Potential targets and mechanisms of Simiao San in intervening rheumatoid arthritis through network pharmacology and animal experiments
10.3969/j.issn.1006-2157.2025.08.005
- VernacularTitle:网络药理学联合动物实验探讨四妙散干预类风湿关节炎的潜在靶点及其作用机制
- Author:
Yuhe SUN
1
;
Haixu JIANG
;
Jie XU
;
Honglin ZHANG
;
Zihan ZHAO
;
Qingyi LU
Author Information
1. 北京中医药大学生命科学学院 北京 100029
- Publication Type:Journal Article
- Keywords:
Simiao San;
rheumatoid arthritis;
network pharmacology;
aryl hydrocarbon receptor;
mice
- From:
Journal of Beijing University of Traditional Chinese Medicine
2025;48(8):1067-1080
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the potential core target and its mechanism of Simiao San(SMS)in the treatment of rheumatoid arthritis(RA)using network pharmacology and animal experiments.Methods Active components and corresponding SMS targets were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and cross-referenced with the Universal Protein(UniProt)database.RA-related targets were screened from The Human Gene Database(GeneCards),Online Mendelian Inheritance in Man(OMIM),Therapeutic Target Database(TTD),DrugBank,and Disease Gene Network(DisGeNet).Protein-protein interaction(PPI)networks were constructed for shared targets between SMS and RA using Search Tool for the Retrieval of Interacting Genes/Proteins(STRING),followed by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses via The Database for Annotation,Visualization and Integrated Discovery(DAVID).A"herb active component-disease target-signaling pathway"network was established to predict the mechanism of SMS in RA treatment.Molecular docking was performed between aryl hydrocarbon receptor(AHR)and the core active components of SMS to identify AHR-targeting constituents.For animal experiments,30 female SPF-grade C57/BL mice were randomly divided into normal,model,methotrexate(1.52 mg/kg,every 3 days),and SMS(12.48 g/kg,daily)groups with a 30-day intervention.Ankle diameter and arthritis index scores were measured.HE staining was used to assess joint inflammation,whereas immunohistochemistry(IHC)was used to measure cytochrome P450 1A1(CYP1A1),nuclear factor kappa B subunit p65(p65),and phosphorylated p65(p-p65)protein expression levels.Multiplex immunofluorescence(mIHC)was used to evaluate forkhead box protein P3(FOXP3)and interleukin-17A(IL-17A)protein expression.Results Forty-one active components and 228 targets of SMS were identified from TCMSP,whereas 1,207 RA-related targets were extracted from GeneCards,OMIM,TTD,DrugBank,and DisGeNet.Ninety-four overlapping targets were analyzed,yielding 612 GO terms and 143 KEGG pathways.Molecular docking of the ligand-binding domain of AHR with the top 10 Degree values of compounds of SMS(quercetin,stigmasterol,wogonin,beta-sitosterol,kaempferol,baicalein,et al.)revealed that stigmasterol,beta-sitosterol,(S)-canadine,and isocorypalmine was able to bind to AHR stably.In vivo,compared to the model group,the mice of the SMS and methotrexate groups joint swelling and arthritis index scores reduced(P<0.01).IHC indicated elevated CYP1A1 protein and decreased p65 and p-p65 protein levels in the SMS and methotrexate groups(P<0.05,P<0.01).mIHC demonstrated reduced IL-17A and increased FOXP3 protein expression in the SMS and methotrexate groups(P<0.05,P<0.01).Conclusion SMS alleviates joint inflammation in RA mice,potentially by targeting AHR,one of the core targets.SMS may suppress excessive inflammatory responses by activating AHR and inhibiting p65 phosphorylation.Additionally,SMS modulates the helper T cells 17/regulatory T cells balance by downregulating IL-17A and upregulating FOXP3.These results suggest that AHR is a key mediator in T-cell immune regulation.
