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      Signaling pathways in rheumatoid arthritis: implications for targeted therapy

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          Abstract

          Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future.

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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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            DNA methylation and its basic function.

            In the mammalian genome, DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA. During development, the pattern of DNA methylation in the genome changes as a result of a dynamic process involving both de novo DNA methylation and demethylation. As a consequence, differentiated cells develop a stable and unique DNA methylation pattern that regulates tissue-specific gene transcription. In this chapter, we will review the process of DNA methylation and demethylation in the nervous system. We will describe the DNA (de)methylation machinery and its association with other epigenetic mechanisms such as histone modifications and noncoding RNAs. Intriguingly, postmitotic neurons still express DNA methyltransferases and components involved in DNA demethylation. Moreover, neuronal activity can modulate their pattern of DNA methylation in response to physiological and environmental stimuli. The precise regulation of DNA methylation is essential for normal cognitive function. Indeed, when DNA methylation is altered as a result of developmental mutations or environmental risk factors, such as drug exposure and neural injury, mental impairment is a common side effect. The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.
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              The pathogenesis of rheumatoid arthritis.

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                Author and article information

                Contributors
                mjczyczx@shutcm.edu.cn
                yzzhu@must.edu.mo
                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                2095-9907
                2059-3635
                17 February 2023
                17 February 2023
                2023
                : 8
                : 68
                Affiliations
                [1 ]GRID grid.259384.1, ISNI 0000 0000 8945 4455, State Key Laboratory of Quality Research in Chinese Medicine & School of Pharmacy, , Macau University of Science and Technology, ; Macau SAR, 999078 China
                [2 ]GRID grid.443382.a, ISNI 0000 0004 1804 268X, School of Basic Medicine, , Guizhou University of Traditional Chinese Medicine, ; Guiyang, China
                [3 ]GRID grid.410560.6, ISNI 0000 0004 1760 3078, Affiliated Hospital of Guangdong Medical University, ; Zhanjiang, China
                [4 ]GRID grid.4563.4, ISNI 0000 0004 1936 8868, School of Biosciences, , University of Nottingham, ; Loughborough, United Kingdom
                [5 ]GRID grid.411480.8, ISNI 0000 0004 1799 1816, Department of Rheumatology, , Longhua Hospital of Shanghai University of Traditional Chinese Medicine, ; Shanghai, 201203 China
                [6 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, , Fudan University, ; Shanghai, 201203 China
                Author information
                http://orcid.org/0000-0001-7700-8041
                Article
                1331
                10.1038/s41392-023-01331-9
                9935929
                36797236
                22c28f73-ab42-4819-9a07-2cf011ba7512
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 September 2022
                : 16 December 2022
                : 18 January 2023
                Funding
                Funded by: Macau Science and Technology Development fund (FDCT 0007/2019/AKP, 0021/2020/AGJ, 0011/2020/A1, 0089/2021/A, 0088/2021/A, 003/2022/ALC), The National Natural Science Foundation of China (Nos. 81973320), Innovative research team of high-level local universities and a key laboratory program of the Educational Commission of Shanghai Municipality (no. ZDSYS14005).
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2023

                rheumatic diseases,drug discovery
                rheumatic diseases, drug discovery

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