Abstract
Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing’s anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing’s pharmacologically significant constituents supports the medicine’s anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.
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Acknowledgements
We thank Juan Li (GCP ClinPlus Co., Guangzhou, China) for statistical assistance and thank Rong-rong He and Zi-xuan Chu (Shanghai Institute of Materia Medica, Shanghai, China) and Chun-liang Jiang, Xiang-cheng Wang, and Yu-kun Li (Tianjin Chasesun Pharmaceutical Co., Tianjin, China) for their technical assistance. This study was funded by National Natural Science Foundation of China (82192912, 82074176, 81801935, and 82272187), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202009), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12050306).
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CL and YMY conceived the investigation and designed the experiments. CC, MZL, YHL, XY, and YCL performed chemical composition analysis, preparation of XueBiJing compounds, bioequivalence study, pharmacokinetic compatibility study, and pharmacokinetic bioanalysis. LXW, RQY, and CR performed cell-based anti-sepsis studies of XueBiJing compounds. CR, YY, JLW, FFD, RQY, LXW, FQW, and FX performed CLP rat-based studies. ND performed flow cytometry analysis. YW, XMZ, and YY performed ELISA analysis. KD, GPZ, SL, and XQY provided samples of XueBiJing injection. CL, YMY, CC, CR, and HZ performed all data analysis. CL, CC, CR, and YMY drafted the manuscript and provided critical revision of the manuscript.
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YY, JLW, KD, GPZ, XQY, and SL are employees of Tianjin Chasesun Pharmaceutical Co. The other authors declare that they have no conflict of interest or financial conflicts to disclose.
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Cheng, C., Ren, C., Li, Mz. et al. Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation. Acta Pharmacol Sin 45, 1077–1092 (2024). https://doi.org/10.1038/s41401-023-01224-1
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DOI: https://doi.org/10.1038/s41401-023-01224-1
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