Abstract：
OBJECTIVE: To investigate the SARS-CoV-2 Spike protein (Spk)-induced inflammatory response and its downmodulation by diminazene aceturate (DIZE).
METHODS: Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction.
RESULTS: Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as β2 integrin, PI3K, and PAD2 due to its intermolecular coupling.
CONCLUSIONS: Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.
METHODS: Through inducing Spk inflammation in murine models, leukocyte migration to the peritoneum, levels of myeloperoxidase (MPO), malondialdehyde (MDA), rolling and adhesion of mesenteric leukocytes, and vascular permeability were investigated. Extracellular DNA traps (DETs) induced by Spk and the production of IL-6 and TNF-α were analyzed using human neutrophils, monocytes, and macrophages. In silico assays assessed the molecular interaction between DIZE and molecules related to leukocyte migration and DETs induction.
RESULTS: Spk triggered acute inflammation, demonstrated by increasing leukocyte migration. Oxidative stress was evidenced by elevated levels of MPO and MDA in the peritoneal liquid. DIZE attenuated cell migration, rolling, and leukocyte adhesion, improved vascular barrier function, mitigated DETs, and reduced the production of Spk-induced pro-inflammatory cytokines. Computational studies supported our findings, showing the molecular interaction of DIZE with targets such as β2 integrin, PI3K, and PAD2 due to its intermolecular coupling.
CONCLUSIONS: Our results outline a novel role of DIZE as a potential therapeutic agent for mitigating Spk-induced inflammation.
摘要：
目的：探讨SARS-CoV-2刺突蛋白(Spk)诱导的炎症反应及其乙酰丙酸二那嗪(DIZE)的下调作用。
方法：通过在小鼠模型中诱导Spk炎症，白细胞迁移到腹膜，髓过氧化物酶（MPO）的水平，丙二醛（MDA），肠系膜白细胞的滚动和粘附，和血管通透性进行了调查。使用人嗜中性粒细胞分析Spk诱导的细胞外DNA陷阱（DET）和IL-6和TNF-α的产生，单核细胞,和巨噬细胞。计算机模拟分析评估了DIZE与白细胞迁移和DES诱导相关分子之间的分子相互作用。
结果：Spk引发急性炎症，通过增加白细胞迁移来证明。腹膜液中MPO和MDA水平升高证明了氧化应激。DIZE减弱细胞迁移，滚动,和白细胞粘附，改善血管屏障功能，缓解的DES，并减少Spk诱导的促炎细胞因子的产生。计算研究支持了我们的发现，显示DIZE与β2整合素等靶标的分子相互作用，PI3K,和PAD2由于其分子间偶联。
结论：我们的结果概述了DIZE作为缓解Spk诱导的炎症的潜在治疗剂的新作用。
方法：通过在小鼠模型中诱导Spk炎症，白细胞迁移到腹膜，髓过氧化物酶（MPO）的水平，丙二醛（MDA），肠系膜白细胞的滚动和粘附，和血管通透性进行了调查。使用人嗜中性粒细胞分析Spk诱导的细胞外DNA陷阱（DET）和IL-6和TNF-α的产生，单核细胞,和巨噬细胞。计算机模拟分析评估了DIZE与白细胞迁移和DES诱导相关分子之间的分子相互作用。
结果：Spk引发急性炎症，通过增加白细胞迁移来证明。腹膜液中MPO和MDA水平升高证明了氧化应激。DIZE减弱细胞迁移，滚动,和白细胞粘附，改善血管屏障功能，缓解的DES，并减少Spk诱导的促炎细胞因子的产生。计算研究支持了我们的发现，显示DIZE与β2整合素等靶标的分子相互作用，PI3K,和PAD2由于其分子间偶联。
结论：我们的结果概述了DIZE作为缓解Spk诱导的炎症的潜在治疗剂的新作用。
