Background: Lung adenocarcinoma (LAC) is the predominant histologic subtype of lung cancer and has a complicated pathogenesis with high mortality. The purpose of this study was to identify differentially expressed genes (DEGs) with prognostic value and determine their underlying mechanisms. Methods: Gene expression data of GSE27262 and GSE118370 were acquired from the Gene Expression Omnibus database, enrolling 31 LAC and 31 normal tissues. Common DEGs between LAC and normal tissues were identified using the GEO2R tool and Venn diagram software. Next, the Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to analyze the Gene Ontology and Kyoto Encyclopedia of Gene and Genome (KEGG) pathways. Then, protein-protein interaction (PPI) network of DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes and central genes were identified via Molecular Complex Detection. Furthermore, the expression and prognostic information of central genes were validated via Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier analysis, respectively. Finally, DAVID, real-time PCR and immunohistochemistry were applied to re-analyze the identified genes, which were also further validated in two additional datasets from ArrayExpress database. Results: First, 189 common DEGs were identified among the two datasets, including 162 downregulated and 27 upregulated genes. Next, Gene Ontology and KEGG pathway analysis of the DEGs were conducted through DAVID. Then, PPI network of DEGs was constructed and 17 downregulated central genes were identified. Furthermore, the 17 downregulated central genes were validated via GEPIA and datasets from ArrayExpress, and 12 of them showed a significantly better prognosis. Finally, six genes were identified significantly enriched in neuroactive ligand-receptor interactions (EDNRB, RXFP1, P2RY1, CALCRL) and Rap1 signaling pathway (TEK, P2RY1, ANGPT1) via DAVID, which were further validated to be weakly expressed in LAC tissues via RNA quantification and immunohistochemistry analysis. Conclusions: The low expression pattern and relation to prognosis indicated that the six genes were potential tumor suppressor genes in LAC. In conclusion, we identified six significantly downregulated DEGs as prognostic markers and potential tumor suppressor genes in LAC based on integrated bioinformatics methods, which could act as potential molecular markers and therapeutic targets for LAC patients.

Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer and imposes a considerable health burden globally. The purpose of this study was to identify significant genes and key pathways participated in the initiation and progression of GAC. Four datasets (GSE13911, GSE19826, GSE54129, and GSE79973) including 171 GAC and 77 normal tissues from Gene Expression Omnibus (GEO) database were collected and analyzed. Through integrated bioinformatics analysis, we obtained 69 commonly differentially expressed genes (DEGs) among the four datasets, including 20 upregulated and 49 downregulated genes. The prime module in protein-protein interaction network of DEGs, including ADAMTS2, COL10A1, COL1A1, COL1A2, COL8A1, BGN, and SPP1, was enriched in protein digestion and absorption, ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and amoebiasis. Furthermore, expression and survival analysis found that all seven hub genes were highly expressed in GAC tissues and 6 of them (except for SPP1) were able to predict poor prognosis of GAC. Finally, we verified the 6 high-expressed hub genes in GAC tissues via immunohistochemistry, Western blot, and RNA quantification analysis. Altogether, we identified six significantly upregulated DEGs as poor prognostic markers in GAC based on integrated bioinformatical methods, which could be potential molecular markers and therapeutic targets for GAC patients.

Pathogen infections remain a significant public health problem worldwide. Accumulating evidence regarding the crosstalk between bile acid (BA) metabolism and immune response reveals that BA metabolism regulates host immunity and microbial pathogenesis, making it an attractive target for disease prevention and infection control. However, the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors remains to be depicted. Here, we investigated the effect of viral (vesicular stomatitis virus, VSV) and bacterial (lipopolysaccharide, LPS) infections on BA metabolism and signaling. Infection models were successfully established by intraperitoneally injecting VSV and LPS, respectively. VSV and LPS injection significantly changed the circulating BA profiles, with highly increased levels of taurine-conjugated BAs and significant decreases in unconjugated BAs. Consistent with the decreased levels of circulating cholic acid (CA) and chenodeoxycholic acid (CDCA), the expression of BA biosynthesis-related rate-limiting enzymes ( Cyp7a1 , Cyp27a1 , Cyp8b1, and Hsd3b7 ) were significantly reduced. Furthermore, hepatic and pulmonary BA receptors (BARs) expression varied in different infection models. LPS treatment had an extensive impact on tested hepatic and pulmonary BARs, resulting in the upregulation of TGR5, S1PR2, and VDR, while VSV infection only promoted VDR expression. Our study provides insights into the involvement of BA metabolism in the pathophysiology of infection, which may provide potential clues for targeting BA metabolism and BAR signaling to boost innate immunity and control infection. IMPORTANCE: This study focuses on the crosstalk between bile acid (BA) metabolism and immune response in VSV infection and LPS treatment models and depicts the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors. These findings provide insights into the effect of infection on BA metabolism and signaling, adding a more comprehensive understanding to the relationship between infection, BA metabolism and immune responses.

Pulmonary infections pose significant challenges in accurate prognosis due to the lack of reliable biomarkers. This study aims to explore the prognostic potential of soluble CD4 (sCD4) and sCD8 for adverse outcomes in hospitalized pulmonary infection patients. This study enrolled 112 hospitalized pulmonary infection patients and 62 healthy controls (HCs). Hospitalized patients were grouped into survivors (n = 87), who recovered and were discharged, and non-survivors (n = 25), who either died or discontinued treatment due to severe conditions. Plasma sCD4 and sCD8 levels were quantified by ELISA. T cell subsets were determined using flow cytometry. IL-6 and procalcitonin (PCT) levels were detected using electrochemiluminescence, and C-reactive protein (CRP) levels were measured using rate nephelometry. Inflammatory markers derived from complete blood count (CBC) were calculated accordingly. Receiver operating characteristic (ROC) analyses, Cox proportional hazard models and correlation analyses were conducted. Non-survivors were significantly older than survivors and HCs. Compared to survivors, non-survivors presented significantly higher levels of sCD8, PCT, IL-6, CRP and CBC-derived inflammatory markers, along with significantly reduced CD3⁺ T and CD8⁺ T cell counts. ROC analyses demonstrated that sCD8 had the highest area under the curve (AUC) value of 0.85 (0.78-0.92) with sensitivity and specificity of 100% and 66.67%, respectively. Other markers showed weak to moderate prognostic power with AUCs ranging from 0.64 to 0.75. Multivariate Cox hazard regression analysis indicated that higher sCD8, lower CD8⁺ T cell counts and the presence of mixed-type pathogenic infections remained independently associated with undesirable outcomes. sCD8 was positively correlated with all inflammatory markers but negatively correlated with T cell subset counts. Our data suggest that a plasma sCD8 level above the optimal cut-off value is independently associated with poor outcomes. Elevated sCD8 may be a novel prognostic biomarker in hospitalized pulmonary infection patients.

Programmed cell death protein 1 (PD-1), an immune checkpoint primarily expressed on T cells, plays a critical role in mediating tumor immune evasion. However, the role of PD-1 in non-immune cells remains poorly understood. Here, we report tumor cell-intrinsic PD-1 expression in malignant ascites from ovarian cancer patients. Using murine ovarian cancer models, we demonstrate that PD-1 directly promotes ovarian cancer progression. Moreover, malignant ascites markedly upregulates PD-1 expression in ID8 ovarian cancer cells, acting as a pathological amplifier that exacerbates PD-1-mediated oncogenic signaling cascades, including enhanced proliferation and metastasis both in vitro and in vivo. Mechanistically, soluble PD-L1 (sPD-L1) in ascites interacts with tumor cell-intrinsic PD-1, activating the MAPK/ERK signaling pathway through enhanced phosphorylation of ERK1/2. In contrast, PD-1 inhibition, achieved by genetic knockout or antibody blockade, reverses these tumor-promoting effects. Furthermore, pharmacological inhibition of phosphorylated ERK1/2 counteracts the tumor progression mediated by the PD-1 and prolongs survival in murine ovarian cancer models. Our study uncovers a previously unrecognized tumor-intrinsic PD-1-ERK signaling axis in ovarian cancer, that accelerates tumorigenesis and provides new insights and perspectives for PD-1/PD-L1 immune checkpoint therapy in ovarian cancer.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder driven by dysregulated immune responses. Macrophage-mediated inflammation is central to the pathology, and it is important to understand the epigenetic mechanisms involved. By screening epigenetic molecules that are differentially expressed in published human IBD datasets, we find Protein Arginine Methyltransferase 6 (PRMT6) consistently downregulated in IBD samples compared to healthy controls. Co-occurrence of Prmt6 suppression and Il1b induction within the myeloid compartment in colon biopsy samples indicates that PRMT6 limits macrophage-driven inflammation. Concordantly, Prmt6-deficient mice exhibit increased susceptibility to both DSS- and TNBS-induced colitis, characterized by exacerbated tissue damage and systemic elevation of IL-1β. Transcriptomic profiling confirms that PRMT6 deficiency selectively upregulates Il1b among inflammatory mediators. Mechanistically, PRMT6 suppresses Il1b transcription by interacting with RBBP5 and disrupting SET1A complex assembly, thereby reducing H3K4me3 enrichment at the Il1b promoter, independently of its canonical H3R2me2a catalytic activity. Furthermore, PRMT6 is transcriptionally silenced by the NF-κB subunit p50 during inflammation. Pharmacological inhibition of p50 restores PRMT6 expression, thus protecting mice from DSS-induced colitis in a PRMT6-dependent manner. Our findings highlight PRMT6 as a pivotal epigenetic regulator of the inflammatory response and provide proof of principle for targeting the p50–PRMT6–IL-1β axis in IBD.