The compatibility effects of sini decoction against doxorubicin-induced heart failure in rats revealed by mass spectrometry-based serum metabolite profiling and computational analysis

Sini decoction (SND) is a famous Traditional Chinese Medicine (TCM) formula composed of Acontium carmichaeli, Zingiber officinale and Glycyrrhiza uralensis, which is considered as an efficient formula against doxorubicin (DOX)-induced heart failure. But the compatibility mechanism of SND remains unclear.The present study aimed to investigate the compatibility mechanism of SND against DOX-induced heart failure in rats.Mass spectrometry-based serum metabolomics were performed. The relative distance values (RDVs) of SND, A. carmichaeli-free decoction (ACFD), Z. officinale-free decoction (ZOFD) and G. uralensis-free decoction (GUFD) treated groups from the control/DOX groups in multidimensional space were calculated to provide a measure of compatibility effect of SND. SND, ACFD, ZOFD, GUFD-targeted metabolic pathways were identified and compared to investigate the synergistic mechanism of SND by computational systems analysis. Real-time quantitative PCR was further employed to validate the key metabolic pathways at the level of the gene.The RDVs combined with the hemodynamic and biochemical analysis showed that the protection effects were sorted as SND > GUFD > ZOFD > ACFD. It revealed that DOX-induced heart failure perturbed 16 metabolic pathways, and SND, GUFD, ZOFD and ACFD-treated groups could significantly reversed 12, 10, 7 and 6 metabolic pathways of these 16 metabolic pathways, respectively. Metabolic pathway and RT-PCR analysis indicated that both SND and GUFD could protect DOX-induced heart failure mainly by regulating PLA2-COX pathway and PLA2-CYP pathway.It can be concluded that A. carmichaeli played an essential role in attenuation of DOX-induced heart failure among the three herb constituents of SND and the constituent herbs mutually reinforced each other. This work demonstrated that metabolomics combined with computational systems analysis was a promising tool for uncovering the compatibility effects of TCM.