High-throughput metabolomics reveals the perturbed metabolic pathways and biomarkers of Yang Huang syndrome as potential targets for evaluating the therapeutic effects and mechanism of geniposide

Abstract

High-throughput metabolomics can clarify the underlying molecular mechanism of diseases via the qualitative and quantitative analysis of metabolites. This study used the established Yang Huang syndrome (YHS) mouse model to evaluate the efficacy of geniposide (GEN). Urine metabolic data were quantified by ultra-performance liquid chromatography–tandem mass spectrometry. The non-target screening of the massive biological information dataset was performed, and a total of 33 metabolites, including tyramine glucuronide, aurine, and L-cysteine, were identified relating to YHS. These differential metabolites directly participated in the disturbance of phase I reaction and hydrophilic transformation of bilirubin. Interestingly, they were completely reversed by GEN. While, as the auxiliary technical means, we also focused on the molecular prediction and docking results in network pharmacological and integrated analysis part. We used integrated analysis to communicate the multiple results of metabolomics and network pharmacology. This study is the first to report that GEN indirectly regulates the metabolite “tyramine glucuronide” through its direct effect on the target heme oxygenase 1 in vivo. Meanwhile, heme oxygenase-1, a prediction of network pharmacology, was the confirmed metabolic enzyme of phase I reaction in hepatocytes. Our study indicated that the combination of high-throughput metabolomics and network pharmacology is a robust combination for deciphering the pathogenesis of the traditional Chinese medicine (TCM) syndrome.

Keywords

metabolomics / liquid chromatography-mass spectrometry / metabolites / metabolic pathways

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Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (No. 2018YFC1706103), Key Program of National Natural Science Foundation of China (Nos. 81830110, 8181101160, 81430093, 81673586, 81703685, 81302905, 81503386, and 81373930), National Key Subject of Drug Innovation (Nos. 2015ZX09101043-005 and 2015ZX09101043-011), TCM State Administration Subject of Public Welfare (No. 2015468004), Major Projects of Application Technology Research and Development Plan in Heilongjiang Province (No. GX16C003), Young Talent Lift Engineering Project of China Association of Traditional Chinese Medicine (No. QNRC2-B06), Natural Science Foundation of Heilongjiang Province (Nos. YQ2019H030 and H2016056), and Foundation of Heilongjiang University of Chinese Medicine (Nos. 2018jc01, 2018bs02, and 201809).

Compliance with ethics guidelines

Heng Fang, Aihua Zhang, Xiaohang Zhou, Jingbo Yu, Qi Song, and Xijun Wang declare that they have no potential financial conflict of interests related to this manuscript. The research program was approved by the Ethics Committee of Heilongjiang University of Chinese Medicine, and the study was conducted in accordance with the Declaration of Helsinki.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-019-0709-5 and is accessible for authorized users.

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