Trans-10-hydroxy-2-decenoic acid alleviates LPS-induced blood-brain barrier dysfunction by activating the AMPK/PI3K/AKT pathway
Trans-10-hydroxy-2-decenoic acid alleviates LPS-induced blood-brain barrier dysfunction by activating the AMPK/PI3K/AKT pathway
复制标题
Trans-10-羟基-2-癸烯酸通过激活 AMPK/PI3K/AKT 通路缓解 LPS 诱导的血脑屏障功能障碍
DOI：
10.1016/j.ejphar.2019.172736
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发表时间：
2019-12-15
影响因子：
5
通讯作者：
Hu，Fuliang
中科院分区：
文献类型：
--
作者：
You，Mengmeng;Miao，Zhuoning;Hu，Fuliang
我们曾报道过皇家浆（RJ）中特有的脂质成分--反式-10-羟基-2-癸烯酸（10-HDA）对脂多糖（LPS）诱导的神经炎症有明显的抑制作用。然而，10-HDA是否可以防止LPS诱导的血脑屏障（BBB）损伤在很大程度上是未知的。在这项研究中，我们首先观察到，10-HDA降低BBB通透性在LPS刺激的C57 BL/6小鼠的伊文思蓝（EB）染料。免疫组化和Western blot结果显示，10-HDA通过抑制紧密连接蛋白（occludin、claudin-5和ZO-1）的降解而减轻BBB功能障碍。在LPS刺激的人脑微血管内皮细胞（HBMEC）中，10-HDA降低趋化因子（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，增加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Escherichia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机制。我们进一步说明10-HDA促进AMPK途径和下游PI 3 K/AKT途径的激活。化合物C（AMPK抑制剂）和LY 294002（PI 3 K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/PI 3 K/AKT通路的激活来抑制LPS诱导的BBB功能障碍。总的来说，这些数据表明，10-HDA可能是一个有趣的候选人在治疗与BBB损伤相关的疾病的临床评价。
We previously reported thattrans-10-hydroxy-2-decenoic acid (10-HDA), the exclusive lipid component of royal jelly (RJ), alleviates Lipopolysaccharide (LPS)-induced neuroinflammation bothin vivoandin 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-2andCCL-3), adhesion molecules (ICAM-1andVCAM-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.