Elucidating key immunological biomarkers and immune microenvironment dynamics in aging-related intracranial aneurysm through integrated multi-omics analysis.

BACKGROUND: The exact cause of intracranial aneurysms (IA) is still unclear. However, pro-inflammatory factors are known to contribute to IA progression. The specific changes in the immune microenvironment of IAs remain largely unexplored. METHODS: This study analyzed single-cell sequencing data from a male mouse model of brain aneurysm, focusing on samples before and after elastase-induced Willis aneurysms. The data helped identify eight distinct cell subpopulations: fibroblasts, macrophages, NK cells, endothelial cells, B cells, granulocytes, and monocytes. The study also involved bulk RNA sequencing of 97 IA samples, utilizing ssGSEA and CIBERSORT algorithms for analysis. Intercellular communication among these cells was inferred to understand the immune dynamics in IA. RESULTS: The study found that fibroblasts and macrophages are predominant in various disease states of IA. Notably, the onset of IA was marked by a significant increase in fibroblasts and a decrease in macrophages. There was a marked increase in cellular interactions, especially involving macrophages, at the onset of the disease. Through enrichment analysis, 12 potential immunogenic biomarkers were identified. Of these, Rgs1 emerged as a critical molecule in IA formation, confirmed through secondary validation in a single-cell sequencing dataset. CONCLUSION: This comprehensive analysis of immune cell composition and intercellular communication in IA tissues highlights the significant roles of macrophages and the molecule Rgs1. These findings shed light on the physiological and pathological conditions of IA, offering new insights into its immune microenvironment.

Comprehensive Bioinformatics Analysis and Machine Learning of TTK as a Transhepatic Arterial Chemoembolization Resistance Target in Hepatocellular Carcinoma.

Transhepatic arterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, a significant proportion of patients are non-responders or poor responders to TACE. Therefore, our aim is to identify the targets of TACE responders or non-responders. GSE104580 was utilized to identify differentially expressed genes (DEGs) in TACE responders and non-responders. Following the protein-protein interaction (PPI) analysis, hub genes were identified using the MCC and MCODE plugins in Cytoscape software, as well as LASSO regression analysis. Gene set enrichment analysis (GSEA) was performed to investigate potential mechanisms. Subsequently, the hub genes were validated using data from The Cancer Genome Atlas (TCGA), the Cancer Cell Line Encyclopedia (CCLE), and The Human Protein Atlas (HPA) database. To evaluate the clinical significance of the hub genes, Kaplan-Meier (KM) survival and Cox regression analysis were employed. A total of 375 DEGs were identified, with 126 remaining following PPI analysis, and TTK, a dual-specificity protein kinase associated with cell proliferation, was ultimately identified as the hub gene through multiple screening methods. Data analysis from TCGA, CCLE, and HPA databases revealed elevated TTK expression in HCC tissues. GSEA indicated that the cell cycle, farnesoid X receptor pathway, PPAR pathway, FOXM1 pathway, E2F pathway, and ferroptosis could be potential mechanisms for TACE non-responders. Analysis of immune cell infiltration showed a significant correlation between TTK and Th2 cells. KM and Cox analysis suggested that HCC patients with high TTK expression had a worse prognosis. TTK may play a pivotal role in HCC patients' response to TACE therapy and could be linked to the prognosis of these patients.

Network Pharmacology to Reveal the Mechanism of Fufang Banmao Capsule for Treating Unresectable Primary Liver Cancer and Clinical Data Validation.

INTRODUCTION: Fufang Banmao capsules (FFBM), a traditional Chinese medicine, has been used to treat primary liver cancer (PLC) for several years. However, the bioactive ingredients, and mechanism of FFBM for treating PLC remains unclear. Our objective is to utilize network pharmacology to investigate these aspects and subsequently validate their effectiveness through clinical data. MATERIALS AND METHODS: The FFBM ingredients were obtained from the HERB database and screened for bioactive ingredients using the SwissTargetPrediction database. The PharmMapper and GEO database were used to acquire targets and differentially expressed genes (DEGs) for FFBM and PLC, respectively. Common targets were identified using Venn diagrams, followed by enrichment and protein-protein interaction (PPI) analysis. Furthermore, the Cytoscape software was utilized to identify Hub genes and construct the ingredienttarget- pathway network. Subsequently, patients diagnosed with unresectable PLC who underwent transcatheter arterial chemoembolization (TACE) at our hospital between January 2008 and December 2019 were retrospectively collected. Finally, Cox analysis was conducted to reveal the role of FFBM in the treatment of unresectable PLC. RESULTS: FFBM had 232 targets, and PLC had 1582 DEGs. HSP90AA1 and SRC were identified as crucial targets. Alpha-santalol, glycyrrhizin, and morroniside were identified as the top three bioactive ingredients. Enrichment analysis revealed a significant connection between FFBM utilization for treating PLC and multiple pathways, such as chemical carcinogenesis, PI3K-AKT, Rap1, FoxO, MAPK, and VEGF pathway. Clinic data revealed that consuming FFBM significantly improved the prognosis of unresectable PLC with a hazard ratio of 0.69. CONCLUSION: Our study identified the bioactive ingredients of FFBM and its potential mechanisms for treating PLC. Additionally, we validated the effectiveness through clinical data.

Schisandra chinensis inhibits the entry of BoHV-1 by blocking PI3K-Akt pathway and enhances the m6A methylation of gD to inhibit the entry of progeny virus.

Schisandra chinensis, a traditional Chinese medicine known for its antitussive and sedative effects, has shown promise in preventing various viral infections. Bovine herpesvirus-1 (BoHV-1) is an enveloped DNA virus that causes respiratory disease in cattle, leading to significant economic losses in the industry. Because the lack of previous reports on Schisandra chinensis resisting BoHV-1 infection, this study aimed to investigate the specific mechanisms involved. Results from TCID50, qPCR, IFA, and western blot analyses demonstrated that Schisandra chinensis could inhibit BoHV-1 entry into MDBK cells, primarily through its extract Methylgomisin O (Meth O). The specific mechanism involved Meth O blocking BoHV-1 entry into cells via clathrin- and caveolin-mediated endocytosis by suppressing the activation of PI3K-Akt signaling pathway. Additionally, findings from TCID50, qPCR, co-immunoprecipitation and western blot assays revealed that Schisandra chinensis blocked BoHV-1 gD transcription through enhancing m6A methylation of gD after virus entry, thereby hindering gD protein expression and preventing progeny virus entry into cells and ultimately inhibiting BoHV-1 replication. Overall, these results suggest that Schisandra chinensis can resist BoHV-1 infection by targeting the PI3K-Akt signaling pathway and inhibiting gD transcription.