Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
J Ethnopharmacol. 2021 Jun 28;274:114042. doi: 10.1016/j.jep.2021.114042. Epub 2021 Mar 26.
Bitter-cold herbs have been used to clearing heat and expelling damp in clinical practice in China for thousands of years.
This study aimed to investigate the common molecular mechanism of bitter-cold herbs through network pharmacology analysis, molecular docking and experimental validation in vivo.
Network pharmacological analysis integrated with molecular docking was employed to identify the active compounds and core action targets of the bitter-cold herbs. Then, the yeast-induced pathological model was established, and the antipyretic effect of the herbs was evaluated by checking rectal temperatures of the mice hourly. Lastly, the protein expression of core targets was examined to reveal the antipyretic mechanism.
A total of 52 lead compounds from the four bitter-cold herbs, Phellodendri Chinensis Cortex (PCC), Sophorae Flavescentis Radix (SFR), Gentianae Radix Et Rhozima (GRER) and Coptidis Rhizoma (CR), and 248 compounds-related targets were screened out with PTGS2 ranking the first. The results from molecular docking showed that 22 compounds adopted the same orientation as aspirin and had an excellent stability in the active site pocket of PTGS2. Furthermore, these herbs exerted potential therapeutic effects through 38 related pathways. On the other hand, the outcome of animal experiments showed that they could significantly attenuate the yeast-induced mice fever with dose-dependent relationship. Further experimental results demonstrated that administration of yeast suspension raised protein expression of PTGS2 significantly, which was evidently inhibited in the high or low-dose groups of GRER as well as in the low-dose group of SFR (P < 0.01) though a higher expression of PTGS2 was shown in the low-dose group of CR compared with FM group (P < 0.01).
The bitter-cold herbs can alleviate fever response and their antipyretic effect may mainly be attributed to regulating the expression of PTGS2 after the formation of ligand-receptor/PTGS2 complexes, and their active compounds might be nominated as antipyretic lead-ligand candidates.
几千年来，在中国的临床实践中，苦寒药一直被用于清热祛湿。
本研究旨在通过网络药理学分析、分子对接和体内实验验证，探讨苦寒药的共同作用机制。
采用网络药理学分析结合分子对接的方法，筛选出苦寒药的活性成分和核心作用靶点。然后，建立酵母诱导的病理模型，通过每小时检查小鼠的直肠温度来评估药物的解热作用。最后，检测核心靶点的蛋白表达，揭示其解热机制。
从黄柏、苦参、龙胆草和黄连四味苦寒药中筛选出 52 种先导化合物，共涉及 248 种化合物相关靶点，其中 PTGS2 排名第一。分子对接结果表明，22 种化合物与阿司匹林具有相同的取向，在 PTGS2 的活性位点口袋中具有极好的稳定性。此外，这些药物通过 38 种相关途径发挥潜在的治疗作用。另一方面，动物实验结果表明，它们能显著减轻酵母诱导的小鼠发热，且具有剂量依赖性。进一步的实验结果表明，酵母悬浮液给药能显著提高 PTGS2 的蛋白表达，而龙胆草高、低剂量组和苦参低剂量组能明显抑制其表达（P<0.01），但苦参低剂量组的表达高于 FM 组（P<0.01）。
苦寒药能缓解发热反应，其解热作用可能主要是通过形成配体-受体/PTGS2 复合物后调节 PTGS2 的表达，其活性化合物可能被提名作为解热先导配体候选物。
