Novel compound from Polygonum multiflorum inhibits inflammatory response in LPS-stimulated microglia by upregulating AMPK/Nrf2 pathways
Novel compound from Polygonum multiflorum inhibits inflammatory response in LPS-stimulated microglia by upregulating AMPK/Nrf2 pathways
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DOI：
10.1016/j.neuint.2016.08.006
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发表时间：
2016-11-01
影响因子：
4.2
通讯作者：
Choi, Young-Whan
中科院分区：
文献类型：
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作者：
Park, Sun Young;Jin, Mei Ling;Choi, Young-Whan
已知何首乌提取物可改善记忆和学习能力，并具有神经保护和抗衰老活性。然而，其功能和神经炎症介导的神经退行性疾病的潜在机制仍然知之甚少。本研究对何首乌中的几个化合物进行了抗炎作用的研究，发现了一个新化合物CRPE 55 IB。在脂多糖（LPS）刺激的小胶质细胞中，CRPE 55 IB诱导的NO和PGE（2）产生的抑制与iNOS和考克斯-2蛋白表达和启动子活性的抑制相关。CRPE 55 IB还减少了由LPS诱导的促炎细胞因子（TNF-α和IL-6）的产生。此外，分子机制的研究表明，CRPE 55 IB通过灭活IKK α/β的磷酸化以及I κ B α的磷酸化和降解来抑制LPS诱导的NF-κ B活化。我们进一步发现CRPE 55 IB在比p38 MAPK更低的浓度下抑制ERK和JNK的磷酸化。进一步的实验表明，CRPE 55 IB处理显著增加了Nrf 2/ARE的活化及其靶基因（包括HO-1和NQO 1）的表达。此外，通过siRNA敲低Nrf 2、HO-1和NQ 01消除了CRPE 55 IB对iNOS和考克斯-2启动子活性的抑制作用。CRPE 55 IB还诱导小胶质细胞中AMPK/LKB/CaMK II的磷酸化。使用AMPK的特异性抑制剂的分析表明，AMPK活化参与CRPE 55 IB诱导的HO-1和NQ 01表达。此外，CRPE 55 IB诱导的抗神经炎症作用被AMPK的特异性抑制剂消除，表明AMPK在CRPE 55 IB诱导的抗神经炎症中的重要作用。总的来说，这些结果表明CRPE 55 IB通过Nrf 2/AMPK信号传导途径对LPS发挥抗神经炎性作用。(C)2016爱思唯尔有限公司版权所有
Polygonum multiflorum extracts are known to improve memory and learning ability, and have neuroprotective and anti-aging activity. However, its function and the underlying mechanisms in neuroinflammation-mediated neurodegenerative disease remain poorly understood. In the present study, we investigated the anti-neuroinflammatory effects of several compounds from P. multiflorum, and found a novel compound, CRPE55IB. The CRPE55IB-induced suppression of NO and PGE(2) production correlated with inhibition of iNOS and COX-2 protein expression and promoter activity in lipopolysaccharide (LPS)-stimulated microglia. CRPE55IB also reduced the production of pro-inflammatory cytokines (TNF-alpha and IL-6) induced by LPS. Furthermore, investigation of the molecular mechanism indicated that CRPE55IB inhibited LPS-induced NF-kappa B activation by inactivating phosphorylation of IKK alpha/beta, and phosphorylation and degradation of I kappa B alpha. We further found that CRPE55IB inhibited the phosphorylation of ERK and JNK at a lower concentration than that for p38 MAPK. Further experiments revealed that CRPE55IB treatment considerably increased the activation of Nrf2/ARE, and the expression of its target genes, including HO-1 and NQO1. Moreover, the Knockdown of Nrf2, HO-1, and NQ01 by siRNA abrogated the inhibitory effect of CRPE55IB on iNOS and COX-2 promoter activity. CRPE55IB also induced phosphorylation of AMPK/LKB/CaMKII in microglia. Analysis using a specific inhibitor of AMPK demonstrated that AMPK activation was involved in CRPE55IB-induced HO-1 and NQ01 expression. In addition, the CRPE55IB-induced anti-neuroinflammatory effect was abrogated by a specific inhibitor of AMPK, indicating the important role of AMPK in CRPE55IB-induced anti-neuroinflammation. Collectively, these results demonstrate that CRPE55IB exerts anti-neuroinflammatory effects against LPS via the Nrf2/AMPK signaling pathways. (C) 2016 Elsevier Ltd. All rights reserved.