Dataset Information

Identification and Validation of Ferroptosis-Related Biomarkers in Septic Cardiomyopathy via Bioinformatics Analysis.

ABSTRACT: Septic cardiomyopathy (SCM) is a cardiac dysfunction caused by severe sepsis and septic shock that increases the risk of heart failure and death and its molecular mechanism remains unclear. Ferroptosis, a novel form of programmed cell death, has been reported to be present in the heart tissue of patients with sepsis, which demonstrated that ferroptosis may be a potential mechanism of myocardial injury in SCM. Therefore, we explored the role of ferroptosis-related genes (FRGs) in SCM and aimed to identify pivotal ferroptosis-related targets in SCM and potential therapeutic targets involved in the pathological process of SCM. To explore the regulatory mechanisms of ferroptosis in SCM, we identified differentially expressed genes (DEGs) in SCM and FRGs by bioinformatics analysis, and further identified hub genes. And the crucial microRNAs (miRNAs)-FRGs regulatory network was subsequently constructed. Finally, several candidate drugs associated with the hub genes were predicted, and Real-time quantitative reverse Transcription PCR (qRT-PCR) and western blotting analysis were performed to confirm the abnormal expression of hub genes. In this study, we identified several FRGs that may be involved in the pathogenesis of SCM, which helps us further clarify the role of ferroptosis in SCM and deeply understand the molecular mechanisms and potential therapeutic targets of SCM.

SUBMITTER: Gong CW

PROVIDER: S-EPMC9043284 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Identification and Validation of Ferroptosis-Related Biomarkers in Septic Cardiomyopathy via Bioinformatics Analysis.

Gong Cheng-Wu CW Yuan Ming-Ming MM Qiu Bai-Quan BQ Wang Li-Jun LJ Zou Hua-Xi HX Hu Tie T Lai Song-Qing SQ Liu Ji-Chun JC

Frontiers in genetics 20220413

Septic cardiomyopathy (SCM) is a cardiac dysfunction caused by severe sepsis and septic shock that increases the risk of heart failure and death and its molecular mechanism remains unclear. Ferroptosis, a novel form of programmed cell death, has been reported to be present in the heart tissue of patients with sepsis, which demonstrated that ferroptosis may be a potential mechanism of myocardial injury in SCM. Therefore, we explored the role of ferroptosis-related genes (FRGs) in SCM and aimed to ...[more]

PMID: 35495160

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Project description:BackgroundChronic Thromboembolic Pulmonary Hypertension (CTEPH) is a form of pulmonary hypertension with a high mortality rate. A new type of iron-mediated cell death is Ferroptosis, which is characterized by the accumulation of lethal iron ions and lipid peroxidation leading to mitochondrial atrophy and increased mitochondrial membrane density. Now, there is a lack of Ferroptosis-related biomarkers (FRBs) associated with pathogenic process of CTEPH.MethodsThe differentially expressed genes (DEGs) of CTEPH were obtained by GEO2R. Genes related to Ferroptosis were obtained from FerrDb database. The intersection of Ferroptosis and DEGs results in FRBs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed in Database for Annotation, Visualization and Integrated Discovery (DAVID) database. The optimal potential biomarkers for CTEPH were analyzed by least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) machine learning. The four hub genes were verified from the Gene Expression Omnibus (GEO) dataset GSE188938. Immune infiltration was analyzed by CIBERSORT. SPSS software was used to analyze the Spearman rank correlation between FRBs identified and infiltration-related immune cells, and p < 0.05 was considered as statistically significant.ResultsIn this study, potential genetic biomarkers associated with Ferroptosis in CTEPH were investigated and explored their role in immune infiltration. In total, we identified 17 differentially expressed Ferroptosis-associated genes by GEOquery package. The key FRBs including ARRDC3, HMOX1, BRD4, and YWHAE were screened using Lasso and SVM-RFE machine learning methods.Through gene set GSE188938 verification, only upregulation of gene ARRDC3 showed statistical difference. In addition, immune infiltration analysis using the CIBERSORT algorithm revealed the infiltration of Eosinophils and Neutrophils in CTEPH samples was less than that in the control group. And correlation analysis revealed that ARRDC3 was positively correlated with T cells follicular helper (r = 0.554, p = 0.017) and negatively correlated with Neutrophils (r = -0.47, p = 0.049).ConclusionsIn conclusion, ARRDC3 upregulation with different immune cell infiltration were involved in the development of CTEPH. ARRDC3 might a potential Ferroptosis-related biomarker for CTEPH treatment. This study provided a new insight into pathogenesis CTEPH.

Project description:Background: Stroke is one of the most common deadly diseases with an estimated 780,000 new cases globally, of which ischemic stroke accounts for over 80% of all cases. Ferroptosis is a new form of programmed cell death that plays a vital role in many diseases, including ischemic stroke and heart diseases. The role of the ferroptosis-related gene in the diagnosis, prognosis, or therapy of ischemic stroke was not fully clarified. Methods: Ferroptosis-related differentially expressed genes (DEGs) in ischemic stroke were identified by bioinformatic analysis of the GSE16561 and GSE22255 datasets. Subsequently, receiver operator characteristic (ROC) monofactor analysis was performed to evaluate the diagnostic value of ferroptosis-related biomarkers in ischemic stroke. Results: A total of 10 ferroptosis-related DEGs were identified in ischemic stroke vs. normal control. GO and KEGG analysis revealed that these 10 ferroptosis-related DEGs were mainly enriched in response to oxidative stress, HIF-1 signaling pathway, ferroptosis, lipid, and atherosclerosis. Moreover, the random forest model suggested three ferroptosis-related biomarkers, namely, PTGS2, MAP1LC3B, and TLR4, for ischemic stroke. Interestingly, the expression of PTGS2, MAP1LC3B, and TLR4 was upregulated in ischemic stroke. ROC monofactor analysis demonstrated a good performance of MAP1LC3B, PTGS2, and TLR4 in the diagnosis of ischemic stroke. The expression and diagnostic value of MAP1LC3B, PTGS2, and TLR4 in ischemic stroke were also verified using GSE22255. We also revealed the transcription factor regulation network and co-expressed protein network of ferroptosis-related biomarkers. Several potential therapeutic compounds corresponding to MAP1LC3B, PTGS2, and TLR4 were also identified for ischemic stroke, including Zinc12503187 (Conivaptan), Zinc3932831 (Avodart), Zinc64033452 (Lumacaftor), Zinc11679756 (Eltrombopag), Zinc100378061 (Naldemedine), and Zinc3978005 (Dihydroergotamine). Conclusion: Our results suggested MAP1LC3B, PTGS2, and TLR4 as potential diagnostic biomarkers for ischemic stroke, providing more evidence about the vital role of ferroptosis in ischemic stroke.

Project description:BackgroundCardiomyocyte death is an important pathophysiological basis for ischemic cardiomyopathy (ICM). Many studies have suggested that ferroptosis is a key link in the development of ICM. We performed bioinformatics analysis and experiment validation to explore the potential ferroptosis-related genes and immune infiltration of ICM.MethodsWe downloaded the datasets of ICM from the Gene Expression Omnibus database and analyzed the ferroptosis-related differentially expressed genes (DEGs). Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and protein-protein interaction network were performed to analyze ferroptosis-related DEGs. Gene Set Enrichment Analysis was used to evaluate the gene enrichment signaling pathway of ferroptosis-related genes in ICM. Then, we explored the immune landscape of patients with ICM. Finally, the RNA expression of the top five ferroptosis-related DEGs was validated in blood samples from patients with ICM and healthy controls using qRT-PCR.ResultsOverall, 42 ferroptosis-related DEGs (17 upregulated and 25 downregulated genes) were identified. Functional enrichment analysis indicated several enriched terms related to ferroptosis and the immune pathway. Immunological analysis suggested that the immune microenvironment in patients with ICM is altered. The immune checkpoint-related genes (PDCD1LG2, LAG3, and TIGIT) were overexpressed in ICM. The qRT-PCR results showed that the expression levels of IL6, JUN, STAT3, and ATM in patients with ICM and healthy controls were consistent with the bioinformatics analysis results from the mRNA microarray.ConclusionOur study showed significant differences in ferroptosis-related genes and functional pathway between ICM patients and healthy controls. We also provided insight into the landscape of immune cells and the expression of immune checkpoints in patients with ICM. This study provides a new road for future investigation of the pathogenesis and treatment of ICM.

Dataset Information

Identification and Validation of Ferroptosis-Related Biomarkers in Septic Cardiomyopathy via Bioinformatics Analysis.

Publications

Identification and Validation of Ferroptosis-Related Biomarkers in Septic Cardiomyopathy via Bioinformatics Analysis.

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