and its slow release of therapeutics contributed to the extended survival of treated mice in a mouse GL261 glioblastoma tumor model. The immunological mechanisms underlying the therapeutic efficacy were further elucidated, revealing the potential of the hydrogel system to modulate macrophage polarization and induce apoptosis in tumor cells via the poly ADP-ribose polymerase (PARP) pathway. The study underscores the potential of the hydrogel-based macrophage delivery strategy as an effective and safe treatment for glioblastoma, offering a promising avenue for clinical management of this aggressive brain cancer.

Background Intracranial aneurysm (IA) is a dangerous, acquired, focal cystic herniation of the artery wall, with unclear pathogenesis. In addition, there is a correlation between cancer treatment and aneurysm progression. This study aimed to show the mechanisms and identify the new biological targets by applying bioinformatics analysis, and explore its relationship with cancers. Methods The intracranial aneurysm expression profile datasets GSE26969, GSE75436, and GSE54083 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes, Functional Correlation Analysis, WGCNA, LASSO, and SVM-RFE, were used to analyze the data set and found the AVPR1A and ANGPTL1. Then, the immune cell infiltration, gene network, and enrichment analysis were carried out. Furthermore, pan-cancer analysis of AVPR1A was performed using TCGA, GEPIA, GISTIC, cBioPortal, and TIMER. Results AVPR1A and ANGPTL1 were identified as the biomarkers for IA. Immunocyte infiltration analysis revealed that plasma cells, memory B cells, CD8 T cells, resting dendritic cells, and M1 macrophages may be involved in the process of IA. In addition, AVPR1A was aberrantly expressed in a variety of cancers and was significantly associated with the prognosis of cancer patients. Conclusions We explored the contributing factors involving IA and some cancers, which may generate a better understanding of the complex interactions among them and inspire a promising strategy for clinical works.

Glioblastoma (GBM) represents the predominant malignant brain tumor, characterized by unfavorable prognoses. The identification of novel molecular markers plays a pivotal role in advancing clinical prognosis. Vasculogenic mimicry (VM) has been reported to serve a crucial role in angiogenesis within glioblastoma (GBM). Thus, we extracted data from The Cancer Genome Atlas Program (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Subsequently, we used Kaplan-Meier (K-M) survival analysis combined with univariate and multivariate COX regression analysis to identify meaningful VM-related genes (VRGs). Based on these analyses, the VM index model and risk score model were built. The reliability of the model was then tested using CGGA data, western blotting, and tube formation assay experiments. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) demonstrated the accuracy of these models. The correlation of TFPI and ROCK1 with tumor characteristics and immune infiltration was explored with the help of TIMER. Vitro experiments revealed that reducing the expression of ROCK1 and TFPI tended to decrease the formation of vascular-like tubes on Matrix-Gel™ compared to the control siRNA groups. Our findings suggest that ROCK1 and TFPI contribute to GBM metastasis through vasculogenic mimicry.

Gliomas are primary intracranial tumors that cause considerable morbidity and mortality. The effect of interleukin 4-induced gene-1 (IL4I1) on the progression of various diseases has been demonstrated to be significant. However, the specific molecular mechanisms of how IL4I1 contributes to the progression and the epithelial-mesenchymal transition (EMT) process of glioma remain inadequately elucidated. IL4I1 expression in glioma was assessed using public datasets and immunohistochemistry. In in vitro experiments, IL4I1 expression was quantified through real-time quantitative PCR and western blotting. The effects of IL4I1 knockdown on the malignant phenotypes of glioma cells were investigated through in vitro studies. The evaluation of biomarkers associated with EMT and the Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway was conducted using western blotting and immunofluorescence assays after IL4I1 knockdown. A xenograft tumor model was established to validate the influence of IL4I1 knockdown in glioma progression. The results revealed that high expression of IL4I1 is linked to an unfavorable prognosis in human gliomas. IL4I1 knockdown effectively impeded the malignant phenotypes of glioma cells. IL4I1 knockdown induced EMT reversal, characterized by alterations in the expression levels and localization of EMT-related biomarkers. This reversal is partially mediated through the JAK2/STAT3 signaling pathway. The results of in vivo experiments confirmed that IL4I1 knockdown effectively suppressed glioma growth. Our research demonstrates that IL4I1 knockdown reverses the EMT process via JAK2/STAT3 signaling pathway and suppresses the malignant phenotypes of glioma, thereby highlighting its potential as both a prognostic marker and therapeutic target for glioma.

OBJECTIVE:The surgical management of petroclival meningioma (PCM) remains a challenge in neurosurgery. This study compared the outcomes of endoscope-assisted microsurgery and conventional microscopic approaches to evaluate the safety and efficacy of endoscope-assisted transcranial techniques for PCM treatment. METHODS:This retrospective case-control study was conducted at our hospital. Clinical data from January 2018 and June 2024 were retrospectively analyzed. The primary outcome was gross total resection (GTR) rate, and the secondary outcomes included patient status, tumor progression or recurrence. Propensity score matching (PSM) was used to account for group differences. RESULTS:We enrolled 62 patients; 18 underwent endoscope-assisted transcranial surgery and 44 underwent transcranial microscopic surgery. The endoscope-assisted transcranial microsurgery group exhibited a higher GTR rate, shorter postoperative hospital stay, and lower tumor progression or recurrence rates than the transcranial microscopic surgery group (GTR: 83.3% vs. 52.3%, P = 0.046); postoperative hospital stay duration: 9.50 days [8.00, 13.75] vs. 13.00 days [10.00, 17.25], P = 0.023; and lower tumor progression or recurrence: 0 vs. 15.9%). After PSM, the endoscope-assisted surgery group had a better GTR rate, compared with the microsurgery group (odds ratio: 7.51 [1.37, 41.10], 95% confidence interval: 1.37-41.10, P = 0.021). CONCLUSIONS:PCM remains a surgical challenge. Endoscope-assisted microsurgery provides an increased GTR rate, offering excellent visualization and access to tumors. Therefore, it may be recommended as a first-line treatment for patients with PCM.

Surgical treatment of complex pituitary adenomas (PAs) presents a significant challenge. Here in, we compared the surgical outcomes between patients undergoing endoscope-assisted transcranial surgery and microscopic regimens to assess the safety and efficacy of endoscope-assisted transcranial surgery in treating complex PA. This retrospective case-control study was conducted at the First Affiliated Hospital of Soochow University, China. Clinical data were retrospectively analysed between January 2018 and January 2023. The primary outcome was gross total resection (GTR), and the secondary outcomes included recurrence, residual tumour volume, and patient status. Propensity score matching was used to account for group differences. We enrolled 73 patients, of whom 29 underwent endoscope-assisted transcranial surgery, and 44 underwent transcranial microscopic surgery. Compared with the microscopic regimen group, the endoscope-assistedgroup had higher postoperative Karnofsky Performance Scale (KPS) scores (p = 0.031), higher GTR rates (GTR: 79.3

As a primary brain cancer, glioma presents significant challenges in treatment and prognosis. Identifying reliable biomarkers is crucial for improving patient outcomes. This study focuses on the ABCC3 gene, exploring its function as a standalone predictive indictor and its correlation with immune infiltration and resistance to chemotherapy in glioma. A multi-faceted approach was adopted for this analysis. We scrutinized the RNA expression patterns of the ABCC3 gene across a spectrum of cancer types, with a concentrated focus on glioma. Our methodological arsenal included bioinformatics analysis, immunohistochemistry (ICH), western blot (WB), and cell counting Kit-8 (CCK8) assays. These techniques were instrumental in gauging the prognostic impact of ABCC3 and elucidating its associations with immune cell infiltration and chemotherapy resistance. The investigation revealed a significant elevated levels of ABCC3 in high grade glioma (HGG) tissues compared to lower grade glioma (LGG) tissues. Notably, upregulation of ABCC3 were associated with a shorter overall survival in patients with glioma. Furthermore, ABCC3 emerged as an independent factor in prognostication, with predictive capability for 1-, 3-, and 5-year survival rates. As far as immune response is concerned, ABCC3's expression correlates positively with the expression of several immune cells and checkpoint genes. The study also uncovered the role of ABCC3 in drug resistance, particularly regarding temozolomide (TMZ), a primary therapeutic agent in glioma treatment. The study reveals ABCC3 as a significant biomarker in glioma, associated with lower survival, enhanced immune infiltration, and increased resistance to chemotherapy. These findings emphasize its promise as a novel target for glioma therapies.

PURPOSE:Circadian locomotor output cycles kaput (CLOCK) and its related genes play important roles in cellular functions. This study aims to construct a predictive model for CLOCK-related genes and identify lncRNAs that may influence Tumor Microenvironment of Glioma. METHOD:We included bulk RNA-sequencing data and clinical information for glioma samples from the TCGA and CGGA databases. Univariate Cox and LASSO-Cox analyses were used to screen CLOCK-related genes. Consensus clustering was applied to classify glioma samples, followed by differential gene expression analysis. CLOCK-related lncRNAs were identified through correlation analyses, hub lncRNAs were selected using LASSO-Cox, and their expression was validated by qPCR in cultured glioma cell lines. FINDING:We identified nine CLOCK-related genes, and unsupervised clustering based on these genes divided glioma samples into three clusters. Enrichment analysis revealed that genes differentially expressed between the high CLOCK-related cluster and other clusters were enriched in immune-related molecular functions. Co-expression analysis detected 102 potentially correlated lncRNAs. We constructed a CLOCK-related lncRNA risk score based on 31 of these lncRNAs. Subsequent multivariable Cox analysis identified 9 hub lncRNAs, and accuracy testing demonstrated the model's good performance. Immune infiltration analysis showed higher stromal, immune, and ESTIMATE scores in the high CLOCK-related lncRNA score group. CONCLUSION:CLOCK-related RNAs and lncRNAs play distinct roles within the glioma microenvironment. These findings offer new insights into the challenges that need to be addressed when using immunotherapeutic approaches to treat gliomas.

OBJECTIVE:The aim of this study was to retrospectively analyze the clinical data of 24 patients with small vestibular schwannomas, explore the surgical outcomes, and summarize the surgical experience. METHODS:Patients with small vestibular schwannomas who underwent surgery between January 2019 and December 2022 at the Department of Neurosurgery of the First Affiliated Hospital of Soochow University were included. Clinical data from all patients were collected and analyzed. RESULTS:Total tumor resection was achieved in all patients. Microscopic surgery alone was sufficient for complete resection in 7 patients, while the remaining 17 patients required combined microscopic and endoscopic approaches for complete removal. At the final follow-up, 16 patients maintained preoperative facial nerve function, 6 patients experienced improvement, while 2 patients experienced deterioration. And there were 13 patients maintained preoperative hearing function, 9 patients experienced improvement, while 2 patients experienced deterioration. Compared with microscopic resection alone, there was no significant difference in the Facial nerve function and Hearing function of patients underwent microscopic and endoscopic resection. During the follow-up period, all patients showed favorable prognosis without disease progression. CONCLUSIONS:Compared with microscopic surgery, the microscopic with endoscopic surgery for small vestibular schwannomas lead to the better results in the degree of tumor resection, with no difference in functional protection.

Intracerebral hemorrhage (ICH) is a highly fatal form of stroke for which there are limited effective treatments. Cuproptosis, a newly discovered type of programmed cell death, has not yet been investigated in relation to ICH. Thus, the main goal of our study was to investigate the involvement of cuproptosis-related genes (CRGs) in predicting the early outcomes of ICH. We used datasets GSE228222 and GSE200575 from the Gene Expression Omnibus (GEO) database to identify and analyze differentially expressed genes (DEGs) between ICH samples and control samples from mice. From this analysis, seven cuproptosis-related DEGs (CuDEGs) were identified: pyruvate dehydrogenase E1 component subunit alpha (Pdha1), glutaminase (Gls), dihydrolipoamide dehydrogenase (Dld), pyruvate dehydrogenase E1 component subunit beta (Pdhb), dihydrolipoamide S-acetyltransferase (Dlat), metal regulatory transcription factor 1(Mtf1), and solute carrier family 31 member 1 (Slc31a1). Pathway enrichment analysis connected these genes to metabolic pathways, while immune cell infiltration analysis revealed increased macrophages and naive CD8 T cells alongside reduced NK resting cells and CD4 T cells in ICH samples. Verification through qRT-PCR and immunohistochemistry demonstrated a lower expression of CuDEGs in ICH samples. Of particular note, Gls, a gene significantly linked to both cuproptosis and immune regulation, exhibited reduced expression, possibly reflecting a protective response to limit glutamate production and mitigate neuronal damage. In summary, Gls emerges as a promising target for improving ICH outcomes by regulating cuproptosis and immune activity. This research provides novel insights into the molecular processes involved in ICH and suggests potential therapeutic approaches.

PURPOSE:Gliomas, the most prevalent type of central nervous system tumors, currently lack effective therapeutic options. Lipolysis-stimulated lipoprotein receptors (LSR) have been implicated in tumor development and progression. This study aims to investigate the influence of LSR on gliomas and elucidate the underlying mechanisms. METHODS:We analyze LSR expression in gliomas and its association with patient prognosis using bioinformatics tools. Western blotting and immunohistochemistry revealed differential expression of LSR across different grades of glioma. The effects of LSR on glioma cell proliferation and invasion are evaluated through a series of cellular assays. Subcutaneous xenografts in nude mice are utilized to assess the impact of LSR on gliomas in vivo. Additionally, western blotting is employed to detect changes in protein levels related to the FOXO3a signaling pathway following LSR overexpression. RESULTS:LSR expression is higher in tissues from low-grade gliomas compared to those from glioblastomas. Patients with low LSR expression exhibit poorer prognoses. Overexpression of LSR inhibit glioma cell proliferation and invasion. The protein levels of PCNA, Cyclin D1, MMP2, and MMP9 are significantly decreased in the OE-LSR group. Tumor volume is reduced in nude mice injected subcutaneously with LSR-overexpressing glioma cells. Overexpression of LSR increases nuclear FOXO3a level while reduces p-FOXO3a and p-14-3-3 levels. Knockdown of FOXO3a reverse the inhibitory effects of LSR overexpression on glioma cell proliferation and invasion. CONCLUSION:Low LSR expression is associated with adverse prognosis in glioma patients. By modulating FOXO3a, LSR overexpression suppresses glioma cell proliferation and invasion.

ObjectiveTo investigate the role of Doppler microvascular ultrasound (MVD) in skull base surgery for the intraoperative assessment and protection of arterial blood flow.MethodsThe clinical data of 56 patients who underwent surgery at the Department of Neurosurgery, First Affiliated Hospital of Soochow University between September 2017 and June 2024 were retrospectively analyzed. All patients underwent skull base tumor resection assisted by intraoperative microvascular Doppler (MVD). The procedures involved complex skull base tumors, including lesions in the sellar region, sphenoid ridge, and cavernous sinus. During surgery, MVD was utilized to monitor blood flow in vessels adjacent to the tumors. The spatial relationship and patency of the vessels and tumors were evaluated in conjunction with preoperative multimodal imaging.ResultsNo intraoperative vascular injuries were observed among the 56 patients, confirmed by intraoperative Doppler monitoring and postoperative imaging. All patients had favorable postoperative outcomes, including no new neurological deficits. MVD facilitated precise intraoperative localization and evaluation of blood vessels, which was quantitatively supported by significant increases in contrast-to-noise ratio (CNR) after Doppler application. In two representative cases, the addition of FLOW800 fluorescence imaging provided further CNR improvement, suggesting enhanced visualization and vascular protection. Details of the CNR quantification process are provided in the Methods section.ConclusionMVD provides real-time intraoperative information on arterial blood flow during skull base surgeries, enabling surgeons to identify and preserve critical vessels, thereby improving surgical safety, resection accuracy, and patient outcomes. With ongoing technological advancements, the integration of MVD and fluorescence imaging is expected to play an increasingly vital role in complex skull base procedures.

Stroke remains a leading cause of global mortality, with neuroinflammation significantly exacerbating clinical outcomes. Microglia serve as key mediators of post-stroke neuroinflammation, though the mechanisms driving their migration to injury sites remain poorly understood. In this study, using publicly available single-cell sequencing data (GSE234052), we identified a migration-associated microglial subtype in a murine model of distal middle cerebral artery occlusion (dMCAO). Additionally, ribosome-bound mRNA sequencing data (GSE225110) from microglia isolated from peri-infarct cortical tissue uncovered dMCAO-induced alterations in microglial mRNA translation. By integrating these datasets, we identified A Disintegrin And Metalloproteinase 8 (Adam8) as a key gene upregulated at both the transcriptional and translational levels post-dMCAO. Protein analysis revealed that both the precursor and active forms of Adam8 were predominantly expressed in microglia and significantly upregulated in peri-infarct regions following dMCAO. Notably, Adam8 inhibition with BK-1361 significantly reduced Adam8 cleavage, M1 microglial migration, inflammation, infarct size, and improved neurological outcomes. Bioinformatics analysis further identified Myo1e as a potential interacting partner of Adam8, a finding validated through immunofluorescence co-localization. These findings highlight Adam8 as a promising therapeutic target for mitigating post-stroke neuroinflammation and offer new insights into the mechanisms of microglial migration.

Cystatin C (CysC) is a cysteine protease inhibitor and previous studies have demonstrated that increasing endogenous CysC expression has therapeutic implications on brain ischemia, Alzheimer's disease, and other neurodegenerative disorders. Our previous reports have demonstrated that the autophagy pathway was activated in the brain after experimental subarachnoid hemorrhage (SAH), and it may play a beneficial role in early brain injury (EBI). This study investigated the effects of exogenous CysC on EBI, cognitive dysfunction, and the autophagy pathway following experimental SAH. All SAH animals were subjected to injections of 0.3 ml fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20 s. As a result, treatment with CysC with low and medial concentrations significantly ameliorated the degree of EBI when compared with vehicle-treated SAH rats. Microtubule-associated protein light chain-3 (LC3), a biomarker of autophagosomes, and beclin-1, a Bcl-2-interacting protein required for autophagy, were significantly increased in the cortex 48 h after SAH and were further up-regulated after CysC therapy. By ultrastructural observation, there was a marked increase in autophagosomes and autolysosomes in neurons of CysC-treated rats. Learning deficits induced by SAH were markedly alleviated after CysC treatment with medial doses. In conclusion, pre-SAH CysC administration may attenuate EBI and neurobehavioral dysfunction in this SAH model, possibly through activating autophagy pathway.

BACKGROUND:Intracerebral Hemorrhage (ICH) is a common acute fatal cerebrovascular disease in surgery. Astilbin, a flavonoid extracted from various plants, has been studied for its excellent anti-inflammatory action. The present study aims to investigate the efficacy and mechanism of astilbin against ICH in mice. METHODS:The ICH in C57BL/6 mice was induced with classical autologous blood injection. We conducted behavioral tests, Perls' staining, Nissl staining, TUNEL staining, Evans blue dye extravasation, water content, Enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining to access the anti-inflammatory function of astilbin. RESULTS:Astilbin demonstrates a capacity to ameliorate neurofunctional impairments induced by ICH in mice. It effectively reduces iron deposition and neuronal death in the peri-hematoma tissue. Astilbin alleviates cerebral edema and mitigates blood-brain barrier (BBB) damage caused by ICH. Furthermore, astilbin promotes the secretion of chemotactic and anti-inflammatory factors post-ICH, including CCL1, CCL20, IL-10, IL-35, and TGFβ. Notably, astilbin facilitates the accumulation of Treg cells in the brain tissue surrounding the hematoma after ICH. CONCLUSION:Astilbin facilitates the enrichment of Treg cells in the brain tissue around the hematoma, thereby alleviating secondary brain injury (SBI) following ICH and improving the overall prognosis of ICH. These findings suggest its potential candidacy as a therapeutic intervention for mitigating the consequences of intracerebral hemorrhage.

BackgroundGlioma, a primary intracranial tumor, is marked by high rates of mortality and disability, making it a significant health concern. Understanding the molecular mechanisms underlying glioma initiation and progression and identifying potential therapeutic targets for gene therapy are crucial for improving patient outcomes. Golgi phosphoprotein 3 (GOLPH3), predominantly localized at the trans-Golgi network, has been implicated in the pathogenesis of various cancers. However, its precise role in glioma progression remains under active investigation.MethodsTo elucidate the function of GOLPH3, U87 glioma cells were transfected with GOLPH3-specific small interfering RNA (siRNA) to suppress its expression. An in vivo glioma model was generated by implanting GOLPH3-knockdown U87 cells into nude mice. Apoptosis was assessed using flow cytometry, immunofluorescence staining, TUNEL assays, and Western blotting. The activation of the JNK signaling pathway was evaluated by analyzing the phosphorylation levels of JNK and c-Jun through Western blotting.ResultsDownregulation of GOLPH3 in U87 glioma cells significantly enhanced apoptosis, as evidenced by increased levels of cleaved caspase-3 and higher apoptosis rates. Furthermore, GOLPH3 knockdown led to the activation of the JNK signaling pathway, as indicated by elevated phosphorylation of JNK and c-Jun. In vivo, suppression of GOLPH3 expression inhibited tumor growth and increased apoptosis within the tumor microenvironment.ConclusionThese findings suggest that GOLPH3 might play a pivotal role in regulating apoptosis in malignant glioma cells via the JNK signaling pathway. Thus, GOLPH3 may represent a promising therapeutic target for glioma treatment.