Metabolomics combined with serum pharmacochemistry discovering the potential effective compounds of Fangji Huangqi Tang against nephrotic syndrome.

Fangji Huangqi Tang (FHT) was first recorded in "Jin Gui Yao Lue," invented by the archaic Chinese medical doctor Zhongjing Zhang, and is a classic medicine that tonifies qi and expels wind, invigorates spleen for diuresis. A large number of literatures indicated that FHT showed a significant effect on Nephrotic Syndrome (NS). A comprehensive strategy was proposed to discover the potential effective compounds and therapeutic targets of FHT against NS as a case study. Serum metabolomics combined with multivariate statistical analysis was employed to analysis and screen the differential endogenous metabolites in serum samples of the control and model rats induced by Adriamycin. The correlation analysis between the efficacy biomarkers and different compounds absorbed in serum of FHT was conducted to explore the potential effective compounds of FHT against NS. With the help of network pharmacology, the therapeutic targets and the possible molecular mechanisms of FHT against NS were further investigated. Fifteen metabolites, including l-phenylalanine, 3-Hydroxybutyric acid and linolenic acid, were associated with renal damage based on the serum metabolomic results. Metabolic pathway analysis indicated that phenylalanine, tyrosine and tryptophan biosynthesis and linoleic acid metabolism were the key pathways associated with NS. Among them, 6 metabolites were defined as efficacy biomarkers such as uric acid, 2-methylbutyrylcarnitine and 10-HDA. The results of correlation analysis suggested that 14 constituents such as fanGhinoline, cycloastragenol, atractylenolide III, and glycyrrhetinic acid were recognized as potential effective compounds, whose potential protein targets participated in the MAPK signaling pathway, GnRH signaling pathway and aldoaterone-regulated sodium reabsorption. This study has clarified the potential effective compounds and therapeutic targets of FHT against NS. The results provided new evidence for the pharmacological mechanism of FHT on NS.