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Potential mechanisms of action of celastrol against rheumatoid arthritis: Transcriptomic and proteomic analysis.

ABSTRACT: The clinical efficacy for treating of celastrol rheumatoid arthritis (RA) has been well-documented, but its mechanism of action remains unclear. Here we explored through what proteins and processes celastrol may act in activated fibroblast-like synoviocytes (FLS) from RA patients. Differential expression of genes and proteins after celastrol treatment of FLS was examined using RNA sequencing, label-free relatively quantitative proteomics and molecular docking. In this paper, expression of 26,565 genes and 3,372 proteins was analyzed. Celastrol was associated with significant changes in genes that respond to oxidative stress and oxygen levels, as well as genes that stabilize or synthesize components of the extracellular matrix. These results identify several potential mechanisms through which celastrol may inhibit inflammation in RA.

SUBMITTER: Xinqiang S

PROVIDER: S-EPMC7390347 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Potential mechanisms of action of celastrol against rheumatoid arthritis: Transcriptomic and proteomic analysis.

Xinqiang Song S Erqin Dai D Yu Zhang Z Hongtao Du D Lei Wang W Ningning Yang Y

PloS one 20200729 7

The clinical efficacy for treating of celastrol rheumatoid arthritis (RA) has been well-documented, but its mechanism of action remains unclear. Here we explored through what proteins and processes celastrol may act in activated fibroblast-like synoviocytes (FLS) from RA patients. Differential expression of genes and proteins after celastrol treatment of FLS was examined using RNA sequencing, label-free relatively quantitative proteomics and molecular docking. In this paper, expression of 26,565 ...[more]

PMID: 32726313

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Project description:BACKGROUND:Rheumatoid arthritis and osteoarthritis are two common musculoskeletal disorders that affect the joints. Despite high prevalence rates, etiological factors involved in these disorders remain largely unknown. Dissecting the molecular aspects of these disorders will significantly contribute to improving their diagnosis and clinical management. In order to identify proteins that are differentially expressed between these two conditions, a quantitative proteomic profiling of synovial fluid obtained from rheumatoid arthritis and osteoarthritis patients was carried out by using iTRAQ labeling followed by high resolution mass spectrometry analysis. RESULTS:We have identified 575 proteins out of which 135 proteins were found to be differentially expressed by ?3-fold in the synovial fluid of rheumatoid arthritis and osteoarthritis patients. Proteins not previously reported to be associated with rheumatoid arthritis including, coronin-1A (CORO1A), fibrinogen like-2 (FGL2), and macrophage capping protein (CAPG) were found to be upregulated in rheumatoid arthritis. Proteins such as CD5 molecule-like protein (CD5L), soluble scavenger receptor cysteine-rich domain-containing protein (SSC5D), and TTK protein kinase (TTK) were found to be upregulated in the synovial fluid of osteoarthritis patients. We confirmed the upregulation of CAPG in rheumatoid arthritis synovial fluid by multiple reaction monitoring assay as well as by Western blot. Pathway analysis of differentially expressed proteins revealed a significant enrichment of genes involved in glycolytic pathway in rheumatoid arthritis. CONCLUSIONS:We report here the largest identification of proteins from the synovial fluid of rheumatoid arthritis and osteoarthritis patients using a quantitative proteomics approach. The novel proteins identified from our study needs to be explored further for their role in the disease pathogenesis of rheumatoid arthritis and osteoarthritis.Sartaj Ahmad and Raja Sekhar Nirujogi contributed equally to this article.

Project description:BackgroundThis bioinformatics study aimed to reveal potential cross-talk genes, related pathways, and transcription factors between periimplantitis and rheumatoid arthritis (RA).MethodsThe datasets GSE33774 (seven periimplantitis and eight control samples) and GSE106090 (six periimplantitis and six control samples) were included from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). A differential expression analysis (p < 0.05 and |logFC (fold change)| ≥ 1) and a functional enrichment analysis (p < 0.05) were performed. Based on this, a protein-protein interaction (PPI) network was constructed by Cytoscape. RA-related genes were extracted from DisGeNET database, and an overlap between periimplantitis-related genes and these RA-related genes was examined to identify potential cross-talk genes. Gene expression was merged between two datasets, and feature selection was performed by Recursive Feature Elimination (RFE) algorithm. For the feature selection cross-talk genes, support vector machine (SVM) models were constructed. The expression of these feature genes was determined from GSE93272 for RA. Finally, a network including cross-talk genes, related pathways, and transcription factors was constructed.ResultsPeriimplantitis datasets included 138 common differentially expressed genes (DEGs) including 101 up- and 37 downregulated DEGs. The PPI interwork of periimplantitis comprised 1,818 nodes and 2,517 edges. The RFE method selected six features, i.e., MERTK, CD14, MAPT, CCR1, C3AR1, and FCGR2B, which had the highest prediction. Out of these feature genes, CD14 and FCGR2B were most highly expressed in periimplantitis and RA. The final activated pathway-gene network contained 181 nodes and 360 edges. Nuclear factor (NF) kappa B signaling pathway and osteoclast differentiation were identified as potentially relevant pathways.ConclusionsThis current study revealed FCGR2B and CD14 as the most relevant potential cross-talk genes between RA and periimplantitis, which suggests a similarity between RA and periimplantitis and can serve as a theoretical basis for future research.

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Potential mechanisms of action of celastrol against rheumatoid arthritis: Transcriptomic and proteomic analysis.

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Potential mechanisms of action of celastrol against rheumatoid arthritis: Transcriptomic and proteomic analysis.

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