Key Lab of New Animal Drug Project of Gansu Province; Key Lab of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou Institute of Husbandry and Pharmaceutical Science of Chinese Academy of Agricultural Sciences, No.335, Jiangouyan, Qilihe district, Lanzhou, 730050, People's Republic of China.
Lipids Health Dis. 2017 Dec 11;16(1):240. doi: 10.1186/s12944-017-0633-0.
Based on the pro-drug principle, aspirin and eugenol were esterified to synthesize aspirin eugenol ester (AEE). The anti-hyperlipidemia effect of aspirin eugenol ester has been confirmed in hyperlipidemic rat induced by high fat diet (HFD). However, its effect on liver and feces metabonomic profiles remains unknown.
Suspension of AEE was prepared in 5% carboxymethyl cellulose sodium (CMC-Na). Thirty rats were divided into control, model and AEE groups. The control and model rats were fed with normal diet or HFD for 13 weeks, respectively. Rats in AEE-treated group were fed with HFD for 8 weeks to induce hyperlipidemia, and then given AEE once daily by oral gavage for 5 weeks at the dosage of 54 mg/kg body weight. After drug intervention, lipid profile analysis and oil red O staining were carried out to confirm the lipid accumulation in liver tissue. UPLC-Q-TOF/MS-based liver and feces metabonomics coupled with pathway analysis were conducted to evaluate the changes of metabolic profile and endogenous metabolites.
In liver tissue, oral administration of AEE significantly reduced lipid droplets and the levels of triglyceride (TG) and low-density lipoprotein (LDL). Using principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA), distinct changes in metabolite patterns in feces and liver were observed. Liver and feces samples in control, model and AEE groups were scattered in PLS-DA score plots. 28 metabolites in liver and 22 in feces were identified as potential biomarkers related to hyperlipidemia. As possible drug targets, the perturbations of those biomarkers can be regulated by administration of AEE.
Anti-hyperlipidemia effect of AEE was confirmed by lipid analysis, oil red O staining and metabolomics analysis. The mechanism of AEE might be associated with the changes in the metabolism of glycerophospholipid, amino acid, fatty acid, sphingolipid, purine, bile acid and glutathione.
基于前药原理，将阿司匹林和丁香酚酯化合成阿司匹林丁香酚酯（AEE）。已在高脂肪饮食（HFD）诱导的高脂血症大鼠中证实了阿司匹林丁香酚酯的抗高血脂作用。然而，其对肝脏和粪便代谢组学谱的影响尚不清楚。
将 AEE 混悬液制备在 5%羧甲基纤维素钠（CMC-Na）中。将 30 只大鼠分为对照组、模型组和 AEE 组。对照组和模型组大鼠分别给予正常饮食或 HFD 喂养 13 周。AEE 治疗组大鼠给予 HFD 喂养 8 周以诱导高血脂，然后每天给予 AEE 灌胃 5 周，剂量为 54mg/kg 体重。药物干预后，进行血脂分析和油红 O 染色，以确认肝脏组织中的脂质堆积。采用 UPLC-Q-TOF/MS 基于肝和粪便代谢组学结合途径分析，评估代谢谱和内源性代谢物的变化。
在肝脏组织中，AEE 的口服给药显著减少了脂滴和甘油三酯（TG）和低密度脂蛋白（LDL）的水平。使用主成分分析（PCA）和偏最小二乘判别分析（PLS-DA），观察到粪便和肝脏代谢物图谱的明显变化。对照组、模型组和 AEE 组的肝和粪便样本在 PLS-DA 得分图中分散。在肝脏中鉴定出 28 种代谢物，粪便中鉴定出 22 种代谢物作为与高血脂相关的潜在生物标志物。作为可能的药物靶点，这些生物标志物的扰动可以通过 AEE 的给药来调节。
通过脂质分析、油红 O 染色和代谢组学分析证实了 AEE 的抗高血脂作用。AEE 的作用机制可能与甘油磷脂、氨基酸、脂肪酸、神经酰胺、嘌呤、胆汁酸和谷胱甘肽代谢的变化有关。
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