Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, School of Pharmacy, Yantai University, Yantai, 264005, China.
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, School of Pharmacy, Yantai University, Yantai, 264005, China.
Chem Biol Interact. 2022 Dec 1;368:110221. doi: 10.1016/j.cbi.2022.110221. Epub 2022 Oct 13.
Sepsis, a clinical syndrome causing multi-organ failure, is one of the leading causes of morbidity and mortality. The effective treatment strategies for sepsis are limited. Some studies have demonstrated the benefits of kaempferol in countering sepsis, but its specific mechanism of action is unclear. The study aimed to investigate the anti-sepsis effects and mechanisms of kaempferol via sphingosine kinase 1/sphingosine-1-phosphate (SphK1/S1P) signaling pathway in a lipopolysaccharide (LPS)-induced sepsis model. We elucidated the effect of kaempferol on sepsis in LPS-induced RAW264.7 cells, HUVECs and septic mice. In RAW264.7 cells. We found that kaempferol decreased the levels of inflammatory mediators NO and PGE2. Western blot showed that kaempferol inhibited the expression of SphK1, p-p65 and p-IκB-α. LC-MS/MS analyze showed that kaempferol decreased S1P content in RAW264.7 cells. In HUVECs, we found that kaempferol promoted the expression of SphK1 and S1P, while kaempferol increased the expression levels of VE-Cadherin and β-catenin. In vivo, consistent with the in vitro results, kaempferol alleviated LPS-induced inflammatory responses and endothelial barrier damage. In addition, by immunofluorescence localization of F4/80, CD31 and SphK1, we found that kaempferol inhibited the expression of SphK1 in macrophages and increased the expression of SphK1 in endothelial cells. In summary, our present results not only suggested that kaempferol alleviated the inflammatory response and stabilizes the endothelial barrier in LPS-induced sepsis by regulating the SphK1/S1P signaling pathway, but also showed that kaempferol exhibited cell-specific effects on the regulation of SphK1 expression.
脓毒症是一种导致多器官衰竭的临床综合征，是发病率和死亡率的主要原因之一。脓毒症的有效治疗策略有限。一些研究表明，山奈酚在对抗脓毒症方面具有益处，但具体作用机制尚不清楚。本研究旨在通过脂多糖（LPS）诱导的脓毒症模型研究山奈酚通过鞘氨醇激酶 1/鞘氨醇-1-磷酸（SphK1/S1P）信号通路的抗脓毒症作用及其机制。我们阐明了山奈酚在 LPS 诱导的 RAW264.7 细胞、HUVEC 和脓毒症小鼠中的脓毒症作用。在 RAW264.7 细胞中，我们发现山奈酚降低了炎症介质 NO 和 PGE2 的水平。Western blot 显示山奈酚抑制 SphK1、p-p65 和 p-IκB-α 的表达。LC-MS/MS 分析表明山奈酚降低了 RAW264.7 细胞中的 S1P 含量。在 HUVEC 中，我们发现山奈酚促进 SphK1 和 S1P 的表达，同时山奈酚增加 VE-Cadherin 和 β-catenin 的表达水平。在体内，与体外结果一致，山奈酚减轻 LPS 诱导的炎症反应和内皮屏障损伤。此外，通过 F4/80、CD31 和 SphK1 的免疫荧光定位，我们发现山奈酚抑制巨噬细胞中 SphK1 的表达，增加内皮细胞中 SphK1 的表达。综上所述，本研究结果不仅表明山奈酚通过调节 SphK1/S1P 信号通路减轻 LPS 诱导的脓毒症中的炎症反应和稳定内皮屏障，还表明山奈酚对 SphK1 表达的调节具有细胞特异性效应。
