[关键词]
[摘要]
目的 基于血浆代谢组学探究蒙药三臣小儿退热贴膏的解热作用及其机制。方法 SD大鼠随机分为对照组、模型组、阿司匹林(100 mg/kg)组以及三臣小儿退热贴膏高、中、低剂量(16、8、4 mg/kg)组和空白基质贴膏组,模型组和各给药组采用干酵母法建立发热模型,造模后第4、7小时各给药组给予相应药物进行干预,造模后每小时测量1次大鼠体温。采集造模后10 h大鼠血浆,采用超高效液相色谱-四极杆-静电场轨道阱高分辨质谱(UPLC-QE-MS)法并结合多元统计分析,检测各组大鼠血浆代谢相关生物标志物的变化。结果 造模4 h后模型组大鼠体温显著升高(P<0.01),造模后5 h三臣小儿退热贴膏组大鼠体温显著降低(P<0.01),呈剂量相关性。基于代谢组学发现模型组大鼠血浆中7种潜在的生物标志物发生明显变化,分别为酮亮氨酸、鞘磷脂[d17:1/24:1(15Z)]、鞘磷脂[d18:1/24:1(15Z)]、鞘磷脂[d18:1/18:1(9Z)]、磷脂酰胆碱(16:0/14:0)、磷脂酰胆碱(18:0/15:0)、磷脂酰胆碱(16:0/16:0);三臣小儿退热贴膏组大鼠血浆中上述7种生物标志物含量均显著回调,且牛磺酸和异柠檬酸含量升高。代谢通路分析显示,三臣小儿退热贴膏能够影响牛磺酸和亚牛磺酸代谢、乙醛酸和二元酸代谢、柠檬酸循环、氨基酸代谢、初级胆汁酸生物合成、α-亚麻酸代谢、烟酸和烟酰胺代谢、鞘脂代谢等多种代谢通路。结论 三臣小儿退热贴膏对干酵母致发热大鼠模型具有较好的解热作用,其药效与阿司匹林相当,其解热机制与酶抑制、脂肪代谢、氨基酸及能量代谢等多通路协同作用有关。
[Key word]
[Abstract]
Objective To explore the antipyretic effect and mechanism of Mongolian medicine Sanchen Xiaoer Antipyretic Plaster (三臣小儿退热贴膏) based on plasma metabolomics. Methods SD rats were randomly divided into control group, model group, aspirin (100 mg/kg) group, high-, medium-, low-dose Sanchen Xiaoer Antipyretic Plaster (16, 8, 4 mg/kg) groups and blank matrix plaster group, fever models were established in model group and each administration group by dry yeast method. At 4th and 7th hours after modeling, rats in each administration group were given corresponding drugs for intervention, and body temperature was measured every hour after modeling. Plasma were collected after 10 h of modeling, and ultra-high performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry (UPLC-QE-MS) combined with multivariate statistical analysis were used to detect the changes of biomarkers related to plasma metabolism in rats of each group. Results Body temperature of rats in model group was significantly increased after 4 h of modeling (P<0.01), and body temperature of rats in Sanchen Xiaoer Antipyretic Plaster group was significantly decreased after 5 h of modeling (P<0.01), showing a dose-related relationship. Seven potential biomarkers in plasma of rats in model group had significant changes based on metabonomics, respectively ketoleucine, sphingomyelin[d17:1/24:1(15Z)], sphingomyelin[d18:1/24:1(15Z)], sphingomyelin[d18:1/18:1(9Z)], phosphatidylcholine (16:0/14:0), phosphatidylcholine (18:0/15:0), phosphatidylcholine (16:0/16:0); Contents of above seven biomarkers in plasma of rats in Sanchen Xiaoer Antipyretic Plaster group were significantly recovered, contents of taurine and isocitrate were increased. Metabolic pathway analysis showed that Sanchen Xiaoer Antipyretic Plaster affected taurine and hypotaurine metabolism, glyoxylic acid and dibasic acid metabolism, citric acid cycle, amino acid metabolism, primary bile acid biosynthesis, α-linolenic acid metabolism, niacin and nicotinamide metabolism, sphingolipid metabolism and other metabolic pathways. Conclusion Sanchen Xiaoer Antipyretic Plaster has a good antipyretic effect on dry yeast-induced fever rats model, and its efficacy is equivalent to aspirin, its antipyretic mechanism is related to multiple pathways such as enzyme inhibition, fat metabolism, amino acid and energy metabolism.
[中图分类号]
R285.5
[基金项目]
内蒙古自治区科技重大专项(蒙医药现代化关键技术研究及蒙药产业化);内蒙古自治区人民政府蒙医药标准化项目(2020-MB018);国家自然科学基金资助项目(81872942)