应用基于NMR代谢组学评价2',3',5'-三氧乙酰基-N_6-(3-羟基苯胺)腺苷剂量相关效应(英文)

Evaluation of dose-related effects of 2',3',5'-tri-O-acetyl-N_6-(3-hydroxylaniline)adenosine using NMR-based metabolomics

2',3',5'-三氧乙酰基-N6-(3-羟基苯胺)腺苷(WS070117)是天然产物虫草素的衍生物,体内外实验证明它具有显著脂质调节活性,并且毒性低。本次研究采用基于NMR代谢组学方法评价不同剂量WS070117调血脂活性。高脂血地鼠用6个不同剂量的WS070117(3、12、50、100、200和400 mg·kg-1·d-1)治疗。采用主成分分析法(PCA)及正交偏最小二乘法-判别分析法(OPLS-DA)两种多变量方法分析地鼠血清氢图谱。结果表明,WS070117能有效调节高脂血地鼠脂代谢、胆碱代谢及糖代谢紊乱,且其效应与剂量呈正相关。3 mg·kg-1·d-1的WS070117具有微弱脂质调节活性,而12和50 mg·kg-1·d-1的WS070117都显著调节代谢物浓度向正常水平转归,当WS070117的剂量达到100 mg·kg-1·d-1时,它的脂质调节活性强于阳性对照药。结果表明,基于NMR代谢组学可能成为评价调血脂化合物剂量效应关系的有效方法。

2＇, 3＇, 5＇-Tri-O-acetyl-N6-（3-hydroxylaniline）adenosine （WS070117） is a derivative compound of natural product cordycepin. It has significant lipids regulating activity and low toxicity which has been proved by in vitro and in vivo experiments. In this study, IH NMR-based metabolomics was used to investigate the dose-related effects of WS070117 on hyperlipidemia of high-fat-fed hamsters. The hyperlipidemic hamsters were administrated with six different doses of WS070117, including 3, 12, 50, 100, 200 and 400 mg .kg-1.d-1. IH NMR spectra of hamster serum were visually and statistically analyzed using two multivariate analyses： principal component analysis （PCA） and orthogonal partial least squares-discriminant analysis （OPLS-DA）. As a result, WS070117-treated groups showed dose-related regulation of metabolites associated with lipid metabolism, choline metabolism and glucose metabolism. The dose of 3 mg·kg-l·d-1 of WS070117 only exhibited a little lipids regulating activity. However, the doses of 12 and 50 mg ·kg-l·d-l of WS070117 both regulated the contents of metabolites to reverse significantly toward normal levels. When the dose of WS070117 reached 100 mg·kg-1·d-1, it was more effective than positive control drugs. The work suggested that NMR-based metabolomics might be a valuable approach to evaluate dose-related effects of lipids regulating comoounds.