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

Su, Jingqian; Lin, Congfan; Lin, Xinrui; Hu, Shan; Deng, Xiaohui; Xie, Lian; Ye, Hui; Zhou, Fen; Wu, Shun

doi:10.1016/j.intimp.2024.112927

International Immunopharmacology

2024

DOI: 10.1016/j.intimp.2024.112927

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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

Jingqian Su,

Congfan Lin,

Xinrui Lin

et al.

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2024

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Cited by 2 publications

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Exploring and Validating the Mechanism of Ulinastatin in the Treatment of Sepsis-Associated Encephalopathy Based on Transcriptome Sequencing

Hu,

Zhang,

et al. 2024

JIR

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Purpose Sepsis can induce sepsis-associated encephalopathy (SAE), with Ulinastatin (UTI) serving a critical anti-inflammatory role. This study aimed to identify the hub genes in an SAE mouse model following UTI intervention and investigate the underlying molecular mechanisms. Materials and Methods Through differential expression analysis to obtain differentially expressed genes (DEGs), ie, UTI vs CLP (DEGs1) and Con vs CLP (DEGs2). After taking the intersection of the genes with opposite differential trends in these two parts and immune-related genes (IRGs), DE-IRGs were obtained. Hub genes in the protein-protein interaction (PPI) network were then determined using six algorithms from the Cytohubba plugin in Cytoscape. Gene set enrichment analysis (GSEA) was employed to explore the functional relevance of these hub genes. Additionally, the immune microenvironment across the three groups was compared, and hub gene-related drugs were predicted using an online database. Finally, qRT-PCR was used to validate the expression of the hub genes in hippocampal tissue from CLP mice. Results RNA sequencing obtained 864 differentially expressed genes (DEGs) (CLP vs Con) and 279 DEGs (UTI vs CLP). Taking the intersection of DEGs with opposite expression trends yielded 165 DEGs. Six key genes (ICAM - 1, IRF7, IL - 1β, CCL2, IL - 6 and SOCS3) were screened by six algorithms. Immune infiltration analysis found that Treg cells were reversed after treatment with UTI in the diseased state. A total of 106 hub - gene - related drugs were predicted, among which BINDARIT - CCL2 and LIFITEGRAST - ICAM1 showed particularly high affinities. The qRT - PCR verification results were consistent with the sequencing results. Conclusion In conclusion, ICAM-1, IRF7, IL-1β, CCL2, IL-6 , and SOCS3 were identified as potential therapeutic targets in SAE mice treated with UTI. This study offers theoretical support for UTI as a treatment option for SAE.

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Exploring and Validating the Mechanism of Ulinastatin in the Treatment of Sepsis-Associated Encephalopathy Based on Transcriptome Sequencing

Hu,

Zhang,

et al. 2024

JIR

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Aloe-emodin plus TIENAM ameliorate cecal ligation and puncture-induced sepsis in mice by attenuating inflammation and modulating microbiota

Su,

Deng,

et al. 2024

Front. Microbiol.

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Despite the high sepsis-associated mortality, effective and specific treatments remain limited. Using conventional antibiotics as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging due to increasing bacterial resistance, diminishing their efficacy and leading to adverse effects. We previously found that aloe-emodin (AE) exerts therapeutic effects on sepsis by reducing systemic inflammation and regulating the gut microbiota. Here, we investigated whether administering AE and TIE post-sepsis onset, using a cecal ligation and puncture (CLP)-induced sepsis model, extends survival and improves physiological functions. Survival rates, inflammatory cytokines, tissue damage, immune cell populations, ascitic fluid microbiota, and key signaling pathways were assessed. Combining AE and TIE significantly enhanced survival rates, and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Moreover, substantial improvements in survival rates of AE + TIE-treated mice (10% to 60%) within 168 h were observed relative to the CLP group. This combination therapy also effectively modulated inflammatory marker (interleukin [IL]-6, IL-1β, and tumor necrosis factor [TNF]-α) levels and immune cell counts by decreasing those of B, NK, and TNFR2+ Treg cells, while increasing that of CD8+ T cells; alleviated tissue damage; reduced bacterial load in the peritoneal cavity; and suppressed the NF-κB signaling pathway. We also observed a significantly altered peritoneal cavity microbiota composition post-treatment, characterized by reduced pathogenic bacteria (Bacteroides) abundance. Our findings underscore the potential of AE + TIE in treating sepsis, and encourage further research and possible clinical implementations to surmount the limitations of TIE and amplify the therapeutic potential of AE.

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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

Cited by 2 publications

References 48 publications

Exploring and Validating the Mechanism of Ulinastatin in the Treatment of Sepsis-Associated Encephalopathy Based on Transcriptome Sequencing

Exploring and Validating the Mechanism of Ulinastatin in the Treatment of Sepsis-Associated Encephalopathy Based on Transcriptome Sequencing

Aloe-emodin plus TIENAM ameliorate cecal ligation and puncture-induced sepsis in mice by attenuating inflammation and modulating microbiota

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