Journal of Natural Medicines ( IF 2.5 ) Pub Date : 2021-05-18 , DOI: 10.1007/s11418-021-01508-y Yongli Guo 1 , Qingling Cui 1 , Shumeng Ren 1 , Deguo Hao 1 , Toshio Morikawa 2 , Dongmei Wang 3 , Xiaoqiu Liu 1 , Yingni Pan 1
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Echinacoside (ECH), acteoside (ACT), and isoacteoside (ISAT), the typical phenylethanoid glycosides (PhGs) in cistanches herba, have various pharmacological activities. However, the ECH, ACT and ISAT have extremely low oral bioavailability, which is related to their metabolism under the intestinal flora. Previous studies showed that intestinal metabolites were the hepatoprotective substances in vivo, but the research on whether PhGs has effects without intestinal bacteria has not been studied. In this paper, ECH, ACT and ISAT were incubated with human or rat intestinal bacteria for 36 h. After incubating with human bacteria for 36 h, three prototype compounds were not detected and were mainly biotransformed to 3-HPP and HT. In the network pharmacology, a total of 6 common targets were obtained by analysing the prototypes, the metabolites and the liver injury. It was found that the combinations of three metabolites and common targets were more stable than those of the prototypes and common targets by molecular docking. Meanwhile, hepatocellular apoptosis, proliferation, inflammation and oxidative responses might play important roles in the mechanisms of the metabolites exerting hepatoprotective activities. Then normal and pseudo-sterile mice experiments were adopted to further compare the hepatoprotective activities of prototypes and metabolites. Animal experiment results showed that the prototypes and the metabolites in the normal mice had significantly hepatoprotective activity. Interestingly, in the pseudo-germfree mice, the metabolites showed significant hepatoprotective effect, but the prototypes had not effect. It indicated that the prototype cannot exert liver protective activity without the effect of intestinal bacteria.
Graphic abstract
中文翻译：
基于肠道细菌和网络药理学的肉苁蓉三种苯乙醇苷及其代谢产物的保肝功效及生物学机制
肉苁蓉中的典型苯乙醇苷 (PhGs) 松果菊苷 (ECH)、立木甙 (ACT) 和异立苦甙 (ISAT) 具有多种药理活性。然而，ECH、ACT和ISAT的口服生物利用度极低，这与其在肠道菌群下的代谢有关。以往的研究表明肠道代谢产物是体内的保肝物质，但尚未研究PhGs在没有肠道细菌的情况下是否具有作用。在本文中，ECH、ACT 和 ISAT 与人或大鼠肠道细菌孵育 36 小时。与人类细菌孵育 36 小时后，未检测到三种原型化合物，主要生物转化为 3-HPP 和 HT。在网络药理学中，通过原型分析，共得到6个共同靶点，代谢物和肝损伤。通过分子对接发现，三种代谢物和共同靶点的组合比原型和共同靶点的组合更稳定。同时，肝细胞凋亡、增殖、炎症和氧化反应可能在代谢物发挥保肝活性的机制中起重要作用。然后通过正常和假不育小鼠实验进一步比较原型和代谢物的保肝活性。动物实验结果表明，原形及其代谢产物在正常小鼠体内均具有显着的保肝活性。有趣的是，在伪无菌小鼠中，代谢物显示出显着的保肝作用，但原型没有作用。
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