LBT is an extract from the Chinese herbal medicine Codonopsis pilosula (Franch.) Nannf., which belongs to the class of polyacetylenic compounds, however, whether it plays a role in the treatment of AR remains to be studied. Network pharmacology is currently receiving increasing attention in drug development and utilization and has been used to study the "complex protein/gene - disease" pathway, capturing the complexity between biological systems, drugs and diseases from a network perspective [17]. Therefore, network pharmacology research methods are used to predict the network of interrelationships between drugs and diseases in different areas of research, such as the discovery of new drugs [18], the elaboration of pharmacological mechanisms [19], and the exploration of new targets [20]. Molecular docking is a method for theoretically predicting the binding mode and affinity of ligands and receptors through energy matching between them based on the "lock-and-key principle" and "induced fit" theory [21], which can be used for the development of new drugs, finding new sites of action for old drugs, and elucidating the mechanism of action of drugs. In this study, we used network pharmacology to predict possible anti-AR targets and mechanisms of action of LBT, visualized the drug-disease network, and performed corresponding molecular docking studies to improve the reliability of target prediction conclusions.
In this study, a total of 64 potential targets of LBT for AR were screened by database analysis, and further analysis by PPI network revealed that the core targets of LBT for AR were mainly tumor necrosis factor (TNF), matrix metalloproteinase family members (MMP9, MMP2), molecular chaperones (HSP90AA1), tyrosine kinase family members (EGFR and ERBB2), receptor classes (TLR4, CXCR4), JUN and KDR.
This study further explored the biological processes, molecular functions and signaling pathways involved in genes during LBT treatment of AR by GO enrichment analysis and KEGG pathway enrichment analysis. GO functional enrichment analysis showed that the gene function of LBT for AR plays an important role mainly through participating in phosphatidylinositol 3-kinase signaling, G protein-coupled serotonin receptor signaling pathway, second-messenger-mediated signaling, cell chemotaxis and other related biological processes. The therapeutic efficacy of LBT on AR is mainly concentrated in the structural regions of secretory granule membrane, postsynaptic membrane, external side of plasma membrane, and membrane raft. The molecular functions involved in LBT for AR include receptor ligand activity, chemokine receptor activity, and binding of cytokine receptors. KEGG pathway enrichment results showed that LBT treatment of AR mainly involved Calcium signaling pathway、Proteoglycans in cancer、Neuroactive ligand-receptor interaction、Regulation of actin cytoskeleton、T cell receptor signaling pathway and other pathways. The "component-target-pathway-disease" diagram further revealed that the core target of LBT for AR, TNF, can act through Proteoglycans in cancer, T cell receptor signaling pathway and Toll-like receptor signaling pathway.
The molecular docking results reveal that LBT has a strong binding energy with all the core genes of AR. Among them, the binding energy with MMP2, MMP9, TNF, JUN and EGFR is relatively stronger. MMP2 and MMP9 belong to the matrix metalloproteinases (MMPs) family and are involved in the cleavage of cell surface receptors, the release of apoptotic ligands, and the inactivation of chemokines and cytokines [22]. In respiratory diseases, MMPs and other substrates, are involved in inflammation and tissue remodeling, as well as in host defense against pathogens, in a complex manner [23]. These MMPs can also lead to increased microvascular permeability, which in turn leads to edema and cell migration and tissue remodeling at the site of inflammation [24]. The above suggests that reducing the expression of MMPs at sites of metabolic inflammation may be an important strategy for the treatment of AR symptoms.
The tumor necrosis factor (TNF) family is a group of cytokines that can cause apoptosis, among which TNF-α plays an important role in the development of AR. TNF-α mediates the aggregation of eosinophils and mast cells at the site of inflammation, increases the production of IL-5 and IL-8, inhibits the apoptosis of eosinophils, and activates the aggregation of mast cells and eosinophils, resulting in a persistent inflammatory response in the organism [25]. Steelant Brecht et al. found that treatment with anti-TNF-α monoclonal antibody restored T1 and T2 induced AR epithelial barrier dysfunction [26].
JUN is a subunit of the constituent transcription factor AP-1 and is involved in the body's immune response, cell proliferation, differentiation, apoptosis, inflammatory response and other processes [27]. One study reported that dexamethasone inhibits the inflammatory response by downregulating the m RNA expression of c-Jun and c-Fos in AP-1 [28]. EGFR is a receptor for epithelial growth factor (EGF) cell proliferation and signaling, and one study found that the EGFR inhibitor AG1478 inhibited upper airway eosinophilic inflammation [29]. The core targets of LBT for the treatment of AR mainly involve anti-inflammation, anti-allergy, tissue remodeling, and participation in immune regulation of the body, suggesting that LBT may exert its therapeutic effect on AR mainly through the regulation of the above-mentioned and other functions.
In summary, this study used network pharmacology and molecular docking to explore the potential mechanism of action of LBT for the treatment of AR, but further in vivo and ex vivo studies are needed to verify the mechanism of action of LBT for the treatment of AR.