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Background Neuroinflammation-induced injury is intimately associated with poor prognosis in patients with cerebral venous sinus thrombosis (CVST). The cyclic GMP-AMP synthase–stimulator of interferon gene (cGAS–STING) axis is a cytoplasmic double-stranded DNA (dsDNA) sensing pathway has recently emerged as a crucial mediator of neuroinflammation in ischemic stroke. However, the role of the cGAS–STING pathway in modulating post-CVST inflammation and the underlying mechanisms involved remain unclear. Methods A CVST model was induced by ferric chloride in male C57BL/6J mice. The selective cGAS inhibitor RU.521, STING agonist 2′3′-cGAMP, and STING siRNA were delivered by intranasal administration or intraventricular injection. Post-CVST assessments included rotarod test, TUNEL staining, Fluoro-Jade C staining, dihydroethidium staining, western blotting, qPCR, immunofluorescence, immunohistochemistry, ELISA and flow cytometry. Results cGAS, STING, NLRP3 and GSDMD were significantly upregulated after CVST and mostly in the microglia of the mouse brain. CVST triggered the release of dsDNA into the cytoplasm and elicited an inflammatory response via activating the cGAS–STING axis. RU.521 decreased the levels of 2′3′-cGAMP, STING and downstream inflammatory cytokines, and suppressed the expressions of NLRP3 inflammasome and pyroptosis-pertinent components containing cleaved caspase-1, GSDMD, GSDMD-C, pro- and cleaved IL-1β, and cleaved IL-1β/pro-IL-1β. Besides, RU.521 treatment also reduced oxidative stress, lessened the numbers of microglia and neutrophils, and ameliorated neuronal apoptosis, degeneration along with neurological deficits post-CVST. 2′3'-cGAMP delivery enhanced the expressions of STING and related inflammatory mediators, NLRP3 inflammasome and pyroptosis-relevant proteins, whereas these alterations were significantly abrogated by the silencing of STING by siRNA. Conclusions Our data demonstrate that repression of the cGAS–STING pathway diminishes the neuroinflammatory burden of CVST and highlight this approach as a potential therapeutic tactic in CVST-mediated pathologies.

Neuroinflammation is considered to be a significant mechanism contributing to depression. Several studies have reported that A1 astrocytes were highly prevalent in human neuroinflammatory and neurodegenerative diseases. However, the precise mechanism by which A1 astrocytes contribute to depression remains unclear. Clinical studies have suggested a correlation between TNF-α, an activator of A1 astrocytes, and the severity of depression. Based on these findings, we hypothesized that TNF-α might worsen depression by activating A1 astrocytes. Our previous studies indicated that Rhodomyrtone (Rho) has the potential to improve depression-like behavior in mice. However, the exact mechanism for this effect has not been fully elucidated. Importantly, it was reported that Rho alleviated skin inflammation in a mouse model of psoriasis by inhibiting the expression of TNF-α. Based on this finding, we hypothesized that rhodomyrtone may exert antidepressant effects by modulating the TNF-α pathway. However, further research is required to investigate and validate these hypotheses, shedding light on the relationships between neuroinflammation, A1 astrocytes, TNF-α, and depression. By obtaining a deeper understanding of the underlying mechanisms, these findings could lead to the development of novel antidepressant strategies that target the TNF-α pathway in the context of neuroinflammation. In vivo, based on the established chronic unpredictable mild stress (CUMS) mouse depression model, we characterized the mechanism of TNF-α and Rho during depression by using several behavioral assays, adeno-associated virus(AAV) transfection, western blotting, immunofluorescence, and other experimental methods. In vitro, we characterized the effect of Rho on inflammation in TNF-α-treated primary astrocytes. TNFR1 expression was significantly increased in the hippocampus of depression-like mice, with increased astrocytes activation and neuronal apoptosis. These processes were further enhanced with increasing levels of TNF-α in the cerebrospinal fluid of mice. However, this process was attenuated by knockdown of TNFR1 and infliximab (Inf; a TNF-α antagonist). Injection of rhodomyrtone decreased the expressions of TNFR1 and TNF-α, resulting in significant improvements in mouse depression-like behaviors and reduction of astrocyte activation. TNF-α could be involved in the pathophysiological process of depression, through mediating astrocytes activation by binding to TNFR1. By blocking this pathway, Rho may be a novel antidepressant.

BackgroundGlioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and limited treatment options. Oncolytic virus (OV) therapy holds promise but is hindered by immune neutralization and poor tumor infiltration. Neural stem cells (NSCs) can enhance OV delivery, and intracerebroventricular (ICV) administration offers broader tumor access. This study evaluates NSC-OV therapy via ICV injection for improved tumor targeting and immune modulation in GBM.MethodsNSCs were infected with OV and assessed for viral uptake and replication. In vitro assays examined NSC-OV effects on glioma proliferation and migration. In vivo xenograft and orthotopic models evaluated tumor targeting, therapeutic efficacy, and immune modulation. Humanized immune system mouse models enabled single-cell RNA sequencing and flow cytometry analysis of immune responses.ResultsNSCs retained their stemness after OV infection. NSCs-OV significantly inhibited glioma cell migration, proliferation, and colony formation in vitro. In orthotopic GBM models, NSCs-OV exhibited enhanced tumor homing, prolonged viral persistence, and reduced tumor burden while minimizing inflammation and systemic toxicity. NSCs protected OV from neutralizing antibodies, leading to sustained efficacy. Single-cell RNA sequencing indicated that NSCs-OV therapy reduced tumor-promoting inflammation by downregulating S100A8/A9, markers of myeloid-derived suppressor cells (MDSCs) and chemotactic factors that recruited MDSCs into tumors. Combining NSCs-OV with Paquinimod further suppressed tumor growth by reducing MDSCs and increasing activated T cells.ConclusionsNSCs serve as efficient OV carriers, enhancing tumor targeting, suppressing GBM progression, and modulating the immune landscape. The combination with Paquinimod amplifies therapeutic benefits, offering a promising strategy for improving GBM treatment outcomes.

To prospectively evaluate the outcomes of ultrasound (US)-guided radiofrequency ablation (RFA) in tertiary hyperparathyroidism (THPT). Patients with THPT underwent RFA between September 2017 and January 2022. Laboratory parameters, including serum intact parathyroid hormone (iPTH) levels, were monitored for 48 months after RFA and compared with the levels at baseline. Complications related to RFA and changes in hyperparathyroidism-related clinical symptoms were recorded before and after RFA. A total of 42 patients with THPT were recruited for this study. Ultimately, 36 patients with renal failure and 2 patients who underwent successful renal transplantation (male:female, 17:21; median age, 54.5 years) were enrolled. The follow-up time was 21.5 ± 19.0 months in the 36 patients with renal failure. In these 36 patients, iPTH levels were significantly decreased to 261.1 pg/mL at 48 months compared with the baseline value of 1284.9 pg/mL ( = 0.012). Persistent hyperparathyroidism, defined as iPTH levels maintained at > 585.0 pg/mL for 6 months after treatment, occurred in 4.0% of patients (1/25). Recurrent hyperparathyroidism, defined as iPTH levels > 585.0 pg/mL after 6 months, were 4.0% (1/25) and 0.0% (0/9) at 6 months and 4 years after treatment, respectively. In two patients with THPT after successful renal transplantation, iPTH decreased from the baseline value of 242.5 and 115.9 pg/mL to 171.0 and 62.0 pg/mL at 6 months after treatment. All complications resolved within 6 months of ablation without medical intervention, except in 10.5% (4/38) patients with permanent hypocalcemia. The overall symptom recovery rate was 58.8% (10/17). The severity scores for bone pain, arthralgia, and itchy skin associated with hyperparathyroidism improved after treatment ( < 0.05). US-guided RFA is an effective and safe alternative to surgery in the treatment of patients with TPTH and improves hyperparathyroidism-related clinical symptoms.

Purpose In the past decade, there has been little progress in the treatment of malignant glioma. Recently, oncolytic virus has made great progress in glioma treatment, and a number of clinical trials have shown their potential of prolonging the survival time of glioma patients. Our objective is to evaluate effectiveness and safety of oncolytic virus (OV) in malignant glioma treatment. Methodology Based upon PRISMA, we collected relevant published clinical trials by searching medical databases up to January 16, 2023, applying the language restrictions in English and Chinese. We cross-searched the terms: ‘glioma’, ‘glioblastoma’, ‘oncolytic viruses’, ‘oncolytic virotherapy’ with filter ‘clinical trial’. Two researchers independently extracted the data regarding case definitions, published years, trial phase, characteristics of patients, administration of drug, overall survival (OS), and adverse events. Results 19 published clinical trials in OV treatment of malignant glioma were included in the further systematic review analysis. None of them induced irresistible adverse effects attributing to OV treatment, median overall survival varied from 3.25 to 20.2 months after treatments. According to trials providing patient’s detailed molecular diagnosis, we find that the effectiveness of OV treatment has no significant difference in patients with different IDH or MGMT status. Conclusions Current clinical trials have initially shown the potential of oncolytic virotherapy as a new treatment for malignant glioma. Besides development of virus types, the strategy of OV use is an urgent problem to be solved in future clinical application, such as repeated administrations, innovative drug delivery systems, and biomarkers.

Background Glioma is the most common primary malignant tumor in the brain, and even with standard treatments including surgical resection, radiotherapy, and chemotherapy, the long-term survival rate of patients remains unsatisfactory. Recurrence is one of the leading causes of death in glioma patients. The molecular mechanisms underlying glioma recurrence remain unclear. Methods Our study utilized single-cell sequencing, spatial transcriptomics, and RNA-seq data to identify a subtype of FN1 + tumor-associated macrophages (FN1 + TAMs) associated with glioma recurrence. Results This study revealed an increased abundance of FN1 + TAMs in recurrent gliomas, indicating their potential involvement as a critical factor in glioma recurrence. A negative correlation was observed between the abundance of FN1 + TAMs in primary gliomas and the interval time to recurrence, suggesting poor prognosis for glioma patients with high levels of FN1 + TAMs. Further investigation showed that FN1 + TAMs were enriched in hypoxic tumor regions, implying that metabolic changes in tumors drive the production and recruitment of FN1 + TAMs. Additionally, FN1 + TAMs were found to contribute to the regulation of an immunosuppressive microenvironment in gliomas, and their abundance might serve as an indicator of patients’ sensitivity to immunotherapy. Finally, we developed a user-friendly website, PRIMEG ( http://www.szflab.site/PRIMEG/ ), for exploring the immune microenvironment of primary and recurrent gliomas. Conclusion Our findings highlight a subtype of FN1 + TAMs associated with glioma recurrence, providing new insights into potential therapeutic targets. Moreover, the abundance of FN1 + TAMs hold promise for predicting immune therapy response and aiding in more precise risk stratification of recurrent glioma patients.

Glioma subtyping is crucial for treatment decisions, but traditional approaches often fail to capture tumor heterogeneity. This study proposes a novel framework integrating multiplex immunohistochemistry (mIHC) and machine learning for glioma subtyping and prognosis prediction. 185 patient samples from the Huashan hospital cohort were stained using a multi‐label mIHC panel and analyzed with an AI‐based auto‐scanning system to calculate cell ratios and determine the proportion of positive tumor cells for various markers. Patients were divided into two cohorts (training: N = 111, testing: N = 74), and a machine learning model was then developed and validated for subtype classification and prognosis prediction. The framework identified two distinct glioma subtypes with significant differences in prognosis, clinical characteristics, and molecular profiles. The high‐risk subtype, associated with older age, poorer outcomes, astrocytoma/glioblastoma, higher tumor grades, elevated mesenchymal scores, and an inhibitory immune microenvironment, exhibited IDH wild‐type, 1p19q non‐codeletion, and MGMT promoter unmethylation, suggesting chemotherapy resistance. Conversely, the low‐risk subtype, characterized by younger age, better prognosis, astrocytoma/oligodendroglioma, lower tumor grades, and favorable molecular profiles (IDH mutation, 1p19q codeletion, MGMT promoter methylation), indicated chemotherapy sensitivity. The mIHC‐based framework enables rapid glioma classification, facilitating tailored treatment strategies and accurate prognosis prediction, potentially improving patient management and outcomes. Our study developed a novel framework for glioma subtyping using multiplexed immunohistochemistry (mIHC) and machine learning. Our study is based on a gating strategy, which utilizes automated image recognition to determine the proportion of tumor cells positive for specific biomarkers within the overall tumor cell population. We refer to this approach as ‘quantitative pathology.’ This mIHC‐based method enables rapid glioma classification, facilitating tailored treatment strategies and more accurate prognosis prediction.

A gelatin@non-woven fabric (gelatin@NWF) hybrid scaffold with tailored micropore structures was fabricated by lyophilizing, using gelatin to support cells and the NWF matrix as a frame to enforce the mechanical stability of gelatin. By freezing the gelatin and NWF hybrid in liquid nitrogen and subsequently lyophilizing and crosslinking the process, the gelatin@NWF scaffold was prepared to support cell growth and promote cell aggregation and spheroids’ formation. The results indicated that by tuning the lyophilizing temperature, the micropore size on the gelatin could be tailored. Consequently, tumor spheroids can be formed on gelatin@NWF scaffolds with honeycomb-like pores around 10 µm. The cell spheroids formed on the tailored gelatin@NWF scaffold were characterized in cancer stem cell (CSC)-associated gene expression, chemotherapy drug sensitivity, and motility. It was found that the expression of the CSC-associated biomarkers SOX2, OCT4, and ALDH1A1 in gene and protein levels in DU 145 cell spheres formed on gelatin@NWF scaffolds were significantly higher than in those cells grown as monolayers. Moreover, cells isolated from spheroids grown on gelatin@NWF scaffold showed higher drug resistance and motility. Tumor spheroids can be formed on a long-term storage scaffold, highlighting the potential of gelatin@NWF as a ready-to-use scaffold for tumor cell sphere generation and culturing.

Wogonin exhibits notable anti‐inflammatory and neuroprotective effects. Current study aimed to investigate the antidepressant potential of wogonin and its underlying mechanisms through in vitro and in vivo experiments. In vitro, wogonin attenuated lipopolysaccharide (LPS)‐induced astrocyte activation. Furthermore, wogonin inhibited the TNF‐α/TNFR1/CXCL1 signalling axis, as evidenced by decreased protein levels of TNF‐α and CXCL1 and reduced interaction between TNF‐α and its receptor TNFR1. The addition of recombinant TNF‐α (r‐TNF‐α) blocked these inhibitory effects of wogonin. In vivo, in a chronic unpredictable mild stress (CUMS) mouse model, wogonin alleviated depression‐like behaviours. Moreover, wogonin rescued CUMS‐induced impairments in hippocampal synaptic plasticity, restoring post‐tetanic potentiation (PTP), long‐term potentiation (LTP) and mitigating neuronal damage in the CA1 region. Further analysis revealed that wogonin reduced levels of TNF‐α and CXCL1 in both the hippocampal CA1 region and cerebrospinal fluid, and decreased the expression of astrocyte activation markers GFAP and C3. These effects of wogonin in vivo were reversed by co‐administration of r‐TNF‐α and were replicated by treatment with the TNF‐α inhibitor etanercept. These results demonstrate that wogonin may exert antidepressant effects by modulating the TNF‐α/TNFR1/CXCL1 pathway, thereby improving neuroinflammation and astrocyte activation.