Title:Network Pharmacology and Experimental Validation to Elucidate the Pharmacological Mechanisms of Luteolin Against Chondrocyte Senescence
Volume: 28
Issue: 2
Author(s): Ling Long, Xiaokai Tang, Yi Wang, Jiaxiang Gu, Jiachao Xiong, Hao Luo, Hao Lv, Faxin Zhou, Kai Cao*Sijian Lin*
Affiliation:
- The Orthopedics Hospital, The
First Affiliated Hospital of Nanchang University, Nanchang, 330209, China
- The Rehabilitation Medicine Department,
The Second Affiliated Hospital of Nanchang University, 330006, China
Keywords:
Luteolin, network pharmacology, senescence, endplate chondrocytes, signal transduction, molecular docking.
Abstract:
Background: Luteolin, a flavonoid found in various medicinal plants, has shown
promising antioxidant, anti-inflammatory, and anti-aging properties. The cartilaginous endplate
(CEP) represents a crucial constituent of the intervertebral disc (IVD), assuming a pivotal responsibility
in upholding both the structural and functional stability of the IVD.
Objective: Exploring the precise mechanism underlying the protective effects of luteolin against
senescence and degeneration of endplate chondrocytes (EPCs).
Methods: Relevant targets associated with luteolin and aging were obtained from publicly available
databases. To ascertain cellular functions and signaling pathways, Gene Ontology (GO) and
Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed. Core genes were
identified through the construction of a protein-protein interaction (PPI) network. Molecular
docking (MD) was utilized to assess the binding affinity of luteolin to these core genes. Finally,
the impact of luteolin on the senescence and degeneration of EPCs was evaluated in an in vitro
cellular senescence model induced by tert-butyl hydroperoxide (TBHP).
Results: There are 145 overlapping targets between luteolin and senescence. Analysis using GO
revealed that these targets primarily participate in cellular response to oxidative stress and reactive
oxygen species. KEGG analysis demonstrated that these markers mainly associate with signaling
pathways such as p53 and PI3K-Akt. MD simulations exhibited luteolin’s binding affinity
to P53, Cyclin-dependent kinase (CDK)2, and CDK4. Cell cycle, cell proliferation, and β-
galactosidase assays confirmed that luteolin mitigated senescence in SW1353 cells. Western blot
assays exhibited that luteolin significantly suppressed the expression of Matrix Metallopeptidase
(MMP) 13, P53, and P21, while concurrently promoting CDK2, CDK4, and Collagen Type II
Alpha 1 (COL2A1) expression.
Conclusion: In summary, luteolin demonstrated beneficial properties against aging and degeneration
in EPCs, offering novel insights to mitigate the progression of intervertebral disc degeneration
(IVDD).
