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      The Underling Mechanisms Exploration of Rubia cordifolia L. Extract Against Rheumatoid Arthritis by Integrating Network Pharmacology and Metabolomics


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          Rubia cordifolia L. (RC) is a classic herbal medicine for the treatment of rheumatoid arthritis (RA) and has been used since ancient times. The ethanol extract of Rubia cordifolia L. (RCE) showed obvious anti-RA effects in our previous study. However, further potential mechanisms require more exploration. We aimed to investigate the mechanism of RCE for the treatment of RA by integrating metabolomics and network pharmacology in this study.


          An adjuvant-induced arthritis (AIA) rat model was established, and we evaluated the therapeutic effects of RCE. Metabolomics of serum and urine was used to identify the differential metabolites. Network pharmacology was applied to determine the key metabolites and potential targets. Finally, the potential targets and compounds of RCE were verified by molecular docking.


          The results indicated that RCE suppressed foot swelling and alleviated joint damage and also had anti-inflammatory properties by inhibiting the expressions of tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, prostaglandin E2 (PGE2), and P65. Ten and seven differential metabolites were found in the serum and urine, respectively, of rats. Six key targets, ie, phospholipase A2 group IIA (PLA2G2A), phospholipase A2 group X (PLA2G10), cytidine deaminase (CDA), uridine-cytidine kinase 2 (UCK2), charcot-leyden crystal galectin (CLC), and 5′,3′-nucleotidase, mitochondrial (NT5M), were discovered by network pharmacology and metabolite analysis and were found to be related to glycerophospholipid metabolism and pyrimidine metabolism. Molecular docking confirmed that the favorable compounds showed affinities with the key targets, including alizarin, 6-hydroxyrubiadin, ruberythric acid, and munjistin.


          This study revealed the underlying mechanisms of RCE and provided evidence that will allow researchers to further investigate the functions and components of RCE against RA.

          Most cited references76

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          Rheumatoid arthritis.

          Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid arthritis.
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            Pathogenetic insights from the treatment of rheumatoid arthritis

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              Understanding the mechanism of IL-1β secretion

              The cytokine interleukin-1β (IL-1β) is a key mediator of the inflammatory response. Essential for the host-response and resistance to pathogens, it also exacerbates damage during chronic disease and acute tissue injury. It is not surprising therefore that there is a huge level of interest in how this protein is produced and exported from cells. However, the mechanism of IL-1β release has proven to be elusive. It does not follow the conventional ER-Golgi route of secretion. A literature full of disparate observations arising from numerous experimental systems, has contributed to a complicated mix of diverse proposals. Here we summarise these observations and propose that secretion of IL-1β occurs on a continuum, dependent upon stimulus strength and the extracellular IL-1β requirement.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                11 February 2023
                : 17
                : 439-457
                [1 ]College of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou, People’s Republic of China
                [2 ]Key Laboratory of Chinese Medicinal Resources from Lingnan (Guangzhou University of Chinese Medicine), Ministry of Education , Guangzhou, People’s Republic of China
                [3 ]Joint Laboratory of Nation Engineering Research Center for the Pharmaceutics of Traditional Chinese Medicines , Guangzhou, People’s Republic of China
                Author notes
                Correspondence: Ruoting Zhan; Ping Yan, Guangzhou University of Chinese Medicine , No. 232, Outer Ring East Road, Guangzhou, Guangdong, People’s Republic of China, Tel/Fax +86 20-39358045, Email ruotingzhan@vip.163.com; yanping@gzucm.edu.cn
                © 2023 Zeng 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).

                : 06 September 2022
                : 02 February 2023
                Page count
                Figures: 7, Tables: 4, References: 76, Pages: 19
                Funded by: Guangdong Provincial;
                This research was funded by the key area special project of the “serving rural revitalization plan” of colleges and universities in Guangdong Province: construction of science and technology service system of the Southern pharmaceutical industry based on Rural Revitalization of Guangdong Province, grant number 2019KZDZX2017; Guangdong Provincial Rural Revitalization Strategy special project—Guangdong modern southern medicine industry technology system innovation team, grant number 2022KJ148; and the research project of Guangdong Provincial Bureau of Traditional Chinese Medicine—study on Rubia alcohol extract in the treatment of rheumatoid arthritis by regulating intestinal flora and restoring Treg/Th17, grant number 20221121.
                Original Research

                Pharmacology & Pharmaceutical medicine
                inflammtion,aia rats,molecular docking,chronic disease
                Pharmacology & Pharmaceutical medicine
                inflammtion, aia rats, molecular docking, chronic disease


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