Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 May;28(9):e18319.
doi: 10.1111/jcmm.18319.

Exploring the pharmacological mechanism of Glycyrrhiza uralensis against KOA through integrating network pharmacology and experimental assessment

Jianbo Xu  1   2   3 , Qi Sun  4 , Min Qiu  1   2 , Yungang Wu  5 , Liangyan Cheng  1   2 , Nanwan Jiang  6 , Ruogu Zhang  1   2   7 , Jiali Chen  1   2   7 , Wenhua Yuan  1   2   7 , Hongting Jin  1   2   7 , Weidong Wang  8 , Yunhuo Cai  9 , Chunchun Zhang  1   2 , Pinger Wang  1   2   7
Affiliations

Exploring the pharmacological mechanism of Glycyrrhiza uralensis against KOA through integrating network pharmacology and experimental assessment

Jianbo Xu et al. J Cell Mol Med. 2024 May.

Abstract

Knee osteoarthritis (KOA), a major health and economic problem facing older adults worldwide, is a degenerative joint disease. Glycyrrhiza uralensis Fisch. (GC) plays an integral role in many classic Chinese medicine prescriptions for treating knee osteoarthritis. Still, the role of GC in treating KOA is unclear. To explore the pharmacological mechanism of GC against KOA, UPLC-Q-TOF/MS was conducted to detect the main compounds in GC. The therapeutic effect of GC on DMM-induced osteoarthritic mice was assessed by histomorphology, μCT, behavioural tests, and immunohistochemical staining. Network pharmacology and molecular docking were used to predict the potential targets of GC against KOA. The predicted results were verified by immunohistochemical staining Animal experiments showed that GC had a protective effect on DMM-induced KOA, mainly in the improvement of movement disorders, subchondral bone sclerosis and cartilage damage. A variety of flavonoids and triterpenoids were detected in GC via UPLC-Q-TOF/MS, such as Naringenin. Seven core targets (JUN, MAPK3, MAPK1, AKT1, TP53, RELA and STAT3) and three main pathways (IL-17, NF-κB and TNF signalling pathways) were discovered through network pharmacology analysis that closely related to inflammatory response. Interestingly, molecular docking results showed that the active ingredient Naringenin had a good binding effect on anti-inflammatory-related proteins. In the verification experiment, after the intervention of GC, the expression levels of pp65 and F4/80 inflammatory indicators in the knee joint of KOA model mice were significantly downregulated. GC could improve the inflammatory environment in DMM-induced osteoarthritic mice thus alleviating the physiological structure and dysfunction of the knee joint. GC might play an important role in the treatment of knee osteoarthritis.

Keywords: Glycyrrhiza uralensis Fisch.; inflammatory response; knee osteoarthritis; molecular docking; network pharmacology.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no conflict of interest exists.

Figures

FIGURE 1
FIGURE 1
The total ion chromatogram of Glycyrrhiza uralensis Fisch. in positive ion modes.
FIGURE 2
FIGURE 2
Glycyrrhiza uralensis Fisch. improved dysmobility and pain in DMM‐induced KOA mice. (A) Stride length (CM), (B) Stance Width (cm), (C) Stance (S), (D) Swing (S) of the right hind limb and (E) hot plate reaction time (S) of mice were detected. (F) Representative 3D reconstruction of the right knee joint and subchondral bone. Scale bar = 100 μm. (G) BV/TV (%) and (H) Tb.Th (mm) were quantitative analysis data of the subchondral bone. All data were taken as means ± standard deviations (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001. BV, bone volume; DMM, destabilization of the medial meniscus; KOA, knee osteoarthritis; Tb.Th, trabecular thickness.
FIGURE 3
FIGURE 3
Glycyrrhiza uralensis Fisch. improved pathological features in DMM‐induced osteoarthritic mice. (A) ABH staining and TB staining of the right knee joint in C57BL/6 mice. Morphological quantitative analysis of (B) area of tibial cartilage (mm2) and (C) thickness of tibial cartilage (μm). (D) OARSI scoring of the sections analysed by histomorphometry. All data were taken as means ± standard deviations (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001. DMM, destabilization of the medial meniscus; OARSI, Osteoarthritis Research Society International.
FIGURE 4
FIGURE 4
Glycyrrhiza uralensis Fisch. promoted extracellular matrix synthesis in osteoarthritic articular cartilage. (A) Immunohistochemical staining of MMP13, Col2 and Aggrecan in cartilage. Scale bar = 100 μm. (B–D) Quantification of the positive repression area of Col2 (mm2), percentage of positive expression of MMP13 and Aggrecan (%). All data were taken as means ± standard deviations (n = 6). *p < 0.05, **p <0.01, **p < 0.001.
FIGURE 5
FIGURE 5
Network pharmacology analysis. (A) Overlaps between KOA's targets and GC drug targets, (B) PPI network visualization, (C) GC‐target‐KOA network. The circular node represents the traditional Chinese medicine component, and the rectangular node represents the disease target. The higher the correlation, the redder the colour, and vice versa, the greener the colour, (D) GO enrichment analysis and (E) KEGG pathways enrichment analysis. Molecular docking analysis. Molecular docking simulation results, including compounds, targets and minimum binding free energies, (F) surface appearances, (G) cartoon appearances of targets, (H) enlarged picture of the active site. GC, Glycyrrhiza uralensis Fisch.; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; KOA, knee osteoarthritis; PPI, protein–protein interaction.
FIGURE 6
FIGURE 6
Glycyrrhiza uralensis Fisch. had anti‐inflammatory effects in DMM‐induced osteoarthritic mice. (A) Immunohistochemical staining of F4/80 and pp65. (B, C) Quantification of the percentage of positive expression of F4/80 and pp65 (%). All data were taken as means ± standard deviations (n = 6). *p < 0.05, **p < 0.01, ***p < 0.001. DMM, destabilization of the medial meniscus.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Kraus VB, Blanco FJ, Englund M, Karsdal MA, Lohmander LS. Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use. Osteoarthr Cartil. 2015;23(8):1233‐1241. doi:10.1016/j.joca.2015.03.036 - DOI - PMC - PubMed
    1. Zhou X, Liu G, Han B, Li H, Zhang L, Liu X. Different prevention and treatment strategies for knee osteoarthritis (KOA) with various lower limb exoskeletons—a comprehensive review. Robotica. 2021;39(8):1345‐1367. doi:10.1017/s0263574720001216 - DOI
    1. Øiestad BE, Juhl CB, Culvenor AG, Berg B, Thorlund JB. Knee extensor muscle weakness is a risk factor for the development of knee osteoarthritis: an updated systematic review and meta‐analysis including 46 819 men and women. Br J Sports Med. 2022;56(6):349‐355. doi:10.1136/bjsports-2021-104861 - DOI - PubMed
    1. Driban JB, Harkey MS, Liu S‐H, Salzler M, McAlindon TE. Osteoarthritis and aging: young adults with osteoarthritis. Curr Epidemiol Rep. 2020;7(1):9‐15. doi:10.1007/s40471-020-00224-7 - DOI
    1. Gracey E, Burssens A, Cambré I, et al. Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis. Nat Rev Rheumatol. 2020;16(4):193‐207. doi:10.1038/s41584-019-0364-x - DOI - PMC - PubMed