4.7 Article

The antimicrobial peptide chensinin-1b alleviates the inflammatory response by targeting the TLR4/NF-?B signaling pathway and inhibits Pseudomonas aeruginosa infection and LPS-mediated sepsis

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BIOMEDICINE & PHARMACOTHERAPY
卷 165, 期 -, 页码 -

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ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2023.115227

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Antimicrobial peptide; Sepsis; Anti-inflammatory; TLR4; NF-& kappa;B

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Excessive inflammatory responses contribute to high mortality in sepsis. Targeting macrophages and reducing proinflammatory cytokine release is a potential therapeutic strategy. Chensinin-1b, derived from Rana chensinensis skin secretion, effectively neutralizes LPS and alleviates LPS-induced inflammatory responses. It prolongs survival, reduces organ damage, and mitigates inflammatory responses in septic shock models.
Excessive inflammatory responses are a major contributor to the high mortality associated with sepsis, a prev-alent global complication. Therefore, the potential therapeutic strategy for sepsis involves targeting macrophages and reducing proinflammatory cytokine release. Chensinin-1b, an analog of the natural antimicrobial peptide derived from Rana chensinensis skin secretion, exhibits broad-spectrum antibacterial activity and adopts a random coil conformation in both PBS and membrane solution. By efficiently neutralizing LPS, chensinin-1b holds promise in alleviating LPS-induced inflammatory responses. In this study, we established a mouse septic shock model by exposing mice to multiple-drug-resistant Pseudomonas aeruginosa, as well as an endotoxin-mediated sepsis model induced by LPS. Administering chensinin-1b significantly prolonged the survival of the experimental mice, concurrently mitigating inflammatory responses and reducing organ damage. Additionally, we investigated the anti-inflammatory mechanism of chensinin-1b using a constructed LPS-induced mouse macrophage RAW264.7 inflammatory model. Our findings demonstrated that chensinin-1b effectively mitigated the excessive activation of the TLR4/NF-KB signaling pathway by directly neutralizing extracellular LPS, thus ameliorating the inflammatory response. Moreover, upon blocking the TLR4 signaling pathway, chensinin-1b further reduced the release of proinflammatory cytokines induced by LPS, indicating alternative modes of regulation. Notably, chensinin-1b rapidly entered RAW264.7 cells within 30 min via endocytosis, diffusing into the cytoplasm while retaining its anti-inflammatory properties intracellularly. Although further investigations are warranted to comprehensively elucidate the intracellular anti-inflammatory mechanism of chensinin-1b, our findings substantiate its possession of anti-inflammatory properties both intracellularly and extracellularly. Thus, chensinin-1b emerges as a promising candidate for mitigating excessive inflammatory responses associated with sepsis.

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