Triptriolide Alleviates Lipopolysaccharide-Induced Liver Injury by Nrf2 and NF-κB Signaling Pathways.
Triptriolide Alleviates Lipopolysaccharide-Induced Liver Injury by Nrf2 and NF-κB Signaling Pathways.
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Triptriolide 通过 Nrf2 和 NF-κB 信号通路减轻脂多糖引起的肝损伤
DOI：
10.3389/fphar.2018.00999
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发表时间：
2018
影响因子：
5.6
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Yang YQ;Yan XT;Wang K;Tian RM;Lu ZY;Wu LL;Xu HT;Wu YS;Liu XS;Mao W;Xu P;Liu B
Nrf2（核因子红细胞 2 相关因子 2）转录因子不仅调节氧化应激反应，还通过调节细胞因子的产生和与 NF-κB 信号通路的交互来抑制炎症。 Nrf2 在氧化应激和炎症引起的肝损伤中发挥重要作用。雷公藤内酯酯(T11)是雷公藤内酯酯(TwHF)的次要成分，可由雷公藤内酯酯(T9)的水解反应得到。本研究的主要目的是阐明T11对体内外氧化应激和炎症的调节作用。采用LPS刺激的RAW 264.7细胞验证T11对氧化应激（ROS和Nrf2信号通路）和炎症细胞因子产生（TNF-α、IL-6和IL-1β）的调节作用。采用抗氧化反应元件（ARE）荧光素酶测定法评估T11在HEK-293T细胞中的Nrf2激活作用。利用脂多糖（LPS）诱导的 BALB/c 小鼠急性肝损伤（ALI），研究 T11 的保护作用（ALT、AST、MDA、SOD、组织病理学和中性粒细胞/巨噬细胞过滤）以及改善 ALI 的潜在保护机制（Nrf2 和 NF-κB 信号通路）。首先，结果表明，T11不仅可以有效减少LPS刺激的RAW 264.7细胞中炎症细胞因子（TNF-α、IL-6和IL-1β）、ROS和NO的产生，而且还可以进一步显着增加HEK-293T细胞中Nrf2的活性。其次，结果表明，T11 可以显着降低 BALB/c 小鼠 LPS 诱导的 ALI 中的氧化应激反应（SOD 和 MDA）和炎症（组织病理学、中性粒细胞/巨噬细胞过滤、TNF-α、IL-6 和 IL-1β 产生）。最后，结果表明，T11 在体内和体外均可显着增加 Nrf2 蛋白表达并降低 p-TAK1、p-IκBα 和 NF-κB 蛋白表达。总之，我们的研究结果表明，T11可以通过在体外和体内调节Nrf2和NF-κB信号通路来减轻LPS诱导的氧化应激和炎症，这为TwHF在临床中的应用提供了新的见解。
Nrf2 (Nuclear Factor Erythroid 2 Related Factor 2) transcription factor not only regulates oxidative stress response, but also represses inflammation by regulating cytokines production and cross-talking with NF-κB signaling pathways. Nrf2 plays an essential role in liver injury induced by oxidative stress and inflammation. Triptriolide (T11) is a minor component of Tripterygium wilfordii Hook F. (TwHF), which can be obtained by hydrolysis reaction of triptolide (T9). The major purpose of this study is to clarify the regulating effects of T11 on oxidative stress and inflammation in vivo and in vitro. LPS-stimulated RAW 264.7 cells were used to verify the regulating effects of T11 on oxidative stress (ROS and Nrf2 signaling pathway) and inflammatory cytokines production (TNF-α, IL-6 and IL-1β). The antioxidant responsive element (ARE) luciferase assay was employed to evaluate Nrf2 activation effect of T11 in HEK-293T cells. Lipopolysaccharides (LPS) induced acute liver injury (ALI) in BALB/c mice were used to study the protective effects (ALT, AST, MDA, SOD, histopathology and neutrophils/macrophages filtration) and the underlying protection mechanisms of ALI amelioration (Nrf2 and NF-κB signaling pathway) of T11. Firstly, the results showed that T11 can not only effectively decrease the productions of inflammatory cytokines (TNF-α, IL-6 and IL-1β), ROS and NO in LPS-stimulated RAW 264.7 cells, but also further significantly increase the activity of Nrf2 in HEK-293T cells. Secondly, the results suggested that T11 could dramatically decrease the oxidative stress responses (SOD and MDA) and inflammation (histopathology, neutrophils/macrophages filtration, TNF-α, IL-6 and IL-1β production) in LPS-induced ALI in BALB/c mice. Finally, the results implied that T11 could dramatically increase Nrf2 protein expression and decrease p-TAK1, p-IκBα and NF-κB protein expression both in vivo and in vitro. In conclusion, our findings indicated that T11 could alleviate LPS induced oxidative stress and inflammation by regulating Nrf2 and NF-κB signaling pathways in vitro and in vivo, which offers a novel insights for the application of TwHF in clinical.
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影响因子：
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作者：
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