Betulin exhibits anti-inflammatory activity in LPS-stimulated macrophages and endotoxin-shocked mice through an AMPK/AKT/Nrf2-dependent mechanism.
Betulin exhibits anti-inflammatory activity in LPS-stimulated macrophages and endotoxin-shocked mice through an AMPK/AKT/Nrf2-dependent mechanism.
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桦木醇通过 AMPK/AKT/Nrf2 依赖性机制在 LPS 刺激的巨噬细胞和内毒素休克的小鼠中表现出抗炎活性
DOI：
10.1038/cddis.2017.39
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发表时间：
2017-05-18
影响因子：
9
通讯作者：
Hua S
中科院分区：
文献类型：
--
作者：
Ci X;Zhou J;Lv H;Yu Q;Peng L;Hua S
持续的氧化应激可导致慢性炎症，而慢性炎症又可介导包括癌症在内的大多数慢性疾病。核因子红细胞2相关因子（Nrf2）是抗氧化反应的关键转录激活因子，已成为治疗或预防人类疾病的一个有吸引力的药物靶点。在本研究中，我们研究了白桦素对Nrf2激活及其参与脂多糖（LPS）引发的炎症系统的影响和机制。在巨噬细胞中，白介素激活Nrf2信号通路，增加Nrf2靶向的抗氧化和解毒酶，包括NADPH、奎宁氧化还原酶1 （NQO1）、血红素加氧酶1 （HO-1）、γ-谷氨酰半胱氨酸合成酶催化亚基（GCLC）和修饰亚基（GCLM），并呈剂量和时间依赖性。重要的是，我们发现白桦林诱导的Nrf2的激活依赖于AMPK/AKT/GSK3β，因为药理学上灭活AMPK会阻断白桦林对AKT、GSK3β和Nrf2的激活作用。此外，白桦素还能减弱lps诱导的炎症介质（iNOS和COX-2）和MAPK炎症信号通路。体外和体内Nrf2缺失时，白桦素对HO-1和NQO1上调、iNOS和COX-2下调以及延长存活时间的作用均明显减弱。我们的研究结果表明，AMPK/AKT/Nrf2通路对于白桦素在lps刺激的巨噬细胞和内毒素休克小鼠中的抗炎作用至关重要。
Continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer. Nuclear factor erythroid 2-related factor (Nrf2), a critical transcriptional activator for antioxidative responses, has envolved to be an attractive drug target for the treatment or prevention of human diseases. In the present study, we investigated the effects and mechanisms of betulin on Nrf2 activation and its involvement in the lipopolysaccharide (LPS)-triggered inflammatory system. In macrophages, betulin activated the Nrf2 signaling pathway and increased Nrf2-targeted antioxidant and detoxifying enzymes, including NADPH, quinine oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), γ-glutamyl cysteine synthetase catalytic subunit (GCLC) and modifier subunit (GCLM) in a dose and time dependent manner. Importantly, we found betulin-induced activation of Nrf2 is AMPK/AKT/GSK3β dependent, as pharmacologically inactivating AMPK blocked the activating effect of betulin on AKT, GSK3β and Nrf2. Furthermore, betulin attenuated LPS-induced inflammatory mediators (iNOS and COX-2) and MAPK inflammatory signaling pathway. The effect of betulin on HO-1 and NQO1 upregulation, iNOS and COX-2 the downregulation, and survival time extension was largely weakened when Nrf2 was depleted in vitro and in vivo. Our results demonstrate that the AMPK/AKT/Nrf2 pathways are essential for the anti-inflammatory effects of betulin in LPS-stimulated macrophages and endotoxin-shocked mice.
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