JAK/STAT通路抑制剂对C57BL/6小鼠血清代谢组影响的1H NMR研究

JAK/STAT通路抑制剂已被应用于多种疾病的临床试验，但其全身性用药对机体组织细胞功能活性的影响目前尚不明确.本研究运用基于核磁共振氢谱（¹H NMR）的代谢组学方法分析了JAK/STAT通路抑制剂WP1066（20 mg/kg.bw，2天一次，持续2周）对C57BL/6小鼠血清代谢组的影响.首先采用¹H NMR技术检测了WP1066处理组和对照组小鼠血清的代谢物，然后对所得的图谱数据进行了主成分分析（PCA）以及正交偏最小二乘法分析（OPLS）.研究结果表明，抑制JAK/STAT通路可明显下调小鼠血清中的N-甲基烟酰胺（N-methylnicotinamide）水平，而上调顺乌头酸（cis-aconitate）、草酰乙酸（oxaloacetate）和乙酰胺（acetamide）水平，这些代谢物改变均与能量代谢密切相关.该结果提示代谢失衡相关指标可能作为JAK/STAT通路抑制剂治疗的临床监测参考指标.

1H NMR Study on Serum Metabonomic Alterations Induced by JAK/STAT Pathway Inhibitor in C57BL/6 Mice

JAK/STAT pathway inhibitor has been used in clinic trial for several diseases. However, the adverse effect of systematic administration of JAK/STAT pathway inhibitors on cellular function is largely unknown. In the present study, alteration of metabolites in C57BL/6 mice serum were characterized using metabonomic analysis after WP1066 (a JAK/STAT pathway inhibitor) treatment (20 mg/kg.bw, once every 2 days for 2 weeks). 1H NMR spectroscopy was used to detect the effect of WP1066 on metabolites component, and the metabolite profile were analyzed by principle component analysis (PCA) and orthogonal partial least squares (OPLS) analysis. Results showed that the level of N-methylnicotinamide was significantly downregulated, while cis-aconitate, oxaloacetate and acetamide were significantly upregulated in mice serum in response to JAK/STAT pathway inhibition. The above metabolic changes are associated with alterations in energy metabolism, indicating that parameters associated with metabolism unbalance may be used for monitoring the efficiency and adverse effect of JAK/STAT pathway inhibitor.