Study of kaempferol in the treatment of rheumatoid arthritis through modulation of the NLRP3/CASP1/GSDMD axis and T-cell activation: Based on network pharmacology, single-cell analysis, and experimental validation.

Autor: He X; Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China; Bengbu Medical University Key Laboratory of Cardiovascular and Cerebrovascular Diseases, 2600 Donghai Avenue, Longzihu District, Bengbu, Anhui 233030, China. Electronic address: hexiaoyu365@163.com., Wu T; Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 21009, China. Electronic address: wty20192021@163.com., He H; Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China; Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233003, China. Electronic address: 2519972881@qq.com., Chen L; Bengbu Medical University Key Laboratory of Cardiovascular and Cerebrovascular Diseases, 2600 Donghai Avenue, Longzihu District, Bengbu, Anhui 233030, China. Electronic address: clily666666@163.com., Han K; Bengbu Medical University Key Laboratory of Cardiovascular and Cerebrovascular Diseases, 2600 Donghai Avenue, Longzihu District, Bengbu, Anhui 233030, China. Electronic address: bbyxyhanke@163.com., Zheng J; Bengbu Medical University Key Laboratory of Cardiovascular and Cerebrovascular Diseases, 2600 Donghai Avenue, Longzihu District, Bengbu, Anhui 233030, China. Electronic address: 13156736811@163.com., Zhang Z; Bengbu Medical University Key Laboratory of Cardiovascular and Cerebrovascular Diseases, 2600 Donghai Avenue, Longzihu District, Bengbu, Anhui 233030, China. Electronic address: 2261861181@qq.com., Yuan S; Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China; Bengbu Medical University Key Laboratory of Cardiovascular and Cerebrovascular Diseases, 2600 Donghai Avenue, Longzihu District, Bengbu, Anhui 233030, China. Electronic address: 17864108632@163.com., Wang Y; Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China; Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233003, China. Electronic address: xin_violet@163.com., Zhang Y; Bengbu Medical University Key Laboratory of Cardiovascular and Cerebrovascular Diseases, 2600 Donghai Avenue, Longzihu District, Bengbu, Anhui 233030, China. Electronic address: 18605667396@163.com., Zhang X; Bengbu Medical University Key Laboratory of Cardiovascular and Cerebrovascular Diseases, 2600 Donghai Avenue, Longzihu District, Bengbu, Anhui 233030, China. Electronic address: zhangxn@bbmu.edu.cn., Xie C; Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical University, 287 Changhuai Road, Bengbu, Anhui, 233004, China; Anhui Provincial Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu 233003, China; Anhui Province Key Laboratory of Basic and Translational Research of Inflammation-Related Diseases, 287 Changhuai Road, Bengbu, Anhui, 233004, China. Electronic address: xiechanghao@bbmu.edu.cn.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Dec 25; Vol. 143 (Pt 1), pp. 113357. Date of Electronic Publication: 2024 Oct 10.
DOI: 10.1016/j.intimp.2024.113357
Abstrakt: Background: Kaempferol (Kae) is a natural flavonol compound with excellent anti-inflammatory and immunomodulatory effects, which is of great importance in the treatment of inflammatory diseases. The efficacy of Kae in the treatment of rheumatoid arthritis (RA) has been demonstrated. However, its relevant pharmacodynamic mechanism requires further investigation.
Purposes: This study aimed to further explore the potential mechanism of action of Kae in the treatment of RA using network pharmacology, single-cell analysis, and animal experiments.
Methods: Drug target genes were downloaded and screened from the Comparative Toxicogenomics Database (CTD), SwissTargetPrediction database, BindingDB database, and TargetNet database. Transcriptome data from GEO databases (GSE55235, GSE89408, and GSE200815) were selected for disease transcriptome analysis and single-cell matrix data. Network pharmacology and molecular docking were used to investigate the potential mechanism of action of Kae in treating RA. Single-cell analysis, immune infiltration co-expression analyses, and Mendelian-Randomization (MR) studies were conducted to explore the relationship between Kae's target genes and immune cells. Collagen-induced arthritis (CIA) was induced in DBA/1 mouse models through enhanced immunization. Therapeutic efficacy of Kae was assessed using arthritis score, paw swelling index, body weight monitoring, microCT, hematoxylin and eosin (HE) staining, Safranin O-Fast green staining, and Tartrate-resistant acid phosphatase (TRAP) staining. Tissue immunofluorescence and flow cytometry were used to detect expression levels of key genes and immune cell activation status.
Results: In vivo experiments demonstrated the efficacy of Kae in treating CIA mice. Network pharmacology indicated that Kae might exert anti-inflammatory effects through the NLRP3/CASP1/GSDMD axis. Immune infiltration, single-cell, and MR analyses revealed close associations between Kae's target genes and CD4 + , CD8 + , and regulatory T cells. Kae inhibited cellular pyroptosis in joint tissues and down-regulated NLRP3, CASP1, and GSDMD expression. Flow cytometry results showed decreased CD4/CD8 ratio, reduced proportion of CD4 + effector memory T cells (Tem), and increased naïve and regulatory T cells (Treg).
Conclusion: Kae might exert anti-inflammatory effects by modulating the NLRP3/CASP1/GSDMD axis to inhibit pyroptosis and suppress overactive immune responses by regulating T-cell proliferation. In summary, Kae demonstrated significant therapeutic efficacy in treating RA.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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