Inhibition of Interleukin-40 prevents multi-organ damage during sepsis by blocking NETosis

Critical Care, Год журнала: 2025, Номер 29(1)

Опубликована: Янв. 16, 2025

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to lack precise biomarkers for patient stratification therapeutic guidance. Interleukin 40 (IL-40), a novel cytokine with immune regulatory functions in human diseases, was elevated at admission two independent cohorts patients sepsis. High levels secreted IL-40 septic were positively correlated PCT, CRP, lactate (LDH), Sequential Organ Failure Assessment (SOFA) scores, which used stratify early death critically ill Moreover, genetic knockout (IL-40−/−) improved outcomes mice experimental sepsis, as evidenced by attenuated storm, multiple-organ failure, mortality, compared those wild-type (WT) mice. Mechanistically, single-cell RNA sequencing (scRNA-seq) bulk (RNA-seq) have revealed that S100A8/9hi neutrophil influx into peritoneal cavity along extracellular trap (NETs) formation accounts predominantly IL-40-mediated worsening outcomes. Clinically, level NET-related MPO/dsDNA ratio patients. Finally, antibiotics (gentamycin), prevented polymicrobial fatalities more efficiently than without gentamycin treatment. In summary, these data reveal prognostic strategy may serve target

Язык: Английский

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SIRT1 Regulates Fumonisin B1-Induced LMH Cell PANoptosis and Antagonism of Lycopene

Journal of Agricultural and Food Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

Mycotoxin contamination is a universal agricultural problem and critical health issue. Fumonisin B1 (FB1) one of the most toxic extensive fumonisins that exist in various agro-products foods. Lycopene (LYC), as natural carotenoid, becoming increasingly favored owing to its oxidation resistance. Here, we aim explore mechanism FB1-induced hepatotoxicity antagonism LYC. In this study, our findings indicated FB1 induced mitochondrial structure damage loss function chicken hepatocytes. Furthermore, upregulated expression PANoptosis-related signal molecules. also reduced levels SIRT1 Ac-FOXO1 protein expression, which then inhibited mitophagy. However, LYC relieved these alterations. Most importantly, knockdown protective effects PANoptosis. Our study provides evidence for role mycotoxin-induced hepatocyte injury points potential target liver protection.

Язык: Английский

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S100A9 in Sepsis: A Biomarker for Inflammation and a Mediator of Organ Damage

Biochemical and Biophysical Research Communications, Год журнала: 2025, Номер unknown, С. 151484 - 151484

Опубликована: Фев. 1, 2025

Язык: Английский

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Tungsten-based polyoxometalate nanoclusters as ferroptosis inhibitors modulating S100A8/A9-mediated iron metabolism pathway for managing intracerebral haemorrhage

Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)

Опубликована: Фев. 19, 2025

Intracerebral haemorrhage (ICH) is a devastating neurological disorder with high morbidity and mortality rates, largely owing to the lack of effective therapeutic strategies. Growing evidence has underscored pivotal role ferroptosis in intracerebral haemorrhage, its contribution neuronal death exacerbation brain injury, thus establishing it as crucial target for intervention. In recent years, polyoxometalate nanoclusters (NCs) have been applied various neurodegenerative diseases, demonstrating neuroprotective effects. However, their impact on iron content function following ICH yet be reported. Here, we explored potential tungsten-based (W-POM) NCs inhibitors targeting metabolic pathway mediated by S100A8/A9 treatment ICH. We successfully synthesized ultra-small reduced W-POM that can rapidly cross blood-brain barrier are cleared through kidney. vitro experiments demonstrated exhibit significant stable ROS scavenging activity while effectively alleviating overload associated damage. vivo, restored metabolism homeostasis, suppressed neuroinflammation oxidative stress, ultimately severe damage motor deficits mice. Proteomic combined bioinformatic analyses identified two core genes, S100A8 S100A9, most intervention Further confirmed act modulating toll-like receptor 4/hepcidin/ferroportin signaling pathway, thereby regulating reducing secondary injury. This study pioneers application polyoxometalates offering novel promising approach management ferroptosis-related injuries.

Язык: Английский

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Extracellular vesicle-bound S100A8/A9 is differentially expressed in septic shock and prompts acute lung injury

Respiratory Research, Год журнала: 2025, Номер 26(1)

Опубликована: Март 18, 2025

Sepsis is a common indirect insult leading to acute respiratory distress syndrome (ARDS). Circulating extracellular vesicles (EVs) have been reported participate in the pathogenesis of sepsis. However, alteration EV-bound S100A8/A9 during septic shock, along with role driving lung injury, remains unexplored. EVs were isolated from plasma patients upon admission sepsis or as well healthy controls. Levels EV assayed via ELISA. To examine effects and underlying mechanisms shock these administered intratracheally into wild-type C57BL/6 mice deficiency advanced glycation end-products (RAGE). In addition, mouse model polymicrobial was introduced using cecal ligation puncture (CLP). significantly elevated compared Receiver operating characteristic (ROC) analysis demonstrated that effectively distinguished between had predictive potential for development ARDS. Notably, levels alveolar macrophages CLP higher than those sham mice. Intratracheal administration directly induced injury M1 macrophage polarization lipopolysaccharide-independent manner. Septic efficiently taken up by vivo, significant increase levels, which inhibited preincubating an neutralizing antibody. Additionally, RAGE, receptor S100A8/A9, partially protected EVs. vitro, prompted proinflammatory response bone marrow-derived macrophages. This blocked Our results suggested has value distinguishing predicting EVs-induced at least mediated through S100A8/A9-RAGE pathway, involving activation

Язык: Английский

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Screening and analysis of programmed cell death related genes and targeted drugs in sepsis

Hereditas, Год журнала: 2025, Номер 162(1)

Опубликована: Март 19, 2025

Abstract Objective This study employed bioinformatics techniques to identify diagnostic genes associated with programmed cell death (PCD) and explore potential therapeutic agents for the treatment of sepsis. Methods Gene expression profiles from sepsis patients were analyzed differentially expressed (DEGs) hub through Weighted Co-expression Network Analysis (WGCNA). Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) analyses conducted elucidate functions DEGs. PCD-related cross-referenced identified Diagnostic selected using Least Absolute Shrinkage Selection Operator (LASSO) Random Forest (RF) methodologies. Single-cell RNA sequencing was utilized assess gene in blood cells, while CIBERSORT evaluate immune infiltration. A transcription factor (TF)-microRNA (miRNA)-hub network constructed, compounds predicted Drug Interaction Database (DGIdb). Mendelian Randomization (MR) methods applied analyze genome-wide association (GWAS) data S100A9, TXN, GSTO1. Results The analysis revealed 2156 genes, 714 DEGs, 1198 88 enriched pathways. Five pivotal (IRAK3, NFATC2, GSTO1) identified, leading construction a comprising six factors 171 microRNAs. Additionally, seven drugs targeting NFATC2 identified. MR suggested that decrease GSTO1 levels is an increased risk sepsis, influences Conclusions Through approaches, this successfully five context research candidate established methodological framework predicting biomarkers drug targets could be applicable other diseases.

Язык: Английский

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Advances in sepsis research: Insights into signaling pathways, organ failure, and emerging intervention strategies

Experimental and Molecular Pathology, Год журнала: 2025, Номер 142, С. 104963 - 104963

Опубликована: Март 27, 2025

Язык: Английский

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Exploring Core Genes Associated with Sepsis and Systemic Inflammatory Response Syndrome Using Single-Cell Sequencing Technology

Journal of Inflammation Research, Год журнала: 2025, Номер Volume 18, С. 1815 - 1838

Опубликована: Фев. 1, 2025

Purpose: As a crucial aspect of emergency critical medicine, sepsis has been in difficult stage. its "preparatory stage", SIRS attracted the attention medical workers all over world. The frequency occurrence is on rise, but there lack certain indicators for timely detection and recognition illnesses. Methods: By virtue scRNA-seq, this research analyzed single-cell transcriptome data from samples taken groups with septic death systemic inflammatory response syndrome so as to identify unique markers patterns immune response. Results: revealing status twelve cell clusters four major types blood through UMAP clustering differences populations between dead patients, results have elucidated components different cells their marker genes two disease states, mechanism beneficial diagnosis samples. Conclusion: establishing theoretical framework centered cellular molecular regulation, study introduced novel approach diagnosing treating group patients early, well differentiating preventing these conditions. Keywords: sepsis, SIRS, single sequencing, biomarkers,

Язык: Английский

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Inhibition of Piezo1 Ameliorates Septic Cardiomyopathy by Blocking Calcium-Dependent PANoptosis

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177438 - 177438

Опубликована: Фев. 1, 2025

Язык: Английский

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Neutrophil-derived exosomal S100A8 aggravates lung injury in sepsis by inducing pyroptosis

Molecular Immunology, Год журнала: 2025, Номер 181, С. 29 - 39

Опубликована: Март 8, 2025

Язык: Английский

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