Identification of sepsis-associated mitochondrial genes through RNA and single-cell sequencing approaches

BMC Medical Genomics, Journal Year: 2024, Volume and Issue: 17(1)

Published: May 3, 2024

Abstract Background Sepsis ranks among the most formidable clinical challenges, characterized by exorbitant treatment costs and substantial demands on healthcare resources. Mitochondrial dysfunction emerges as a pivotal risk factor in pathogenesis of sepsis, underscoring imperative to identify mitochondrial-related biomarkers. Such biomarkers are crucial for enhancing accuracy sepsis diagnostics prognostication. Methods In this study, adhering SEPSIS 3.0 criteria, we collected peripheral blood within 24 h admission from 20 patients at ICU Southwest Medical University Affiliated Hospital 10 healthy volunteers control group RNA-seq. The RNA-seq data were utilized differentially expressed RNAs. Concurrently, mitochondrial-associated genes (MiAGs) retrieved MitoCarta3.0 database. intersected with MiAGs. then subjected GO (Gene Ontology), KEGG (Kyoto Encyclopedia Genes Genomes) analyses core filtered using PPI (Protein-Protein Interaction) network. Subsequently, relevant datasets (GSE65682, GSE28750, GSE54514, GSE67652, GSE69528, GSE95233) downloaded GEO Expression Omnibus) database perform bioinformatic validation these genes. Survival analysis was conducted assess prognostic value genes, while ROC (Receiver Operating Characteristic) curves determined their diagnostic value, meta-analysis confirmed data. Finally, 5 samples (2 normal controls (NC); 2 sepsis; 1 SIRS (Systemic Inflammatory Response Syndrome), used single-cell sequencing expression levels different cell types. Results Integrating high-throughput bioinformatics, study identified two mitochondrial ( COX7B, NDUFA4 ) closely linked prognosis. demonstrated that lower COX7B exhibited higher day survival rate over 28 days, inversely correlating mortality. highlighted significant sensitivity specificity both AUC values 0.985 0.988 , respectively. Meta-analysis indicated overexpression contrast P < 0.01). Additionally, RNA revealed predominant monocytes-macrophages, T cells, B cells. Conclusion intimately prognosis offering potential guidance research into mechanisms underlying sepsis.

Language: Английский

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Parthenolide improves sepsis-induced coagulopathy by inhibiting mitochondrial-mediated apoptosis in vascular endothelial cells through BRD4/BCL-xL pathway

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 17, 2025

Sepsis is a systemic inflammatory syndrome that can cause coagulation abnormalities, leading to damage in multiple organs. Vascular endothelial cells (VECs) are crucial the development of sepsis-induced coagulopathy (SIC). The role Parthenolide (PTL) regulating SIC by protecting VECs remains unclear. study utilized septic rats and lipopolysaccharide (LPS)-stimulated simulate model observe therapeutic effects PTL. Additionally, nanotechnology was employed produce Nano-PTL (N-PTL), whether it has advantages over PTL treating SIC. been shown mitigate lung injury rats, significantly reduce tumor necrosis factor-α (TNF-α) levels, increase survival rates. treatment also enhances function, augments vascular cell (VEC) reduces mitochondrial fragmentation, increases both oxygen consumption rate (OCR) membrane potential (MMP), while inhibiting reactive species (ROS) production. By increasing BRD4/BCL-xL prevent mitochondrial-mediated apoptosis VECs, improve VEC consequently ameliorate nanotechnology-synthesized N-PTL further protective on function. This clarifies mechanisms SIC, offering new strategies directions for sepsis.

Language: Английский

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Mitochondrial-related genome-wide Mendelian randomization identifies putatively causal genes in the pathogenesis of sepsis

Surgery, Journal Year: 2025, Volume and Issue: 181, P. 109150 - 109150

Published: Feb. 10, 2025

The dysfunction of mitochondria has been associated with the development sepsis, but specific mitochondrial-related genes and their roles in sepsis have not fully elucidated. We employed Mendelian randomization colocalization analysis to investigate association between by integrating multi-omics data. Summary-level data on mitochondrial gene methylation, expression, protein abundance levels were obtained from corresponding studies quantitative trait loci, respectively. Genetic associations genome-wide catalog database. used MitoCarta3.0 database, which contains an updated list 1,136 human genes, identify genes. To assess gene-related molecular features we conducted summary data-based analysis. In addition, performed determine whether identified signal pairs shared a causal genetic variant. After methylation loci- expression loci loci-protein FIS1 as having tier 1 evidence for its sepsis. Methylation cg01299997 was found be lower FIS1, increased risk positive role methylation. Furthermore, NUDT2, IMMP2L, LYRM4, MRPL10, MRPL17, MTIF3, TFAM 2 evidence. Both NUDT2 observed ATP5MC1 VWA8 3 Among these tertiary level showed negative correlation (posterior probability H4 = 0.9242), whereas exhibited 0.7270). that TFAM, ATP5MC1, putatively levels. This study relation may enhance understanding pathogenic mechanisms development.

Language: Английский

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Identification and Experimental Validation of Biomarkers Associated With Mitochondria and Macrophage Polarization in Sepsis

Emergency Medicine International, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Background: Sepsis is a common and serious condition, where mitochondria macrophage polarization play crucial role. Therefore, this study aimed to identify validate biomarkers for sepsis associated with mitochondria‐related genes (MCRGs) polarization–related (MPRGs), providing new targets strategies therapeutic intervention. Methods: This utilized the GSE95233 GSE28750 datasets. Initially, intersection were identified by overlapping MCRGs results from differential expression analysis weighted gene co‐expression network (WGCNA). Biomarkers through machine learning analysis. A nomogram was developed evaluated based on these biomarkers. Finally, functional enrichment, immune infiltration, reverse transcription quantitative polymerase chain reaction (RT‐qPCR) analyses conducted further elucidate biological mechanisms underlying sepsis. Results: The YME1L1, ECHDC3, THEM4, COQ10A as Among them, showed significantly lower levels in samples, while ECHDC3 exhibited markedly higher expression. Notably, RT‐qPCR confirmed that samples. validated, effectively predicting risk. Enrichment indicated co‐enriched oxidative phosphorylation pathway. Additionally, 13 different cell types between control Biomarker association revealed CD8 T cells had strongest positive correlation YME1L1 (cor = 0.84, p < 0.05) negative −0.76, 0.05), suggesting their potential role disease mechanism. Conclusion: In study, sepsis, validated clinical These findings provided promising theoretical foundation development of targeted treatments

Language: Английский

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Prognostic gene landscapes and therapeutic insights in sepsis-induced coagulopathy

Thrombosis Research, Journal Year: 2024, Volume and Issue: 237, P. 1 - 13

Published: March 12, 2024

Language: Английский

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Screening and Identification of Neutrophil Extracellular Trap-related Diagnostic Biomarkers for Pediatric Sepsis by Machine Learning

Inflammation, Journal Year: 2024, Volume and Issue: unknown

Published: May 25, 2024

Language: Английский

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Identification and verification of disulfidptosis-related genes in sepsis-induced acute lung injury

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Aug. 28, 2024

Background Sepsis-induced acute lung injury (ALI) is a common and serious complication of sepsis that eventually progresses to life-threatening hypoxemia. Disulfidptosis newly discovered type cell death associated with the pathogenesis different diseases. This study investigated potential association between sepsis-induced disulfidptosis by bioinformatics analysis. Methods In order identify differentially expressed genes (DEGs) linked sepsis, we screened appropriate data sets from GEO database carried out differential The key shared DEGs 39 disulfidptosis–related were identified: ACSL4 MYL6 mRNA levels detected in datasets. We then used series analysis techniques, such as immune infiltration analysis, protein–protein interaction (PPI) network, genetic regulatory receiver operating characteristic (ROC), investigate possible relationship sepsis. Then, experimental verification was obtained for changes injury. Finally, variants or Mendelian randomization (MR) applied. Results Two found this investigation: myosin light chain 6 (MYL6) Acyl-CoA synthetase long-chain family member 4 (ACSL4). verified increased training Immune showed multiple levels. Building PPI network allowed us determine their related had distinct biological functions. co-expression involved networks. addition, both validation datasets confirmed diagnostic capabilities using ROC curves. Additionally, vivo vitro experiments consistent results MR revealed causal Conclusion have MYL6, which are injury, may be useful diagnosis management septic

Language: Английский

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Mitochondrial related genome-wide mendelian randomization identifies putatively causal genes in the pathogenesis of sepsis

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 13, 2024

Background The dysfunction of mitochondria has been associated with the development sepsis, but specific mitochondrial-related genes and their roles in sepsis have not fully elucidated. We employed Mendelian randomization colocalization analysis to investigate association between by integrating multi-omics data. Methods Summary-level data on mitochondrial gene methylation, expression, protein abundance levels were obtained from corresponding studies quantitative trait loci, respectively. Genetic associations GWAS catalog database. utilized MitoCarta3.0 database, which contains an updated list 1,136 human genes, identify genes. To assess gene-related molecular features we conducted summary-data-based analysis. Additionally, performed determine whether identified signal pairs shared a causal genetic variant. Findings After mQTL-eQTL eQTL-pQTL, FIS1 as having tier 1 evidence for its sepsis. Methylation cg01299997 was found be lower expression FIS1, increased risk positive role methylation. Furthermore, NUDT2, IMMP2L, LYRM4, MRPL10, MRPL17, MTIF3, TFAM 2 evidence. Both NUDT2 observed ATP5MC1 VWA8 3 Among these tertiary level showed negative correlation (PPH4=0.9242), while exhibited (PPH4=0.7270). Interpretations that TFAM, putatively levels. This study relation may enhance understanding pathogenic mechanisms development. Funding work supported Wuxi Health Commission Scientific Research Project [grant number No. Z202102].

Language: Английский

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