Network pharmacology and bioinformatics approach to unravel the mechanism of Xiao-chai-hu-tang herbal formula in tinnitus treatment

Abstract

Background: Tinnitus treatment remains a global challenge, and current therapeutic approaches are still controversial. This study aims to elucidate the potential mechanisms of Xiao-Chai-Hu-Tang (XCHT) in treating tinnitus through the analysis of network pharmacology, mendelian randomization and molecular docking, and molecular dynamics simulation analysis. We hope to contribute to the research on the target of action of traditional Chinese medicine and exploration of the mechanism of tinnitus.

Methods: We utilized network pharmacology to screen potential targets of action of XCHT on tinnitus. Mendelian randomization was employed to determine the causal relationship between potential targets of action and tinnitus. Finally, molecular docking and molecular dynamics simulation with clear targets and the combination of the active ingredient in effectiveness.

Results: Through network pharmacology, we identified 38 potential targets of action. Mendelian randomization analysis revealed that HIF1A (OR [95 % CI] = 0.78 [0.65, 0.94], P = 0.008) and CCND1 (OR [95 % CI] = 1.22 [1.00, 1.49], P = 0.04) exhibited significant results with tinnitus. Molecular docking and molecular dynamics simulation of HIF1A and active ingredients demonstrated good binding efficacy.

Conclusion: HIF1A may play a key role in the treatment of tinnitus by XCHT, which may play a certain protective role in tinnitus patients and may inhibit the occurrence and development of tinnitus. However, the specific mechanism and effect need to be further studied and verified.

Keywords: HIF1A; Mendelian randomization; Molecular docking; Network pharmacology; Tinnitus; Xiao-chai-hu-tang.

Fig. 1

Flow chart of this study.

Fig. 2

Prescription-Herbal-ingredient-target network diagram.V is Prescription, triangle is Herbal, octagon is ingredient,diamond is target. The formula-TCM composition-target network diagram is used to describe the relationship between TCM drug components and their targets. In the network diagram, Chinese medicine is usually represented as a node that represents the entity of the entire Chinese medicine. The drug ingredient is represented by another node, which represents the active ingredient in the traditional Chinese medicine. The action target is represented as the third node, which represents the action target of the drug ingredient in the biological body, such as receptors, enzymes, etc. The connecting lines between these nodes represent the interaction between the components of a traditional Chinese medicine and its target. By analyzing the network diagram, we can reveal the complex interaction between the components of traditional Chinese medicine and the target of action, and provide important reference for the research and development of traditional Chinese medicine.

Fig. 3

Venn diagram of Xiaochaihutang and Tinnitus.

Fig. 4

Xiaochaihutang-Tinnitus PPI network.

Fig. 5

Forest plot of the relationship between significant genes and the risk of tinnitus onset by Mendelian randomization analysis.

Fig. 6

Volcano plot illustrating the association of significant genes with tinnitus risk.

Fig. 7

Regional association map: HIF1A and tinnitus.

Fig. 8

Regional association map: CCND1 and tinnitus.

Fig. 9

Molecular docking diagram of HIF1A with quercetin, kaempferol, and wogonin. Panel A illustrates HIF1A and quercetin with a binding energy of −3.2 kcal/mol, Panel B shows HIF1A and kaempferol with a binding energy of −4.9 kcal/mol, and Panel C depicts HIF1A and wogonin with a binding energy of −3.9 kcal/mol. Numbers 1 to 3 represent the binding site diagram between the ligand and HIF1A, the 3D hydrogen bond diagram, and the interaction force diagram, respectively. In number 3, the dashed lines represent hydrogen bonds between the ligand and key amino acid residues, and the green lines represent hydrophobic interaction forces. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 10

Molecular dynamics simulation results of small molecule-HIF1A complexes and individual HIF1A. In the figure, Panels A–D represent the Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and Root Mean Square Fluctuation (RMSF) of the small molecule-HIF1A complexes and individual HIF1A, respectively. Panel E represents the number of hydrogen bonds formed between Quercetin, Kaempferol, and Wogonin with HIF1A during the 100 ns Molecular dynamics simulation process.