Dehydrozaluzanin C-衍生物通过减轻过度激活的炎症反应和促进巨噬细胞的吞噬作用来保护脓毒症小鼠,bioRxiv - Pharmacology and Toxicology

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Dehydrozaluzanin C-衍生物通过减轻过度激活的炎症反应和促进巨噬细胞的吞噬作用来保护脓毒症小鼠
bioRxiv - Pharmacology and Toxicology Pub Date : 2023-12-22 , DOI: 10.1101/2023.11.01.565192
Ying-xiang Zou , Tian-nan Xiang , Li-rong Xu , Huan Zhang , Yu-he Ma , Lu Zhang , Chun-xian Zhou , Xiao Wu , Qi-lin Huang , Biao Lei , Jing-wen Mu , Xiang-yang Qin , Xin Jiang , Yue-juan Zheng

宿主定向治疗（HDT）是一种新的辅助策略，可干扰病原体复制或持久性所需的宿主细胞因子。在这项研究中，我们评估了脱氢扎鲁扎宁 C 衍生物 (DHZD)（脱氢扎鲁扎宁 C (DHZC) 的修饰化合物）作为治疗严重感染的潜在 HDT 药物的效果。采用LPS诱导的脓毒症小鼠模型和耐碳青霉烯类肺炎克雷伯菌（CRKP）感染小鼠模型进行体内测试。RAW264.7细胞、小鼠原代巨噬细胞和DC用于体外实验。地塞米松（DXM）用作阳性对照剂。DHZD 可改善小鼠 LPS 或 CRKP 感染引起的组织损伤（肺、肾和肝）和过度炎症反应。此外，DHZD还可以改善CRKP引起的急性腹膜炎的低体温症状，抑制热灭活CRKP（HK-CRKP）诱导的巨噬细胞炎症反应，并上调肺部吞噬细胞类型的比例。体外数据表明，DHZD 通过 PI3K/Akt/p70S6K 信号通路降低巨噬细胞中 LPS 刺激的 IL-6、TNF-α 和 MCP-1 表达。有趣的是，DXM 和 DHZD 联合治疗组比 DXM 治疗组有更高的存活率和更低的 IL-6 水平；DHZD与DXM联用在减少血清中IL-6分泌方面发挥协同作用。此外，DHZD 可以增加巨噬细胞中的吞噬细胞受体 CD36，同时以网格蛋白和肌动蛋白依赖性方式增加细菌吞噬作用。该数据表明 DHZD 可能是治疗细菌感染的潜在候选药物。

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Dehydrozaluzanin C- derivative protects septic mice by alleviating over-activated inflammatory response and promoting the phagocytosis of macrophages

Host-directed therapy (HDT) is a new adjuvant strategy that interfere with host cell factors that are required by a pathogen for replication or persistence. In this study, we assessed the effect of dehydrozaluzanin C-derivative (DHZD), a modified compound from dehydrozaluzanin C (DHZC), as a potential HDT agent for severe infection. LPS-induced septic mouse model and Carbapenem resistant Klebsiella pneumoniae (CRKP) infection mouse model was used for testing in vivo. RAW264.7 cells, mouse primary macrophages, and DCs were used for in vitro experiments. Dexamethasone (DXM) was used as a positive control agent. DHZD ameliorated tissue damage (lung, kidney, and liver) and excessive inflammatory response induced by LPS or CRKP infection in mice. Also, DHZD improved the hypothermic symptoms of acute peritonitis induced by CRKP, inhibited heat-killed CRKP (HK-CRKP)-induced inflammatory response in macrophages, and upregulated the proportions of phagocytic cell types in lungs. In vitro data suggested that DHZD decreases LPS-stimulated expression of IL-6, TNF-α and MCP-1 via PI3K/Akt/p70S6K signaling pathway in macrophages. Interestingly, the combined treatment group of DXM and DHZD had a higher survival rate and lower level of IL-6 than those of the DXM-treated group; the combination of DHZD and DXM played a synergistic role in decreasing IL-6 secretion in sera. Moreover, the phagocytic receptor CD36 was increased by DHZD in macrophages, which was accompanied by increased bacterial phagocytosis in a clathrin- and actin-dependent manner. This data suggests that DHZD may be a potential drug candidate for treating bacterial infections.

更新日期：2023-12-22

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