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首页> 外文期刊>Frontiers in Neuropharmacology >Suppression of the RAC1/MLK3/p38 Signaling Pathway by β-Elemene Alleviates Sepsis-Associated Encephalopathy in Mice
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Suppression of the RAC1/MLK3/p38 Signaling Pathway by β-Elemene Alleviates Sepsis-Associated Encephalopathy in Mice

机译：β-榄香烯抑制RAC1 / MLK3 / p38信号通路可减轻败血症相关性脑病

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It is still difficult to treat sepsis-associated encephalopathy (SAE) which is a diffuse brain dysfunction caused by sepsis, with excessive activation of microglia as one of the main mechanisms. Ras-related C3 botulinum toxin substrate 1 (RAC1) is proven to be a key molecule in the inflammatory signaling network. By using microglial cell line BV-2 and a mouse model of cecal ligation puncture (CLP), we herein evaluated the effects of β-elemene, an extract of Curcuma zedoaria Rosc., on RAC1 signaling in microglia, as well as the mechanism. β-Elemene decreased the expressions of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6) and attenuated translocation of nuclear factor-κB (NF-κB) p65 from the cytosol to the nucleus of BV-2 cells after lipopolysaccharide (LPS) treatment. It also inhibited the activation of RAC1, mixed-lineage protein kinase 3 (MLK3) and p38 mitogen-activated protein kinase (MAPK). The phosphorylation of the RAC1 Ser71 site was increased by β-elemene. Moreover, the learning and memory abilities of CLP mice in the water maze test and fear conditioning test were improved after β-elemene treatment. It reduced the expression of the microglial marker IBA1, significantly increased RAC1 Ser71 phosphorylation, and suppressed RAC1/MLK3/p38 signaling activation and inflammatory response in the hippocampus. In conclusion, β-elemene effectively alleviated SAE in mice and inhibited the RAC1/MLK3/p38 signaling pathway in microglia, probably as a safe and eligible potential candidate for clinical SAE treatment.
机译：脓毒症相关性脑病（SAE）仍然是很难治疗的，脓毒症相关性脑病是由脓毒症引起的弥漫性脑功能障碍，小胶质细胞过度激活是其主要机制之一。 Ras相关的C3肉毒毒素底物1（RAC1）被证明是炎症信号网络中的关键分子。通过使用小胶质细胞系BV-2和盲肠结扎穿刺（CLP）小鼠模型，我们在本文中评估了姜黄提取物β-榄香烯对小胶质细胞中RAC1信号的影响。 β-榄香烯降低促炎细胞因子（肿瘤坏死因子-α（TNF-α），白介素-1β（IL-1β）和IL-6）的表达，并减弱核因子-κB（NF-κB）p65的易位脂多糖（LPS）处理后从胞浆到BV-2细胞核。它还抑制了RAC1，混合谱系蛋白激酶3（MLK3）和p38丝裂原活化蛋白激酶（MAPK）的激活。 β-榄香烯增加了RAC1 Ser71位点的磷酸化。此外，β-榄香烯处理后，在水迷宫测试和恐惧适应测试中，CLP小鼠的学习和记忆能力得到改善。它减少了小胶质细胞标记物IBA1的表达，显着增加了RAC1 Ser71的磷酸化，并抑制了RAC1 / MLK3 / p38信号在海马中的激活和炎症反应。总之，β-榄香烯可有效减轻小鼠的SAE并抑制小胶质细胞中的RAC1 / MLK3 / p38信号通路，这可能是临床SAE治疗的安全且合格的潜在候选药物。

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