School of Life Science, Liaoning Normal University, Dalian 116081, China.
School of Life Science, Liaoning Normal University, Dalian 116081, China; Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116081, China.
Biomed Pharmacother. 2023 Sep;165:115227. doi: 10.1016/j.biopha.2023.115227. Epub 2023 Aug 2.
Excessive inflammatory responses are a major contributor to the high mortality associated with sepsis, a prevalent 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-κB 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.
过度的炎症反应是导致脓毒症高死亡率的主要原因之一，脓毒症是一种普遍存在的全球并发症。因此，脓毒症的潜在治疗策略涉及靶向巨噬细胞和减少促炎细胞因子的释放。Chensinin-1b 是一种源自中国林蛙皮肤分泌物的天然抗菌肽的类似物，具有广谱抗菌活性，在 PBS 和膜溶液中均采用无规卷曲构象。Chensinin-1b 通过有效中和 LPS，有望缓解 LPS 诱导的炎症反应。在本研究中，我们通过暴露小鼠于多药耐药铜绿假单胞菌建立了小鼠脓毒性休克模型，以及通过 LPS 诱导的内毒素介导的脓毒症模型。给予 Chensinin-1b 显著延长了实验小鼠的存活时间，同时减轻了炎症反应和减少了器官损伤。此外，我们使用构建的 LPS 诱导的小鼠巨噬细胞 RAW264.7 炎症模型研究了 Chensinin-1b 的抗炎机制。我们的研究结果表明，Chensinin-1b 通过直接中和细胞外 LPS 有效减轻了 TLR4/NF-κB 信号通路的过度激活，从而改善了炎症反应。此外，在阻断 TLR4 信号通路后，Chensinin-1b 进一步减少了 LPS 诱导的促炎细胞因子的释放，表明存在替代的调节模式。值得注意的是，Chensinin-1b 通过内吞作用在 30 分钟内迅速进入 RAW264.7 细胞，在细胞内扩散到细胞质中，同时保持其抗炎特性。尽管需要进一步研究来全面阐明 Chensinin-1b 的细胞内抗炎机制，但我们的研究结果证实了其具有细胞内和细胞外抗炎特性。因此，Chensinin-1b 是一种有前途的候选药物，可以减轻与脓毒症相关的过度炎症反应。
