Yeke Wu,1 Jiawei Li,2 Min Liu,3 Ranran Gao,4 Huijing Li,5 Yunfei Xie,6 Qiongying Hu,7 Jing Wei,5 Lixing Zhao,8 Li Li9 

1Department of Stomatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China; 2School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China; 3Department of Gynaecology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China; 4Department of Gynaecology, Henan Provincial People’s Hospital, Zhengzhou, 450000, People’s Republic of China; 5College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China; 6Department of Nuclear Medicine, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of China; 7Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China; 8State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610072, People’s Republic of China; 9Department of Radiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China

Correspondence: Li Li, Department of Radiology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, People’s Republic of China, TelFax +86 028 87783457, Email cddrlili@hotmail.com

Background: Periodontitis (PD) and type 2 diabetes mellitus (T2DM) represent interlinked global health burdens, commonly causing significant clinical complications when coincident. Therefore, managing both conditions (T2DM with periodontitis, DP) simultaneously poses considerable challenges, necessitating novel therapeutic strategies. KQJF has been clinically proven to treat DP with good efficacy, but its pharmacological substances and targets are not clear and urgently need to be clarified.
Aim: To define the potential active components and targets of KQJF for the treatment of DP.
Materials and Methods: The investigation commenced with the application of UPLC-Q-TOF/MS analysis to delineate the active constituents of KQJF and their associated targets in addressing DP. Additionally, the research incorporated subsequent methodologies such as machine learning, network pharmacology, molecular docking, molecular dynamics simulations, and a DP rat model was established and validated by in vivo experiments using H&E staining, immunohistochemistry, quantitative real-time PCR, and Western blot.
Results: KQJF was found to contain 49 prototype compounds and 121 metabolites with potential activity against PD and T2DM. Network pharmacology revealed 66 overlapping genes between the pharmacological targets of KQJF and known targets of PD and T2DM. Further exploration through PPI network and enrichment analyses illuminated the involvement of multi-target and multi-pathway mechanisms. Molecular docking and dynamics simulations confirmed the robust interactions between key compounds within KQJF and proteins associated with the diseases. In vivo validation demonstrated that KQJF treatment ameliorated DP-associated histopathological changes and modulated the expression of crucial proteins (including ABCG2, CCND1, CDKN1B, HIF1A, and PIK3R1) in a DP rat model.
Conclusion: In summary, KQJF exhibits potential therapeutic benefits for DP through a multi-component and multi-target approach, potentially offering a novel integrative treatment strategy. This study underscores the importance of integrating traditional medicine with modern molecular techniques to explore novel therapeutic avenues for complex comorbid conditions, providing a blueprint for future pharmacological explorations.

Keywords: Kouqiangjie Formula, T2DM with periodontitis, network pharmacology, machine learning, molecular dynamics