Recombinant Antithrombin Alleviated Pulmonary Injury and Inflammation in LPS-Induced ARDS by Inhibiting IL17a/NF-κB Signaling

ImmunoTargets and Therapy, Год журнала: 2025, Номер Volume 14, С. 433 - 449

Опубликована: Апрель 1, 2025

Recombinant antithrombin (rAT) has been shown to protect lungs from ARDS and modulate immune responses, but its anti-inflammatory mechanisms remain unclear. This study aimed explore the immunomodulatory effects of rAT in LPS-induced mice. mouse model was established by intraperitoneally administration 20 mg/kg LPS. After 3 hours LPS administration, or PBS injected intravenously. Lung injury, alveolar permeability, serum inflammatory cytokines, cell infiltration lung tissue, proportion Th17 were assessed 36 after administration. The functional roles differential expressed genes (DEGs), obtained mice treated with without rAT, analyzed GO, KEGG GSEA enrichment analysis. activation NF-κB NLRP3 inflammasome evaluated Western blot immunofluorescence staining. We found that alleviated reduced pulmonary decreased suppressed activation. Moreover, cells tissues peripheral blood, downregulated IL17a expression, inhibited signaling pathway tissues. Additionally, IL-17A diminished efficacy mitigating suppressing response, inhibiting findings this suggest alleviates injury suppresses responses IL17a/NF-κB axis, suggesting may serve as a potential therapeutic agent for inflammation improving prognosis induced sepsis. Furthermore, provides important research data theoretical basis clinical translation application rAT.

Язык: Английский

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Integration of Transcriptomic and Single-Cell Data to Uncover Senescence- and Ferroptosis-Associated Biomarkers in Sepsis

Biomedicines, Год журнала: 2025, Номер 13(4), С. 942 - 942

Опубликована: Апрель 11, 2025

Background: Sepsis is a life-threatening condition characterized by organ dysfunction due to an imbalanced immune response infection, with high mortality. Ferroptosis, iron-dependent cell death process, and cellular senescence, which exacerbates inflammation, have recently been implicated in sepsis pathophysiology. Methods: Weighted gene co-expression network analysis (WGCNA) was used identify ferroptosis- senescence-related modules sepsis. Differentially expressed genes (DEGs) were analyzed using public datasets (GSE57065, GSE65682, GSE26378). Receiver operating characteristic (ROC) performed evaluate their diagnostic potential, while single-cell RNA sequencing (scRNA-seq) assess immune-cell-specific expression. Molecular docking conducted predict drug interactions key proteins. Results: Five (CD82, MAPK14, NEDD4, TXN, WIPI1) significantly upregulated patients highly correlated infiltration. MAPK14 TXN exhibited strong potential (AUC = 0.983, 0.978). suggested therapeutic diclofenac, flurbiprofen, N-acetyl-L-cysteine. Conclusions: This study highlights ferroptosis senescence as critical mechanisms identifies promising biomarkers for diagnosis targeted therapy. Future studies should focus on clinical validation precision medicine applications.

Язык: Английский

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Combining ulinastatin with TIENAM improves the outcome of sepsis induced by cecal ligation and puncture in mice by reducing inflammation and regulating immune responses

International Immunopharmacology, Год журнала: 2024, Номер 141, С. 112927 - 112927

Опубликована: Авг. 19, 2024

Язык: Английский

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Tim-3 pathway dysregulation and targeting in sepsis-induced immunosuppression

European journal of medical research, Год журнала: 2024, Номер 29(1)

Опубликована: Дек. 18, 2024

Sepsis is a major medical problem which causes millions of deaths worldwide every year. The host immune response in sepsis characterized by acute inflammation and simultaneous state immunosuppression. In the later stage sepsis, immunosuppression crucial factor that increases susceptibility septic patients to secondary infection mortality. It T cell exhaustion, excessive production anti-inflammatory cytokines, hyperproliferation suppressor cells aberrant expression checkpoint molecules. immunoglobulin mucin domain 3 (Tim-3), an molecule, found on surface various cells, including macrophages, NK NKT cells. There are four different ligands for Tim-3, accumulating evidence indicates Tim-3 its play role regulating dysfunction during sepsis. Anti-Tim-3 antibodies have been applied field cancer immunotherapy achieved positive therapeutic effects some clinical trials. However, efficacy blockade still controversial animal models These challenges highlight need deeper understanding signaling This review examines comprehensive effect development sepsis-induced blockade.

Язык: Английский

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mTOR Deletion Alleviates CD4+ T‐Cell Dysfunction in Sepsis through Reducing CTLA4 Accumulation Mediated by Rescuing Autophagy

Mediators of Inflammation, Год журнала: 2024, Номер 2024(1)

Опубликована: Янв. 1, 2024

Sepsis has been the leading cause of death in ICU patients. CD4+ T cells are mainstay body’s immune system, and depletion sepsis is great concern. Cytotoxic lymphocyte‐associated protein 4 (CTLA4) a negative immunomodulator for cell activation degradation through autophagy‐lysosome pathway. Mammalian target rapamycin (mTOR) most classical upstream regulator autophagy. With mouse model cecal ligation puncture (CLP), specific‐mTOR/tuberous sclerosis complex 1 (TSC1)‐knockout mice, bafilomycin A1, specific autophagosome‐lysosome (A‐L) fusion inhibitor, we primarily proved that mTOR could modulate expression accumulation CTLA4 by regulating onset process autophagy such as A‐L fusion. Given regulatory relationship, targeting provide new light to improve function sepsis, prospect using clinic would be worth exploring further.

Язык: Английский

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Th17-Mediated Immune Responses in Pathogenesis of Neuroinflammatory Disorders

Springer eBooks, Год журнала: 2024, Номер unknown, С. 1 - 30

Опубликована: Янв. 1, 2024

Язык: Английский

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Pharmacodynamic Response to Deucravacitinib, an Oral, Selective, Allosteric TYK2 Inhibitor, in a Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled Psoriasis Trial

Dermatology and Therapy, Год журнала: 2024, Номер 14(10), С. 2827 - 2839

Опубликована: Сен. 16, 2024

Psoriasis, a chronic, immune-mediated, inflammatory disease, affects 2‒3% of the population. Tyrosine kinase 2 (TYK2) mediates cytokine signaling involved in adaptive [interleukin (IL)-12, IL-23] and innate (type-I interferons) immune responses; IL-23-driven T-helper (Th)17 pathways play key role chronic inflammation psoriasis. In phase trial, deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, reduced IL-23/Th17 type-I interferon pathway expression skin patients with moderate to severe plaque psoriasis, reductions that were accompanied by clinical improvement psoriatic lesions.

Язык: Английский

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Identification of sepsis-related genes by integrating eQTL data with Mendelian randomization analysis

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Сен. 24, 2024

Background Sepsis is defined as a life-threatening organ dysfunction caused by dysfunctional host response to infection and associated with high mortality. However, there currently no effective treatment strategy for sepsis. Methods We obtained GSE263789, GSE54514 GSE66099 from the Gene Expression Omnibus (GEO) database selected differentially expressed genes (DEGs). extracted expression quantitative trait loci (eQTL) exposure sepsis GWAS outcome IEU Open database. MR analysis was used assess causality between eQTL The overlapping of DEGs significant were identified key genes. Enrichment immune cell infiltration performed verified in validation cohort. Results 18 sepsis-related genes, including 11 up-regulated (SEMA4A, LRPAP1, FAM89B, TOMM40L, SLC22A15, MACF1, MCTP2, NTSR1, PNKD, ACTR10, CPNE3) 7 down-regulated (IKZF3, TNFRSF25, HDC, HCP5, LYRM4, TFAM, RPS15A). analyses showed that these are mainly involved biological processes related inflammatory response. Compared healthy controls, abundance neutrophils activated mast cells increased group. Most correlated cells, neutrophils, CD8 T resting NK plasma memory B macrophage subtypes. Conclusion By combining bioinformatics analysis, we sepsis, enhancing our understanding genetic pathogenesis providing new insights into therapeutic targets

Язык: Английский

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Th17-Mediated Immune Responses in Pathogenesis of Neuroinflammatory Disorders

Опубликована: Янв. 1, 2024

Язык: Английский

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