Search

Ischemic stroke (IS) is a severe condition regulated by complex molecular alterations. This study aimed to identify potential nicotinamide adenine dinucleotide (NAD+) metabolism-associated diagnostic markers of IS and explore their associations with immune dynamics. Weighted Gene Co-expression Network Analysis and single-sample gene set enrichment analysis (ssGSEA) were employed to identify key gene modules on the GEO dataset (GSE16561). LASSO regression was used to identify diagnostic genes. A diagnostic model was then developed using the training dataset, and its performance was assessed using a validation dataset (GSE22255 dataset). Associations between hub genes and immune cells, immune response genes, and human leukocyte antigen (HLA) genes were assessed by ssGSEA. A regulatory network was constructed using mirBase and TRRUST databases. A total of 20 NAD+ metabolic genes exhibited noteworthy expression variations. Within the module notably associated with NAD+ metabolism, 19 specific genes were included in the diagnostic model, which was validated on the GSE22255 dataset (AUC: 0.733). There were significant disparities in immune cell populations, immune response genes, and HLA gene expression, all of which were associated with the hub genes. A regulatory network composed of 153 edges and 103 nodes was constructed. This study advances our understanding of IS by providing insights into NAD+ metabolism and gene interactions, contributing to potential diagnostic innovations in IS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lymphocyte antigen 96 (LY96) plays an important role in innate immunity and has been reported to be associated with various neurological diseases. However, its role in Parkinson's disease (PD) remains unclear., Methods: Transcriptome data from a total of 49 patients with PD and 34 healthy controls were downloaded from the Gene Expression Omnibus (GEO) database to analyse the expression pattern of LY96 and its relationship with gene function and immune-related markers. In addition, peripheral blood samples were collected from clinical patients to validate LY96 mRNA expression levels. Finally, an in vitro cell model of PD based on highly differentiated SH-SY5Y cells was constructed, with small interfering RNA-silenced LY96 expression, and LY96 mRNA level, cell viability, flow cytometry, and mitochondrial membrane potential assays were performed., Results: The results of the analyses of the GEO database and clinical samples revealed significantly abnormally high LY96 expression in patients with PD compared with healthy controls. The results of cell experiments showed that inhibiting LY96 expression alleviated adverse cellular effects by increasing cell viability, reducing apoptosis, and reducing oxidative stress. Gene set enrichment analysis showed that LY96 was positively correlated with T1 helper cells, T2 helper cells, neutrophils, natural killer T cells, myeloid-derived suppressor cells, macrophages, and activated CD4 cells, and may participate in PD through natural killer cell-mediated cytotoxicity pathways and extracellular matrix receptor interaction pathways., Conclusion: These findings suggested that LY96 might be a novel potential biomarker for PD, and offer insights into its immunoregulatory role., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sialic acid-binding immunoglobulin-like lectin 15 (Siglec15) is an immune checkpoint molecule that can inhibit T cell proliferation and have anti-tumor immunity. We explored the correlation between Siglct15 and the clinical features, mutation frequency, and prognosis of breast cancer. 122 upregulated and 11 downregulated genes between Siglet15-high and -low expression groups of 1109 breast invasive cancer samples (BRCA) obtained from the Cancer Genome Atlas (TCGA) were identified. Three subtypes (C1-C3) of BRCA based on Siglec15 were identified from TCGA datasets via consensus cluster plus analysis. The clinical characteristics, functional enrichments, immune environment, mutation frequency, prognosis were compared among these subgroups and were verified using GSE20685 and GSE31448 cohorts. C3 with highest level of Siglec15 expression was correlated with early tumor stage, hormone receptor-positive tumors, luminal A molecular subtype, lowest tumor mutational burden (TMB) score, lowest programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) expression, upregulated PI3K-Akt pathway and advantage of prognosis. C2 with lowest level of Siglec15 was associated with advanced stage, basal-like subtype, highest TMB score, highest PD-1 and PD-L1 expression, upregulated p53 signaling pathway and worse prognosis. Univariate and multivariate Cox regression analysis demonstrated that Siglec15-related subtype was an independent prognostic factor for breast cancer patients. Siglec15 related immunotherapy may be an important candidate for breast cancer patients especially for luminal subtype, independently of blockade of PD-1/PD-L1 immunotherapy. In conclusion, we identified three Siglec15-related subtypes of BRCA, helping us to understand the immunological function and significance of Siglec15 in the BRCA., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Large-scale epidemiological surveys have shown that patients with Down syndrome, which is caused by a chromosomal abnormality (an extra chromosome 21), are significantly less likely to develop solid tumors, including breast cancer, than those without. This feature has prompted the search for oncogenes located on chromosome 21. Junctional adhesion molecule 2 (JAM2), which is located on chromosome 21, is expressed at low levels in breast cancer and is associated with a good prognosis. These findings strongly suggest that JAM2 may be a potential oncogene suppressor in breast cancer. However, the role and function of JAM2 in breast cancer are not yet clear. Therefore, this study aimed to explore the biological functions and mechanisms of JAM2 in breast cancer., Methods: Several databases were used to explore JAM2 expression in breast cancer and to analyze its diagnostic and prognostic value in breast cancer. Changes in relevant markers were examined at the gene and protein levels using RT-qPCR and Western blot techniques, in addition, cell migration and invasion abilities were identified by scratch assays and transwell assays. Untargeted metabolomics, transcriptome sequencing and Luminex liquid suspension chip detection were performed in combination to study the mechanisms., Results: JAM2 is expressed at low levels in breast cancer, and patients with high JAM2 expression have a good prognosis, indicating that JAM2 has good clinical diagnostic and prognostic value. Overexpression of JAM2 can block the invasion and migration of breast cancer cells, and the mechanism may be that JAM2 inhibits the EMT pathway. Finally, combined multiomics analysis revealed that JAM2 may affect the immune microenvironment of breast cancer by influencing the secretion of CXCL9/10 from tumor cells., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Pyroptosis, a type of regulated cell death controlled by the gasdermin family of proteins to form plasma membrane pores is known. Nonetheless, the function of pyroptosis-related long non-coding RNAs (lncRNAs) in this process still lacks exhaustive elucidation in head and neck squamous cell carcinoma (HNSCC). Other attributes encompassing the function of such lncRNAs in the immune microenvironment and potential prognosis for HNSCC are yet to see the light of the day. This work was designed to probe the possible prognostic worth of pyroptosis-related lncRNAs along with their impact on the immune microenvironment in the case of HNSCC., Methods: The Cancer Genome Atlas (TCGA) database was the source of RNA-sequencing data of HNSCC patients. Pearson correlation analysis was employed to scour for lncRNAs linked to pyroptosis based on 40 genes related to the process. Following the construction of a pyroptosis-related lncRNA signature employing univariate, Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses, survival and nomogram analyses ensued to scrutinize the predictive value of the prognostic signature., Results: The segregation of patients into two risk groups was done by the constructed pyroptosis-related-lncRNA signature (encompassing 14 lncRNAs). The prognosis was poorer for individuals of the high-risk group versus (vs.) the low-risk group with the risk score emerging as an independent prognostic factor by regression analyses. The accuracy of this signature was corroborated by Receiver operating characteristic curve (ROC) analysis with the three-years area under time-dependent ROC curve (AUC) reaching 0.767. Further analyses unveiled a conspicuous enrichment of immune-related pathways in the low-risk group. The high-risk group demonstrated an immunologically "cold" profile based on the immune cell infiltration landscape., Conclusions: The lncRNA signature encompassing 14 pyroptosis-related lncRNAs could be a prognostic marker for HNSCC, suggesting pyroptosis might be a promising therapeutic target in HNSCC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Ferroptosis plays an important role across variable cancer types. However, few studies have focused on the prognostic patterns of ferroptosis-related genes in HNSCC. Cohorts with mRNA expression profiles, as well as corresponding clinical data of HNSCC patients from published studies, were collected and consolidated from public databases. We performed random survival forest analysis, Kaplan-Meier (KM) analysis of best combinations, and Cox regression analysis on 231 ferroptosis-related genes to construct a gene signature in the discovery cohort (TCGA), and later validated it in the validation cohort (GEO). The 7-gene signature was constructed to stratify patients into two groups according to their level of risk. Poorer overall survival (OS) was detected in the high risk (HRisk) group than in the low risk (LRisk) group in both the TCGA cohort (P < 0.0001, HR = 1.71, 95%CI:1.41-2.07) and the GEO cohort (P < 0.001, HR = 1.68, 95%CI:1.32-2.13). The risk score was identified as an independent predictive factor of OS in multivariate Cox regression analyses (HR > 1, P < 0.0001) in both cohorts. The signature's predictive capacity was proven by the time-dependent receiver operating characteristic (ROC) curve analysis and nomogram analysis. Functional enrichment analysis revealed that immunosuppressive pathways such as matrix extracellular space, and (transforming growth factor-β)TGF-β were enriched. The HRisk group was strongly associated with upregulation of both cancer-related pathways and stromal scores, while higher proportions of anti-tumor immune cells and immune signatures were enriched in the LRisk group. In conclusion, the signature based on 7 ferroptosis-related genes could be applicable for predicting the prognosis of HNSCC, indicating that ferroptosis may be a potential therapeutic target for HNSCC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Oral enrofloxacin treatment altered the gut microbiome promoting anti-inflammatory bacteria. The dysbiosis promotes regulatory cell induction in the intestines and in the periphery, which suppresses contact sensitivity. Bacterial-derived signals promote regulatory cell induction both directly and indirectly by influencing the phenotype of dendritic cells (DC)., Methods: Oral treatment with broad-spectrum antibiotic enrofloxacin was used to evaluate how gut flora perturbation shapes the immune response in the gut and the periphery., Results: Enrofloxacin-induced dysbiosis creates an anti-inflammatory environment characterized by increased IL-10 concentration in the gut lumen and tissues. The production of IFN-γ and IL-17A did not change. Oral enrofloxacin treatment skewed the profile of the immune response towards an anti-inflammatory phenotype locally in small intestinal Peyer's Patches (PP) and systematically in the spleen (SPL). Enrofloxacin administration changed immune response in PP by increasing TGF-β secretion from an increased percentage of TGF-β-producing. In the SPL, enrofloxacin treatment increased the secretion of TGF-β and IL-10 and decreased the secretion of IL-17A and IFN-γ. The shift in cytokine profile correlated with a higher percentage of latency-associated peptide and IL-10-producing cells and a decreased percentage of IFN-γ-producing T cells. This anti-inflammatory immune response in the PP and SPL promoted a higher frequency of tolerogenic DC., Conclusion: Our data indicate that two-week enrofloxacin treatment induces dysbiosis, skews immune response towards an anti-inflammatory phenotype, and elevates secretion of TGF-β and IL-10 in the intestines and periphery. Additionally, we observed higher frequencies of tolerogenic DC, characterized by CD11b and IL-10 expression, which are known inducers of Treg cells., (Copyright © 2019 Elsevier B.V. All rights reserved.)