PMID- 37359526 OWN - NLM STAT- MEDLINE DCOM- 20230628 LR - 20230701 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Six potential biomarkers in septic shock: a deep bioinformatics and prospective observational study. PG - 1184700 LID - 10.3389/fimmu.2023.1184700 [doi] LID - 1184700 AB - BACKGROUND: Septic shock occurs when sepsis is related to severe hypotension and leads to a remarkable high number of deaths. The early diagnosis of septic shock is essential to reduce mortality. High-quality biomarkers can be objectively measured and evaluated as indicators to accurately predict disease diagnosis. However, single-gene prediction efficiency is inadequate; therefore, we identified a risk-score model based on gene signature to elevate predictive efficiency. METHODS: The gene expression profiles of GSE33118 and GSE26440 were downloaded from the Gene Expression Omnibus (GEO) database. These two datasets were merged, and the differentially expressed genes (DEGs) were identified using the limma package in R software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs were performed. Subsequently, Lasso regression and Boruta feature selection algorithm were combined to identify the hub genes of septic shock. GSE9692 was then subjected to weighted gene co-expression network analysis (WGCNA) to identify the septic shock-related gene modules. Subsequently, the genes within such modules that matched with septic shock-related DEGs were identified as the hub genes of septic shock. To further understand the function and signaling pathways of hub genes, we performed gene set variation analysis (GSVA) and then used the CIBERSORT tool to analyze the immune cell infiltration pattern of diseases. The diagnostic value of hub genes in septic shock was determined using receiver operating characteristic (ROC) analysis and verified using quantitative PCR (qPCR) and Western blotting in our hospital patients with septic shock. RESULTS: A total of 975 DEGs in the GSE33118 and GSE26440 databases were obtained, of which 30 DEGs were remarkably upregulated. With the use of Lasso regression and Boruta feature selection algorithm, six hub genes (CD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4) with expression differences in septic shock were screened as potential diagnostic markers for septic shock among the significant DEGs and were further validated in the GSE9692 dataset. WGCNA was used to identify the co-expression modules and module-trait correlation. Enrichment analysis showed significant enrichment in the reactive oxygen species pathway, hypoxia, phosphatidylinositol 3-kinases (PI3K)/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, nuclear factor-kappabeta/tumor necrosis factor alpha (NF-kappabeta/TNF-alpha), and interleukin-6 (IL-6)/Janus Kinase (JAK)/Signal Transducers and Activators of Transcription 3 (STAT3) signaling pathways. The receiver operating characteristic curve (ROC) of these signature genes was 0.938, 0.914, 0.939, 0.956, 0.932, and 0.914, respectively. In the immune cell infiltration analysis, the infiltration of M0 macrophages, activated mast cells, neutrophils, CD8 T cells, and naive B cells was more significant in the septic shock group. In addition, higher expression levels of CD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4 messenger RNA (mRNA) were observed in peripheral blood mononuclear cells (PBMCs) isolated from septic shock patients than from healthy donors. Higher expression levels of CD177 and MMP8 proteins were also observed in the PBMCs isolated from septic shock patients than from control participants. CONCLUSIONS: CD177, CLEC5A, CYSTM1, MCEMP1, MMP8, and RGL4 were identified as hub genes, which were of considerable value in the early diagnosis of septic shock patients. These preliminary findings are of great significance for studying immune cell infiltration in the pathogenesis of septic shock, which should be further validated in clinical studies and basic studies. CI - Copyright (c) 2023 Kong, Zhu, Xie, Wu and Qian. FAU - Kong, Chang AU - Kong C AD - Department of Anesthesiology and Critical Care Medicine, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China. FAU - Zhu, Yurun AU - Zhu Y AD - Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Xie, Xiaofan AU - Xie X AD - Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Wu, Jiayu AU - Wu J AD - Department of General Practice, Central Health Center of Yayang Town, Taishun County (Yayang Branch of Medical Community of Taishun County People's Hospital), Wenzhou, Zhejiang, China. FAU - Qian, Meizi AU - Qian M AD - Department of Anesthesia, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. AD - Key Laboratory of Intelligent Treatment and Life Support for Critical Diseases of Zhejiang Province, Wenzhou Medical University, Wenzhou, China. LA - eng PT - Journal Article PT - Observational Study PT - Research Support, Non-U.S. Gov't DEP - 20230608 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - EC 3.4.24.34 (Matrix Metalloproteinase 8) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (Biomarkers) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (CLEC5A protein, human) RN - 0 (Receptors, Cell Surface) RN - 0 (Lectins, C-Type) SB - IM MH - Humans MH - *Shock, Septic/diagnosis/genetics MH - Matrix Metalloproteinase 8 MH - Leukocytes, Mononuclear MH - Phosphatidylinositol 3-Kinases MH - Biomarkers MH - Tumor Necrosis Factor-alpha MH - Computational Biology MH - Receptors, Cell Surface MH - Lectins, C-Type PMC - PMC10285480 OTO - NOTNLM OT - WGCNA OT - bioinformatic analysis OT - biomarker OT - prognosis OT - septic shock COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/06/26 19:07 MHDA- 2023/06/28 06:42 PMCR- 2023/01/01 CRDT- 2023/06/26 12:25 PHST- 2023/03/12 00:00 [received] PHST- 2023/05/15 00:00 [accepted] PHST- 2023/06/28 06:42 [medline] PHST- 2023/06/26 19:07 [pubmed] PHST- 2023/06/26 12:25 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1184700 [doi] PST - epublish SO - Front Immunol. 2023 Jun 8;14:1184700. doi: 10.3389/fimmu.2023.1184700. eCollection 2023.