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Liao H, Zheng J, Lu J, Shen HL. NF-κB Signaling Pathway in Rheumatoid Arthritis: Mechanisms and Therapeutic Potential. Mol Neurobiol 2025; 62:6998-7021. [PMID: 39560902 DOI: 10.1007/s12035-024-04634-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 11/12/2024] [Indexed: 11/20/2024]
Abstract
Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that imposes a heavy economic burden on patients and society. Bone and cartilage destruction is considered an important factor leading to RA, and inflammation, oxidative stress, and mitochondrial dysfunction are closely related to bone erosion and cartilage destruction in RA. Currently, there are limitations in the clinical treatment methods for RA, which urgently necessitates finding new effective treatments for patients. Nuclear transcription factor-κB (NF-κB) is a signaling transcription factor that is widely present in various cells. It plays an important role as a stress source in the cellular environment and regulates gene expression in processes such as immunity, inflammation, cell proliferation, and apoptosis. NF-κB has long been recognized as a pathogenic factor of RA, and its activation can exacerbate RA by promoting inflammation, oxidative stress, mitochondrial dysfunction, and bone destruction. Conversely, inhibiting the activity of the NF-κB pathway effectively inhibits these pathological processes, thereby alleviating RA. Therefore, NF-κB may be a potential therapeutic target for RA. This article describes the physiological structure of NF-κB and its important role in RA through the regulation of oxidative stress, inflammatory response, mitochondrial function, and bone destruction. Meanwhile, we also summarized the impact of NF-κB crosstalk with other signaling pathways on RA and the effect of related drugs or inhibitors targeting NF-κB on RA. The purpose of this article is to provide evidence for the role of NF-κB in RA and to emphasize its significant role in RA by elucidating the mechanisms, so as to provide a theoretical basis for targeting the NF-κB pathway as a treatment for RA.
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Affiliation(s)
- Haiyang Liao
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, 730000, People's Republic of China
| | - Jianxiong Zheng
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, 730000, People's Republic of China
| | - Jinyue Lu
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, People's Republic of China
- Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, 730000, People's Republic of China
| | - Hai-Li Shen
- The Second Clinical Medical College of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, 730000, People's Republic of China.
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Christensen MD, Allahgholi L, Dobruchowska JM, Moenaert A, Guðmundsson H, Friðjónsson Ó, Karlsson EN, Hreggviðsson GÓ, Freysdottir J. Laminarins and their derivatives affect dendritic cell activation and their crosstalk with T cells. Int J Biol Macromol 2025; 306:141287. [PMID: 39984067 DOI: 10.1016/j.ijbiomac.2025.141287] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/28/2025] [Accepted: 02/17/2025] [Indexed: 02/23/2025]
Abstract
This research explores the impact of structural variations in laminarins derived from seaweed on their immunomodulatory properties. Laminarins from Laminaria digitata, L. hyperborea, and Saccharina latissima, were obtained using a two-step water extraction protocol, followed by structural characterization by FT-IR spectroscopy, 1H NMR, and MALDI-TOF MS. The laminarin backbones were confirmed as β-1,3-linked glucans with species-specific percentages of β-1,6-linkages (~10 %, ~4 %, and ~21 %, respectively). Each polymer chain consists of approximately 24 to 25 monomer units, while oligosaccharide fractions, produced using the enzyme LPHase, displayed distinct DP-ranges, degrees of β-1,6-branching and intrachain linkages. Laminarin from L. hyperborea and specific oligosaccharide fractions from L. hyperborea and S. latissima influenced cytokine secretion by dendritic cells (DCs). L. hyperborea laminarin and the fraction LhF5 (DP5-DP8) stimulated increased IL-6 and IL-10 secretion by DCs, suggesting a dual role in promoting inflammation and regulating the immune response. In contrast, LhF5, LhF4 (DP6-DP10), and S. latissima laminari-oligosaccharide fraction SlF3 (DP6-DP9) caused decreased TNFα secretion, reflecting anti-inflammatory potential. Co-culturing of treated DCs and CD4+ T-cells showed that L. hyperborea laminarin caused increased IL-17 and IL-10 secretion, whereas SlF3 caused reduced IL-12p40 and IFN-γ secretion. These findings show that DC maturation and T-cell activation are affected by laminarins of certain size-distribution and branching, implying therapeutic potential for the treatment of inflammatory diseases or vaccine enhancement.
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Affiliation(s)
- Monica Daugbjerg Christensen
- Department of Biotechnology and Biomedicine, Matís ohf, Vínlandsleið 12, IS-113 Reykjavík, Iceland; Faculty of Food Science and Nutrition, University of Iceland, Sæmundargata12, IS-102 Reykjavík, Iceland; Department of Immunology, Landspitali-The National University Hospital of Iceland, IS-101 Reykjavik, Iceland.
| | - Leila Allahgholi
- Division of Biotechnology, Department of Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden
| | - Justyna M Dobruchowska
- Department of Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Bijvoet Center for Biomolecular Research, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, the Netherlands
| | - Antoine Moenaert
- Department of Biotechnology and Biomedicine, Matís ohf, Vínlandsleið 12, IS-113 Reykjavík, Iceland; Faculty of Life and Environmental Sciences, University of Iceland, Sturlugata 7, IS-102 Reykjavík, Iceland
| | - Hörður Guðmundsson
- Department of Biotechnology and Biomedicine, Matís ohf, Vínlandsleið 12, IS-113 Reykjavík, Iceland
| | - Ólafur Friðjónsson
- Department of Biotechnology and Biomedicine, Matís ohf, Vínlandsleið 12, IS-113 Reykjavík, Iceland
| | - Eva Nordberg Karlsson
- Division of Biotechnology, Department of Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden
| | - Guðmundur Ó Hreggviðsson
- Department of Biotechnology and Biomedicine, Matís ohf, Vínlandsleið 12, IS-113 Reykjavík, Iceland; Faculty of Life and Environmental Sciences, University of Iceland, Sturlugata 7, IS-102 Reykjavík, Iceland
| | - Jona Freysdottir
- Department of Immunology, Landspitali-The National University Hospital of Iceland, IS-101 Reykjavik, Iceland; Faculty of Medicine, Biomedical Center, University of Iceland, Vatnsmyrarvegur 16, IS-101 Reykjavik, Iceland
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Huang YH, Qiu L, Peng Y, Cai R, Xiao QQ, Li MC, Xu LJ, Fu Q. Ecdysteroid-enriched fraction of Cyathula officinalis suppresses synovial proliferation and inflammation to ameliorate RA by inhibiting the AKT/PI3K/mTOR signaling pathway. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2025:1-23. [PMID: 40257367 DOI: 10.1080/10286020.2025.2492357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 04/07/2025] [Accepted: 04/08/2025] [Indexed: 04/22/2025]
Abstract
This study investigated the chemical compositions isolated from Cyathula officinalis (CES) and elucidated its anti-RA effects and potential mechanisms. In vitro results revealed that CES suppressed interleukin (IL)-1β-stimulated proliferation, migration, and invasion of MH7A cells in a concentration-dependent manner. In vivo results indicated that CES could reduce the arthritis score, paw swelling, and improve histopathological deterioration. The levels of inflammatory factors, matrix metalloproteinases, and proteins expressed in rat synovial tissue were suppressed after treatment with CES. These findings illustrate that CES is involved in the PI3K/AKT/mTOR/SREBP1/SCD-1/GPX4 axis-mediated ferroptosis and anti-inflammation, exerting its protective effects against the progression of RA.
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Affiliation(s)
- Yue-Hui Huang
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu610106, China
- School of Traditional Chinese Medicine and Nutritional Health Care, Meishan Pharmaceutical College, Meishan620000, China
| | - Lu Qiu
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu610106, China
| | - Yi Peng
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu610106, China
| | - Rui Cai
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu610106, China
| | - Qing-Qing Xiao
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu610106, China
| | - Mei-Chen Li
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu610106, China
| | - Li-Jia Xu
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu610106, China
| | - Qiang Fu
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu610106, China
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Chen M, Wang Z, Chen H, Li J, Guo X, Zhou S. Biomimetic Nanoparticles Inhibit the HIF-1α/iNOS/NLRP3 Pathway to Alleviate Rheumatoid Arthritis. NANO LETTERS 2025; 25:3807-3816. [PMID: 40033154 DOI: 10.1021/acs.nanolett.4c05782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease distinguished by inflammatory synovitis. Chrysin can alleviate the inflammatory response and inhibit the progression of RA. However, unfavorable physicochemical properties and nonselective biodistribution of chrysin make it difficult to achieve good therapeutic efficacy. To address these challenges, we developed a biomimetic nanocarrier to enhance the targeted delivery of chrysin to synoviocytes, a key cellular component in RA pathology. Our nanodrug, FMPlipo@C, was engineered by integrating fibroblast-like synoviocyte (FLS) membrane proteins into chrysin-loaded liposomes. This innovative approach harnesses homologous targeting mediated by FLS membrane proteins to direct liposomes to inflamed joints, facilitating cargo release within synoviocytes. We showed that FMPlipo@C reduces inflammation in collagen-induced rheumatoid arthritis (CIA) model mice by inhibiting the HIF-1α/iNOS/NLRP3 pathway, protecting cartilage, and preventing bone erosion, thus reducing swelling and stiffness. This study offers valuable insights into the development of novel therapeutic strategies for the treatment of RA.
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MESH Headings
- Animals
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/pathology
- Arthritis, Rheumatoid/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors
- Mice
- Nanoparticles/chemistry
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors
- Biomimetic Materials/chemistry
- Biomimetic Materials/pharmacology
- Liposomes/chemistry
- Synoviocytes/drug effects
- Synoviocytes/metabolism
- Humans
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/pathology
- Arthritis, Experimental/metabolism
- Flavonoids/chemistry
- Flavonoids/pharmacology
- Flavonoids/administration & dosage
- Signal Transduction/drug effects
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Affiliation(s)
- Mo Chen
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, P. R. China
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P. R. China
| | - Zhenhua Wang
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, P. R. China
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P. R. China
| | - Haolong Chen
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P. R. China
| | - Jin Li
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, P. R. China
- Key Laboratory of Advanced Technologies of Materials Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P. R. China
| | - Xing Guo
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, P. R. China
| | - Shaobing Zhou
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, P. R. China
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Zhang ZE, Kim A, Suboc N, Mancuso N, Gazal S. Efficient count-based models improve power and robustness for large-scale single-cell eQTL mapping. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.18.25320755. [PMID: 40093202 PMCID: PMC11908335 DOI: 10.1101/2025.01.18.25320755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Population-scale single-cell transcriptomic technologies (scRNA-seq) enable characterizing variant effects on gene regulation at the cellular level (e.g., single-cell eQTLs; sc-eQTLs). However, existing sc-eQTL mapping approaches are either not designed for analyzing sparse counts in scRNA-seq data or can become intractable in extremely large datasets. Here, we propose jaxQTL, a flexible and efficient sc-eQTL mapping framework using highly efficient count-based models given pseudobulk data. Using extensive simulations, we demonstrated that jaxQTL with a negative binomial model outperformed other models in identifying sc-eQTLs, while maintaining a calibrated type I error. We applied jaxQTL across 14 cell types of OneK1K scRNA-seq data (N=982), and identified 11-16% more eGenes compared with existing approaches, primarily driven by jaxQTL ability to identify lowly expressed eGenes. We observed that fine-mapped sc-eQTLs were further from transcription starting site (TSS) than fine-mapped eQTLs identified in all cells (bulk-eQTLs; P=1x10-4) and more enriched in cell-type-specific enhancers (P=3x10-10), suggesting that sc-eQTLs improve our ability to identify distal eQTLs that are missed in bulk tissues. Overall, the genetic effect of fine-mapped sc-eQTLs were largely shared across cell types, with cell-type-specificity increasing with distance to TSS. Lastly, we observed that sc-eQTLs explain more SNP-heritability (h2 ) than bulk-eQTLs (9.90 ± 0.88% vs. 6.10 ± 0.76% when meta-analyzed across 16 blood and immune-related traits), improving but not closing the missing link between GWAS and eQTLs. As an example, we highlight that sc-eQTLs in T cells (unlike bulk-eQTLs) can successfully nominate IL6ST as a candidate gene for rheumatoid arthritis. Overall, jaxQTL provides an efficient and powerful approach using count-based models to identify missing disease-associated eQTLs.
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Affiliation(s)
- Zixuan Eleanor Zhang
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California
| | - Artem Kim
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California
| | - Noah Suboc
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California
| | - Nicholas Mancuso
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California
- Department of Quantitative and Computational Biology, University of Southern California
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
| | - Steven Gazal
- Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California
- Department of Quantitative and Computational Biology, University of Southern California
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
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Mawhinney JA, Oestreich K, Lindau T. Role of Synovectomy in Rheumatoid Hand and Wrist. Hand Clin 2025; 41:57-64. [PMID: 39521590 DOI: 10.1016/j.hcl.2024.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
Synovectomy refers to the removal of all or part of the hypertrophied soft tissue membrane on the inside of the joint capsule or around tendons. Historically, this was typically performed for rheumatoid arthritis and other inflammatory conditions of the hand, but following the development of more advanced medical treatments, the role of synovectomy has come into question. In this article, the authors outline the biologic basis for synovectomy and then consider its present and future role in the management of joint and tendon disease, followed by what further research is needed.
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Affiliation(s)
| | - Kerstin Oestreich
- Department of Plastic and Reconstructive Surgery, Birmingham Women's and Children's Hospital, Birmingham, B15 2TG, UK
| | - Tommy Lindau
- Pulvertaft Hand Centre, Royal Derby Hospital, Derby, DE22 3NE, UK
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Ma L, Jiang X, Gao J. Revolutionizing rheumatoid arthritis therapy: harnessing cytomembrane biomimetic nanoparticles for novel treatment strategies. Drug Deliv Transl Res 2025; 15:66-83. [PMID: 38758497 DOI: 10.1007/s13346-024-01605-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2024] [Indexed: 05/18/2024]
Abstract
Rheumatoid arthritis (RA) is a systemic immune disease with severe implications for joint health. The issue of non-specific drug distribution potentially limits the therapeutic efficacy and increases the risk associated with RA treatment. Researchers employed cytomembrane-coated biomimetic nanoparticles (NPs) to enhance the targeting delivery efficacy to meet the demand for drug accumulation within the affected joints. Furthermore, distinct cytomembranes offer unique functionalities, such as immune cell activation and augmented NP biocompatibility. In this review, the current strategies of RA treatments were summarized in detail, and then an overview of RA's pathogenesis and the methodologies for producing cytomembrane-coated biomimetic NPs was provided. The application of cytomembrane biomimetic NPs derived from various cell sources in RA therapy is explored, highlighting the distinctive attributes of individual cytomembranes as well as hybrid membrane configurations. Through this comprehensive assessment of cytomembrane biomimetic NPs, we elucidate the prospective applications and challenges in the realm of RA therapy, and the strategy of combined therapy is proposed. In the future, cytomembrane biomimetic NPs have a broad therapeutic prospect for RA.
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Affiliation(s)
- Lan Ma
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China
- College of Pharmacy, Inner Mongolia Medical University, Chilechuan dairy economic development zone, Hohhot, Inner Mongolia Autonomous Region, 010110, China
| | - Xinchi Jiang
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China.
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
| | - Jianqing Gao
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China.
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
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You K, Yang L, Su Z, Shen J, Fan X, Guo Y, Yuan Z, Lu H. Butyric Acid Modulates Gut Microbiota to Alleviate Inflammation and Secondary Bone Loss in Ankylosing Spondylitis. Biomedicines 2024; 13:9. [PMID: 39857593 PMCID: PMC11762490 DOI: 10.3390/biomedicines13010009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/11/2024] [Accepted: 12/17/2024] [Indexed: 01/27/2025] Open
Abstract
Background: Ankylosing spondylitis (AS) is a chronic inflammatory and autoimmune disease that primarily affects the sacroiliac joints and axial skeleton. While the exact pathogenetic mechanism of AS remains unclear, previous reports have highlighted the involvement of genetic factors, immune responses, and gut microbiota dysregulation in the development of this condition. Short-chain fatty acids (SCFAs), which are microbial fermentation products derived from sugar, protein, and dietary fibers, play a role in maintaining the intestinal barrier function and reducing inflammatory responses. The aim of this study was to investigate the therapeutic potential of butyric acid (BA), an important SCFA, in the treatment of AS. Methods: To evaluate the anti-inflammatory and anti-bone loss effects of BA, a murine AS model was established using proteoglycan and dimethyl dioctadecyl ammonium (DDA) adjuvants. Various techniques, including an enzyme-linked immunosorbent assay (ELISA), magnetic resonance imaging (MRI), micro-CT, histology, quantitative PCR (qPCR) for intestinal tight junction protein expression, and 16S rDNA sequencing to analyze gut microbiota abundance, were employed to assess the inflammation and bone health in the target tissues. Results: The results indicated that BA demonstrated potential in alleviating the inflammatory response in the peripheral joints and the axial spine affected by AS, as evidenced by the reductions in inflammatory infiltration, synovial hyperplasia, and endplate erosion. Furthermore, BA was found to impact the intestinal barrier function positively. Notably, BA was associated with the downregulation of harmful inflammatory factors and the reversal of bone loss, suggesting its protective effects against AS. Conclusions: These beneficial effects were attributed to the modulation of gut microbiota, anti-inflammatory properties, and the maintenance of skeletal metabolic homeostasis. This study contributes new evidence supporting the relationship between gut microbiota and bone health.
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Affiliation(s)
- Ke You
- Department of Spine Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519082, China; (K.Y.); (L.Y.); (Z.S.); (Y.G.)
- Faculty of Health Sciences, University of Macau, Macau 999078, China
| | - Lianjun Yang
- Department of Spine Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519082, China; (K.Y.); (L.Y.); (Z.S.); (Y.G.)
| | - Zhihai Su
- Department of Spine Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519082, China; (K.Y.); (L.Y.); (Z.S.); (Y.G.)
- Faculty of Health Sciences, University of Macau, Macau 999078, China
| | - Jun Shen
- Department of Spine Surgery, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen 518107, China;
| | - Xinyang Fan
- Centre of Education Development, South China Normal University, Guangzhou 510006, China;
| | - Yuanqing Guo
- Department of Spine Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519082, China; (K.Y.); (L.Y.); (Z.S.); (Y.G.)
| | - Zhen Yuan
- Faculty of Health Sciences, University of Macau, Macau 999078, China
| | - Hai Lu
- Department of Spine Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519082, China; (K.Y.); (L.Y.); (Z.S.); (Y.G.)
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Zhang E, Zhang Q, Wang S, Zhang G, Li A, Lu W, Ju P. A dual-emission fluorescent probe with independent polarity and viscosity responses: The synthesis, spectroscopy and bio-imaging applications. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2024; 323:124873. [PMID: 39084016 DOI: 10.1016/j.saa.2024.124873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/15/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024]
Abstract
Viscosity and polarity are essential parameters that play critical roles in various physiological processes. Thus, dual-emission fluorescent probes that respond to both polarity and viscosity are highly sought-after tools for studying these processes. In addressing this need, a novel fluorescent probe (L), with dual emissions centered at 460 nm and 780 nm, which can sensitively respond to polarity and viscosity respectively, has been developed. Probe (L) is constructed through rational molecular design, utilizing two conjugated synthons connected by a π-bond to form a D-π-A system. The twisted intramolecular charge transfer (TICT) state is dominant in low-viscosity environments, resulting in weak near-infrared (NIR) fluorescence. Conversely, the intramolecular charge transfer (ICT) state is expected to prevail in high-viscosity environments, leading to strong NIR fluorescence. The polarity-sensitive fluorescence centered at 460 nm can be attributed to the emission of the coumarin unit. Moreover, probe (L) exhibits low cytotoxicity and primarily targets mitochondria. By leveraging the dual-emission properties of probe (L), real-time imaging of polarity and viscosity fluctuations within cells has been achieved. Additionally, probe (L) can be used for in situ and in vivo imaging of rheumatoid arthritis (RA) with good imaging resolution.
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Affiliation(s)
- Ensheng Zhang
- Key Laboratory of Life-Organic Analysis of Shandong Province, College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong, 273165, China.
| | - Qingxiang Zhang
- Key Laboratory of Life-Organic Analysis of Shandong Province, College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong, 273165, China
| | - Shuping Wang
- Key Laboratory of Life-Organic Analysis of Shandong Province, College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong, 273165, China
| | - Guixue Zhang
- Key Laboratory of Life-Organic Analysis of Shandong Province, College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong, 273165, China
| | - Anzhang Li
- Key Laboratory of Life-Organic Analysis of Shandong Province, College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong, 273165, China
| | - Wenhui Lu
- Key Laboratory of Life-Organic Analysis of Shandong Province, College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong, 273165, China
| | - Ping Ju
- Key Laboratory of Life-Organic Analysis of Shandong Province, College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong, 273165, China.
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10
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Panwar P, Andrault PM, Saha D, Brömme D. Immune regulatory and anti-resorptive activities of tanshinone IIA sulfonate attenuates rheumatoid arthritis in mice. Br J Pharmacol 2024; 181:5009-5027. [PMID: 39294929 DOI: 10.1111/bph.17312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/30/2024] [Accepted: 06/27/2024] [Indexed: 09/21/2024] Open
Abstract
BACKGROUND AND PURPOSE Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and painful joint destruction. Current treatments are helpful in RA remission, but strong immunosuppressive activity and patient resistance are clinical issues. This study explores a dual-action inhibitor, possessing both anti-inflammatory and anti-resorptive properties, as a novel treatment for RA. EXPERIMENTAL APPROACH Therapeutic efficacy and mechanisms of ectosteric (tanshinone IIA sulfonate [T06]) and active site-directed (odanacatib [ODN]) inhibitors of cathepsin K (CatK) were evaluated in RA mouse models. Pathology was assessed through biochemical analyses and histopathological examination. Flow cytometry analysis was performed to characterize immune cells. Anti-inflammatory effects of T06 on nuclear factor kappa beta (NF-κB) pathway were studied in macrophages. KEY RESULTS T06 effectively lowered the number of joint-resident immune cells, accompanied by significantly reduced production of inflammatory cytokines and collagenolytic proteases. This also included the suppression of Th17 cells and IL-17, resulting in the reduction of osteoclasts in arthritic joints and amplification of the overall anti-resorptive effect of T06, which has been attributed to its selective inhibition of the collagenolytic activity of CatK by preventing its oligomerization. The anti-inflammatory mechanism of T06 was based on blocking the phosphorylation of IκBα in the NF-κB pathway, resulting in reduced activation and expression of inflammatory cytokines. In contrast, ODN had no effect on inflammation and disease progression and was limited to the inhibition of CatK. CONCLUSIONS The combined anti-resorptive and anti-inflammatory activities characterize T06 as a novel therapeutic agent for RA.
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Affiliation(s)
- Preety Panwar
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Pharmaceutical Sciences, Elizabeth City State University, Elizabeth City, North Carolina, USA
| | - Pierre Marie Andrault
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
| | - Dipon Saha
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
| | - Dieter Brömme
- Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, British Columbia, Canada
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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11
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Wei S, Cheng RJ, Li S, Lu C, Zhang Q, Wu Q, Zhao X, Tian X, Zeng X, Liu Y. MSC-microvesicles protect cartilage from degradation in early rheumatoid arthritis via immunoregulation. J Nanobiotechnology 2024; 22:673. [PMID: 39497131 PMCID: PMC11536868 DOI: 10.1186/s12951-024-02922-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 10/10/2024] [Indexed: 11/06/2024] Open
Abstract
OBJECTIVE As research into preclinical rheumatoid arthritis (pre-RA) has advanced, a growing body of evidence suggests that abnormalities in RA-affected joint cartilage precede the onset of arthritis. Thus, early prevention and treatment strategies are imperative. In this study, we aimed to explore the protective effects of mesenchymal stem cell (MSC)-derived microvesicles (MVs) on cartilage degradation in a collagen-induced arthritis (CIA) mouse model. METHODS A CIA mouse model was established to observe early pathological changes in cartilage (days 21-25) through histological and radiological examinations. On day 22, MSCs-MVs were intravenously injected into the mice with CIA. Radiological, histological, and flow cytometric examinations were conducted to observe inflammation and cartilage changes in these mice compared to the mice with CIA and the control mice. In vitro, chondrocytes were cultured with inflammatory factors such as IL-1β and TNFα to simulate inflammatory damage to cartilage. After the addition of MVs, changes in inflammatory levels and collagen expression were measured via Western blotting, immunofluorescence, enzyme-linked immunosorbent assays (ELISAs), and quantitative PCR to determine the role of MVs in maintaining chondrocytes. RESULTS MSC-MVs expressed vesicular membrane proteins (CD63 and Annexin V) and surface markers characteristic of MSCs (CD44, CD73, CD90, and CD105). In the early stages of CIA in mice, a notable decrease in collagen content was observed in the joint cartilage. In mice with CIA, injection of MSCs-MVs resulted in a significant reduction in the peripheral blood levels of IL-1β, TNFα, and IL-6, along with a decrease in the ratio of proinflammatory T and B cells. Additionally, MSC-MVs downregulated the expression of IL-1β, TNFα, MMP-13, and ADAMTS-5 in cartilage while maintaining the stability of type I and type II collagen. These MVs also attenuated the destruction of cartilage, which was evident on imaging. In vitro experiments demonstrated that MSC-MVs effectively suppressed the secretion of the inflammatory factors IL-1β, TNFα, and IL-6 in stimulated peripheral blood mononuclear cells (PBMCs). CONCLUSIONS MSCs-MVs can inhibit the decomposition of the inflammation-induced cartilage matrix by regulating immune cell inflammatory factors to attenuate cartilage destruction. MSC-MVs are promising effective treatments for the early stages of RA.
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Affiliation(s)
- Shixiong Wei
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College. National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology. State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital. Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Rui-Juan Cheng
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Sujia Li
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Chenyang Lu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Qiuping Zhang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Qiuhong Wu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xueting Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xinping Tian
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College. National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology. State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital. Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College. National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology. State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital. Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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12
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Ma L, Wu H, Cao J, Zhang N, Li Y, Zheng J, Jiang X, Gao J. Mesenchymal Stem Cell-Based Biomimetic Liposome for Targeted Treatment of Rheumatoid Arthritis. ACS APPLIED MATERIALS & INTERFACES 2024; 16:47206-47215. [PMID: 39190615 DOI: 10.1021/acsami.4c09080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disorder that severely compromises joint health. The primary therapeutic strategy for advanced RA aims to inhibit joint inflammation. However, the nonspecific distribution of pharmacological agents has limited therapeutic efficacy and heightens the risks associated with RA treatment. To address this issue, we developed mesenchymal stem cell (MSC)-based biomimetic liposomes, termed MSCsome, which were composed of a fusion between MSC membranes and liposomes. MSC some with relatively simple preparation method effectively enhanced the targeting efficiency of drug to diseased joints. Interaction between lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1 enhanced the affinity of the MSCsome for polarized macrophages, thereby improving its targeting capability to affected joints. The effective targeted delivery facilitated drug accumulation in joints, resulting in the significant inhibition of the inflammation, as well as protection and repair of the cartilage. In conclusion, this study introduced MSCsome as a promising approach for the effective treatment of advanced RA, providing a novel perspective on targeted drug delivery therapy for inflammatory diseases.
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Affiliation(s)
- Lan Ma
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- College of Pharmacy, Inner Mongolia Medical University, Chilechuan Dairy Economic Development Zone, Hohhot, Inner Mongolia Autonomous Region 010110, China
| | - Honghui Wu
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Jinhua Institute of Zhejiang University, Jinhua 321002, China
| | - Jian Cao
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Nan Zhang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yaosheng Li
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Juanjuan Zheng
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xinchi Jiang
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianqing Gao
- State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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13
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Khawaja G, El-Orfali Y, Shoujaa A, Abou Najem S. Galangin: A Promising Flavonoid for the Treatment of Rheumatoid Arthritis-Mechanisms, Evidence, and Therapeutic Potential. Pharmaceuticals (Basel) 2024; 17:963. [PMID: 39065811 PMCID: PMC11279697 DOI: 10.3390/ph17070963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 06/24/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by progressive joint inflammation and damage. Oxidative stress plays a critical role in the onset and progression of RA, significantly contributing to the disease's symptoms. The complex nature of RA and the role of oxidative stress make it particularly challenging to treat effectively. This article presents a comprehensive review of RA's development, progression, and the emergence of novel treatments, introducing Galangin (GAL), a natural flavonoid compound sourced from various plants, as a promising candidate. The bioactive properties of GAL, including its anti-inflammatory, antioxidant, and immunomodulatory effects, are discussed in detail. The review elucidates GAL's mechanisms of action, focusing on its interactions with key targets such as inflammatory cytokines (e.g., TNF-α, IL-6), enzymes (e.g., SOD, MMPs), and signaling pathways (e.g., NF-κB, MAPK), which impact inflammatory responses, immune cell activation, and joint damage. The review also addresses the lack of comprehensive understanding of potential treatment options for RA, particularly in relation to the role of GAL as a therapeutic candidate. It highlights the need for further research and clinical studies to ascertain the effectiveness of GAL in RA treatment and to elucidate its mechanisms of action. Overall, this review provides valuable insights into the potential of GAL as a therapeutic option for RA, shedding light on its multifaceted pharmacological properties and mechanisms of action, while suggesting avenues for future research and clinical applications.
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Affiliation(s)
- Ghada Khawaja
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut 11-5020, Lebanon
| | - Youmna El-Orfali
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut 11-5020, Lebanon
- Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut 11-0236, Lebanon
| | - Aya Shoujaa
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut 11-5020, Lebanon
| | - Sonia Abou Najem
- Health Sciences Division, Abu Dhabi Women’s College, Higher Colleges of Technology, Abu Dhabi P.O. Box 25026, United Arab Emirates;
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14
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Wang C, Cheng J, Song L, Zhou Z, Zhao Q, Zhao Y, Wang H, Tan Y, Zhao B, Yang M. Self-Assembled Multilayer-Modified Needles Simulate Acupuncture and Diclofenac Sodium Delivery for Rheumatoid Arthritis. ACS APPLIED MATERIALS & INTERFACES 2024; 16:29876-29890. [PMID: 38829728 DOI: 10.1021/acsami.4c04815] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
A novel therapeutic approach combining acupuncture and diclofenac sodium (DS) administration was established for the potential treatment for rheumatoid arthritis (RA). DS is a commonly used anti-inflammatory and analgesic drug but has short duration and adverse effects. Acupoints are critical linkages in the meridian system and are potential candidates for drug delivery. Herein, we fabricated a DS-loaded multilayer-modified acupuncture needle (DS-MMAN) and investigated its capacity for inhibiting RA. This DS-MMAN possesses sustained release properties and in vitro anti-inflammatory effects. Experimental results showed that the DS-MMAN with microdoses can enhance analgesia and efficiently relieve joint swelling compared to the oral or intra-articular administration of DS with gram-level doses. Moreover, the combination of acupoint and DS exerts a synergistic improvement in inflammation and joint damage. Cytokine and T cell analyses in the serum indicated that the application of DS-MMAN suppressed the levels of pro-inflammatory factors and increased the levels of anti-inflammatory factors. Furthermore, the acupoint administration via DS-MMAN could decrease the accumulation of DS in the liver and kidneys, which may express better therapeutic efficiency and low toxicity. The present study demonstrated that the acupuncture needle has the potential to build a bridge between acupuncture and medication, which would be a promising alternative to the combination of traditional and modern medicine.
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Affiliation(s)
- Chen Wang
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
- School of Life Sciences, Beijing University of Chinese Medicine, North 3rd Ring East Road 11#, Chaoyang District, Beijing 100029, China
| | - Jinlai Cheng
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
| | - Lixia Song
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
| | - Ziyu Zhou
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
| | - Qinghe Zhao
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
| | - Yu Zhao
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
| | - Huajing Wang
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
| | - Yuqing Tan
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
| | - Baosheng Zhao
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, North 3rd Ring East Road 11#, Chaoyang District, Beijing 100029, China
| | - Miyi Yang
- China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica, Dongzhimen Nei Ave. Nanxiaojie 16#, Dongcheng District, Beijing 100700, China
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Danieli MG, Casciaro M, Paladini A, Bartolucci M, Sordoni M, Shoenfeld Y, Gangemi S. Exposome: Epigenetics and autoimmune diseases. Autoimmun Rev 2024; 23:103584. [PMID: 39097180 DOI: 10.1016/j.autrev.2024.103584] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 07/27/2024] [Accepted: 07/27/2024] [Indexed: 08/05/2024]
Abstract
Systemic autoimmune diseases are complex conditions characterized by an immune system dysregulation and an aberrant activation against self-antigens, leading to tissue and organ damage. Even though genetic predisposition plays a role, it cannot fully explain the onset of these diseases, highlighting the significant impact of non-heritable influences such as environment, hormones and infections. The exposome represents all those factors, ranging from chemical pollutants and dietary components to psychological stressors and infectious agents. Epigenetics, which studies changes in gene expression without altering the DNA sequence, is a crucial link between exposome and the development of autoimmune diseases. Key epigenetic mechanisms include DNA methylation, histone modifications, and non-coding RNAs. These epigenetic modifications could provide a potential piece of the puzzle in understanding systemic autoimmune diseases and their connection with the exposome. In this work we have collected the most important and recent evidence in epigenetic changes linked to systemic autoimmune diseases (systemic lupus erythematosus, idiopathic inflammatory myopathies, ANCA-associated vasculitis, and rheumatoid arthritis), emphasizing the roles these changes may play in disease pathogenesis, their potential as diagnostic biomarkers and their prospective in the development of targeted therapies.
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Affiliation(s)
- Maria Giovanna Danieli
- SOS Immunologia delle Malattie Rare e dei Trapianti, AOU delle Marche & Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, via Tronto 10/A, 60126 Torrette di Ancona, Italy; Postgraduate School of Allergy and Clinical Immunology, Università Politecnica delle Marche, via Tronto 10/A, 60126 Ancona, Italy.
| | - Marco Casciaro
- Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy.
| | - Alberto Paladini
- PostGraduate School of Internal Medicine, Università Politecnica delle Marche, via Tronto 10/A, 60126 Ancona, Italy
| | - Martina Bartolucci
- Postgraduate School of Allergy and Clinical Immunology, Università Politecnica delle Marche, via Tronto 10/A, 60126 Ancona, Italy
| | - Martina Sordoni
- Postgraduate School of Allergy and Clinical Immunology, Università Politecnica delle Marche, via Tronto 10/A, 60126 Ancona, Italy
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel; Reichman University, Herzelia 46101, Israel.
| | - Sebastiano Gangemi
- Operative Unit of Allergy and Clinical Immunology, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy.
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16
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Carvalho-Santos A, Ballard Kuhnert LR, Hahne M, Vasconcellos R, Carvalho-Pinto CE, Villa-Verde DMS. Anti-inflammatory role of APRIL by modulating regulatory B cells in antigen-induced arthritis. PLoS One 2024; 19:e0292028. [PMID: 38691538 PMCID: PMC11062543 DOI: 10.1371/journal.pone.0292028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 04/02/2024] [Indexed: 05/03/2024] Open
Abstract
APRIL (A Proliferation-Inducing Ligand), a member of the TNF superfamily, was initially described for its ability to promote proliferation of tumor cells in vitro. Moreover, this cytokine has been related to the pathogenesis of different chronic inflammatory diseases, such as rheumatoid arthritis. This study aimed to evaluate the ability of APRIL in regulating B cell-mediated immune response in the antigen-induced arthritis (AIA) model in mice. AIA was induced in previously immunized APRIL-transgenic (Tg) mice and their littermates by administration of antigen (mBSA) into the knee joints. Different inflammatory cell populations in spleen and draining lymph nodes were analyzed using flow cytometry and the assay was performed in the acute and chronic phases of the disease, while cytokine levels were assessed by ELISA. In the acute AIA, APRIL-Tg mice developed a less severe condition and a smaller inflammatory infiltrate in articular tissues when compared with their littermates. We also observed that the total cellularity of draining lymph nodes was decreased in APRIL-Tg mice. Flow cytometry analysis revealed an increase of CD19+IgM+CD5+ cell population in draining lymph nodes and an increase of CD19+CD21hiCD23hi (B regulatory) cells in APRIL-Tg mice with arthritis as well as an increase of IL-10 and CXCL13 production in vitro.
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Affiliation(s)
- Adriana Carvalho-Santos
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Lia Rafaella Ballard Kuhnert
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Michael Hahne
- Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, CNRS, Label "Equipe FRM", Montpellier, France
| | - Rita Vasconcellos
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Carla Eponina Carvalho-Pinto
- Experimental Pathology Laboratory, Department of Immunobiology, Biology Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - Déa Maria Serra Villa-Verde
- Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
- INOVA-IOC Network on Neuroimmunomodulation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, RJ, Brazil
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Roghani SA, Lotfi R, Soroush MG, Khorasanizadeh A, Feizollahi P, Assar S, Soufivand P, Pournazari M, Mohammadi Kish Z, Taghadosi M. Increased gene expression of CCR6 and RORγt in peripheral blood cells of rheumatoid arthritis patients and their correlation with anti-cyclic citrullinated peptide and disease activity. Immun Inflamm Dis 2023; 11:e1112. [PMID: 38156398 PMCID: PMC10698821 DOI: 10.1002/iid3.1112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 11/13/2023] [Accepted: 11/18/2023] [Indexed: 12/30/2023] Open
Abstract
OBJECTIVES The significance of T helper 17 (Th17) cells in the pathogenesis of rheumatoid arthritis (RA) has recently been demonstrated in many studies. Retinoic acid receptor-related orphan receptor γt (RORγt) is a transcription factor that is specifically involved in the generation of Th17 cells. Besides, the chemokine receptor CCR6, the receptor for CCL20, is characteristically expressed by these cells. Considering the pivotal roles of Th17 cells in RA pathogenesis, in this study, we assessed the gene expression of CCR6 and RORγt in the peripheral blood leukocytes of new case RA patients. Also, we evaluated their association with anticyclic citrullinated peptide (anti-CCP) antibodies and disease activity. METHODS Forty-five new case RA patients and 45 healthy persons have been recruited in this investigation. The gene expression of CCR6 and RORγt was evaluated by quantitative real-time PCR (qRT-PCR), and anti-CCP antibodies plasma levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique. Disease activity was measured according to the disease activity score-28 (DAS-28) formula. RESULTS The gene expression of CCR6 and RORγt increased remarkably in new case RA patients compared to healthy controls (p < .05 and p < .01, respectively). Moreover, there was a positive correlation between RORγt gene expression and parameters, including gene expression of CCR6 (p = .001, r = .461), plasma levels of CCL20 (p = .0009, r = .477), ESR (p = .004, r = .419), DAS-28 (p = .006, r = .402), anti-CCP (p = .019, r = .346), and RF (p = .001, r = .451). Also, CCR6 gene expression was positively associated with the DAS-28 (p = .037, r = .310), plasma levels of anti-CCP (p = .037, r = .312), and ESR (p = .029, r = .327). CONCLUSION Increased gene expression of CCR6 and RORγt in peripheral blood leukocytes of new case RA patients may contribute to the exacerbation and pathogenesis of RA.
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Affiliation(s)
- Seyed Askar Roghani
- Student Research Committee, Medical SchoolKermanshah University of Medical SciencesKermanshahIran
- Immunology Department, Faculty of MedicineKermanshah University of Medical SciencesKermanshahIran
- Medical Biology Research Center, Health Technology InstituteKermanshah University of Medical SciencesKermanshahIran
| | - Ramin Lotfi
- Clinical Research Development Center, Tohid HospitalKurdistan University of Medical SciencesSanandajIran
- Lung Diseases and Allergy Research Center, Research Institute for Health DevelopmentKurdistan University of Medical SciencesSanandajIran
| | | | - Ali Khorasanizadeh
- Student Research Committee, School of MedicineAhvaz Jundishapur University of Medical SciencesAhvazIran
| | - Parisa Feizollahi
- Immunology Department, Faculty of MedicineKermanshah University of Medical SciencesKermanshahIran
| | - Shirin Assar
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
| | - Parviz Soufivand
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
| | - Mehran Pournazari
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
| | - Zahra Mohammadi Kish
- Clinical Research Development Center, Imam Reza HospitalKermanshah University of Medical SciencesKermanshahIran
| | - Mahdi Taghadosi
- Immunology Department, Faculty of MedicineKermanshah University of Medical SciencesKermanshahIran
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Park JS, Yang S, Song D, Kim SM, Choi J, Kang HY, Jeong HY, Han G, Min DS, Cho ML, Park SH. A newly developed PLD1 inhibitor ameliorates rheumatoid arthritis by regulating pathogenic T and B cells and inhibiting osteoclast differentiation. Immunol Lett 2023; 263:87-96. [PMID: 37722567 DOI: 10.1016/j.imlet.2023.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 09/20/2023]
Abstract
Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline, plays multiple roles in inflammation. We investigated the therapeutic effects of the newly developed PLD1 inhibitors A2998, A3000, and A3773 in vitro and in vivo rheumatoid arthritis (RA) model. A3373 reduced the levels of LPS-induced TNF-α, IL-6, and IgG in murine splenocytes in vitro. A3373 also decreased the levels of IFN-γ and IL-17 and the frequencies of Th1, Th17 cells and germinal-center B cells, in splenocytes in vitro. A3373 ameliorated the severity of collagen-induced arthritis (CIA) and suppressed infiltration of inflammatory cells into the joint tissues of mice with CIA compared with vehicle-treated mice. Moreover, A3373 prevented systemic bone demineralization in mice with CIA and suppressed osteoclast differentiation and the mRNA levels of osteoclastogenesis markers in vitro. These results suggest that A3373 has therapeutic potential for RA.
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Affiliation(s)
- Jin-Sil Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - SeungCheon Yang
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Doona Song
- Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon 21983, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Sung-Min Kim
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - JeongWon Choi
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Hye Yeon Kang
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Ha Yeon Jeong
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Gyoonhee Han
- Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon 21983, Republic of Korea; Department of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea
| | - Do Sik Min
- Graduate Program of Industrial Pharmaceutical Science, Yonsei University, Incheon 21983, Republic of Korea; Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.
| | - Mi-La Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea Seoul 06591, Republic of Korea.
| | - Sung-Hwan Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 06591, Republic of Korea; Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
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19
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He ZH, Zou JT, Chen X, Gong JS, Chen Y, Jin L, Liu YW, Rao SS, Yin H, Tan YJ, Wang Z, Du W, Li HM, Qian YX, Wang ZX, Wang YY, Wan TF, Luo Y, Zhu H, Chen CY, Xie H. Ångstrom-scale silver particles ameliorate collagen-induced and K/BxN-transfer arthritis in mice via the suppression of inflammation and osteoclastogenesis. Inflamm Res 2023; 72:2053-2072. [PMID: 37816881 DOI: 10.1007/s00011-023-01778-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 10/12/2023] Open
Abstract
OBJECTIVE Nanoparticles (NPs) hold a great promise in combating rheumatoid arthritis, but are often compromised by their toxicities because the currently used NPs are usually synthesized by chemical methods. Our group has previously fabricated Ångstrom-scale silver particles (AgÅPs) and demonstrated the anti-tumor and anti-sepsis efficacy of fructose-coated AgÅPs (F-AgÅPs). This study aimed to uncover the efficacy and mechanisms of F-AgÅPs for arthritis therapy. METHODS We evaluated the efficacy of F-AgÅPs in collagen-induced arthritis (CIA) mice. We also compared the capacities of F-AgÅPs, the commercial AgNPs, and the clinical drug methotrexate (MTX) in protecting against K/BxN serum-transfer arthritis (STA) mice. Moreover, we evaluated the effects of F-AgÅPs and AgNPs on inflammation, osteoclast formation, synoviocytes migration, and matrix metalloproteinases (MMPs) production in vitro and in vivo. Meanwhile, the toxicities of F-AgÅPs and AgNPs in vitro and in vivo were also tested. RESULTS F-AgÅPs significantly prevented bone erosion, synovitis, and cartilage damage, attenuated rheumatic pain, and improved the impaired motor function in mouse models of CIA or STA, the anti-rheumatic effects of which were comparable or stronger than AgNPs and MTX. Further studies revealed that F-AgÅPs exhibited similar or greater inhibitory abilities than AgNPs to suppress inflammation, osteoclast formation, synoviocytes migration, and MMPs production. No obvious toxicities were observed in vitro and in vivo after F-AgÅPs treatment. CONCLUSIONS F-AgÅPs can effectively alleviate arthritis without notable toxicities and their anti-arthritic effects are associated with the inhibition of inflammation, osteoclastogenesis, synoviocytes migration, and MMPs production. Our study suggests the prospect of F-AgÅPs as an efficient and low-toxicity agent for arthritis therapy.
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Affiliation(s)
- Ze-Hui He
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Jing-Tao Zou
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Xia Chen
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jiang-Shan Gong
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Ya Chen
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Ling Jin
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Yi-Wei Liu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Shan-Shan Rao
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hao Yin
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Yi-Juan Tan
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Zun Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Xiangya School of Nursing, Central South University, Changsha, Hunan, China
| | - Wei Du
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Rehabilitation, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Hong-Ming Li
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Yu-Xuan Qian
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Zhen-Xing Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yi-Yi Wang
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Teng-Fei Wan
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Yi Luo
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Hao Zhu
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China
- Angmedicine Research Center, Central south university, Changsha, China
| | - Chun-Yuan Chen
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China.
- Angmedicine Research Center, Central south university, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Hui Xie
- Department of Orthopedics, Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- Hunan Key Laboratory of Angmedicine, Changsha, Hunan, China.
- Angmedicine Research Center, Central south university, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Dai X, Li L, Yan X, Fan Q, Wang R, Zhang W, Chen W, Liu Y, Meng J, Wang J. Myeloid Vamp3 deletion attenuates CFA-induced inflammation and pain in mice via ameliorating macrophage infiltration and inflammatory cytokine production. Front Immunol 2023; 14:1239592. [PMID: 37965323 PMCID: PMC10641732 DOI: 10.3389/fimmu.2023.1239592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/12/2023] [Indexed: 11/16/2023] Open
Abstract
Persistent inflammation and associated pain significantly impact individuals' quality of life, posing substantial healthcare challenges. Proinflammatory cytokines, released by activated macrophages, play crucial roles in the development of chronic inflammatory conditions such as rheumatoid arthritis. To identify and evaluate potential therapeutic interventions targeting this process for mitigating inflammation and pain, we created myeloid cell-specific knockout of Vamp3 (vesicle-associated membrane protein 3) mice (Vamp3 Δmyel) by crossing LysM-Cre mice with newly engineered Vamp3flox/flox mice. Bone marrow-derived macrophages and peritoneal resident macrophages from Vamp3 Δmyel mice exhibited a significant reduction in TNF-α and IL-6 release compared to control mice. Moreover, Vamp3 deficiency led to decreased paw edema and ankle joint swelling induced by intraplantar injection of complete Freund's adjuvant (CFA). Furthermore, Vamp3 depletion also mitigated CFA-induced mechanical allodynia and thermal hyperalgesia. Mechanistically, Vamp3 loss ameliorated the infiltration of macrophages in peripheral sites of the hind paw and resulted in reduced levels of TNF-α and IL-6 in the CFA-injected paw and serum. RT-qPCR analysis demonstrated downregulation of various inflammation-associated genes, including TNF-α, IL-6, IL-1β, CXCL11, TIMP-1, COX-2, CD68, and CD54 in the injected paw at the test day 14 following CFA administration. These findings highlight the novel role of Vamp3 in regulating inflammatory responses and suggest it as a potential therapeutic target for the development of novel Vamp-inactivating therapeutics, with potential applications in the management of inflammatory diseases.
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Affiliation(s)
- Xiaolong Dai
- School of Life Sciences, Henan University, Kaifeng, China
| | - Lianlian Li
- School of Life Sciences, Henan University, Kaifeng, China
| | - Xinrong Yan
- School of Life Sciences, Henan University, Kaifeng, China
| | - Qianqian Fan
- School of Life Sciences, Henan University, Kaifeng, China
| | - Ruizhen Wang
- School of Life Sciences, Henan University, Kaifeng, China
| | - Wenhao Zhang
- School of Life Sciences, Henan University, Kaifeng, China
| | - Weiwei Chen
- School of Life Sciences, Henan University, Kaifeng, China
| | - Yang Liu
- School of Life Sciences, Henan University, Kaifeng, China
| | - Jianghui Meng
- School of Life Sciences, Henan University, Kaifeng, China
- School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland
| | - Jiafu Wang
- School of Life Sciences, Henan University, Kaifeng, China
- School of Biotechnology, Faculty of Science and Health, Dublin City University, Dublin, Ireland
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21
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Luo P, Gao FQ, Sun W, Li JY, Wang C, Zhang QY, Li ZZ, Xu P. Activatable fluorescent probes for imaging and diagnosis of rheumatoid arthritis. Mil Med Res 2023; 10:31. [PMID: 37443101 DOI: 10.1186/s40779-023-00467-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 07/01/2023] [Indexed: 07/15/2023] Open
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease that is primarily manifested as synovitis and polyarticular opacity and typically leads to serious joint damage and irreversible disability, thus adversely affecting locomotion ability and life quality. Consequently, good prognosis heavily relies on the early diagnosis and effective therapeutic monitoring of RA. Activatable fluorescent probes play vital roles in the detection and imaging of biomarkers for disease diagnosis and in vivo imaging. Herein, we review the fluorescent probes developed for the detection and imaging of RA biomarkers, namely reactive oxygen/nitrogen species (hypochlorous acid, peroxynitrite, hydroxyl radical, nitroxyl), pH, and cysteine, and address the related challenges and prospects to inspire the design of novel fluorescent probes and the improvement of their performance in RA studies.
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Affiliation(s)
- Pan Luo
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Fu-Qiang Gao
- Department of Orthopedics, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Wei Sun
- Department of Orthopaedic Surgery of the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Jun-You Li
- School of Mechanical Engineering, Sungkyunkwan University, Suwon, 16419, South Korea
| | - Cheng Wang
- Department of Orthopaedic Surgery, Peking University Third Hospital, Peking University, Beijing, 100191, China
| | - Qing-Yu Zhang
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China
| | - Zhi-Zhuo Li
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Peng Xu
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
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Makkar R, Sehgal A, Singh S, Sharma N, Rawat R, Rashid S, Vargas-De-La-Cruz C, Yadav S, Bungau SG, Behl T. Current trends in epigenetic, cellular and molecular pathways in management of rheumatoid arthritis. Inflammopharmacology 2023:10.1007/s10787-023-01262-5. [PMID: 37335368 DOI: 10.1007/s10787-023-01262-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/01/2023] [Indexed: 06/21/2023]
Abstract
Rheumatoid arthritis is a systemic chronic polyarticular autoimmune disorder of joints and joint membrane mainly affecting feet and hands. The pathological manifestation of the disease includes infiltration of immune cells, hyperplasia of the lining of synovium, formation of pannus and bone and cartilage destruction. If left untreated, the appearance of small focal necrosis, adhesion of granulation, and formation of fibrous tissue on the surface of articular cartilage is noted. The disease primarily affects nearly 1% of the population globally, women being more affected than men with a ratio 2:1 and can initiate regardless of any age. The synovial fibroblast in rheumatoid arthritis individuals exhibits an aggressive phenotype which upregulates the manifestation of protooncogenes, adhesive compounds, inflammatory cytokines and matrix-deteriorating enzymes. Apart from the inflammatory effects of cytokines, chemokines are also noted to induce swelling and pain in arthritic individuals by residing in synovial membrane and forming pannus. The current treatment of rheumatoid arthritis includes treatment with non-steroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, treatment with biologics such as inhibitors of TNF-α, interleukins, platelet activating factor, etc. which provides significant relief from symptoms and aids in management of the disease. The current review highlights the pathogenesis involved in the onset of rheumatoid arthritis and also covers epigenetic, cellular and molecular parameters associated with it to aid better and advanced therapeutic approaches for management of the debilitating disease.
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Affiliation(s)
- Rashita Makkar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
| | - Aayush Sehgal
- GHG Khalsa College of Pharmacy, Gurusar Sadhar, Ludhiana, Punjab, India
| | - Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, India
| | - Ravi Rawat
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Bidholi, Uttarakhand, India
| | - Summya Rashid
- Department of Pharmacology and Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima, 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima, 15001, Peru
| | - Shivam Yadav
- School of Pharmacy, Babu Banarasi Das University, Lucknow, Uttar Pradesh, 226028, India
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028, Oradea, Romania.
- Doctoral School of Biomedical Sciences, University of Oradea, 410087, Oradea, Romania.
| | - Tapan Behl
- School of Health Sciences and Technology, University of Petroleum and Energy Studies, Bidholi, Uttarakhand, India.
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23
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Yuan G, Yang ST, Yang S. Regulator of G protein signaling 12 drives inflammatory arthritis by activating synovial fibroblasts through MYCBP2/KIF2A signaling. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 31:197-210. [PMID: 36700049 PMCID: PMC9843488 DOI: 10.1016/j.omtn.2022.12.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022]
Abstract
Synovial fibroblasts are the active and aggressive drivers in the progression of arthritis, but the cellular and molecular mechanisms remain unknown. Here, our results showed that regulator of G protein signaling 12 (RGS12) maintained ciliogenesis in synovial fibroblasts, which is critical for the development of inflammatory arthritis. Deletion of RGS12 led to a significant decrease in ciliogenesis, adhesion, migration, and secretion of synovial fibroblasts. Mechanistically, RGS12 overexpression in synovial fibroblasts increased the length and number of cilia but decreased the protein level of kinesin family member 2A (KIF2A). The results of LC-MS analyses showed that RGS12 interacted with MYC binding protein 2 to enhance its ubiquitination activity, through which the KIF2A protein was degraded in synovial fibroblasts. Moreover, overexpression of KIF2A blocked the increases in cilia length and number. Mice with RGS12 deficiency or treatment of RGS12 shRNA nanoparticles significantly decreased the clinical score, paw swelling, synovitis, and cartilage destruction during inflammatory arthritis by inhibiting the activation of synovial fibroblasts. Therefore, this study provides evidence that RGS12 activates synovial fibroblasts' pathological function via promoting MCYBP2-mediated degradation of KIF2A and ciliogenesis. Our data suggest that RGS12 may be a potential drug target for the treatment of inflammatory arthritis.
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Affiliation(s)
- Gongsheng Yuan
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shu-ting Yang
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shuying Yang
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- The Penn Center for Musculoskeletal Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Center for Innovation & Precision Dentistry, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
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Chen G, Mao Y, Wang J, Zhou J, Diao L, Wang S, Zhao W, Zhu X, Yu X, Zhao F, Liu X, Liu M. Phillyrin ameliorated collagen-induced arthritis through inhibition of NF-κB and MAPKs pathways in fibroblast-like synoviocytes. ARAB J CHEM 2023. [DOI: 10.1016/j.arabjc.2023.104844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023] Open
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Heng H, Li D, Su W, Liu X, Yu D, Bian Z, Li J. Exploration of comorbidity mechanisms and potential therapeutic targets of rheumatoid arthritis and pigmented villonodular synovitis using machine learning and bioinformatics analysis. Front Genet 2023; 13:1095058. [PMID: 36685864 PMCID: PMC9853060 DOI: 10.3389/fgene.2022.1095058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 12/21/2022] [Indexed: 01/08/2023] Open
Abstract
Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease. Pigmented villonodular synovitis (PVNS) is a tenosynovial giant cell tumor that can involve joints. The mechanisms of co-morbidity between the two diseases have not been thoroughly explored. Therefore, this study focused on investigating the functions, immunological differences, and potential therapeutic targets of common genes between RA and PVNS. Methods: Through the dataset GSE3698 obtained from the Gene Expression Omnibus (GEO) database, the differentially expressed genes (DEGs) were screened by R software, and weighted gene coexpression network analysis (WGCNA) was performed to discover the modules most relevant to the clinical features. The common genes between the two diseases were identified. The molecular functions and biological processes of the common genes were analyzed. The protein-protein interaction (PPI) network was constructed using the STRING database, and the results were visualized in Cytoscape software. Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) logistic regression and random forest (RF) were utilized to identify hub genes and predict the diagnostic efficiency of hub genes as well as the correlation between immune infiltrating cells. Results: We obtained a total of 107 DEGs, a module (containing 250 genes) with the highest correlation with clinical characteristics, and 36 common genes after taking the intersection. Moreover, using two machine learning algorithms, we identified three hub genes (PLIN, PPAP2A, and TYROBP) between RA and PVNS and demonstrated good diagnostic performance using ROC curve and nomogram plots. Single sample Gene Set Enrichment Analysis (ssGSEA) was used to analyze the biological functions in which three genes were mostly engaged. Finally, three hub genes showed a substantial association with 28 immune infiltrating cells. Conclusion: PLIN, PPAP2A, and TYROBP may influence RA and PVNS by modulating immunity and contribute to the diagnosis and therapy of the two diseases.
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Affiliation(s)
- Hongquan Heng
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Dazhuang Li
- Department of Orthopedics, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Wenxing Su
- Department of Plastic and Burn Surgery, The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, China
| | - Xinyue Liu
- Department of Radiology, Wangjiang Hospital of Sichuan University, Chengdu, China
| | - Daojiang Yu
- Department of Plastic and Burn Surgery, The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, China,*Correspondence: Daojiang Yu, ; Zhengjun Bian, ; Jian Li,
| | - Zhengjun Bian
- Department of Orthopedics, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China,*Correspondence: Daojiang Yu, ; Zhengjun Bian, ; Jian Li,
| | - Jian Li
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China,*Correspondence: Daojiang Yu, ; Zhengjun Bian, ; Jian Li,
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Umbreen H, Zhang X, Tang KT, Lin CC. Regulation of Myeloid Dendritic Cells by Synthetic and Natural Compounds for the Treatment of Rheumatoid Arthritis. Int J Mol Sci 2022; 24:ijms24010238. [PMID: 36613683 PMCID: PMC9820359 DOI: 10.3390/ijms24010238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/12/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Different subsets of dendritic cells (DCs) participate in the development of rheumatoid arthritis (RA). In particular, myeloid DCs play a key role in the generation of autoreactive T and B cells. Herein, we undertook a literature review on those synthetic and natural compounds that have therapeutic efficacy/potential for RA and act through the regulation of myeloid DCs. Most of these compounds inhibit both the maturation of DCs and their secretion of inflammatory cytokines and, subsequently, alter the downstream T-cell response (suppression of Th1 and Th17 responses while expanding the Treg response). The majority of the synthetic compounds are approved for the treatment of patients with RA, which is consistent with the importance of DCs in the pathogenesis of RA. All of the natural compounds are derived from plants. Their DC-modulating effect has been demonstrated both in vitro and in vivo. In addition, these natural products ameliorate arthritis in rodents and are potential therapeutics for human RA.
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Affiliation(s)
- Hira Umbreen
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Xiang Zhang
- Department of Molecular Medicine and Surgery, Karolinska Institute, 171 76 Stockholm, Sweden
| | - Kuo-Tung Tang
- Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung 407, Taiwan
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Correspondence: (K.-T.T.); (C.-C.L.); Tel.: +886-4-23592525 (ext. 3334) (K.-T.T.); +886-4-23592525 (ext. 3003) (C.-C.L.); Fax: +886-4-23503285 (K.-T.T. & C.-C.L.)
| | - Chi-Chien Lin
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
- Institute of Biomedical Science, The iEGG and Animal Biotechnology Center, National Chung-Hsing University, Taichung 402, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: (K.-T.T.); (C.-C.L.); Tel.: +886-4-23592525 (ext. 3334) (K.-T.T.); +886-4-23592525 (ext. 3003) (C.-C.L.); Fax: +886-4-23503285 (K.-T.T. & C.-C.L.)
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Wu Q, Jiang Y, You C. The SUMO components in rheumatoid arthritis. Rheumatology (Oxford) 2022; 61:4619-4630. [PMID: 35595244 DOI: 10.1093/rheumatology/keac297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 03/30/2022] [Accepted: 04/19/2022] [Indexed: 01/10/2023] Open
Abstract
Small ubiquitin-like modifier (SUMO) proteins can reversibly attach covalently or non-covalently to lysine residues of various substrates. The processes are named SUMOylation and de-SUMOylation, which maintain a dynamic balance in the physiological state, and are regulated by SUMO components. However, the dysregulation of components disturbs the balance and alters the functions of target proteins, which causes the occurrence of diseases. To date, certain SUMO components, including SUMO-1, SUMO-2/3, SAE1/Uba2, Ubc9, PIASs (protein inhibitors of activated signal transducer and activator of transcription) and SENPs (SUMO-specific proteases), have been found to participate in the pathogenesis of RA and their potential value as therapeutic targets also have been highlighted. In addition, single nucleotide polymorphisms (SNPs) in the SUMO components have been reported to be associated with disease susceptibility. Until now, only the SNP site of SUMO-4 has been reported in RA. Here we provided a systematic overview of the general characteristics of SUMO components and highlighted a summary of their impact on RA.
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Affiliation(s)
- Qian Wu
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Yao Jiang
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Chongge You
- Laboratory Medicine Center, Lanzhou University Second Hospital, Lanzhou, China
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Zhao B, Zeng L, Chen D, Xie S, Jin Z, Li G, Tang W, He Q. NIR-photocatalytic regulation of arthritic synovial microenvironment. SCIENCE ADVANCES 2022; 8:eabq0959. [PMID: 36197972 PMCID: PMC9534508 DOI: 10.1126/sciadv.abq0959] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 08/19/2022] [Indexed: 05/28/2023]
Abstract
Synovial microenvironment (SME) plays a vital role in the formation of synovial pannus and the induction of cartilage destruction in arthritis. In this work, a concept of the photocatalytic regulation of SME is proposed for arthritis treatment, and monodispersive hydrogen-doped titanium dioxide nanorods with a rutile single-crystal structure are developed by a full-solution method to achieve near infrared-photocatalytic generation of hydrogen molecules and simultaneous depletion of overexpressed lactic acid (LA) for realizing SME regulation in a collagen-induced mouse model of rheumatoid arthritis. Mechanistically, locally generated hydrogen molecules scavenge overexpressed reactive oxygen species to mediate the anti-inflammatory polarization of macrophages, while the simultaneous photocatalytic depletion of overexpressed LA inhibits the inflammatory/invasive phenotypes of synoviocytes and macrophages and ameliorates the abnormal proliferation of synoviocytes, thereby remarkably preventing the synovial pannus formation and cartilage destruction. The proposed catalysis-mediated SME regulation strategy will open a window to realize facile and efficient arthritis treatment.
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Affiliation(s)
- Bin Zhao
- School of Biomedical Engineering, Health Science Center, Shenzhen University, 1066 Xueyuan Road, Shenzhen, Guangdong 518060, China
| | - Lingting Zeng
- School of Biomedical Engineering, Health Science Center, Shenzhen University, 1066 Xueyuan Road, Shenzhen, Guangdong 518060, China
- Center of Hydrogen Science, School of Materials Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Danyang Chen
- School of Biomedical Engineering, Health Science Center, Shenzhen University, 1066 Xueyuan Road, Shenzhen, Guangdong 518060, China
- Center of Hydrogen Science, School of Materials Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Songqing Xie
- Key Laboratory of Human-Machine-Intelligence Synergic System, Research Center for Neural Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Zhaokui Jin
- School of Biomedical Engineering, Health Science Center, Shenzhen University, 1066 Xueyuan Road, Shenzhen, Guangdong 518060, China
- Center of Hydrogen Science, School of Materials Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Guanglin Li
- Key Laboratory of Human-Machine-Intelligence Synergic System, Research Center for Neural Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Wei Tang
- Key Laboratory of Human-Machine-Intelligence Synergic System, Research Center for Neural Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China
| | - Qianjun He
- School of Biomedical Engineering, Health Science Center, Shenzhen University, 1066 Xueyuan Road, Shenzhen, Guangdong 518060, China
- Center of Hydrogen Science, School of Materials Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
- Shenzhen Research Institute, Shanghai Jiao Tong University, Shenzhen, Guangdong 518057, China
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Wang Z, Gong J, Wang P, Xiong J, Zhang F, Mao Z. An activatable fluorescent probe enables in vivo evaluation of peroxynitrite levels in rheumatoid arthritis. Talanta 2022; 252:123811. [DOI: 10.1016/j.talanta.2022.123811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 10/15/2022]
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Lin X, Wang Q, He Z, Huang L, Wen C, Zhou D. Evaluating the Similarity of Different Collagen-Induced Arthritis Models to the Pre-Clinical Phase of RA in Female Rats. Inflammation 2022; 45:1559-1567. [PMID: 35260952 DOI: 10.1007/s10753-022-01641-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/20/2022] [Accepted: 01/30/2022] [Indexed: 11/24/2022]
Abstract
Since the development of RA is a multistep process, it is critical to take action to prevent RA in the pre-clinical phase. Animal models are currently one of the important methods to study RA, but there are very few animal models for studying the pre-clinical phase of RA (Pre-RA). This study aimed to evaluate the similarity of different collagen-induced arthritis models to Pre-RA in rats. Three types of collagen-induced arthritis (CIA) were as follows: (i) standard collagen-induced group (Std-CIA), injected with 200 μg type II collagen at day 0 and 100 μg type II collagen at day 7; (ii) single collagen-induced group (Mono-CIA), injected with 200 μg type II collagen at day 0; (iii) half-dose collagen-induced group (Half-CIA), injected with 100 μg type II collagen at day 0 and 50 μg type II collagen at day 7. Arthritis score, hind paw swelling, serum antibodies, and inflammatory cytokines were measured every 7 days. Gut microbiota analyses were performed on days 0, 11, 21, 28, and 35. Pain threshold measurement, digital radiography, and joint pathology were also assessed. Both Std-CIA and Mono-CIA could successfully cause RA symptoms, including joint swelling and bone erosion, Half-CIA induced only mild swelling in rats. Serum autoantibodies (anti-CCP and anti-CoII) showed no difference among the three types of CIA models, and so did the pain threshold at day 42. In addition, the pathological changes of joint tissues in the Mono-CIA group were the slightest among the collagen-immunized groups. Gut microbiota analysis demonstrated that Half-CIA could impose similar effects on upregulating genus Prevotella as Std-CIA, but Mono-CIA was weaker than them in rats. According to the characteristics of pre-RA, the Half-CIA model is the best suitable animal model for pre-RA among three types of CIA models in rats and can be a valuable model for pre-RA research.
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Affiliation(s)
- Xiaoying Lin
- College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Qiao Wang
- College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Zhixing He
- College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Lin Huang
- College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Chengping Wen
- College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Donghai Zhou
- Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, China.
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Arunsi UO, Chioma OE, Etusim PE, Owumi SE. Indigenous Nigeria medicinal herbal remedies: A potential source for therapeutic against rheumatoid arthritis. Exp Biol Med (Maywood) 2022; 247:1148-1178. [PMID: 35708153 PMCID: PMC9335509 DOI: 10.1177/15353702221102901] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Rheumatoid arthritis (RA) is a debilitating disease associated with locomotion impairment, and conventional therapeutic drugs are not optimal for managing RA. There is an avalanche of medications used for the management of RA. Still, studies have shown that they are associated with severe side effects, including hepatotoxicity, retinopathy, and cardiotoxicity disorders of the central nervous system (CNS), skin, blood, and infections. Complementary and alternative medicine (CAM) is currently gaining attention as a novel panacea for managing debilitating diseases, such as RA. Nigerian folk herbal remedies are replete with a plethora of curative medicine, albeit unvalidated scientifically but with seemingly miraculous provenance. Studies of the identification of bioactive compounds present in these botanicals using advanced spectral analytical techniques have enhanced our understanding of the role of Nigerian herbal remedies in the treatment and management of RA. Interestingly, experimental studies abound that the bioactive compounds present in the extracts of plant botanicals protected animals from the development of RA in different experimental models and reduced the toxicity associated with conventional therapeutics. Validated mechanisms of RA amelioration in human and animal models include suppression of the expression of NF-κB, IL-1β, TNF-α, IL-6, IL-8, IL-17, IL-23, chemokines, TGF-β, RANKL, RANK, iNOS, arginase, COX-2, VEGFA, VEGFR, NFATC1, and TRAP in the synoviocytes. Decreased ROS, NO, MDA, carbonyl groups, and PGE2 in the synovial fluid increased the expression of PPARα/γ; antioxidant and anti-inflammatory molecules also improve RA etiology. In this mini-review, we discuss the global burden of RA, the novel role of plant-based botanicals as potential therapeutics against signaling pathways in RA. Also addressed is the possible repurposing/reprofiling of plant botanicals to increase their therapeutic index among RA patients that patronize traditional healers in Nigeria with a global projection.
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Affiliation(s)
- Uche O Arunsi
- Cancer Immunology and Biotechnology, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK,Department of Biochemistry, Faculty of Biological and Physical Sciences, Abia State University, Uturu, 440001, Nigeria
| | - Ogbuka E Chioma
- Department of Social and Environmental Forestry, Faculty of Renewable Natural Resources, University of Ibadan, Ibadan 200005, Nigeria
| | - Paschal E Etusim
- Department of Animal and Environmental Biology, Faculty of Biological and Physical Sciences, Abia State University, Uturu 200, Nigeria
| | - Solomon E Owumi
- Cancer Research and Molecular Biology Laboratories, Department of Biochemistry, Faculty of Basic Medical Sciences, University of Ibadan, Ibadan 200005, Nigeria,Solomon Owumi.
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Karimi A, Azar PS, Kadkhodayi M, Tandorost A, Vajdi M, Shoorei H, Farhangi MA. A comprehensive insight into effects of resveratrol on molecular mechanism in rheumatoid arthritis: A literature systematic review. Int J Rheum Dis 2022; 25:827-843. [PMID: 35754354 DOI: 10.1111/1756-185x.14356] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/29/2022] [Accepted: 05/15/2022] [Indexed: 02/01/2023]
Abstract
AIM Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, which is characterized by massive pain and destruction of synovial joints, leads to bone erosion, damage to cartilage, and disability. Several studies suggested that resveratrol supplementation may be effective in the prevention and management of RA. Therefore, a systematic review was conducted to summarize published studies that assess the effect of resveratrol supplementation on the complications of RA. METHODS A comprehensive search to identify in vitro, animal, and human studies investigating the impact of resveratrol on the complications of RA was performed up to February 2022. Two independent reviewers evaluated studies based on inclusion/exclusion criteria and performed data extraction. RESULTS All studies examining the effects of resveratrol supplementation on the complications of RA were included. From a total of 571 retrieved articles, 32 studies were eligible for the current systematic review. The evidence reviewed here indicates that resveratrol supplementation may exert beneficial effects on the complications of RA by attenuating inflammation and oxidative stress, modulating the immune response, and down-regulating the messenger RNA expression of genes related to inflammatory pathways. CONCLUSION Due to the promising therapeutic effects of resveratrol on RA complications and limited number of human studies in this subject, further clinical trials are suggested.
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Affiliation(s)
- Arash Karimi
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Pouria Sefidmooye Azar
- Department of Nutrition and Hospitality Management, School of Applied Sciences, The University of Mississippi, University Park, Mississippi, USA
| | - Mahtab Kadkhodayi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Tandorost
- Traditional Medicine and Hydrotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Mahdi Vajdi
- Student Research Committee, Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
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Ji M, Ryu HJ, Baek HM, Shin DM, Hong JH. Dynamic synovial fibroblasts are modulated by NBCn1 as a potential target in rheumatoid arthritis. Exp Mol Med 2022; 54:503-517. [PMID: 35414711 PMCID: PMC9076869 DOI: 10.1038/s12276-022-00756-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 01/09/2022] [Accepted: 01/26/2022] [Indexed: 11/09/2022] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive fibroblast-like synoviocytes (FLSs) and pannus formation. Various therapeutic strategies have been developed against inflammatory cytokines in RA in recent decades. Based on the migratory features of FLSs, we examined whether modulation of the migratory module attenuates RA severity. In this study, inflamed synovial fluid-stimulated FLSs exhibited enhanced migration and migratory apparatus expression, and sodium bicarbonate cotransporter n1 (NBCn1) was identified in primary cultured RA-FLSs for the first time. The NBC inhibitor S0859 attenuated the migration of FLSs induced with synovial fluid from patients with RA or with TNF-α stimulation. Inhibition of NBCs with S0859 in a collagen-induced arthritis (CIA) mouse model reduced joint swelling and destruction without blood, hepatic, or renal toxicity. Primary FLSs isolated from the CIA-induced mouse model also showed reduced migration in the presence of S0859. Our results suggest that inflammatory mediators in synovial fluid, including TNF-α, recruit NBCn1 to the plasma membrane of FLSs to provide dynamic properties and that modulation of NBCn1 could be developed into a therapeutic strategy for RA.
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Affiliation(s)
- Minjeong Ji
- Department of Physiology, College of Medicine, Gachon University, Lee Gil Ya Cancer and Diabetes Institute, 155 Getbeolro, Yeonsu-gu, Incheon, South Korea
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea
| | - Hee Jung Ryu
- Division of Rheumatology, Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdongdae-ro 774-gil, Nandong-gu, Incheon, South Korea
| | - Hyeon-Man Baek
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, South Korea
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon, South Korea
| | - Dong Min Shin
- Department of Oral Biology, Yonsei University College of Dentistry, Seoul, South Korea.
| | - Jeong Hee Hong
- Department of Physiology, College of Medicine, Gachon University, Lee Gil Ya Cancer and Diabetes Institute, 155 Getbeolro, Yeonsu-gu, Incheon, South Korea.
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, South Korea.
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon, South Korea.
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Wu H, Liu Q, Meng C, Xia Q, Pan Y, Zhang H, Zhang F, Song W, Liu H. Web Crawling and mRNA Sequencing Analyze Mechanisms of Photobiomodulation. Photobiomodul Photomed Laser Surg 2022; 40:252-260. [PMID: 35452301 DOI: 10.1089/photob.2021.0142] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background: Photobiomodulation (PBM) is praised as a promising physical therapy, which has many advantages, such as being noninvasive and painless. However, the mechanisms are not fully elucidated. Methods: Using web crawling, mRNA sequence, and bioinformatics analysis, we selected genes, functional annotation, and mechanisms. The expressions of inflammatory cytokines were measured using quantitative real-time PCR (RT-qPCR). Results: A total of 146 human genes and 57 pathways were identified about PBM. The 630 nm light-emitting diode (LED)-stimulated-MH7A cells were sequenced to further analyze the mechanism of PBM. Two thousand nine hundred fifty differentially expressed genes were identified, and the gene ontology term enrichment analysis and Kyoto encyclopedia of genes and genomes pathway analysis were performed to better understand functions and pathways. The 12 pathways were matched with the KEGG results of PBM and MH7A cells. A protein-protein interaction network was performed among genes in 12 pathways, and 10 outstanding proteins were identified. Importantly, the 9 genes were predicted with potential research value. And we also demonstrated that expression of inflammatory factors [interleukin (IL)-6, IL-1β, IL-8, and matrix metalloproteinase-3 (MMP-3)] was reduced; meanwhile, the expression of anti-inflammatory factor IL-10 was promoted after 630 nm LED. Conclusions: Using web crawling, bioinformatics analysis, and mRNA sequence, we obtained 9 key genes and 12 important pathways about PBM. Importantly, we demonstrated the anti-inflammatory effect of 630 nm LED red light by RT-qPCR.
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Affiliation(s)
- Hao Wu
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
| | - Qiannan Liu
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
| | - Caiyun Meng
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
| | - Qing Xia
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
| | - Yue Pan
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
| | - Hanxu Zhang
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
| | - Fengmin Zhang
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
| | - Wuqi Song
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
| | - Hailiang Liu
- The Heilongjiang Key Laboratory of Immunity and Infection Harbin Medical University, Department of Microbiology, Wu Lien-Teh Institute, Harbin, P.R. China
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Elkomy MH, Alruwaili NK, Elmowafy M, Shalaby K, Zafar A, Ahmad N, Alsalahat I, Ghoneim MM, Eissa EM, Eid HM. Surface-Modified Bilosomes Nanogel Bearing a Natural Plant Alkaloid for Safe Management of Rheumatoid Arthritis Inflammation. Pharmaceutics 2022; 14:pharmaceutics14030563. [PMID: 35335939 PMCID: PMC8951435 DOI: 10.3390/pharmaceutics14030563] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/27/2022] [Accepted: 02/28/2022] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory illness affecting the joints. The characteristic of RA is gradual joint deterioration. Current RA treatment alleviates signs such as inflammation and pain and substantially slows the progression of the disease. In this study, we aimed to boost the transdermal delivery of berberine (a natural product) by encapsulating it in chitosan, surface-modified bilosomes nanogel for better management of the inflammation of RA. The chitosan-coated bilosomes loaded with berberine (BER-CTS-BLS) were formulated according to the thin-film hydration approach and optimized for various causal variables, considering the effect of lipid, sodium deoxycholate, and chitosan concentrations on the size of the particles, entrapment, and the surface charge. The optimized BER-CTS-BLS has 202.3 nm mean diameter, 83.8% entrapment, and 30.8 mV surface charge. The optimized BER-CTS-BLS exhibited a delayed-release profile in vitro and increased skin permeability ex vivo. Additionally, histological examination revealed that the formulated BLS had no irritating effects on the skin. Furthermore, the optimized BER-CTS-BLS ability to reduce inflammation was evaluated in rats with carrageenan-induced paw edema. Our results demonstrate that the group treated with topical BER-CTS-BLS gel exhibited a dramatic reduction in rat paw edema swelling percentage to reach 24.4% after 12 h, which was substantially lower than other groups. Collectively, chitosan-coated bilosomes containing berberine have emerged as a promising therapeutic approach to control RA inflammation.
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Affiliation(s)
- Mohammed H. Elkomy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia; (N.K.A.); (M.E.); (K.S.); (A.Z.); (N.A.)
- Correspondence: author: ; Tel.: +966-56-096-7705
| | - Nabil K. Alruwaili
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia; (N.K.A.); (M.E.); (K.S.); (A.Z.); (N.A.)
| | - Mohammed Elmowafy
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia; (N.K.A.); (M.E.); (K.S.); (A.Z.); (N.A.)
| | - Khaled Shalaby
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia; (N.K.A.); (M.E.); (K.S.); (A.Z.); (N.A.)
| | - Ameeduzzafar Zafar
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia; (N.K.A.); (M.E.); (K.S.); (A.Z.); (N.A.)
| | - Naveed Ahmad
- Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia; (N.K.A.); (M.E.); (K.S.); (A.Z.); (N.A.)
| | - Izzeddin Alsalahat
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff CF24 1TP, UK;
- Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science Private University, Amman 11931, Jordan
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, Faculty of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia;
| | - Essam M. Eissa
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62511, Egypt; (E.M.E.); (H.M.E.)
| | - Hussein M. Eid
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62511, Egypt; (E.M.E.); (H.M.E.)
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36
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Gouveia VM, Rizzello L, Vidal B, Nunes C, Poma A, Lopez‐Vasquez C, Scarpa E, Brandner S, Oliveira A, Fonseca JE, Reis S, Battaglia G. Targeting Macrophages and Synoviocytes Intracellular Milieu to Augment Anti‐Inflammatory Drug Potency. ADVANCED THERAPEUTICS 2022. [DOI: 10.1002/adtp.202100167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Virgínia M. Gouveia
- Department of Chemistry University College London London WC1H 0AJ UK
- Institute of Physics of Living Systems University College London London WC1H 0AJ UK
- SomaServe Ltd Babraham Research Campus Cambridge CB22 3AT UK
- LAQV REQUIMTE Department of Chemical Sciences Faculty of Pharmacy University of Porto Porto 4050‐313 Portugal
- Abel Salazar Biomedical Sciences Institute University of Porto Porto 4050‐313 Portugal
| | - Loris Rizzello
- Department of Chemistry University College London London WC1H 0AJ UK
- Institute for Bioengineering of Catalonia (IBEC) The Barcelona Institute of Science and Technology Barcelona 08028 Spain
- Department of Pharmaceutical Sciences University of Milan Milan 20133 Italy
- National Institute of Molecular Genetics (INGM) Milan 20122 Italy
| | - Bruno Vidal
- Rheumatology Research Unit Institute of Molecular Medicine – IMM João Lobo Antunes Faculty of Medicine University of Lisbon Lisbon 1649‐028 Portugal
| | - Claudia Nunes
- LAQV REQUIMTE Department of Chemical Sciences Faculty of Pharmacy University of Porto Porto 4050‐313 Portugal
| | - Alessandro Poma
- Department of Chemistry University College London London WC1H 0AJ UK
- Division of Biomaterials and Tissue Engineering Eastman Dental Institute Royal Free Hospital UCL Medical School London NW3 2PF UK
| | - Ciro Lopez‐Vasquez
- Department of Chemistry University College London London WC1H 0AJ UK
- Institute of Physics of Living Systems University College London London WC1H 0AJ UK
| | - Edoardo Scarpa
- Department of Chemistry University College London London WC1H 0AJ UK
- Department of Pharmaceutical Sciences University of Milan Milan 20133 Italy
- National Institute of Molecular Genetics (INGM) Milan 20122 Italy
| | - Sebastian Brandner
- Department of Neurodegenerative Disease Queen Square Institute of Neurology University College London London WC1N 3BG UK
| | - António Oliveira
- Abel Salazar Biomedical Sciences Institute University of Porto Porto 4050‐313 Portugal
| | - João E. Fonseca
- Rheumatology Research Unit Institute of Molecular Medicine – IMM João Lobo Antunes Faculty of Medicine University of Lisbon Lisbon 1649‐028 Portugal
- Serviço de Reumatologia Centro Hospitalar Universitário Lisboa Norte Centro Academico de Medicina de Lisboa Lisbon 1649‐028 Portugal
| | - Salette Reis
- LAQV REQUIMTE Department of Chemical Sciences Faculty of Pharmacy University of Porto Porto 4050‐313 Portugal
| | - Giuseppe Battaglia
- Department of Chemistry University College London London WC1H 0AJ UK
- Institute of Physics of Living Systems University College London London WC1H 0AJ UK
- Institute for Bioengineering of Catalonia (IBEC) The Barcelona Institute of Science and Technology Barcelona 08028 Spain
- Catalan Institution for Research and Advanced Studies (ICREA) Barcelona 08010 Spain
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Yu Z, Chen F, Liu H, Fan J, Ding X, Zhu X, Cui S, Yi H, Zhou X, Hu Y, Liu W. Silencing CoREST inhibits the viability and migration of fibroblast‑like synoviocytes in TNF‑α‑induced rheumatoid arthritis. Exp Ther Med 2021; 23:148. [PMID: 35069829 PMCID: PMC8756401 DOI: 10.3892/etm.2021.11071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 10/08/2021] [Indexed: 11/05/2022] Open
Abstract
Fibroblast-like synoviocytes (FLSs) have functions in the pathogenesis of rheumatoid arthritis (RA) through the onset of synovitis, the growth of pannus and the destruction of cartilage and bone. The significant increase in the proliferation, migration and invasion of FLSs induces the onset and advancement of RA. To date, the exact function of corepressor element-1 silencing transcription factor (CoREST) in RA remains unclear, but its expression has been determined in RA synovial tissues. In this study, the effects of CoREST were investigated in a TNF-α-induced FLS activation model. Following the silencing of CoREST expression with small interfering (si)RNA, the viability and migration of FLSs were evaluated. Furthermore, the possible molecular mechanisms were explored by detecting the expression of key factors, including matrix metalloproteinases (MMPs), lysine-specific histone demethylase 1 (LSD1) and associated cytokines, via reverse transcription-quantitative PCR and western blotting. CoREST expression increased not only in the RA synovial tissues, but also in the TNF-α-induced FLS activation model. Following the silencing of CoREST in the FLSs treated with TNF-α, cell viability was inhibited, and the migratory capacity of FLSs was suppressed, which was accompanied by the reduced expression of MMP-3 and MMP-9. The expression of LSD1 was also downregulated. There was a notable decrease in the synthesis of interferon-γ and interleukin (IL)-17, while IL-10 expression was increased. The knockdown of CoREST inhibited the viability and migration of FLSs stimulated with TNF-α. Thus, the suppression of CoREST may have crucial roles in the occurrence and development of RA.
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Affiliation(s)
- Ziliang Yu
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Feihu Chen
- Department of Orthopaedics, Xuyi People's Hospital, Xuyi, Jiangsu 211700, P.R. China
| | - Hao Liu
- School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
| | - Jianbo Fan
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiaomin Ding
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xinhui Zhu
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Shengyu Cui
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Hong Yi
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiaogang Zhou
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yalong Hu
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Wei Liu
- Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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Zhao Y, Sun X, Lin J, Zhang T, Liu S, Yan Z. Panaxynol induces fibroblast-like synovial cell apoptosis, inhibits proliferation and invasion through TLR4/NF-κB pathway to alleviate rheumatoid arthritis. Int Immunopharmacol 2021; 101:108321. [PMID: 34741869 DOI: 10.1016/j.intimp.2021.108321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/24/2021] [Accepted: 10/26/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND PURPOSE Panaxynol (PAL, PubChem CID: 5281149) is a common natural minor component in Umbelliferae plants, such as Radix Saposhnikoviae Divaricatae. Modern pharmacology studies show that PAL has nutritional value and anti-inflammatory and other pharmaceutical activities. Therefore, the scientific hypothesis of PAL in the treatment of rheumatoid arthritis was put forward, and the hypothesis was further verified by Fibroblast-like synovial cells (RA-FLS) and Collagen Induced Arthritis (CIA) rats models. EXPERIMENTAL METHOD CIA method was used to establish a rat arthritis model. After extracting RA-FLS, flow cytometry and immunofluorescence were used to explore the effect of PAL on the apoptosis and proliferation of RA-FLS. Wound healing and transwell experiment explored the effect of PAL on the migration and invasion of RA-FLS. Western blot analysis explored the inner mechanism of the effect of PAL on RA-FLS. At the same time, it also explored the role of PAL in CIA rats, including pathological section detection and western blot analysis. MAIN RESULTS PAL can promote the apoptosis and inhibit the proliferation, migration and invasion of RA-FLS. PAL can also reduce joint swelling in CIA rats, reduce pannus formation and inflammatory infiltration in the joints. Western blot analysis showed that PAL mainly played a role through the TLR4/NF-κB signaling pathway. CONCLUSION The results of in vivo and in vitro experiments show that PAL can effectively alleviate the condition of RA, and may be a potential drug for the treatment of RA.
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Affiliation(s)
- Yan Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Xialin Sun
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Jun Lin
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Tingwen Zhang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Shuangli Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China; State Local Joint Engineering Research Center for Ginseng Breeding and Application, Jilin Agricultural University, Changchun 130118, China.
| | - Zhaowei Yan
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
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Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes. Biomedicines 2021; 9:biomedicines9101413. [PMID: 34680530 PMCID: PMC8533088 DOI: 10.3390/biomedicines9101413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 12/29/2022] Open
Abstract
Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi affect pro- and anti-inflammatory circuits in the bidirectional interplay between SF and immune cells. Here, we examined the effects of tofacitinib, baricitinib and upadacitinib on crosstalk between SF and T or B lymphocytes in vitro and compared them with those of biologic disease modifying anti-rheumatic drugs (bDMARDs). JAKi dose-dependently suppressed cytokine secretion of T helper (Th) cells and decreased interleukin (IL)-6 and matrix metalloproteinase (MMP)3 secretion of SF stimulated by Th cells. Importantly, JAK inhibition attenuated the enhanced memory response of chronically stimulated SF. Vice versa, JAKi reduced the indoleamine-2,3-dioxygenase (IDO)1-mediated suppression of T cell-proliferation by SF. Remarkably, certain bDMARDs were as efficient as JAKi in suppressing the IL-6 and MMP3 secretion of SF stimulated by Th (adalimumab, secukinumab) or B cells (canakinumab) and combining bDMARDs with JAKi had synergistic effects. In conclusion, JAKi limit pro-inflammatory circuits in the crosstalk between SF and lymphocytes; however, they also weaken the immunosuppressive functions of SF. Both effects were dose-dependent and may contribute to heterogeneity in clinical response to treatment.
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Yu R, Zhang J, Zhuo Y, Hong X, Ye J, Tang S, Zhang Y. Identification of Diagnostic Signatures and Immune Cell Infiltration Characteristics in Rheumatoid Arthritis by Integrating Bioinformatic Analysis and Machine-Learning Strategies. Front Immunol 2021; 12:724934. [PMID: 34691030 PMCID: PMC8526926 DOI: 10.3389/fimmu.2021.724934] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/17/2021] [Indexed: 01/07/2023] Open
Abstract
Background Rheumatoid arthritis (RA) refers to an autoimmune rheumatic disease that imposes a huge burden on patients and society. Early RA diagnosis is critical to preventing disease progression and selecting optimal therapeutic strategies more effectively. In the present study, the aim was at examining RA's diagnostic signatures and the effect of immune cell infiltration in this pathology. Methods Gene Expression Omnibus (GEO) database provided three datasets of gene expressions. Firstly, this study adopted R software for identifying differentially expressed genes (DEGs) and conducting functional correlation analyses. Subsequently, we integrated bioinformatic analysis and machine-learning strategies for screening and determining RA's diagnostic signatures and further verify by qRT-PCR. The diagnostic values were assessed through receiver operating characteristic (ROC) curves. Moreover, this study employed cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) website for assessing the inflammatory state of RA, and an investigation was conducted on the relationship of diagnostic signatures and infiltrating immune cells. Results On the whole, 54 robust DEGs received the recognition. Lymphocyte-specific protein 1 (LSP1), Granulysin (GNLY), and Mesenchymal homobox 2 (MEOX2) (AUC = 0.955) were regarded as RA's diagnostic markers and showed their statistically significant difference by qRT-PCR. As indicated from the immune cell infiltration analysis, resting NK cells, neutrophils, activated NK cells, T cells CD8, memory B cells, and M0 macrophages may be involved in the development of RA. Additionally, all diagnostic signatures might be different degrees of correlation with immune cells. Conclusions In conclusion, LSP1, GNLY, and MEOX2 are likely to be available in terms of diagnosing and treating RA, and the infiltration of immune cells mentioned above may critically impact RA development and occurrence.
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Affiliation(s)
- Rongguo Yu
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Jiayu Zhang
- School of Clinical Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Youguang Zhuo
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Xu Hong
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Jie Ye
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Susu Tang
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Yiyuan Zhang
- Department of Orthopedics, Fuzhou Second Hospital Affiliated to Xiamen University, Xiamen University, Xiamen, China
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Wang W, Deng Z, Liu G, Yang J, Zhou W, Zhang C, Shen W, Zhang Y. Platelet-derived extracellular vesicles promote the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes via CXCR2 signaling. Exp Ther Med 2021; 22:1120. [PMID: 34504574 PMCID: PMC8383774 DOI: 10.3892/etm.2021.10554] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 07/09/2021] [Indexed: 12/15/2022] Open
Abstract
Platelet-derived extracellular vesicles (PEVs), which are generated from the plasma membrane during platelet activation, may be involved in the inflammatory processes of rheumatoid arthritis (RA). The motility of RA fibroblast-like synoviocytes (RA-FLS) plays a key role in the development of synovial inflammation and joint erosion. However, the effects of PEVs on the motility of RA-FLS remain unclear. Thus, the present study aimed to investigate the active contents and potential molecular mechanisms underlying the role of PEVs in regulating the migration and invasion of RA-FLS. The results demonstrated that PEVs contain certain chemokines associated with cell migration and invasion, including C-C motif chemokine ligand 5, C-X-C motif chemokine ligand (CXCL)4 and CXCL7. Furthermore, SB225002, an antagonist of C-X-C motif chemokine receptor 2 (CXCR2; a CXCL7 receptor), partially prevented the migration and invasion of RA-FLS induced by PEVs, suggesting that PEVs may activate a CXCR2-mediated signaling pathway in RA-FLS. In addition, SB225002 antagonized the phosphorylation of IκB and NF-κB in RA-FLS induced by PEVs. Taken together, the results of the present study suggested that PEVs may promote the migration and invasion of RA-FLS by activating the NF-κB pathway mediated by the CXCR2 signaling pathway.
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Affiliation(s)
- Wenwen Wang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China.,Department of Rheumatology, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226000, P.R. China
| | - Zijing Deng
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Guiping Liu
- Department of Rheumatology, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China
| | - Jie Yang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Wei Zhou
- Department of Internal Medicine, Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Chen Zhang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Weigan Shen
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
| | - Yu Zhang
- Department of Cell Biology, School of Medicine of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China
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42
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Yamada H, Saegusa J, Sendo S, Ueda Y, Okano T, Shinohara M, Morinobu A. Effect of resolvin D5 on T cell differentiation and osteoclastogenesis analyzed by lipid mediator profiling in the experimental arthritis. Sci Rep 2021; 11:17312. [PMID: 34453072 PMCID: PMC8397777 DOI: 10.1038/s41598-021-96530-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 08/04/2021] [Indexed: 12/21/2022] Open
Abstract
Resolvins, are specialized pro-resolving mediators (SPMs) derived from n-3 polyunsaturated fatty acids. They contribute actively to the resolution of inflammation, but little is known concerning their role in chronic inflammation, such as in rheumatoid arthritis (RA). Here, we performed lipid mediator (LM) profiling in tissues from the paws of SKG arthritic mice using lipid chromatography (LC)/mass spectrometry (MS)/MS-based LM metabololipidomics. We found elevated levels of SPMs including resolvin D5 (RvD5) in these tissues. Moreover, RvD5 levels were significantly correlated with arthritis disease activity. From experiments to assess the role of RvD5 in the pathology of RA, we concluded that RvD5 suppressed Th17 cell differentiation and facilitated regulatory T cell differentiation, as well as inhibiting CD4+ T cell proliferation. Furthermore, RvD5 attenuated osteoclast differentiation and interfered with osteoclastogenesis. Targeting the resolution of inflammation could be promising as a novel treatment for RA.
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Affiliation(s)
- Hirotaka Yamada
- Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Jun Saegusa
- Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan. .,Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan.
| | - Sho Sendo
- Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yo Ueda
- Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takaichi Okano
- Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan.,Department of Clinical Laboratory, Kobe University Hospital, Kobe, Japan
| | - Masakazu Shinohara
- Division of Epidemiology, Kobe University Graduate School of Medicine, Kobe, Japan.,The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Akio Morinobu
- Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan
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Kun-Liu, Wang JY, Zhang L, Pan YY, Chen XY, Yuan Y. Effects of betulinic acid on synovial inflammation in rats with collagen-induced arthritis. Int J Immunopathol Pharmacol 2021; 34:2058738420945078. [PMID: 32718263 PMCID: PMC7388086 DOI: 10.1177/2058738420945078] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Betulinic acid (BA) inhibits the migration, invasion, and cytoskeletal reorganization of fibroblast-like synoviocytes (RA-FLS) in patients with rheumatoid arthritis. Here, to further explore the mechanism of action of BA in collagen-induced arthritis (CIA) rats, we investigated the pharmacodynamic effects of BA on synovial inflammation in a rat model of type II CIA. After inducing hind paw swelling, the rats were divided into four groups: healthy controls (normal), and rats that underwent CIA and received methotrexate treatment (MTX), BA treatment (BA), or no treatment (CIA). Body weight and hind paw swelling were determined regularly, and arthritis scores were calculated weekly. On day 35, rats were sacrificed and their hind ankle joints sectioned and stained with hematoxylin and eosin for histopathological evaluation. BA significantly reduced CIA-induced hind paw swelling, synovial tissue proliferation, cartilage destruction, and vasospasm. BA treatment also decreased serum interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels in rats with CIA. The CCK-8 assay was used to detect the proliferation of isolated vimentin+CD68- RA-FLS; RA-FLS were stimulated with TNF-α in vitro. BA significantly inhibited TNF-α-stimulated RA-FLS proliferation, as well as IL-1β and IL-6 secretion. BA also downregulated the transcription of vascular endothelial growth factor (VEGF) and transforming growth factor β (TGF-β) and decreased the expression of the NF-кB pathway proteins (NF-kB-P65, IkBα, and IKKα/β) in the TNF-α-stimulated RA-FLS. These results indicate that BA alleviated the symptoms of CIA by inhibiting synoviocyte proliferation, modifying TNF-α- and NF-кB-related inflammatory pathways, and downregulating inflammatory mediators and growth factors including IL-1β, IL-6, VEGF, and TGF-β.
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Affiliation(s)
- Kun-Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jian-Ying Wang
- Shanghai Innovation Center of Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Zhang
- Shanghai Innovation Center of Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying-Yi Pan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-Yun Chen
- Rheumatoid Department, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ying Yuan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Bartoli DMF, Felizatti AL, do Bomfim FRC, Bovo JL, de Aro AA, do Amaral MEC, Esquisatto MAM. Laser treatment of synovial inflammatory process in experimentally induced microcrystalline arthritis in Wistar rats. Lasers Med Sci 2021; 36:529-540. [PMID: 32519204 DOI: 10.1007/s10103-020-03055-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Accepted: 06/01/2020] [Indexed: 01/11/2023]
Abstract
The presence of intra-articular crystals is detected in different articular pathologies of acute or chronic nature. The aim of this work was to analyze the action of the indium gallium aluminum and phosphorus (InGaAlP) (λ = 670 nm) laser on the synovial membrane present in the knee joint in experimentally induced microcrystalline arthritis in male adult Wistar rats. The animals were divided into three experimental groups (n = 24): control (A), experimentally induced arthritis (B), experimentally induced arthritis+InGaAlP laser therapy (C). The laser treatment was made daily in the patellar region of the right knee after 48 h of the experimental induction. After 7, 14, and 21 days of therapy, the rats were euthanized and the right knees were removed and processed for histomorphometric, immunohistochemical, ultrastructural, and biochemical investigation of the synovium. The number of granulocytes on the 14th and 21st days was higher in B and lower in C and, lastly, in A. The number of fibroblasts on the 14th and 21st days was similar between A and C and below B. The number of blood vessels on the 21st day was higher in B than in the other groups. The positive number of cells for the TUNEL test was higher on the 14th and 21st days in B compared to the others. The percentage of tissue area occupied by birefringent collagen fibers was higher in B on the 21st day than in the others. The ultrastructure of cells showed fibroblast-like morphology in all groups and periods evaluated. The quantification of glycosaminoglycans did not present significant differences between the groups in all the experimental periods. The amount of hydroxyproline was higher in B compared to the other groups on the 14th and 21st days. The content of non-collagen proteins was higher in B on the 21st day in relation to the other groups. Quantification of TNF-α on the 21st day was higher in A and B than in C. For TGF-β on the 21st day, groups B and C presented similar and higher values than A. For MMP-13, groups A and B presented data similar to and above C. In relation to ADAMT-S4, on the 21st day, groups B and C presented data similar to and lower than A. InGaAlP-670 nm therapy reduced the inflammatory process and tissue injuries of the synovial membrane in comparison to the untreated group, indicating its potential utilization in clinical studies aiming in the recovery of acute arthritis in patients.
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Affiliation(s)
- Débora Mara Fortes Bartoli
- Graduate Program in Biomedical Sciences, University Center of Herminio Ometto Foundation - FHO, Av. Dr. Maximiliano Baruto, 500, Jd. Universitário, Araras, SP, 13607-339, Brazil
| | - Airton Luiz Felizatti
- Graduate Program in Biomedical Sciences, University Center of Herminio Ometto Foundation - FHO, Av. Dr. Maximiliano Baruto, 500, Jd. Universitário, Araras, SP, 13607-339, Brazil
| | - Fernando Russo Costa do Bomfim
- Graduate Program in Biomedical Sciences, University Center of Herminio Ometto Foundation - FHO, Av. Dr. Maximiliano Baruto, 500, Jd. Universitário, Araras, SP, 13607-339, Brazil
| | - Julia Leme Bovo
- Graduate Program in Biomedical Sciences, University Center of Herminio Ometto Foundation - FHO, Av. Dr. Maximiliano Baruto, 500, Jd. Universitário, Araras, SP, 13607-339, Brazil
| | - Andrea Aparecida de Aro
- Graduate Program in Biomedical Sciences, University Center of Herminio Ometto Foundation - FHO, Av. Dr. Maximiliano Baruto, 500, Jd. Universitário, Araras, SP, 13607-339, Brazil
| | - Maria Esméria Corezzola do Amaral
- Graduate Program in Biomedical Sciences, University Center of Herminio Ometto Foundation - FHO, Av. Dr. Maximiliano Baruto, 500, Jd. Universitário, Araras, SP, 13607-339, Brazil
| | - Marcelo Augusto Marretto Esquisatto
- Graduate Program in Biomedical Sciences, University Center of Herminio Ometto Foundation - FHO, Av. Dr. Maximiliano Baruto, 500, Jd. Universitário, Araras, SP, 13607-339, Brazil.
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Tavasolian F, Hosseini AZ, Soudi S, Naderi M, Sahebkar A. A Systems Biology Approach for miRNA-mRNA Expression Patterns Analysis in Rheumatoid Arthritis. Comb Chem High Throughput Screen 2021; 24:195-212. [DOI: 10.2174/1386207323666200605150024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/22/2020] [Accepted: 04/04/2020] [Indexed: 11/22/2022]
Abstract
Objective:
Considering the molecular complexity and heterogeneity of rheumatoid
arthritis (RA), the identification of novel molecular contributors involved in RA initiation and
progression using systems biology approaches will open up potential therapeutic strategies. The
bioinformatics method allows the detection of associated miRNA-mRNA as both therapeutic and
prognostic targets for RA.
Methods:
This research used a system biology approach based on a systematic re-analysis of the
RA-related microarray datasets in the NCBI Gene Expression Omnibus (GEO) database to find out
deregulated miRNAs. We then studied the deregulated miRNA-mRNA using Enrichr and
Molecular Signatures Database (MSigDB) to identify novel RA-related markers followed by an
overview of miRNA-mRNA interaction networks and RA-related pathways.
Results:
This research mainly focused on mRNA and miRNA interactions in all tissues and
blood/serum associated with RA to obtain a comprehensive knowledge of RA. Recent systems
biology approach analyzed seven independent studies and presented important RA-related
deregulated miRNAs (miR-145-5p, miR-146a-5p, miR-155-5p, miR-15a-5p, miR-29c-3p, miR-
103a-3p, miR-125a-5p, miR-125b-5p, miR-218); upregulation of miR-125b is shown in the study
(GSE71600). While the findings of the Enrichr showed cytokine and vitamin D receptor pathways
and inflammatory pathways. Further analysis revealed a negative correlation between the vitamin
D receptor (VDR) and miR-125b in RA-associated gene expression.
Conclusion:
Since vitamin D is capable of regulating the immune homeostasis and decreasing the
autoimmune process through its receptor (VDR), it is regarded as a potential target for RA.
According to the results obtained, a comparative correlation between negative expression of the
vitamin D receptor (VDR) and miR-125b was suggested in RA. The increasing miR-125b
expression would reduce the VitD uptake through its receptor.
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Affiliation(s)
- Fataneh Tavasolian
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ahmad Zavaran Hosseini
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahmood Naderi
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Liu J, Zhang Q, Li RL, Wei SJ, Gao YX, Ai L, Wu CJ, Pu XF. Anti-proliferation and anti-migration effects of an aqueous extract of Cinnamomi ramulus on MH7A rheumatoid arthritis-derived fibroblast-like synoviocytes through induction of apoptosis, cell arrest and suppression of matrix metalloproteinase. PHARMACEUTICAL BIOLOGY 2020; 58:863-877. [PMID: 32878533 PMCID: PMC8641682 DOI: 10.1080/13880209.2020.1810287] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/13/2020] [Accepted: 08/10/2020] [Indexed: 06/11/2023]
Abstract
CONTEXT Cinnamomi ramulus, the dry twig of Cinnamomum cassia Presl. (Lauraceae), has been reported to exert several activities such as antitumor, anti-inflammatory, and analgesic effects. OBJECTIVE This study investigates the effects of an aqueous extract of Cinnamomi ramulus (ACR) on rheumatoid arthritis (RA). MATERIALS AND METHODS TNF-α-induced RA-derived fibroblast-like synoviocyte MH7A cells were incubated with ACR (0.1-2 mg/mL) for 24 h. The proliferation was tested using CCK-8 and colony formation assays. The migration and invasion abilities were measured using transwell tests and wound healing assays. Apoptosis and cell cycle were examined by flow cytometry. The potential mechanisms were determined by western blotting and quantitative real-time PCR. UPLC-QE-MS/MS was used for chromatographic analysis of ACR and its compounds were identified. Molecular docking strategy was used to screen the potential anti-RA active compounds of ACR. RESULTS We found that ACR induced apoptosis in MH7A cells at concentrations of 0.4, 0.8, and 1.2 mg/mL. The proliferation of MH7A cells was reduced and the cell cycle was blocked in the G2/M phase at concentrations of 0.2, 0.4, 0.6 mg/mL. Migration and invasion of MH7A cells were reduced through inhibiting the expression of MMP-1, MMP-2, and MMP-3. The molecular docking strategy results showed that 9 compounds in ACR have good affinity with protein crystal, and benzyl cinnamate (10-100 µg/mL) could inhibit cell migration and induce apoptosis. CONCLUSIONS The anti-RA effect of ACR may be attributed to its anti-proliferative and anti-migration effects on synovial fibroblasts. These data suggest that Cinnamomi ramulus may have therapeutic value for the treatment of RA.
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Affiliation(s)
- Jia Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, P.R. China
- Chengdu Institute for Food and Drug Control, Chengdu, P.R. China
| | - Qing Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, P.R. China
| | - Ruo-Lan Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, P.R. China
| | - Shu-Jun Wei
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, P.R. China
| | - Yong-Xiang Gao
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, P.R. China
| | - Li Ai
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, P.R. China
| | - Chun-Jie Wu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, P.R. China
| | - Xu-Feng Pu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, P.R. China
- Chengdu Institute for Food and Drug Control, Chengdu, P.R. China
- Chengdu Medical and Health Investment Group Co. Ltd, Chengdu, P.R. China
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Sun X, Xie YZ, Jiang YY, Wang GY, Wang YJ, Mei Y, Gao RH, Li YH, Xiao W, Wang WF, Li DS. FGF21 Enhances Therapeutic Efficacy and Reduces Side Effects of Dexamethasone in Treatment of Rheumatoid Arthritis. Inflammation 2020; 44:249-260. [PMID: 33098521 DOI: 10.1007/s10753-020-01327-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 08/08/2020] [Accepted: 08/19/2020] [Indexed: 11/24/2022]
Abstract
In order to investigate efficacy of FGF21 combine dexamethasone (Dex) on rheumatoid arthritis (RA) meanwhile reduce side effects of dexamethasone. We used combination therapy (Dex 15 mg/kg + FGF21 0.25 mg/kg, Dex 15 mg/kg + FGF21 0.5 mg/kg or Dex 15 mg/kg + FGF21 1 mg/kg) and monotherapy (Dex 15 mg/kg or FGF21 1 mg/kg) to treat CIA mice induced by chicken type II collagen, respectively. The effects of treatment were determined by arthritis severity score, histological damage, and cytokine production. The levels of oxidative stress parameters, liver functions, and other blood biochemical indexes were detected to determine FGF21 efficiency to side effects of dexamethasone. Oil red O was performed to detect the effects of FGF21 and dexamethasone on fat accumulation in HepG2 cells. The mechanism of FGF21 improves the side effects of dexamethasone which was analyzed by Western blotting. This combination proved to be therapeutically more effective than dexamethasone or FGF21 used singly. FGF21 regulates oxidative stress and lipid metabolism by upregulating dexamethasone-inhibited SIRT-1 and then activating downstream Nrf-2/HO-1and PGC-1. FGF21 and dexamethasone are highly effective in the treatment of arthritis; meanwhile, FGF21 may overcome the limited therapeutic response and Cushing syndrome associated with dexamethasone.
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Affiliation(s)
- Xu Sun
- School of Life Science, Northeast Agricultural University, Harbin, China
| | - Yin-Zhuo Xie
- School of Life Science, Northeast Agricultural University, Harbin, China
| | | | - Guan-Ying Wang
- School of Life Science, Northeast Agricultural University, Harbin, China
| | - Yu-Jia Wang
- School of Life Science, Northeast Agricultural University, Harbin, China
| | - Yu Mei
- School of Life Science, Northeast Agricultural University, Harbin, China
| | - Rong-Hui Gao
- School of Life Science, Northeast Agricultural University, Harbin, China
| | - Yan-Hua Li
- School of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Wei Xiao
- Jiangsu kangyuan pharmaceutical co. Ltd, Lianyungang, China.
| | - Wen-Fei Wang
- School of Life Science, Northeast Agricultural University, Harbin, China.
- Harbin Veterinary Research Institute, Harbin, China.
| | - De-Shan Li
- School of Life Science, Northeast Agricultural University, Harbin, China.
- Jiangsu kangyuan pharmaceutical co. Ltd, Lianyungang, China.
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48
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Villa T, Kim M, Oh S. Fangchinoline Has an Anti-Arthritic Effect in Two Animal Models and in IL-1β-Stimulated Human FLS Cells. Biomol Ther (Seoul) 2020; 28:414-422. [PMID: 32713853 PMCID: PMC7457174 DOI: 10.4062/biomolther.2020.113] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 07/13/2020] [Accepted: 07/13/2020] [Indexed: 12/31/2022] Open
Abstract
Fangchinoline (FAN) is a bisbenzylisoquinoline alkaloid that is widely known for its anti-tumor properties. The goal of this study is to examine the effects of FAN on arthritis and the possible pathways it acts on. Human fibroblast-like synovial cells (FLS), carrageenan/ kaolin arthritis rat model (C/K), and collagen-induced arthritis (CIA) mice model were used to establish the efficiency of FAN in arthritis. Human FLS cells were treated with FAN (1, 2.5, 5, 10 μM) 1 h before IL-1β (10 ng/mL) stimulation. Cell viability, reactive oxygen species measurement, and western blot analysis of inflammatory mediators and the MAPK and NF-κB pathways were performed. In the animal models, after induction of arthritis, the rodents were given 10 and 30 mg/kg of FAN orally 1 h before conducting behavioral experiments such as weight distribution ratio, knee thickness measurement, squeaking score, body weight measurement, paw volume measurement, and arthritis index measurement. Rodent knee joints were also analyzed histologically through H&E staining and safranin staining. FAN decreased the production of inflammatory cytokines and ROS in human FLS cells as well as the phosphorylation of the MAPK pathway and NF-κB pathway in human FLS cells. The behavioral parameters in the C/K rat model and CIA mouse model and inflammatory signs in the histological analysis were found to be ameliorated in FAN-treated groups. Cartilage degradation in CIA mice knee joints were shown to have been suppressed by FAN. These findings suggest that fangchinoline has the potential to be a therapeutic source for the treatment of rheumatoid arthritis.
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Affiliation(s)
- Thea Villa
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Mijin Kim
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
| | - Seikwan Oh
- Department of Molecular Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Republic of Korea
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Edilova MI, Akram A, Abdul-Sater AA. Innate immunity drives pathogenesis of rheumatoid arthritis. Biomed J 2020; 44:172-182. [PMID: 32798211 PMCID: PMC8178572 DOI: 10.1016/j.bj.2020.06.010] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the general population. This disease is characterized by persistent articular inflammation and joint damage driven by the proliferating synovial tissue fibroblasts as well as neutrophil, monocyte and lymphocyte trafficking into the synovium. The factors leading to RA pathogenesis remain poorly elucidated although genetic and environmental factors have been proposed to be the main contributors to RA. The majority of the early studies focused on the role of lymphocytes and adaptive immune responses in RA. However, in the past two decades, emerging studies showed that the innate immune system plays a critical role in the onset and progression of RA pathogenesis. Various innate immune cells including monocytes, macrophages and dendritic cells are involved in inflammatory responses seen in RA patients as well as in driving the activation of the adaptive immune system, which plays a major role in the later stages of the disease. Here we focus the discussion on the role of different innate immune cells and components in initiation and progression of RA. New therapeutic approaches targeting different inflammatory pathways and innate immune cells will be highlighted here. Recent emergence and the significant roles of innate lymphoid cells and inflammasomes will be also discussed.
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Affiliation(s)
- Maria I Edilova
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Ali Akram
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, Ontario Canada; The University Health Network, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Ali A Abdul-Sater
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, Ontario Canada.
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50
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Sehnert B, Burkhardt H, Dübel S, Voll RE. Cell-Type Targeted NF-kappaB Inhibition for the Treatment of Inflammatory Diseases. Cells 2020; 9:E1627. [PMID: 32640727 PMCID: PMC7407293 DOI: 10.3390/cells9071627] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 12/29/2022] Open
Abstract
Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenesis of chronic inflammatory diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). Ideally, therapeutic NF-KappaB inhibition should only take place in those cell types that are involved in disease pathogenesis to maintain physiological cell functions in all other cells. In contrast, unselective NF-kappaB inhibition in all cells results in multiple adverse effects, a major hindrance in drug development. Hitherto, various substances exist to inhibit different steps of NF-kappaB signaling. However, powerful tools for cell-type specific NF-kappaB inhibition are not yet established. Here, we review the role of NF-kappaB in inflammatory diseases, current strategies for drug delivery and NF-kappaB inhibition and point out the "sneaking ligand" approach. Sneaking ligand fusion proteins (SLFPs) are recombinant proteins with modular architecture consisting of three domains. The prototype SLC1 binds specifically to the activated endothelium and blocks canonical NF-kappaB activation. In vivo, SLC1 attenuated clinical and histological signs of experimental arthritides. The SLFP architecture allows an easy exchange of binding and effector domains and represents an attractive approach to study disease-relevant biological targets in a broad range of diseases. In vivo, SLFP treatment might increase therapeutic efficacy while minimizing adverse effects.
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Affiliation(s)
- Bettina Sehnert
- Department of Rheumatology and Clinical Immunology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79098 Freiburg, Germany
| | - Harald Burkhardt
- Division of Rheumatology, University Hospital Frankfurt, Goethe University, and Branch for Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 60590 Frankfurt am Main, Germany;
| | - Stefan Dübel
- Institute of Biochemistry and Biotechnology, Technical University Braunschweig, 38106 Braunschweig, Germany;
| | - Reinhard E. Voll
- Department of Rheumatology and Clinical Immunology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, 79098 Freiburg, Germany
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