We previously reported that trans-10-hydroxy-2-decenoic acid (10-HDA), the exclusive lipid component of royal jelly (RJ), alleviates Lipopolysaccharide (LPS)-induced neuroinflammation both in vivo and in vitro. However, whether 10-HDA can protect against LPS-induced blood-brain barrier (BBB) damage is largely unexplored. In this study, we first observed that 10-HDA decreased BBB permeability in LPS-stimulated C57BL/6 mice by Evan's blue (EB) dye. Immunostaining and Western blot results showed that 10-HDA alleviated BBB dysfunction by inhibiting the degradation of tight junction proteins (occludin, claudin-5 and ZO-1). In LPS-stimulated human brain microvascular endothelial cells (HBMECs), 10-HDA decreased the expression of chemokines (CCL-2 and CCL-3), adhesion molecules (ICAM-1 and VCAM-1), reactive oxygen species, matrix metalloproteinases (MMP-2 and MMP-9) and increased the expression of tight junction proteins. Interestingly, LC-MS/MS analysis showed that 10-HDA pretreatment upregulated the expression of mitochondria-associated proteins, which may reflect the mechanism underlying the regulatory effect of 10-HDA on reactive oxygen species. We further illustrated that 10-HDA promoted the activation of the AMPK pathway and the downstream PI3K/AKT pathway. Compound C (an AMPK inhibitor) and LY294002 (a PI3K inhibitor) markedly reversed the alleviating effect of 10-HDA on the expression of tight junction proteins, indicating that 10-HDA inhibited LPS-induced BBB dysfunction by triggering the activation of the AMPK/PI3K/AKT pathway. Collectively, these data reveal that 10-HDA may be an interesting candidate for clinical evaluation in the treatment of diseases related to BBB damage.

译文

我们以前曾报道过蜂王浆 (RJ) 的唯一脂质成分trans-10-hydroxy-2-decenoic (10-HDA) 在体内和体外均减轻脂多糖 (LPS) 诱导的神经炎症。但是,10-hda是否可以防止LPS诱导的血脑屏障 (BBB) 损伤尚未得到广泛研究。在这项研究中,我们首先观察到10-hda降低了Evan's blue (EB) 染料在LPS刺激的C57BL/6小鼠中的BBB渗透性。免疫染色和Western印迹结果表明,10-hda通过抑制紧密连接蛋白 (occludin,claudin-5和ZO-1) 的降解来减轻BBB功能障碍。在LPS刺激的人脑微血管内皮细胞 (HBMECs) 中,10-hda降低了趋化因子 (CCL-2和CCL-3),粘附分子 (ICAM-1和VCAM-1),活性氧,基质金属蛋白酶 (MMP-2和MMP-9) 的表达,并增加了紧密连接蛋白的表达。有趣的是,lc-ms/MS分析表明10-hda预处理上调了线粒体相关蛋白的表达,这可能反映了10-hda对活性氧的调节作用的潜在机制。我们进一步说明10-hda促进了AMPK途径和下游PI3K/AKT途径的激活。化合物C (一种AMPK抑制剂) 和LY294002 (一种PI3K抑制剂) 显著逆转了10-hda对紧密连接蛋白表达的缓解作用,表明10-hda通过触发AMPK/PI3K/AKT途径的激活来抑制LPS诱导的BBB功能障碍。总的来说,这些数据表明10-hda可能是治疗与BBB损伤相关的疾病的临床评估的有趣候选者。

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