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Study on the Mechanism of the Combination of Methotrexate and Leflunomide in the Treatment of Rheumatoid Arthritis Based on Network Pharmacology, Molecular Docking, and in vitro Experimental Verification.
Shi, Jinyang; Cui, Xinhua; Wang, Yang; Song, Yuli; Tang, Xudong; Fan, Junwen; Xu, Hongyue; Zhu, Mingmei; Yu, Wanlu; Yu, Lu.
Afiliación
  • Shi J; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Center of Infectious Diseases and Pathogen Biology, Department of Infectious D
  • Cui X; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Center of Infectious Diseases and Pathogen Biology, Department of Infectious D
  • Wang Y; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Center of Infectious Diseases and Pathogen Biology, Department of Infectious D
  • Song Y; Shenzhen Liyunde Biotechnology Co., Ltd., Shenzhen 518057, China.
  • Tang X; Key Lab for New Drug Research of TCM, Research Institute of Tsinghua University in Shenzhen, Shenzhen 518057, China.
  • Fan J; Beijing Center for Animal Disease Control and Prevention Beijing Beijing China.
  • Xu H; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Center of Infectious Diseases and Pathogen Biology, Department of Infectious D
  • Zhu M; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Center of Infectious Diseases and Pathogen Biology, Department of Infectious D
  • Yu W; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Center of Infectious Diseases and Pathogen Biology, Department of Infectious D
  • Yu L; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine Jilin University, Center of Infectious Diseases and Pathogen Biology, Department of Infectious D
Comb Chem High Throughput Screen ; 2024 Jun 20.
Article en En | MEDLINE | ID: mdl-38910477
ABSTRACT

BACKGROUND:

To date, disease-modifying antirheumatic drugs (DMARDs) are widely used as the primary first-line treatment option for patients with rheumatoid arthritis (RA), and the curative effect of methotrexate (MTX) and leflunomide (LEF; MTX + LEF) is greater than that of single-agent MTX therapy, but the synergistic mechanism of MTX + LEF is unclear.

METHODS:

First, we explored the mechanism of action of MTX + LEF in RA through network pharmacology and molecular docking. Venn diagram analysis revealed 97 overlapping gene targets of MTX + LEF-RA and STRING, along with Cytoscape plug-in MOCDE and cytoHubba; and GO enrichment analysis revealed that the functions of 97 synergistic targets were related to 123 molecular functions (MF), 63 cell components (CC), and 1,068 biological processes (BP). The Cytoscape plug-in ClueGO demonstrated that these targets were enriched in KEGG pathways of 52 terms, whereas 9 pivotal genes were mainly involved in the signaling pathways of estrogen, Ras, Rap1, PI3K-Akt, relaxin, TNF, AMPK, FoxO, prolactin, IL-17, and adherens junction. Finally, CETSA and DARTS validated the direct binding of MTX or LEF to the selected target proteins EGFR, PPARG, MMP9, and SRC in RAW264.7 cells.

RESULTS:

We identified 292 MTX targets and 247 LEF targets from 7 databases. Furthermore, 2,814 potential targets of RA were identified by merging 1,925 targets from 7 databases and 999 differentially expressed genes (DEGs) between normal controls and patients with RA extracted from 5 GEO databases. Nine pivotal genes, ESR1, ALB, CASP3, EGFR, HSP90AA1, SRC, MMP9, PPARG, and IGF1, were identified. Molecular docking verified that both MTX and LEF strongly bind to most of the 9 pivotal proteins except ESR1 and IGF1.

CONCLUSION:

These results contribute to our understanding of the enhancement mechanism of MTX combined with LEF and provide a targeted basis for the clinical treatment of RA.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Comb Chem High Throughput Screen Asunto de la revista: BIOLOGIA MOLECULAR / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Emiratos Árabes Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Comb Chem High Throughput Screen Asunto de la revista: BIOLOGIA MOLECULAR / QUIMICA Año: 2024 Tipo del documento: Article Pais de publicación: Emiratos Árabes Unidos