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Integrative Pharmacology Powers the Active Components Detection and Mechanism Exploration of Wang Bi Granules Acting on Rheumatoid Arthritis

ABSTRACT: Wang Bi Granule (WBG), composed of 16 botanical drugs and 1 animal drug, is clinically used to treat “Wang Bi” syndrome, which mainly refers to later rheumatoid arthritis (RA) in modern medicine, as well as ankylosing spondylitis, tuberculous arthritis, and Kashin-Beck disease characterized by joint pain and swelling deformation. However, its chemical composition and pharmacological mechanisms have not been clarified. Therefore, in the present study we aimed to characterize the chemical components of WBG and explore its mechanism in treating RA using integrative pharmacology, including chemical composition detection, efficacy evaluation, and mechanism exploration. We employed UPLC-QTOF-MS/MS to describe the chemical profile of WBG, TNF-α-stimulated RAW264.7 cells to simulate inflammatory process of RA and evaluate the anti-inflammatory effect of WBG, and network pharmacology to mine the mechanism of WBG acting on RA. As a result, a total of 278 chemical components were identified or tentatively characterized and the water extract of WBG improved the imbalance of inflammation by regulating 179 differential genes in RAW264.7 cells induced by TNF-α. 55 key active constituents were obtained based on the interactions among “components’ targets, RA-related genes, and differential genes (WBG vs TNF-α group)”, which may ameliorate RA conditions by regulating 161 hub genes that mainly involved in inflammation-immune related pathways. The present study, for the first time, employed integrative pharmacology to characterize the chemical profile of WBG and reveal its mechanism against RA through inflammation-immune regulation system.

ORGANISM(S): Mus musculus

PROVIDER: GSE181156 | GEO | 2022/06/01

REPOSITORIES: GEO

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Project description:Wang Bi Tablet (WBT) exhibits effective power in clinic during the treatment of rheumatoid arthritis (RA) in China. We aimed to employ the “integrative pharmacology strategy”, including rapid analysis of chemical composition, pharmacological experiment, and network pharmacology analysis, to delineate the main active components and reveal the underlying mechanism of WBT acting on RA. UPLC-QTOF-MS/MS provided the chemical fingerprint of WBT and UNIFI 1.8 software assisted in chemical composition identification by matching the MSE raw data to the in-house library. The anti-inflammatory effect of WBT was evaluated in TNF-α- stimulated RAW264.7 cells by ELISA and transcriptome sequencing. Network pharmacology analysis was carried out based on Integrative Pharmacology-based Network Computational Research Platform of Traditional Chinese Medicine (TCMIP V2.0, http://www.tcmip.cn/). Functional enrichment and network visualization was performed by DAVID v6.8 and NaviGator v3.0 respectively. Altogether, 293 chemical constituents were preliminarily identified or tentatively characterized in the extract of WBT, and it could effectively against inflammatory response in TNF-α-stimulated RAW264.7 cells. One hundred and thirty-five hub genes were delineated based on the network construction of “Anti-inflammatory Core Genes-Putative Targets-RA genes”, which were mainly involved in inflammation-immune regulation, closely relating to the occurrence and development of RA, such as Cytokine-cytokine receptor interaction, Chemokine signaling pathway, etc., Forty-eight key active constituents were selected according to the frequency binding to hub targets and contents in WBT, corresponding to 13 herbal medicines. In summary, it is the first time to explore the active constituents and underlying mechanism of WBT acting on RA using integrative pharmacology strategy, which may provide an efficient way for the analysis of chemical constituents and exploration of pharmacological mechanism of TCM.

Project description:The purpose of this study was (1) to identify novel genes involved in the pathogenesis of Rheumatoid Arthritis (RA) disease, which may provide additional targets for therapeutic intervention and (2) to examine the molecular mechanisms associated with the response to anti-TNF treatment. Microarray analysis of LPS-stimulated whole blood from RA patients pre and post anti-TNF treatment was conducted. This study identified 818 transcripts, differentially expressed in RA patients pre-treatment compared to non-RA control samples. While a number of these genes were associated with RA in previous studies, validating our data, a number of novel genes with possible functions in RA disease were also identified. The number of transcripts (1051) significantly altered post anti-TNF treatment indicates the impact of anti-TNF therapy on systemic gene expression. A number of these transcripts were confirmed to be altered in a larger patient group and may represent potential genetic markers of a patientâs clinical response to anti-TNF treatment. Experiment Overall Design: Transcriptome profiling was performed on two RA patients, pre- and three months post-Enbrel therapy and two matched non-RA controls. The whole blood model described by Wang et al (2000) was used with minor modifications. Briefly, to EDTA anti-coagulated blood, LPS (30ng/ml) was added immediately after drawing, and incubated at 37oC for 4 hours, mixing at 80s. After 4 hours red blood cells were lysed and pelleted, white cells were washed once in PBS (Gibco) and frozen at â70oC for subsequent RNA extraction. Total RNA was extracted using the RNeasy kit (QIAGEN) as per manufacturerâs instructions. Samples were treated with DNA-Free (Ambion) to remove genomic DNA and checked using intron-overlapping primers prior to generating cRNA probes or cDNA (data not shown). Affymetrix array data was normalised (globally) and statistically (t-test) analysed using GeneSight software (Biodiscovery). Gene expression changes with a p value of < 0.05 and a fold change of 3 or greater were considered differentially expressed.

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Integrative Pharmacology Powers the Active Components Detection and Mechanism Exploration of Wang Bi Granules Acting on Rheumatoid Arthritis

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