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Introduction: Shizao decoction (SZD) is a traditional Chinese medicine decoction that has therapeutic effects on cirrhotic ascites (CAS). Because of the unclear treatment mechanism, in the current study, the anti-CAS activity of SZD and molecular mechanisms were analyzed by network analysis combined with pharmacokinetics and metabolomics. Methods: Firstly, we assessed the anti-CAS efficacy of SZD by hematoxylin-eosin (H&E), liver function tests, NO and ET-1 levels, and portal venous pressure. Secondly, network analysis was applied to dig out the metabolites, targets, and pathways related to SZD and CAS. Then, the pharmacokinetics of the pharmacokinetically relevant metabolites (PRM) were analyzed. Thirdly, the serum and urine metabolic biomarkers of rats with CAS were identified using metabolomics by comparing them with the SZD treatment group. In addition, MetaboAnalyst was utilized to conduct metabolic pathway analysis. Finally, the correlation analysis established a dynamic connection between absorbed PRM from SZD and CAS-associated endogenous metabolites. Results: Pharmacodynamic analysis indicated that SZD effectively mitigated liver injury symptoms by ameliorating inflammatory cell infiltration in CAS rats. The network analysis results indicated that twelve RPM contribute to the therapeutic efficacy of SZD against CAS; the key signaling pathways involved might be hepatitis B and PI3K-Akt. Pharmacokinetics results showed that the 12 RPM were efficiently absorbed into rat plasma, ensuring desirable bioavailability. The metabolomic analysis yielded 21 and 23 significantly distinct metabolites from the serum and urine, respectively. The 12 bioavailable SZD-PRM, such as luteolin, apigenin, and rutin, may be associated with various CAS-altered metabolites related to tryptophan metabolism, alpha-linolenic acid metabolism, glycine metabolism, etc. Discussion: A novel paradigm was provided in this study to identify the potential mechanisms of pharmacological effects derived from a traditional Chinese medicine decoction.
RESUMO
Hepatic fibrosis (HF) is a kind of chronic epidemic liver disease. Glycyrrhiza Uralensis and Salvia Miltiorrhiza (GUSM), traditional Chinese medicine, has the obvious clinical treatment of liver fibrosis. This study aimed to investigate the mechanisms of GUSM against HF by an integrated strategy combining untargeted metabolomics with network pharmacology. The results showed that GUSM prescription can improve the morphology and structure of liver tissue, inhibit the proliferation of collagen fibers and reducing the inflammatory response of the liver and so on. Endogenous metabolites and HF-related potential biomarkers in serum and urine were detected by ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The metabolic pathways were enriched by MetaboAnalyst. GUSM prescription showed an antifibrotic effect on rats by regulating metabolic pathways, mainly pentose and glucuronate interconversions and arachidonic acid metabolism. Network pharmacology was then applied to find 42 overlapping targets of GUSM-HF. Quercetin was found to be the main active component and STAT3 was the main active target in GUSM prescription. Molecular docking showed high affinities between quercetin and STAT3. Therefore, GUSM has protective effects on HF by regulating the metabolism and different signaling pathways. The work also shows that the metabolomic and network pharmacology methods are promising tools to gain insight into the efficacy and mechanism research of traditional Chinese medicines.