TanshinonellA phenanthroimidazole derivative polarizes macrophage to improve metabolic homeostasis
TanshinonellA phenanthroimidazole derivative polarizes macrophage to improve metabolic homeostasis
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丹参酮 — 一种菲咪唑衍生物，可使巨噬细胞极化，改善代谢稳态
DOI：
10.1016/j.bbrc.2019.05.056
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发表时间：
2019
影响因子：
3.1
通讯作者：
Yang Zhonghan
中科院分区：
文献类型：
--
作者：
Ma Lei;Luo Shiya;Zhou Lin;Zhao Zewei;Li Qiao;Xu Lin;Gong Baoyong;Qi Weiwei;Zhou Ti;Yang Xia;Gao Guoquan;Mei Wenjie;Yang Zhonghan
脂肪组织中浸润的巨噬细胞在肥胖中起关键作用。一些传统的药物化合物可能会改变募集的巨噬细胞的极化，以改善代谢稳态。丹参酮ⅡA （TAN2A）是丹参的主要活性成分，是一种传统的抗炎心血管药物。在我们的研究中，我们首先通过化学合成的方法构建了TAN2A的phenanthroimidazole衍生物TAN20，然后通过色谱和氢光谱鉴定其结构，最后研究其对免疫代谢反应的影响。我们发现TAN20主要通过释放II型细胞因子显著诱导选择性活化（M2）而非经典活化（M1）巨噬细胞。这种效果比TAN2A的效果更明显。与TAN2A相比，TAN20显著降低肥胖诱导的糖尿病小鼠的体重，降低血清游离脂肪酸和HOMA-IR，并增加胰岛素敏感性。TAN20的这些作用在更接近人类生理状态的糖尿病食蟹猴身上得到进一步验证。综上所述，我们的研究结果明确表明，TAN20在肥胖诱导的糖尿病模型中显著极化巨噬细胞并改善代谢稳态，这表明TAN20可能是一种潜在的抗糖尿病和肥胖药物。
Macrophages infiltrated in adipose tissue play a key role in obesity. Some traditional pharmaceutical compounds may shift the polarization of recruited macrophages to improve metabolic homeostasis. TanshinoneⅡA (TAN2A) is a major active component ofSalvia miltiorrhiza,a traditional anti-inflammatory cardiovascular medicine. In our study, we firstly constructed a phenanthroimidazole derivative of TAN2A named TAN20 by chemical synthesis, then identified its structure by chromatography and hydrogen spectroscopy, and finally examined its effects on immunometabolic responses. We found that TAN20 significantly induced the alternatively-activated (M2) rather than the classically-activated macrophages (M1), mainly through releasing the type II cytokines. Such effects were more pronounced than that from TAN2A. Compared to TAN2A, TAN20 substantially reduced body weight, decreased serum free fatty acid and HOMA-IR, and increased insulin sensitivity in obesity-induced diabetic mice. These effects of TAN20 were further validated on diabetic cynomolgus monkeys, which are closer to human physiological conditions. Taken together, our findings explicitly showed that TAN20 significantly polarized the macrophage and improved metabolic homeostasis in obesity-induced diabetic models, suggesting that TAN20 may be a potential drug against diabetes and obesity.