Research on the compatibility mechanism of the Tingli Dazao Xiefei Decoction by multi-organ metabolomics strategy.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: The Tingli Dazao Xiefei Decoction (TD) is a traditional phlegm-eliminating prescription composed of Descurainia sophia (L.) Webb. ex Prantl (TLZ) and Ziziphus jujuba Mill. (DZ), which can relieve lung, heart and kidney injury in asthma. TLZ acts as the monarch drug in the TD. Based on the research mode of "material basis of traditional Chinese medicinal properties can be divided and combined", we have confirmed that the flavonoid glycosides components/the oligosaccharide components/the fatty oil components (FG/Oli/FO) are effective components of TLZ. However, the compatibility mechanism of the TD, and the contribution of the effective components of TLZ to the efficacy were still unclear. AIM OF THE STUDY: To clarify the compatibility mechanism of TD, and the contribution of the effective components of TLZ to the efficacy from a comprehensive perspective of lung, heart, and kidney. METHODS: First, we chose the asthma model corresponding to the efficacy of TD in purging the lungs and relieving asthma, and the rats were divided into the normal (NC) group, model (M) group, dexamethasone (DEX) group, and treatment groups of TD/TLZ/DZ/FG + DZ/Oli + DZ/FO + DZ. Second, metabolomics and network pharmacology were applied to elucidate the comprehensive protective effect of TD/FG + DZ/Oli + DZ/FO + DZ. Third, the multi-omics results were validated using Western blotting, RT-qPCR, flow cytometry, and immunofluorescence. RESULTS: FG + DZ/Oli + DZ/FO + DZ had different degrees of protective effects against lung/heart/kidney injury in asthma. In metabolomics research, the principal component analysis (PCA) and cluster analysis results showed that the TLZ group was closer to TD group than DZ group, the FO + DZ and Oli + DZ groups clustered with TD/NC groups in the lung and kidney, and the FO + DZ and FG + DZ groups clustered with TD/NC groups in the heart. Pathway enrichment analysis suggested that the comprehensive protective effect of TLZ and its effective components combined with DZ on lung/heart/kidney may be achieved by regulating the arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and unsaturated fatty acid biosynthesis. Multi-organ metabolomics and network pharmacology revealed consistent biological functions in KEGG pathways. Validation experiment showed that TLZ and its effective components combined with DZ could reverse the abnormal expression of proteins and RNA related to inflammation, airway remodeling, excitotoxicity, and energy-supply, apoptosis at different levels. Furthermore, FO + DZ may reduce asthma damage by inhibiting the FABP4/PPAR-γ/NF-κB signaling pathway. CONCLUSION: TLZ played the key role in TD, and FO had the best therapeutic effect on each organ; the efficacy of Oli was mainly reflected in reducing lung and kidney damage, and FG was mainly involved in enhancing energy metabolism in the heart. These findings proved that traditional Chinese medicine could exert comprehensive efficacy in a 'multi-components trigger multi-channel' way.