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      Network Pharmacology Analysis and Experimental Validation to Investigate the Mechanism of Total Flavonoids of Rhizoma Drynariae in Treating Rheumatoid Arthritis

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          Abstract

          Objective

          The study aimed to explore the mechanism of total flavonoids of Rhizoma Drynariae (TFRD) in the treatment of rheumatoid arthritis (RA) based on network pharmacology and experimental validation.

          Methods

          The active components of TFRD were identified from TCMSP and TCMID databases. Relevant targets of the active compounds of TFRD and RA-related targets were predicted by public databases online. A component-target (C-T) regulatory network was constructed by Cytoscape. The genes of TFRD regulating RA were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. KEGG enrichment analysis was performed to predict the crucial mechanism of TFRD against RA. The active components of TFRD underwent molecular docking with the key proteins. Collagen-induced arthritis (CIA) model of rats and inflammatory factors-stimulated fibroblast-like synoviocytes were used in vivo and in vitro to validate the efficacy and predicted critical mechanisms of TFRD.

          Results

          Network Pharmacology analysis revealed that TFRD had 14 active compounds, corresponding to 213 targets, and RA related to 2814 genes. There were 137 intersection genes between TFRD and RA. KEGG indicated that therapeutic effects of TFRD on RA involves T cell receptor signaling pathway, Th17 cell differentiation, IL-17 signaling pathway, TNF signaling pathway, MAPK signaling pathway and PI3K/AKT signaling pathway. In vivo experiments suggested TFRD can alleviate the inflammatory response, joint swelling and synovial abnormality of CIA rats. TFRD contributed to the decrease of Th17 cells and the down-regulated secretion of IL-17A and TNF-α of activated lymphocyte in CIA model. In vitro experiments confirmed TFRD can effectively inhibit the inflammatory response of fibroblast-like synoviocytes and suppress the abnormal activation of MAPK, PI3K/AKT and NFκB signaling pathways.

          Conclusion

          The treatment of RA with TFRD is closely related to inhibiting Th17 differentiation and inflammatory response of synoviocytes.

          Most cited references51

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          TCMSP: a database of systems pharmacology for drug discovery from herbal medicines

          Background Modern medicine often clashes with traditional medicine such as Chinese herbal medicine because of the little understanding of the underlying mechanisms of action of the herbs. In an effort to promote integration of both sides and to accelerate the drug discovery from herbal medicines, an efficient systems pharmacology platform that represents ideal information convergence of pharmacochemistry, ADME properties, drug-likeness, drug targets, associated diseases and interaction networks, are urgently needed. Description The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was built based on the framework of systems pharmacology for herbal medicines. It consists of all the 499 Chinese herbs registered in the Chinese pharmacopoeia with 29,384 ingredients, 3,311 targets and 837 associated diseases. Twelve important ADME-related properties like human oral bioavailability, half-life, drug-likeness, Caco-2 permeability, blood-brain barrier and Lipinski’s rule of five are provided for drug screening and evaluation. TCMSP also provides drug targets and diseases of each active compound, which can automatically establish the compound-target and target-disease networks that let users view and analyze the drug action mechanisms. It is designed to fuel the development of herbal medicines and to promote integration of modern medicine and traditional medicine for drug discovery and development. Conclusions The particular strengths of TCMSP are the composition of the large number of herbal entries, and the ability to identify drug-target networks and drug-disease networks, which will help revealing the mechanisms of action of Chinese herbs, uncovering the nature of TCM theory and developing new herb-oriented drugs. TCMSP is freely available at http://sm.nwsuaf.edu.cn/lsp/tcmsp.php.
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            Pathogenetic insights from the treatment of rheumatoid arthritis

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              Novel treatment strategies in rheumatoid arthritis

              New treatment strategies have substantially changed the course of rheumatoid arthritis. Many patients can achieve remission if the disease is recognised early and is treated promptly and continuously; however, some individuals do not respond adequately to treatment. Rapid diagnosis and a treat-to-target approach with tight monitoring and control, can increase the likelihood of remission in patients with rheumatoid arthritis. In this Series paper, we describe new insights into the management of rheumatoid arthritis with targeted therapy approaches using classic and novel medications, and outline the potential effects of precision medicine in this challenging disease. Articles are included that investigate the treat-to-target approach, which includes adding or de-escalating treatment. Rheumatoid arthritis treatment is impeded by delayed diagnosis, problematic access to specialists, and difficulties adhering to treat-to-target principles. Clinical management goals in rheumatoid arthritis include enabling rapid access to optimum diagnosis and care and the well informed use of multiple treatments approved for this disease.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                08 June 2022
                2022
                : 16
                : 1743-1766
                Affiliations
                [1 ]Graduate School, Beijing University of Chinese Medicine , Beijing, 100029, People’s Republic of China
                [2 ]Department of TCM Rheumatology, China-Japan Friendship Hospital , Beijing, 100029, People’s Republic of China
                [3 ]Beijing Key Lab for Immune-Mediated Inflammatory Diseases, China-Japan Friendship Hospital , Beijing, 100029, People’s Republic of China
                [4 ]Humanities School, Beijing University of Chinese Medicine , Beijing, 100029, People’s Republic of China
                [5 ]School of Traditional Chinese Medicine, Beijing University of Chinese Medicine , Beijing, 100029, People’s Republic of China
                Author notes
                Correspondence: Qing-wen Tao, Department of TCM Rheumatology, China-Japan Friendship Hospital , Beijing, People’s Republic of China, Tel +8613910528490, Email taoqg1@outlook.com
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-6004-289X
                http://orcid.org/0000-0002-2454-2168
                http://orcid.org/0000-0003-3970-4606
                http://orcid.org/0000-0003-2366-5147
                http://orcid.org/0000-0002-9415-1197
                Article
                354946
                10.2147/DDDT.S354946
                9188779
                35702063
                c72827dc-80d3-416b-9fc1-3f4c461dc4e9
                © 2022 Chen et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 20 December 2021
                : 26 May 2022
                Page count
                Figures: 16, Tables: 3, References: 51, Pages: 24
                Funding
                Funded by: the National Natural Science Foundation of China;
                Funded by: National Famous Traditional Chinese Medicine Experts inheritance studio of Xiaoping Yan;
                Funded by: National Regional Chinese Medicine Diagnostic and Treatment Centre for Rheumatic Diseases Project;
                Funded by: National Key Clinical Specialty Capacity Building Project;
                This study was supported by the National Natural Science Foundation of China (No. 81804042, 81673941), National Famous Traditional Chinese Medicine Experts inheritance studio of Xiaoping Yan (2019-PP-001), National Regional Chinese Medicine Diagnostic and Treatment Centre for Rheumatic Diseases Project (2019-ZX-006), National Key Clinical Specialty Capacity Building Project (2011-ZDZK-001).
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                total flavonoids of rhizoma drynariae,rheumatoid arthritis,network pharmacology,t cell differentiation,inflammatory response

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