Isoorientin Inhibits Inflammation in Macrophages and Endotoxemia Mice by Regulating Glycogen Synthase Kinase 3β.
Isoorientin Inhibits Inflammation in Macrophages and Endotoxemia Mice by Regulating Glycogen Synthase Kinase 3β.
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DOI：
10.1155/2020/8704146
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发表时间：
2020
影响因子：
4.6
通讯作者：
Dong Y
中科院分区：
文献类型：
--
作者：
Li Y;Zhao Y;Tan X;Liu J;Zhi Y;Yi L;Bai S;Du Q;Li QX;Dong Y
Isoorientin具有抗炎作用;然而，其机制仍不清楚。我们以前发现异orientin是体外糖原合成酶激酶3β（GSK 3 β）的抑制剂。GSK 3 β的过度活化与炎症反应有关。GSK 3 β通过在Ser 9处磷酸化而失活（即，p-GSK 3 β）。氯化锂（LiCl）抑制GSK 3 β，也增加p-GSK 3 β（Ser 9）。本研究探讨了异orientin通过调节GSK 3 β对脂多糖（LPS）诱导的RAW264.7小鼠巨噬细胞样细胞和内毒素血症小鼠的抗炎作用及其机制。LiCl用作对照。虽然AKT使GSK 3 β磷酸化，但MK-2206（一种选择性AKT抑制剂）用于通过AKT抑制来激活GSK 3 β（即，在Ser 9不磷酸化GSK 3 β）。采用ELISA或实时荧光定量PCR检测促炎细胞因子TNF-α、IL-6和IL-1β，Western blotting检测考克斯-2。Western blotting检测p-GSK 3 β和GSK 3 β下游信号分子NF-κB、ERK、Nrf 2和HO-1，以及紧密连接蛋白ZO-1和occludin。结果表明，异orientin在体内外均能降低TNF-α、IL-6和IL-1β的产生，增加p-GSK 3 β的表达，与LiCl相似。同时给予异orientin和LiCl显示拮抗作用。异orientin可降低LPS诱导的RAW 264. 7细胞考克斯-2表达，抑制ERK和NF-κB的活化，增加Nrf 2/HO-1的活化。异orientin可增加内毒素血症小鼠脑内occludin和ZO-1的表达。综上所述，异orientin可通过增加p-GSK 3 β抑制GSK 3 β，调节下游信号分子，从而抑制炎症反应，保护血脑屏障的完整性和脑内环境的稳定。
Isoorientin has anti-inflammatory effects; however, the mechanism remains unclear. We previously found isoorientin is an inhibitor of glycogen synthase kinase 3β (GSK3β) in vitro. Overactivation of GSK3β is associated with inflammatory responses. GSK3β is inactivated by phosphorylation at Ser9 (i.e., p-GSK3β). Lithium chloride (LiCl) inhibits GSK3β and also increases p-GSK3β (Ser9). The present study investigated the anti-inflammatory effect and mechanism of isoorientin via GSK3β regulation in lipopolysaccharide- (LPS-) induced RAW264.7 murine macrophage-like cells and endotoxemia mice. LiCl was used as a control. While AKT phosphorylates GSK3β, MK-2206, a selective AKT inhibitor, was used to activate GSK3β via AKT inhibition (i.e., not phosphorylate GSK3β at Ser9). The proinflammatory cytokines TNF-α, IL-6, and IL-1β were detected by ELISA or quantitative real-time PCR, while COX-2 by Western blotting. The p-GSK3β and GSK3β downstream signal molecules, including NF-κB, ERK, Nrf2, and HO-1, as well as the tight junction proteins ZO-1 and occludin were measured by Western blotting. The results showed that isoorientin decreased the production of TNF-α, IL-6, and IL-1β and increased the expression of p-GSK3β in vitro and in vivo, similar to LiCl. Coadministration of isoorientin and LiCl showed antagonistic effects. Isoorientin decreased the expression of COX-2, inhibited the activation of ERK and NF-κB, and increased the activation of Nrf2/HO-1 in LPS-induced RAW264.7 cells. Isoorientin increased the expressions of occludin and ZO-1 in the brain of endotoxemia mice. In summary, isoorientin can inhibit GSK3β by increasing p-GSK3β and regulate the downstream signal molecules to inhibit inflammation and protect the integrity of the blood-brain barrier and the homeostasis in the brain.
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影响因子：
--
作者：
Nguyen DN;Huyghens L;Zhang H;Schiettecatte J;Smitz J;Vincent JL
通讯作者：
Vincent JL
影响因子：
4
作者：
Bohrmann, Bernd;Baumann, Karlheinz;Loetscher, Hansruedi
通讯作者：
Loetscher, Hansruedi
影响因子：
4.7
作者：
Onishi, Tomohiro;Iwashita, Hiroki;Takizawa, Masayuki
通讯作者：
Takizawa, Masayuki
影响因子：
2.5
作者：
Borghi, R;Piccini, A;Tabaton, M
通讯作者：
Tabaton, M
DOI：
10.1016/j.msec.2017.03.207
发表时间：
2017-08-01
影响因子：
7.9
作者：
Ge, Lingqing;Hu, Qiaozhen;Zhu, Guoji
通讯作者：
Zhu, Guoji