Integrative Analysis of Systems Pharmacology and Proteomics to Identify Key Targets and Pathways of Tuomin-Zhiti-Decoction for Allergic Rhinitis

Abstract Background: Tuomin-Zhiti-Decoction (TZD) is a polyherbal medicine consisting of eleven different herbs and has a significant effect on Allergic rhinitis (AR), yet its underlying mechanism is still unknown. Methods: Mice were sensitized and intranasally challenged with ovalbumin (OVA), the nasal symptoms, Th1/Th2-related cytokines and histopathology were examinated after TZD treatments. Bio-active compounds, potential therapeutic targets and underlying mechanisms of TZD against AR were systematically elucidated by integrating systems pharmacology approach and proteomics analysis. Then we validated the binding affinity between key targets and their corresponding active compounds using molecular docking evaluation.Results: A total of 280 active ingredients, 240 targets of TZD and 643 AR-related targets were obtained. Furthermore, 74 overlapping targets were identified. TZD oral administrations inhibited allergic responses via reduction of OVA-specific immunoglobulin E (IgE) levels and histamine release. In nasal tissue, TZD not only decreased nasal rubbing and sneezing to AR mice, but also reduced AR-induced damage to nasal mucosa, accordingly, the nasal symptoms were also clearly ameliorated. Moreover, TZD modulated the balance of Th1/Th2/Th17. The proteomics analysis identified 41 differentially expressed proteins (DEPs), protein function analysis showed that the DEPs were mainly involved in PI3K-AKT, MAPK, EGFR tyrosine kinase inhibitor resistance, NF-kappa B signaling pathway. Our results indicate that TZD plays important roles by restoring DEPs, through the selection of key DEPs, IL-6 and CD40 may be potential protein targets of TZD in treatment of AR. Combining the systems pharmacology, quercetin and wogonin may play more effective roles in AR. Molecular docking confirmed that most active compounds of TZD could bind tightly to the key targets.Conclusion: TZD may have therapeutic potential for treating AR, integrating analysis of systems pharmacology and proteomics uncovered the underlying mechanism and targets of TZD, which provides a scientific method for the rational development of traditional Chinese medicine.