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Tripterygium Ingredients for Pathogenicity Cells in Rheumatoid Arthritis.

ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by chronic polyarthritis. Many types of cells play pivotal roles in the pathogenicity of RA, such as T cells, B cells, macrophages, dendritic cells (DCs), osteoclasts (OCs), and fibroblast-like synoviocytes (FLS). Tripterygium wilfordii Hook f. (TwHf) and its ingredients are able to control disease activity by regulating the functions of cells mentioned above, and the clinical studies have highlighted the importance of TwHf ingredients in RA treatment. They have been demonstrated to improve the RA symptoms of animal models and patients. In this review, we discussed the effect of TwHf ingredients on pathogenicity cells, including disease/cell phenotypes and molecular mechanisms. Here, we constructed a cell-cell interaction network to visualize the effect of TwHf ingredients. We found that TwHf ingredients could inhibit the differentiation and proliferation of the pathogenicity cells. Besides, the components could decrease the levels of pathogenicity cytokines [i.e., interleukin-6 (IL-6), interleukin-1? (IL-1?), and tumor necrosis factor-? (TNF-?)]. Many signaling pathways are involved in the underlying mechanisms, such as PI3K, NF-?B, and MAPK signaling pathways.

SUBMITTER: Tang Y

PROVIDER: S-EPMC7567162 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tripterygium Ingredients for Pathogenicity Cells in Rheumatoid Arthritis.

Tang Yujun Y Liu Qiuping Q Feng Yuxiang Y Zhang Yi Y Xu Zhenghao Z Wen Chengping C Zhang Yun Y

Frontiers in pharmacology 20201002

Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by chronic polyarthritis. Many types of cells play pivotal roles in the pathogenicity of RA, such as T cells, B cells, macrophages, dendritic cells (DCs), osteoclasts (OCs), and fibroblast-like synoviocytes (FLS). Tripterygium wilfordii Hook f. (TwHf) and its ingredients are able to control disease activity by regulating the functions of cells mentioned above, and the clinical studies have highlighted the importance of TwHf ...[more]

PMID: 33123015

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Project description:Rheumatoid arthritis (RA), a chronic inflammatory synovitis systemic disease, can lead to joint deformities, loss of function and even death. The pathogenesis of RA may be related to genetics, infection and/or sex hormones; however, detailed accounts of the molecular mechanisms underlying its pathogenesis are lacking. In the present study, the synovial tissues of patients with RA and healthy individuals were analyzed to identify the pathogenic signaling pathways and key candidate genes involved in RA. Gene Ontology (GO), pathway enrichment and protein-protein interaction analysis were further used to identify the differentially expressed genes (DEGs) and their potential roles in RA. Molecular docking was used to screen the potential candidate drugs for management of RA. Small interfering RNA was used for knockdown of the CD2 protein. A Cell Counting Kit-8 assay was used to detect the proliferation of cells. Changes in the levels of inflammatory cytokines were detected using ELISA. A total of 279 DEGs were identified in RA; amongst these genes, 166 and 113 were upregulated and downregulated, respectively. GO analysis revealed that the upregulated DEGs were primarily enriched in the activation of the immune and adaptive immune responses, as well as the inflammatory response. The T-cell surface antigen CD2 (CD2) was identified as the most important hub gene by selecting the most important module from the protein-protein interaction network. Knockout of CD2 reduced the damaging effects of TNF-α on synovial cells. Through in situ screening using computer-aided drug design, the triptolide derivative (5R)-5-hydroxytriptolide (LLDT-8) was determined to have the highest docking score based on the CD2 protein structure. Cell experiments showed that LLDT-8 could inhibit the expression of CD2. Cell proliferation and inflammatory cytokine assays confirmed that CD2 was the direct target of LLDT-8. Together, the results of the present study determined factors involved in the pathogenesis of RA and the important role of CD2 in this process by analyzing the DEGs in the RA process. LLDT-8 inhibited CD2 and may thus be used to treat RA. These candidate genes and signaling pathways may serve as potential targets for the clinical treatment of RA.

Project description:ObjectivesTo summarize the quantity and quality of evidence for using Tripterygium wilfordii Hook. f. (TwHF) preparations in patients with rheumatoid arthritis (RA) and to find the reasons of the disparity by comprehensively appraising the related systematic reviews (SRs).MethodsWe performed an overview of evidence for the effectiveness and safety of TwHF preparations for patients with RA. We searched seven literature databases from inception to July 15, 2021. We included SRs of TwHF preparations in the treatment of RA. Four tools were used to evaluate the reporting quality, methodological quality, risk of bias, and the certainty of evidence for the included SRs, which are the PRISMA, the AMSTAR-2, the ROBIS, and the GRADE approach.ResultsWe included 27 SRs (with 385 studies and 33,888 participants) for this overview. The AMSTAR-2 showed that 19 SRs had critically low methodological quality and the remaining 8 had low methodological quality. The rate of overlaps was 68.31% (263/385), and the CCA (corrected covered area) was 0.53, which indicated the degree of overlap is slight. Based on the assessment of ROBIS, all 27 SRs were rated as low risk in phase 1; one SR was rated as low risk in domain 1, 9 SRs were in low risk in domain 2, 16 SRs were in low risk in domain 3, and 16 SRs were in low risk in domain 4 in phase 2; 7 SRs were rated as low risk in phase 3. Among 27 items of PRISMA, 15 items were reported over 70% of compliance, the reporting quality of 16 SRs was rated as "fair," and 11 were "good." Using GRADE assessment, moderate quality of evidence was found in 5 outcomes, and 5 outcomes were low quality.ConclusionThe use of TwHF preparations for the treatment of RA may be clinically effective according to the moderate-quality evidence. There are methodological issues, risk of bias, and reporting deficiencies still needed to be improved. SRs with good quality and further randomized clinical trials that focus on clinical important outcomes are needed.

Project description:BackgroundExtracts of the medicinal plant Tripterygium wilfordii Hook F (TwHF) have been used in China for centuries to treat a spectrum of inflammatory diseases.ObjectiveTo compare the benefits and side effects of TwHF extract with those of sulfasalazine for the treatment of active rheumatoid arthritis.DesignRandomized, controlled trial. A computer-generated code with random, permuted blocks was used to assign treatment.Setting2 U.S. academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan).Patients121 patients with active rheumatoid arthritis and 6 or more painful and swollen joints.InterventionTwHF extract, 60 mg 3 times daily, or sulfasalazine, 1 g twice daily. Patients could continue stable doses of oral prednisone or nonsteroidal anti-inflammatory drugs but had to stop taking disease-modifying antirheumatic drugs at least 28 days before randomization.MeasurementsThe primary outcome was the rate of achievement of 20% improvement in the American College of Rheumatology criteria (ACR 20) at 24 weeks. Secondary end points were safety; radiographic scores of joint damage; and serum levels of interleukin-6, cholesterol, cortisol, and adrenocorticotropic hormone.ResultsOutcome data were available for only 62 patients at 24 weeks. In a mixed-model analysis that imputed data for patients who dropped out, 65.0% (95% CI, 51.6% to 76.9%) of the TwHF group and 32.8% (CI, 21.3% to 46.0%) of the sulfasalazine group met the ACR 20 response criteria (P=0.001). Patients receiving TwHF also had significantly higher response rates for ACR 50 and ACR 70 in mixed-model analyses. Analyses of only completers showed similar significant differences between the treatment groups. Significant improvement was demonstrated in all individual components of the ACR response, including the Health Assessment Questionnaire disability score. Interleukin-6 levels rapidly and significantly decreased in the TwHF group. Although not statistically significant, radiographic progression was lower in the TwHF group. The frequency of adverse events was similar in both groups.LimitationsOnly 62% and 41% of patients continued receiving TwHF extract and sulfasalazine, respectively, during the 24 weeks of the study. Long-term outcome data were not collected on participants who discontinued treatment.ConclusionIn patients who continued treatment for 24 weeks and could also use stable oral prednisone and nonsteroidal anti-inflammatory drugs, attainment of the ACR 20 response criteria was significantly greater with TwHF extract than with sulfasalazine.

Project description:ObjectivesThe mammalian target of Rapamycin (mTOR) is a metabolic master regulator of both innate and adaptive immunity; however, its exact role in stromal cell biology is unknown. In this study we explored the role of the mTOR pathway on Rheumatoid Arthritis synovial fibroblast (RASF) metabolism and activation and determined if crosstalk with the Hippo-YAP pathway mediates their effects.MethodsPrimary RA synovial fibroblasts (RASF) were cultured with TNFα alone or in combination with the mTOR inhibitor Rapamycin or YAP inhibitor Verteporfin. Chemokine production, matrix metalloproteinase (MMP) production, and adhesion marker expression were quantified by real-time PCR, ELISA, and/or Flow Cytometry. Invasion assays were performed using Transwell invasion chambers, while wound repair assays were used to assess RASF migration. Cellular bioenergetics was assessed using the Seahorse XFe96 Analyzer. Key metabolic genes (GLUT-1, HK2, G6PD) were measured using real-time PCR. Reanalysis of RNA-Seq analysis was performed on RA (n = 151) and healthy control (HC) (n = 28) synovial tissue biopsies to detect differential gene and pathway expression. The expression of YAP was measured by Western Blot.ResultsTranscriptomic analysis of healthy donor and RA synovial tissue revealed dysregulated expression of several key components of the mTOR pathway in RA. Moreover, the expression of phospho-ribosomal protein S6 (pS6), the major downstream target of mTOR is specifically increased in RA synovial fibroblasts compared to healthy tissue. In the presence of TNFα, RASF display heightened phosphorylation of S6 and are responsive to mTOR inhibition via Rapamycin. Rapamycin effectively alters RASF cellular bioenergetics by inhibiting glycolysis and the expression of rate limiting glycolytic enzymes. Furthermore, we demonstrate a key role for mTOR signaling in uniquely mediating RASF migratory and invasive mechanisms, which are significantly abrogated in the presence of Rapamycin. Finally, we report a significant upregulation in several genes involved in the Hippo-YAP pathway in RA synovial tissue, which are predicted to converge with the mTOR pathway. We demonstrate crosstalk between the mTOR and YAP pathways in mediating RASF invasive mechanism whereby Rapamycin significantly abrogates YAP expression and YAP inhibition significantly inhibits RASF invasiveness.ConclusionmTOR drives pathogenic mechanisms in RASF an effect which is in part mediated via crosstalk with the Hippo-YAP pathway.

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Tripterygium Ingredients for Pathogenicity Cells in Rheumatoid Arthritis.

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Tripterygium Ingredients for Pathogenicity Cells in Rheumatoid Arthritis.

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