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Zhang Y, Zang C, Mao M, Zhang M, Tang Z, Chen W, Zhu W. Advances in RNA therapy for the treatment of autoimmune diseases. Autoimmun Rev 2025; 24:103753. [PMID: 39842534 DOI: 10.1016/j.autrev.2025.103753] [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: 01/15/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/24/2025]
Abstract
Autoimmune diseases (ADs) are a group of complex, chronic conditions characterized by disturbance of immune tolerance, with examples including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. These diseases have unclear pathogenesis, and traditional therapeutic approaches remain limited. However, advances in high-throughput histology technology and scientific discoveries have led to the identification of various pathogenic factors contributing to ADs. Coupled with improvements in RNA nucleic acid-based drug synthesis, design, and delivery, RNA-based therapies have been extensively investigated for their potential in treating ADs. This paper reviews the progress in the use of miRNAs, lncRNAs, circRNAs, siRNAs, antisense oligonucleotides (ASOs), aptamers, mRNAs, and other RNA-based therapies in ADs, focusing on their therapeutic potential and application prospects, providing insights for future research and clinical treatment of autoimmune diseases.
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Affiliation(s)
- Ying Zhang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China
| | - Chenyang Zang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China
| | - Manyun Mao
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China
| | - Mi Zhang
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China
| | - Zhenwei Tang
- Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wangqing Chen
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China.
| | - Wu Zhu
- The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Changsha, Hunan, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Changsha, Hunan, China.
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Smolinska V, Klimova D, Danisovic L, Harsanyi S. Synovial Fluid Markers and Extracellular Vesicles in Rheumatoid Arthritis. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1945. [PMID: 39768826 PMCID: PMC11678482 DOI: 10.3390/medicina60121945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 01/11/2025]
Abstract
In recent years, numerous potential prognostic biomarkers for rheumatoid arthritis (RA) have been investigated. Despite these advancements, clinical practice primarily relies on autoantibody tests-for rheumatoid factor (RF) and anti-citrullinated protein antibody (anti-CCP)-alongside inflammatory markers, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Expanding the repertoire of diagnostic and therapeutic biomarkers is critical for improving clinical outcomes in RA. Emerging evidence highlights the significance of synovial fluid biomarkers, including aggrecan, matrix metalloproteinases, glucosyl-galactosyl-pyridinoline, hyaluronic acid, S100 proteins, calprotectin, and various cytokines, as well as immunological markers. Additionally, specific components of extracellular vesicles, such as non-coding RNAs, heat shock proteins, and lipids, are gaining attention. This review focuses on molecular markers found in synovial fluid and extracellular vesicles, excluding clinical and imaging biomarkers, and explores their potential applications in the diagnosis and management of RA.
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Affiliation(s)
- Veronika Smolinska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (V.S.); (D.K.); (L.D.)
- National Institute of Rheumatic Diseases, Nábrežie Ivana Krasku 4, 921 12 Piestany, Slovakia
| | - Daniela Klimova
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (V.S.); (D.K.); (L.D.)
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (V.S.); (D.K.); (L.D.)
- National Institute of Rheumatic Diseases, Nábrežie Ivana Krasku 4, 921 12 Piestany, Slovakia
| | - Stefan Harsanyi
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Sasinkova 4, 811 08 Bratislava, Slovakia; (V.S.); (D.K.); (L.D.)
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Seyedi D, Espandar N, Hojatizadeh M, Mohammadi Y, Sadri F, Rezaei Z. Noncoding RNAs in rheumatoid arthritis: modulators of the NF-κB signaling pathway and therapeutic implications. Front Immunol 2024; 15:1486476. [PMID: 39530095 PMCID: PMC11550995 DOI: 10.3389/fimmu.2024.1486476] [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: 08/26/2024] [Accepted: 10/11/2024] [Indexed: 11/16/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and gradual tissue destruction. New research has shown how important noncoding RNAs (ncRNAs) are for changing immune and inflammatory pathways, such as the WNT signaling pathway, which is important for activating synovial fibroblasts and osteoblasts to work. This article examines the current understanding of several ncRNAs, such as miRNAs, lncRNAs, and circRNAs, that influence NF-κB signaling in the pathogenesis of RA. We investigate how these ncRNAs impact NF-κB signaling components, altering cell proliferation, differentiation, and death in joint tissues. The paper also looks at how ncRNAs can be used as potential early detection markers and therapeutic targets in RA because they can change important pathogenic pathways. This study highlights the therapeutic potential of targeting ncRNAs in RA therapy techniques, with the goal of reducing inflammation and stopping disease progression. This thorough analysis opens up new possibilities for understanding the molecular foundations of RA and designing novel ncRNA-based treatments.
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Affiliation(s)
- Dina Seyedi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Najmadin Espandar
- Department of Exercise Physiology and Corrective Exercises, Faculty of Sport Sciences, Urmia University, Urmia, Iran
| | - Maryam Hojatizadeh
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Yaser Mohammadi
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farzad Sadri
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Zohreh Rezaei
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
- Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran
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Ali YB, Hasan NM, El-Maadawy EA, Bassyouni IH, El-Shahat M, Talaat RM. Association between IL-6, miRNA-146a, MALAT1 genetic polymorphisms and risk of rheumatoid arthritis. Per Med 2024; 21:277-294. [PMID: 39263956 DOI: 10.1080/17410541.2024.2393072] [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: 04/12/2022] [Accepted: 10/14/2022] [Indexed: 09/13/2024]
Abstract
Aim: This study aimed to investigate the associations between single nucleotide polymorphisms (SNPs) of IL-6 (-174G/C), microRNA146a (rs2910164C/G) and MALAT1 (rs619586A/G) and susceptibility to rheumatoid arthritis (RA) in Egyptians.Methods: SNPs were genotyped in 101 RA patients and 104 controls. Expression levels were evaluated either by Enzyme-linked immunosorbent assay (ELISA) for IL-6 or quantitative real-time PCR (qRT-PCR) for miR-146a and MALAT1.Results: IL-6-174 GC (OR = 3.422) genotype, IL-6-174 C allele (OR = 2.565), miR-146a (rs2910164) CG (OR = 2.190) and MALAT1 (rs619586) AA (OR = 4.125) genotypes and A allele (OR = 6.122) could be considered as risk factors for RA. An increase in the expression of IL-6, miR-146a and MALAT1 was detected in RA patients, which was independent of any SNP.Conclusion: SNPs of IL-6, miR-146a and MALAT1were linked to RA predisposition in Egyptians.
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Affiliation(s)
- Yasser Bm Ali
- Molecular Biology Department, Genetic Engineering & Biotechnology Research Institute (GEBRI), University of Sadat City, 32958, Egypt
| | - Noura Ma Hasan
- Molecular Biology Department, Genetic Engineering & Biotechnology Research Institute (GEBRI), University of Sadat City, 32958, Egypt
| | - Eman A El-Maadawy
- Molecular Biology Department, Genetic Engineering & Biotechnology Research Institute (GEBRI), University of Sadat City, 32958, Egypt
| | - Iman H Bassyouni
- Rheumatology & Rehabilitation Department, Faculty of Medicine, Cairo University, Cairo, 32958, Egypt
| | - Mohamed El-Shahat
- Molecular Biology Department, Genetic Engineering & Biotechnology Research Institute (GEBRI), University of Sadat City, 32958, Egypt
| | - Roba M Talaat
- Molecular Biology Department, Genetic Engineering & Biotechnology Research Institute (GEBRI), University of Sadat City, 32958, Egypt
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Gavriilidi IK, Wielińska J, Bogunia-Kubik K. Updates on the Pathophysiology and Therapeutic Potential of Extracellular Vesicles with Focus on Exosomes in Rheumatoid Arthritis. J Inflamm Res 2024; 17:4811-4826. [PMID: 39051053 PMCID: PMC11268846 DOI: 10.2147/jir.s465653] [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: 03/01/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Rheumatoid arthritis (RA) is an incurable autoimmune disease with high morbidity and socioeconomic burden. Advances in therapeutics have improved patients' quality of life, however due to the complex disease pathophysiology and heterogeneity, 30% of patients do not respond to treatment. Understanding how different genetic and environmental factors contribute to disease initiation and development as well as uncovering the interactions of immune components is key to the implementation of effective and safe therapies. Recently, the role of extracellular vesicles (EVs) in RA development and possible treatment has been an area of interest. EVs are small lipid-bound entities, often containing genetic material, proteins, lipids and amino acids, facilitating paracrine intercellular communication. They are secreted by all cells, and it is believed that they possess regulatory functions due to high complexity and functional diversity. Although it has been shown that EVs participate in RA pathophysiology, through immune modulation, their exact role remains elusive. Furthermore, EVs could be a promising therapeutic agent in various diseases including RA, due to their biocompatibility, low toxicity and possible manipulation, but further research is required in this area. This review provides a comprehensive discussion of disease pathophysiology and summarizes the latest knowledge regarding the role and therapeutic potential of EVs in RA.
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Affiliation(s)
- Ioulia Karolina Gavriilidi
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Joanna Wielińska
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
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Sharma SD, Bluett J. Towards Personalized Medicine in Rheumatoid Arthritis. Open Access Rheumatol 2024; 16:89-114. [PMID: 38779469 PMCID: PMC11110814 DOI: 10.2147/oarrr.s372610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic, incurable, multisystem, inflammatory disease characterized by synovitis and extra-articular features. Although several advanced therapies targeting inflammatory mechanisms underlying the disease are available, no advanced therapy is universally effective. Therefore, a ceiling of treatment response is currently accepted where no advanced therapy is superior to another. The current challenge for medical research is the discovery and integration of predictive markers of drug response that can be used to personalize medicine so that the patient is started on "the right drug at the right time". This review article summarizes our current understanding of predicting response to anti-rheumatic drugs in RA, obstacles impeding the development of personalized medicine approaches and future research priorities to overcome these barriers.
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Affiliation(s)
- Seema D Sharma
- Centre for Musculoskeletal Research, Division of Musculoskeletal & Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK
| | - James Bluett
- Centre for Musculoskeletal Research, Division of Musculoskeletal & Dermatological Sciences, School of Biological Sciences, University of Manchester, Manchester, UK
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Tao T, Chen L, Lin X, Fan Z, Zhu C, Mao L. Deregulated miR-146a-3p alleviates disease progression in atherosclerosis through inactivating NF-κB: An experimental study. Medicine (Baltimore) 2024; 103:e38061. [PMID: 38758895 PMCID: PMC11098229 DOI: 10.1097/md.0000000000038061] [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] [Received: 12/08/2023] [Accepted: 04/08/2024] [Indexed: 05/19/2024] Open
Abstract
BACKGROUND Atherosclerosis (AS), as a complex chronic inflammatory disease, is 1 of the main causes of cardiovascular and cerebrovascular diseases. This study aimed to confirm the direct interaction between miR-146a-3p and NF-κB, and explore the role of miR-146a-3p/NF-κB in the regulation of inflammation in AS. METHODS Bioinformatic prediction and dual-luciferase reporter assay were used to confirm the interaction between miR-146a-3p and NF-κB. Lipopolysaccharides stimulation was performed to establish AS inflammatory cell model, and the levels of pro-inflammatory cytokines were estimated using an enzyme-linked immunosorbent assay. miR-146a-3p and NF-κB expression were evaluated using reverse transcription quantitative PCR, and their clinical value was examined using a receiver operating characteristic curve. RESULTS Inflammatory cell model showed increased IL-1β, IL-6, and TNF-α. NF-κB was a target gene of miR-146a-3p, and mediated the inhibitory effects of miR-146a-3p on inflammatory responses in the cell model. In patients with AS, miR-146a-3p/NF-κB was associated with patients' clinical data and inflammatory cytokine levels, and aberrant miR-146a-3p and NF-κB showed diagnostic accuracy to distinguish AS patients from healthy populations. CONCLUSION miR-146a-3p might inhibit inflammation by targeting NF-κB in AS progression, and miR-146a-3p/ NF-κB might provide novel biomarkers and therapeutic targets for the prevention of AS and related vascular events.
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Affiliation(s)
- Taotao Tao
- Department of Neurology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Linkao Chen
- Department of Neurology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Xia Lin
- Department of Neurology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Zijian Fan
- Department of Neurology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Chengfei Zhu
- Department of Neurology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Lingqun Mao
- Department of Neurology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
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Wysoczańska B, Dratwa M, Nieszporek A, Niepiekło-Miniewska W, Kamińska D, Ramuś T, Rasała J, Krajewska M, Bogunia-Kubik K. Analysis of IL-17A, IL-17F, and miR-146a-5p Prior to Transplantation and Their Role in Kidney Transplant Recipients. J Clin Med 2024; 13:2920. [PMID: 38792460 PMCID: PMC11122464 DOI: 10.3390/jcm13102920] [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: 04/04/2024] [Revised: 04/29/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024] Open
Abstract
Background/Objectives: The balance between regulatory and Th17 cells plays an important role in maintaining the immune tolerance after kidney transplantation (KTx) which is essential for transplantation success, defined as a long graft survival and an absence of organ rejection. The present study aimed to assess whether the pretransplant characteristics of IL-17A and IL-17F, their receptors, as well as miR-146a-5p, an miRNA associated with IL-17A/F regulation, can predict KTx outcomes. Methods: A group of 108 pre-KTx dialysis patients and 125 healthy controls were investigated for single nucleotide substitutions within genes coding for IL-17A, IL-17F, their IL-17RA/RC receptors, and miR-146a-5p. Genotyping was performed using LightSNiP assays. In addition, IL17-A/F serum concentrations were determined using ELISA while miR-146a-5p expression was analyzed by RT-PCR. Results: The IL-17F (rs763780) G allele prevailed in KTx recipients as compared to healthy individuals (OR = 23.59, p < 0.0001) and was associated with a higher IL-17F serum level (p = 0.0381) prior to transplantation. Higher miR-146a-5p expression before KTx was more frequently detected in recipients with an increased IL-17A serum concentration (p = 0.0177). Moreover, IL-17A (rs2275913) GG homozygosity was found to be associated with an increased incidence of deaths before KTx (OR = 4.17, p = 0.0307). T-cell or acute rejection episodes were more frequently observed among patients with the C allele of miR-146a-5p (rs2910164) (OR = 5.38, p = 0.0531). IL17-RA/-RC genetic variants (p < 0.05) seem to be associated with eGFR values. Conclusions: These results imply that IL-17F (rs763780) polymorphism is associated with the serum level of this cytokine and may be related to the risk of renal disease and transplant rejection together with miR-146a-5p (rs2910164), while the IL-17A (rs2275913) genotype may affect patients' survival before KTx.
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Affiliation(s)
- Barbara Wysoczańska
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.D.); (K.B.-K.)
| | - Marta Dratwa
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.D.); (K.B.-K.)
| | - Artur Nieszporek
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.D.); (K.B.-K.)
- Biobank Research Group, Lukasiewicz Research Network—PORT Polish Center for Technology Development, 54-066 Wroclaw, Poland
| | - Wanda Niepiekło-Miniewska
- Laboratory of Tissue Immunology, Medical Center, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland;
| | - Dorota Kamińska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (D.K.); (M.K.)
| | - Tomasz Ramuś
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | | | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland; (D.K.); (M.K.)
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland; (M.D.); (K.B.-K.)
- Laboratory of Tissue Immunology, Medical Center, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland;
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Perera J, Delrosso CA, Nerviani A, Pitzalis C. Clinical Phenotypes, Serological Biomarkers, and Synovial Features Defining Seropositive and Seronegative Rheumatoid Arthritis: A Literature Review. Cells 2024; 13:743. [PMID: 38727279 PMCID: PMC11083059 DOI: 10.3390/cells13090743] [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: 02/13/2024] [Revised: 04/11/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disorder which can lead to long-term joint damage and significantly reduced quality of life if not promptly diagnosed and adequately treated. Despite significant advances in treatment, about 40% of patients with RA do not respond to individual pharmacological agents and up to 20% do not respond to any of the available medications. To address this large unmet clinical need, several recent studies have focussed on an in-depth histological and molecular characterisation of the synovial tissue to drive the application of precision medicine to RA. Currently, RA patients are clinically divided into "seropositive" or "seronegative" RA, depending on the presence of routinely checked antibodies. Recent work has suggested that over the last two decades, long-term outcomes have improved significantly in seropositive RA but not in seronegative RA. Here, we present up-to-date differences in epidemiology, clinical features, and serological biomarkers in seronegative versus seropositive RA and discuss how histological and molecular synovial signatures, revealed by recent large synovial biopsy-based clinical trials, may be exploited to refine the classification of RA patients, especially in the seronegative group.
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Affiliation(s)
- James Perera
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, London EC1M 6BQ, UK
| | - Chiara Aurora Delrosso
- Department of Translational Medicine, University of Piemonte Orientale and Maggiore della Carità Hospital, 28100 Novara, Italy
| | - Alessandra Nerviani
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, London EC1M 6BQ, UK
| | - Costantino Pitzalis
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, London EC1M 6BQ, UK
- Department of Biomedical Sciences, Humanitas University & IRCCS Humanitas Research Hospital, 20089 Milan, Italy
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Huang X, Huang L, Gao X, Liu C. Global research trends in DNA methylation in rheumatoid arthritis: A bibliometric analysis and visual analysis. Medicine (Baltimore) 2024; 103:e36218. [PMID: 38181259 PMCID: PMC10766281 DOI: 10.1097/md.0000000000036218] [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] [Received: 09/21/2023] [Accepted: 10/30/2023] [Indexed: 01/07/2024] Open
Abstract
Rheumatoid arthritis (RA) is a prevalent autoimmune disorder with a significant global economic burden. Epigenetic modifications, particularly DNA methylation, play a crucial role in RA. This study conducted a bibliometric analysis to explore the evolving trends and predominant themes in RA and DNA methylation research over the past two decades. A total of 1800 articles met the inclusion criteria, and the analysis revealed consistent growth in the literature, with a notable increase in output after 2019. The research involved 70 countries, 2139 academic institutions, 23,365 unique authors, and 58,636 co-cited authors. The United States emerged as a dominant contributor in this research domain. The significance of DNA methylation in shaping research directions for RA management is increasingly evident. Recent investigations have shed light on the pivotal role of DNA methylation in RA, particularly in characterizing synovial tissue and exploring the underlying mechanisms of disease pathogenesis. This study provides valuable insights into the landscape of DNA methylation research in RA and highlights the importance of epigenetics in autoimmune diseases.
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Affiliation(s)
- Xin Huang
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Longxiang Huang
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Xiang Gao
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
| | - Changhua Liu
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China
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Wen J, Liu J, Wan L, Jiang H, Xin L, Sun Y, Fang Y, Wang X, Wang J. m 6A-mediated lncRNA MAPKAPK5-AS1 induces apoptosis and suppresses inflammation via regulating miR-146a-3p/SIRT1/NF-κB axis in rheumatoid arthritis. Cell Cycle 2023; 22:2602-2621. [PMID: 38225924 PMCID: PMC10936687 DOI: 10.1080/15384101.2024.2302281] [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: 11/24/2022] [Revised: 03/28/2023] [Accepted: 01/03/2024] [Indexed: 01/17/2024] Open
Abstract
To investigate the role of m6A-mediated lncRNA MAPKAPK5-AS1 (MK5-AS1) in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and its underlying molecular mechanism. RT-qPCR, western blot, flow cytometry (FCM), and enzyme-linked immunosorbent assay (ELISA) were utilized for evaluating inflammation and apoptosis. Next, RIP, RNA pull-down, dual-luciferase reporter gene assay, and a series of rescue experiments were performed to explore the regulatory mechanisms of MK5-AS1 and its sponge-like action in RA-FLSs. The regulatory relationships between MK5-AS1 and WTAP were explored using the MeRIP-qPCR assay and RT-qPCR. Finally, the critical RNAs in the ceRNA axis were verified in the clinical cohort. MK5-AS1 was poorly expressed and miR-146a-3p was overexpressed in co-cultured RA-FLSs. MK5-AS1 overexpression could inhibit inflammatory responses and promote cell apoptosis in the co-cultured RA-FLSs. MK5-AS1 bound to miR-146a-3p to target SIRT1, thereby affecting inflammatory responses and cell apoptosis in the co-cultured RA-FLSs. SIRT1 knockdown or miR-146a-3p overexpression reversed the impacts of MK5-AS1 overexpression on co-cultured RA-FLSs inflammation and apoptosis. Moreover, WTAP was downregulated, and induced the inhibition of MK5-AS1 by promoting its RNA transcript stability. Clinically, MK5-AS1 was downregulated in RA-PBMCS and correlated with the clinical characteristics of RA. Our study elucidated that m6A-mediated MK5-AS1 sequestered miR-146a-3p to suppress SIRT1 expression in co-cultured RA-FLSs, thus providing a new insight into the treatment of rheumatoid arthritis.
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Affiliation(s)
- Jianting Wen
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Institute of Rheumatology, Anhui Academy of Chinese Medicine, Hefei, Anhui Province, China
- Key Laboratory of Xin’an Medicine of the Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, P. R. China
| | - Jian Liu
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Institute of Rheumatology, Anhui Academy of Chinese Medicine, Hefei, Anhui Province, China
- Department of Internal Medicine Application Foundation Research and Development, Anhui Province Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, China
| | - Lei Wan
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Institute of Rheumatology, Anhui Academy of Chinese Medicine, Hefei, Anhui Province, China
- Department of Internal Medicine Application Foundation Research and Development, Anhui Province Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, China
| | - Hui Jiang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Department of Internal Medicine Application Foundation Research and Development, Anhui Province Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, China
| | - Ling Xin
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Department of Internal Medicine Application Foundation Research and Development, Anhui Province Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, China
| | - Yue Sun
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Department of Internal Medicine Application Foundation Research and Development, Anhui Province Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, China
| | - Yanyan Fang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Department of Internal Medicine Application Foundation Research and Development, Anhui Province Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, China
| | - Xin Wang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Department of Internal Medicine Application Foundation Research and Development, Anhui Province Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, China
| | - Jie Wang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province, China
- Department of Internal Medicine Application Foundation Research and Development, Anhui Province Key Laboratory of Modern Chinese Medicine, Hefei, Anhui, China
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Zhang H, Shang H, Wang Z, Li K. Associations of miRNA-146a and miRNA-223 with Rheumatoid Arthritis and Their Predictive Values. Int J Gen Med 2023; 16:3211-3218. [PMID: 37546237 PMCID: PMC10402887 DOI: 10.2147/ijgm.s416317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/19/2023] [Indexed: 08/08/2023] Open
Abstract
Purpose To analyze the independent associations of miRNA-146a and miRNA-223 with rheumatoid arthritis (RA) and evaluate their predictive values for RA. Patients and Methods A total of 68 RA patients were selected as cases, and meanwhile 68 patients with a traumatic knee condition were selected as controls by matching to the cases according to sex and age at the ratio of 1:1. The independent associations of miRNA-146a and miRNA-223 with RA were identified by binary logistic regression analysis. Receiver operating characteristic (ROC) curve was used to evaluate their predictive values for RA. Results MiRNA-146a and miRNA-223 expression levels in both synovial tissues and serums were statistically higher in cases than in controls, and their expression levels in serums were not statistically different from those in synovial tissues in both cases and controls. The expression levels of miRNA-146a and miRNA-223 in synovial tissues were independently associated with RA, as well as the expression levels of miRNA-146a and miRNA-223 in serums. The area under curve (AUC) of combination of miRNA-146a and miRNA-223 in synovial tissues for the prediction of RA was 0.910 [95% confidence interval (CI): 0.863-0.962], and the AUC of combination of miRNA-146a and miRNA-223 in serums was 0.904 (95% CI: 0.851-0.957). Their difference was not statistically significant (P=0.873), but the AUC of combination prediction was statistically higher than those of individual predictions (synovial tissues: 0.910 vs 0.773, P=0.005, 0.910 vs 0.788, P=0.009; serums: 0.904 vs 0.766, P=0.005, 0.904 vs 0.784, P=0.011). Conclusion MiRNA-146a and miRNA-223 in both synovial tissues and serums could be applied in predicting RA, and their combination could elevate the predictive value significantly.
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Affiliation(s)
- Haoshaqiang Zhang
- Department of Orthopedics Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
| | - Hua Shang
- Department of Orthopedics Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
- Department of Human Resources, People's Hospital of Xinjiang Uygur Autonomous Region, UrumqiPeople's Republic of China
| | - Zhigang Wang
- Department of Orthopedics Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
| | - Kun Li
- Department of Orthopedics Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China
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Les I, Martínez M, Pérez-Francisco I, Cabero M, Teijeira L, Arrazubi V, Torrego N, Campillo-Calatayud A, Elejalde I, Kochan G, Escors D. Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events. Cancers (Basel) 2023; 15:1629. [PMID: 36900420 PMCID: PMC10000735 DOI: 10.3390/cancers15051629] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 03/09/2023] Open
Abstract
Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site.
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Affiliation(s)
- Iñigo Les
- Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Autoimmune Diseases Unit, Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Mireia Martínez
- Osakidetza Basque Health Service, Department of Medical Oncology, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain
- Lung Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Inés Pérez-Francisco
- Breast Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - María Cabero
- Clinical Trials Platform, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Lucía Teijeira
- Medical Oncology Department, Navarre University Hospital, 31008 Pamplona, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Navarre University Hospital, 31008 Pamplona, Spain
| | - Nuria Torrego
- Osakidetza Basque Health Service, Department of Medical Oncology, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain
- Lung Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Ana Campillo-Calatayud
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Iñaki Elejalde
- Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Autoimmune Diseases Unit, Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Grazyna Kochan
- Oncoimmunology Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - David Escors
- Oncoimmunology Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
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Doghish AS, Ismail A, El-Mahdy HA, Elkhawaga SY, Elsakka EGE, Mady EA, Elrebehy MA, Khalil MAF, El-Husseiny HM. miRNAs insights into rheumatoid arthritis: Favorable and detrimental aspects of key performers. Life Sci 2023; 314:121321. [PMID: 36574943 DOI: 10.1016/j.lfs.2022.121321] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/05/2022] [Accepted: 12/20/2022] [Indexed: 12/25/2022]
Abstract
Rheumatoid arthritis (RA) is a severe autoimmune inflammation that mostly affects the joints. It's a multifactorial disease. Its clinical picture depends on genetic and epigenetic factors such as miRNAs. The miRNAs are small noncoding molecules that are able to negatively or positively modulate their target gene expression. In RA, miRNAs are linked to its pathogenesis. They disrupt immunity balance by controlling granulocytes, triggering the release of several proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, finally leading to synovium hyperplasia and inflammation. Besides, they also may trigger activation of some pathways as nuclear factor kappa-β disrupts the balance between osteoclast and osteoblast activity, leading to increased bone destruction. Moreover, miRNAs are also applied with efficiency in RA diagnosis and prognosis. Besides the significant association between miRNAs and RA response to treatment, they are also applied as a choice for treatment based on their effects on the immune system and inflammatory cytokines. Hence, the review aims to present an updated overview of miRNAs, their biogenesis, implications in RA pathogenesis, and finally, the role of miRNAs in RA treatment.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Samy Y Elkhawaga
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt.
| | - Eman A Mady
- Department of Animal Hygiene, Behavior and Management, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukfh, Elqaliobiya 13736, Egypt; Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A F Khalil
- Department of Microbiology and Immunology, Faculty of Pharmacy, Fayoum University, Fayoum 63514, Egypt
| | - Hussein M El-Husseiny
- Laboratory of Veterinary Surgery, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan; Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Elqaliobiya 13736, Egypt
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15
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Zhou J, Liu L, Wu P, Zhao L, Wu Y. Identification and characterization of non-coding RNA networks in infected macrophages revealing the pathogenesis of F. nucleatum-associated diseases. BMC Genomics 2022; 23:826. [PMID: 36513974 DOI: 10.1186/s12864-022-09052-z] [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: 04/21/2022] [Accepted: 11/28/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND F. nucleatum, as an important periodontal pathogen, is not only closely associated with the development of periodontitis, but also implicated in systemic diseases. Macrophages may act as an important mediator in the pathogenic process of F. nucleatum infection. As non-coding RNAs (ncRNAs) have attracted extensive attention as important epigenetic regulatory mechanisms recently, we focus on the competing endogenous RNA (ceRNA) regulatory networks to elucidate the pathogenesis of F. nucleatum-associated diseases. RESULTS We screen abnormally expressed mRNAs, miRNAs, lncRNAs and circRNAs in macrophages after F. nucleatum infection via the whole transcriptome sequencing technology, including 375 mRNAs, 5 miRNAs, 64 lncRNAs, and 180 circRNAs. The accuracy of RNA-seq and microRNA-seq result was further verified by qRT-PCR analysis. GO and KEGG analysis show that the differentially expressed genes were mainly involved in MAPK pathway, Toll-like receptor pathway, NF-κB pathway and apoptosis. KEGG disease analysis reveals that they were closely involved in immune system diseases, cardiovascular disease, cancers, inflammatory bowel disease (IBD) et al. We constructed the underlying lncRNA/circRNA-miRNA-mRNA networks to understand their interaction based on the correlation analysis between the differentially expressed RNAs, and then screen the core non-coding RNAs. In which, AKT2 is controlled by hsa_circ_0078617, hsa_circ_0069227, hsa_circ_0084089, lncRNA NUP210, lncRNA ABCB9, lncRNA DIXDC1, lncRNA ATXN1 and lncRNA XLOC_237387 through miR-150-5p; hsa_circ_0001165, hsa_circ_0008460, hsa_circ_0001118, lncRNA XLOC_237387 and lncRNA ATXN1 were identified as the ceRNAs of hsa-miR-146a-3p and thereby indirectly modulating the expression of MITF. CONCLUSIONS Our data identified promising candidate ncRNAs responsible for regulating immune response in the F. nucleatum-associated diseases, offering new insights regarding the pathogenic mechanism of this pathogen.
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Affiliation(s)
- Jieyu Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lin Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Peiyao Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lei Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. .,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
| | - Yafei Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. .,Department of Periodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
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16
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Ibrahim AM, Hassan NM, Saad MN, Mabrouk MS, Shaker OG. A genetic study of the association of six polymorphisms with rheumatoid arthritis in the Egyptian population. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00343-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Rheumatoid arthritis (RA) is an autoimmune disease in which the immune system attacks the tissues of the joints by mistake. Different factors—either genetic or environmental—affect the development of the RA disease in patients. A lot of studies aimed to examine the genetic associations with this disease in different populations. This research aspires to perform a genetic association study between six single-nucleotide polymorphisms (SNPs) and RA disease in the Egyptian population with 49 controls and 52 patients. The SNPs that are included in this study are MIR146A rs2910164 (C:G), MIR499/MIR499A rs3746444 (T:C), MTMR3 rs12537(C:T), MIR155HG rs767649 (A:T), IRAK1 rs3027898 (A:C) and PADI4 rs1748033 (C:T).
Methods
Real-time PCR with TaqMan allelic discrimination assay were both used to perform the genotyping. The Odds ratio models with 95% confidence interval were used to test the associations. The used models are multiplicative, recessive, dominant and co-dominant.
Result
The demonstrated results indicated that rs2910164 and rs12537 were associated with RA, while rs3746444 showed no association in all the tested models. The remaining SNPs were excluded as they didn't pass the Hardy–Weinberg equilibrium test.
Conclusion
The MIR146A and MTMR3 polymorphisms showed susceptibility to RA. Moreover, MIR499/MIR499A had no role in the disease.
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17
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-Omic Approaches and Treatment Response in Rheumatoid Arthritis. Pharmaceutics 2022; 14:pharmaceutics14081648. [PMID: 36015273 PMCID: PMC9412998 DOI: 10.3390/pharmaceutics14081648] [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: 06/29/2022] [Revised: 07/22/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022] Open
Abstract
Rheumatoid arthritis (RA) is an inflammatory disorder characterized by an aberrant activation of innate and adaptive immune cells. There are different drugs used for the management of RA, including disease-modifying antirheumatic drugs (DMARDs). However, a significant percentage of RA patients do not initially respond to DMARDs. This interindividual variation in drug response is caused by a combination of environmental, genetic and epigenetic factors. In this sense, recent -omic studies have evidenced different molecular signatures involved in this lack of response. The aim of this review is to provide an updated overview of the potential role of -omic approaches, specifically genomics, epigenomics, transcriptomics, and proteomics, to identify molecular biomarkers to predict the clinical efficacy of therapies currently used in this disorder. Despite the great effort carried out in recent years, to date, there are still no validated biomarkers of response to the drugs currently used in RA. -Omic studies have evidenced significant differences in the molecular profiles associated with treatment response for the different drugs used in RA as well as for different cell types. Therefore, global and cell type-specific -omic studies analyzing response to the complete therapeutical arsenal used in RA, including less studied therapies, such as sarilumab and JAK inhibitors, are greatly needed.
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18
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Rangon CM, Niezgoda A. Understanding the Pivotal Role of the Vagus Nerve in Health from Pandemics. Bioengineering (Basel) 2022; 9:352. [PMID: 36004877 PMCID: PMC9405360 DOI: 10.3390/bioengineering9080352] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/25/2022] [Accepted: 07/28/2022] [Indexed: 11/22/2022] Open
Abstract
The COVID-19 pandemic seems endless with the regular emergence of new variants. Is the SARS-CoV-2 virus particularly evasive to the immune system, or is it merely disrupting communication between the body and the brain, thus pre-empting homeostasis? Retrospective analysis of the COVID-19 and AIDS pandemics, as well as prion disease, emphasizes the pivotal but little-known role of the 10th cranial nerve in health. Considering neuroimmunometabolism from the point of view of the vagus nerve, non-invasive bioengineering solutions aiming at monitoring and stimulating the vagal tone are subsequently discussed as the next optimal and global preventive treatments, far beyond pandemics.
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Affiliation(s)
- Claire-Marie Rangon
- Child Neurologist and Pain Specialist, INWE’CARE Medical Center, 92210 Saint-Cloud, France
| | - Adam Niezgoda
- Chair and Department of Neurology, University of Medical Sciences, 60-355 Poznań, Poland;
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Bonek K, Kuca Warnawin E, Kornatka A, Plebańczyk M, Burakowski T, Maśliński W, Wisłowska M, Głuszko P, Ciechomska M. Circulating miRNA Correlates with Lipid Profile and Disease Activity in Psoriatic Arthritis, Rheumatoid Arthritis, and Ankylosing Spondylitis Patients. Biomedicines 2022; 10:biomedicines10040893. [PMID: 35453643 PMCID: PMC9024741 DOI: 10.3390/biomedicines10040893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
This study aimed to investigate the associations of microRNA (miRs) signatures with cytokines, serum lipids, and disease activity in patients with psoriatic arthritis (PsA), ankylosing spondylitis (AS), and rheumatoid arthritis (RA). In total, 65 patients (PsA n = 25, AS n = 25, RA n = 15) and 25 healthy controls (HC) were enrolled into the study. The expression of miR-223-5p, miR-92b-3p, miR-485-3p, miR-10b-5p, let-7d-5p, miR-26a-2-3p, miR-146b-3p, and cytokines levels were measured in sera. DIANA-mirPath analysis was used to predict pathways targeted by the dysregulated miRs. Disease activity scores were calculated. Lipid profile, uric acid, glucose level, and C-reactive protein (CRP) concentrations were determined in the blood. Based on lipid profiles, the PsA group had hypertriglyceridaemia, and RA patients revealed mixed dyslipidaemia, while in AS, no specific changes were found. miR expression analysis revealed upregulation of miR-26a-2-3p and miR-10b-5p in PsA, miR-485-3p in AS, and let-7d-5p in RA. Several correlations between disease activity indexes, metabolites levels, and expression of miRs were observed in PsA, RA, and AS patients. Finally, in ROC analysis, miR-26a-2-3p/miR-485-3p, and let-7d-5p/miR-146b-3p tandems revealed high sensitivity and specificity in distinguishing between PsA, AS, and RA. Our study illustrates the superiority of miR expressions in distinguishing between RA, PsA, and AS. In PsA, a unique regulatory pathway exists through miR-26a-2-3p, miR-223-5p, miR-10b-5p, and miR-92b-3p that converges proatherogenic metabolism and disease activity.
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Affiliation(s)
- Krzysztof Bonek
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.W.); (P.G.)
- Correspondence: (K.B.); (M.C.)
| | - Ewa Kuca Warnawin
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Anna Kornatka
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Magdalena Plebańczyk
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Tomasz Burakowski
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Włodzimierz Maśliński
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
| | - Małgorzata Wisłowska
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.W.); (P.G.)
| | - Piotr Głuszko
- Department of Rheumatology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (M.W.); (P.G.)
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland; (E.K.W.); (A.K.); (M.P.); (T.B.); (W.M.)
- Correspondence: (K.B.); (M.C.)
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Chang C, Xu L, Zhang R, Jin Y, Jiang P, Wei K, Xu L, Shi Y, Zhao J, Xiong M, Guo S, He D. MicroRNA-Mediated Epigenetic Regulation of Rheumatoid Arthritis Susceptibility and Pathogenesis. Front Immunol 2022; 13:838884. [PMID: 35401568 PMCID: PMC8987113 DOI: 10.3389/fimmu.2022.838884] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 03/02/2022] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) play crucial roles in regulating the transcriptome and development of rheumatoid arthritis (RA). Currently, a comprehensive map illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interactions with terminal cells such as fibroblast-like synoviocytes (FLS), immune-cells, osteoblasts, and osteoclasts are still laking. In this review, we summarize the roles of miRNAs in the susceptibility, pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA and regulate target genes and pathways, including NF-κB, Fas-FasL, JAK-STAT, and mTOR pathways. We outline how functional genetic variants of miR-499 and miR-146a partly explain susceptibility to RA. By regulating gene expression, miRNAs affect T cell differentiation into diverse cell types, including Th17 and Treg cells, thus constituting promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the opportunity to combine these miRNAs with antibodies to cyclic citrullinated peptide (ACCP) to allow accurate diagnosis and prognosis, particularly for seronegative patients. Furthermore, we review the evidence implicating miRNAs as promising biomarkers of efficiency and response of, and resistance to, disease-modifying anti-rheumatic drugs and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.
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Affiliation(s)
- Cen Chang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lingxia Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Runrun Zhang
- The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yehua Jin
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ping Jiang
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Wei
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Linshuai Xu
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yiming Shi
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianan Zhao
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Momiao Xiong
- Department of Biostatistics and Data Science, School of Public Health, University of Texas Health Science Center, Houston, TX, United States
| | - Shicheng Guo
- Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Dongyi He
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
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21
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Gunter S, Michel FS, Fourie SS, Singh M, le Roux R, Manilall A, Mokotedi LP, Millen AME. The effect of TNF-α inhibitor treatment on microRNAs and endothelial function in collagen induced arthritis. PLoS One 2022; 17:e0264558. [PMID: 35213638 PMCID: PMC8880872 DOI: 10.1371/journal.pone.0264558] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 02/11/2022] [Indexed: 11/18/2022] Open
Abstract
Chronic inflammation causes dysregulated expression of microRNAs. Aberrant microRNA expression is associated with endothelial dysfunction. In this study we determined whether TNF-α inhibition impacted the expression of miRNA-146a-5p and miRNA-155-5p, and whether changes in the expression of these miRNAs were related to inflammation-induced changes in endothelial function in collagen-induced arthritis (CIA). Sixty-four Sprague-Dawley rats were divided into control (n = 24), CIA (n = 24) and CIA+etanercept (n = 16) groups. CIA and CIA+etanercept groups were immunized with bovine type-II collagen, emulsified in incomplete Freund’s adjuvant. Upon signs of arthritis, the CIA+etanercept group received 10mg/kg of etanercept intraperitoneally, every three days. After six weeks of treatment, mesenteric artery vascular reactivity was assessed using wire-myography. Serum concentrations of TNF-α, C-reactive protein, interleukin-6, vascular adhesion molecule-1 (VCAM-1) and pentraxin-3 (PTX-3) were measured by ELISA. Relative expression of circulating miRNA-146a-5p and miRNA-155-5p were determined using RT-qPCR. Compared to controls, circulating miRNA-155-5p, VCAM-1 and PTX-3 concentrations were increased, and vessel relaxation was impaired in the CIA (all p<0.05), but not in the CIA+etanercept (all p<0.05) groups. The CIA group had greater miRNA-146a-5p expression compared to the CIA+etanercept group (p = 0.005). Independent of blood pressure, miRNA-146a-5p expression was associated with increased PTX-3 concentrations (p = 0.03), while miRNA-155-5p expression was associated with impaired vessel relaxation (p = 0.01). In conclusion, blocking circulating TNF-α impacted systemic inflammation-induced increased expression of miRNA-146a-5p and miRNA-155-5p, which were associated with endothelial inflammation and impaired endothelial dependent vasorelaxation, respectively.
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Affiliation(s)
- Sulè Gunter
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- * E-mail:
| | - Frederic S. Michel
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Serena S. Fourie
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Mikayra Singh
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Regina le Roux
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Ashmeetha Manilall
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Lebogang P. Mokotedi
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Aletta M. E. Millen
- School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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22
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Ayón-Pérez MF, Topete-Córdoba JJ, Agraz-Cibrián JM, Ortiz-Martínez L, Durán-Avelar MDJ, Vázquez-Reyes A, Vibanco-Pérez N, Gutiérrez-Franco J, Zambrano-Zaragoza JF. The influence of the -94 Ins/Del ATTG polymorphism of NFkB on the anti-CCP antibody levels in patients with rheumatoid arthritis. Medicine (Baltimore) 2021; 100:e28301. [PMID: 34918708 PMCID: PMC8677897 DOI: 10.1097/md.0000000000028301] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/24/2021] [Indexed: 01/05/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by an inflammatory process that affects mainly synovial tissue in joints, and by the production of cyclic citrullinated peptides (anti-CCP) antibodies. In the inflammatory process the regulation of the nuclear factor kappa B (NFkB) transcription factor activation is a key point in the production of inflammatory cytokines. On the other hand, polymorphisms in several genes could contribute to the promotion of the inflammatory process observed in RA, and the association of the rs28362491 polymorphism in the NFkB gene with RA has been studied in different population. Therefore, it could be one of the interest targets to analyze their association with RA in a Mexican population.This is a case-control study to determine the influence of rs28362491 in the NFkB gene on RA and on clinical features of this disease, such as anti-CCP antibody levels, Disease Activity Score, and Health Assessment Questionnaire-Disability Index.The genotype of rs28362491 in the NFkB gene was determined in 140 RA patients and 135 healthy controls using the polymerase chain reaction-restriction fragment length polymorphism method with the enzyme PflMI. The following clinical variables were also determined: anti-CCP levels, Disease Activity Score, and Spanish version of the Health Assessment Questionnaire Disability-Index.Although no association of the polymorphism as a risk/protection factor with RA was found, the RA patients who carried the Ins/Ins genotype showed higher anti-CCP levels, while those with the Del/Del genotype showed higher Spanish version of the Health Assessment Questionnaire-Disability Index levels, compared to the other genotypes.The NFkB -94 Ins/Del ATTG (rs28362491) polymorphism is, therefore, associated with higher levels of anti-CCP antibodies, though no significant association as a risk or protection factor in RA cases was identified.
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Affiliation(s)
- Miriam Fabiola Ayón-Pérez
- Unidad Academica de Ciencias Quimico Biológicas y Farmaceuticas-Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
| | | | - Juan Manuel Agraz-Cibrián
- Unidad Academica de Ciencias Quimico Biológicas y Farmaceuticas-Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
- Maestria en Salud Pública, Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
| | - Liliana Ortiz-Martínez
- Clinica de Reumatologia, Servicio de Medicina Interna, Instituto Mexicano del Seguro Social HGZ No. 1, Tepic, Nayarit, Mexico
| | - Ma. de Jesús Durán-Avelar
- Unidad Academica de Ciencias Quimico Biológicas y Farmaceuticas-Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
| | - Alejandro Vázquez-Reyes
- Unidad Academica de Ciencias Quimico Biológicas y Farmaceuticas-Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
| | - Norberto Vibanco-Pérez
- Unidad Academica de Ciencias Quimico Biológicas y Farmaceuticas-Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
| | - Jorge Gutiérrez-Franco
- Unidad Academica de Ciencias Quimico Biológicas y Farmaceuticas-Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
| | - José Francisco Zambrano-Zaragoza
- Unidad Academica de Ciencias Quimico Biológicas y Farmaceuticas-Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
- Maestria en Salud Pública, Universidad Autonoma de Nayarit, Tepic, Nayarit, Mexico
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23
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Exploring the Extracellular Vesicle MicroRNA Expression Repertoire in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis Treated with TNF Inhibitors. DISEASE MARKERS 2021; 2021:2924935. [PMID: 34691284 PMCID: PMC8529175 DOI: 10.1155/2021/2924935] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 09/03/2021] [Indexed: 12/17/2022]
Abstract
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) belong to the most common inflammatory rheumatic diseases. MicroRNAs (miRNAs) are small 18–22 RNA molecules that function as posttranscriptional regulators. They are abundantly present within extracellular vesicles (EVs), small intercellular communication vesicles that can be found in bodily fluids and that have key functions in pathological and physiological pathways. Recently, EVs have gained much interest because of their diagnostic and therapeutic potential. Using NanoString profiling technology, the miRNA repertoire of serum EVs was determined and compared in RA and AS patients before and after anti-TNF therapy to assess its potential use as a diagnostic and prognostic biomarker. Furthermore, possible functional effects of those miRNAs that were characterized by the most significant expression changes were evaluated using in silico prediction algorithms. The analysis revealed a unique profile of differentially expressed miRNAs in RA and AS patient serum EVs. We identified 12 miRNAs whose expression profiles enabled differentiation between RA and AS patients before induction of anti-TNF treatment, as well as 4 and 14 miRNAs whose repertoires were significantly changed during the treatment in RA and AS patients, respectively. In conclusion, our findings suggest that extracellular vesicle miRNAs could be used as potential biomarkers associated with RA and AS response to biological treatment.
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24
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Meta-Analysis of miRNA Variants Associated with Susceptibility to Autoimmune Disease. DISEASE MARKERS 2021; 2021:9978460. [PMID: 34659590 PMCID: PMC8519726 DOI: 10.1155/2021/9978460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022]
Abstract
Purpose Various studies have shown an association between miRNA polymorphisms and susceptibility to autoimmune disease (AD); however, the results are inconclusive. To evaluate whether miRNA polymorphisms account for a significant risk of AD, a total of 87 articles, including 39431 patients and 56708 controls, were identified to estimate their association with 12 AD subtypes. Methods Several electronic databases were searched to analyze population-based studies on the relationship between miRNA variants and AD risk. Fixed effects or random effect models were used in the meta-analysis for the risk assessment. Results In our meta-analysis, miR-146a rs2910164/rs57095329 conferred a marginally elevated risk for AD (allele model, OR = 1.08, 95% CI: 1.01-1.15, P = 0.019; allele model, OR = 1.09, 95 CI: 1.05-1.15, P < 0.001, respectively). Furthermore, miR-196a2 rs11614913 was also associated with AD risk (allele model, OR = 0.92, 95% CI: 0.88-0.97, P = 0.001) as well as miR-499 rs3746444 (allele model, OR = 1.16, 95% CI: 1.03-1.29, P = 0.011). In addition, associations were observed between miR-149 rs2292832/miR-27a rs895819 and AD susceptibility in the overall population (allele model, OR = 1.15, 95% CI: 1.06-1.24, P < 0.001; allele model, OR = 1.11, 95% CI:1.01-1.22, P = 0.043, respectively). Conclusions Evidence from our systematic review suggests that miR-146a, miR-196a2, miR-499, miR-149, and miR-27a polymorphisms are associated with susceptibility to AD.
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25
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Kazemi S, Afshar S, Karami M, Saidijam M, Keramat F, Hashemi SH, Alikhani MY. Association between risk of brucellosis and genetic variations in MicroRNA-146a. BMC Infect Dis 2021; 21:1070. [PMID: 34656082 PMCID: PMC8520608 DOI: 10.1186/s12879-021-06775-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 10/08/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Single nucleotide polymorphisms (SNPs) are the most common types of DNA changes in the human genome that leading to phenotypic differences in humans. MicroRNAs (miRNAs) are usually affected by various bacterial infections, and they are involved in controlling the immune responses. MicroRNA-146a (miR-146a) plays an essential role in the development of infectious and inflammatory diseases. The aim of the present study was to investigate the association between risk of brucellosis and genetic variations in miR-146a. METHODS This case-control study was conducted on 108 Brucellosis patients and 108 healthy controls. We genotyped two SNPs (rs2910164 and rs57095329) of the miR-146a using tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods. RESULTS The rs2910164 SNP was significantly associated with brucellosis in co-dominant [OR = 4.27, 95% CI = (2.35-7.79, P = 0.001] and dominant [OR = 3.52, 95% CI = (1.97-6.30, P = 0.001] models. Co-dominant (P = 0.047) and recessive (P = 0.018) models were significant at position rs57095329 between the two groups of patient and healthy. The A C haplotype (rs2910164 and rs57095329) was associated with brucellosis in the assessed population [OR (95% CI) = 1.98 (1.22-3.20), P = 0.0059]. CONCLUSIONS Consequently, our study demonstrated significant differences in genotype and haplotype frequencies of miR-146a variants between brucellosis patients and controls. Further studies on the larger sample sizes are required to verify the observed associations.
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Affiliation(s)
- Sima Kazemi
- Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Saeid Afshar
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Manoochehr Karami
- Department of Biostatistics and Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fariba Keramat
- Brucellosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Seyed Hamid Hashemi
- Brucellosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Yousef Alikhani
- Department of Microbiology, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran. .,Brucellosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
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26
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Disease Differentiation and Monitoring of Anti-TNF Treatment in Rheumatoid Arthritis and Spondyloarthropathies. Int J Mol Sci 2021; 22:ijms22147389. [PMID: 34299006 PMCID: PMC8307996 DOI: 10.3390/ijms22147389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/03/2021] [Accepted: 07/07/2021] [Indexed: 01/16/2023] Open
Abstract
Rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are comprehensive immunological disorders. The treatment of these disorders is limited to ameliorating the symptoms and improving the quality of life of patients. In this study, serum samples from RA, AS, and PsA patients were analyzed with metabolomic tools employing the 1H NMR method in combination with univariate and multivariate analyses. The results obtained in this study showed that the changes in metabolites were the highest for AS > RA > PsA. The study demonstrated that the time until remission or until low disease activity is achieved is shortest (approximately three months) for AS, longer for RA and longest for PsA. The statistically common metabolite that was found to be negatively correlated with the healing processes of these disorders is ethanol, which may indicate the involvement of the gut microflora and/or the breakdown of malondialdehyde as a cell membrane lipid peroxide product.
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27
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Aravilli RK, Vikram SL, Kohila V. The Functional Impact of Alternative Splicing and Single Nucleotide Polymorphisms in Rheumatoid Arthritis. Curr Pharm Biotechnol 2021; 22:1014-1029. [PMID: 33001009 DOI: 10.2174/1389201021666201001142416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/05/2020] [Accepted: 09/08/2020] [Indexed: 11/22/2022]
Abstract
Advances in genomics and proteomics aid the identification of genes associated with various diseases. Genome-Wide Association Studies (GWAS) have identified multiple loci as risk alleles for susceptibility to Rheumatoid Arthritis (RA). A bisection of RA risk can be attributed to genetic factors. Over 100 associated genetic loci that encompass immune regulatory factors have been found to be linked with RA. Aberrant Single Nucleotide Polymorphisms (SNPs) and alternative splicing mechanisms in such loci induce RA. These aberrations are viewed as potential therapeutic targets due to their association with a multitude of diseases. This review presents a few imperious genes whose alterations can cause severe bone deformities culminating in RA.
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Affiliation(s)
- R Kowshik Aravilli
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, India
| | - S Laveen Vikram
- Department of Computer Science and Engineering, Alagappa University, Karaikudi, India
| | - V Kohila
- Department of Biotechnology, National Institute of Technology Warangal, Warangal, India
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28
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Zhu C, Wen S, Li J, Meng H, Zhang J, Zhao K, Wang L, Zhang Y. FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4 + T Lymphocytes. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:1981-1992. [PMID: 34007158 PMCID: PMC8123953 DOI: 10.2147/dddt.s293876] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 04/06/2021] [Indexed: 12/15/2022]
Abstract
Background Fingolimod (FTY720), a novel immunomodulator, was found to suppress the severity of collagen-induced arthritis (CIA) in mice. However, the potential molecular mechanisms are still unknown, and the effect of FTY720 on the recruitment of immune cells in the affected joints in the CIA model is not clear. Materials and Methods Following the oral administration of FTY720 (2 mg/kg) was treated into CIA mice per day for 35 days, intravital microscopy and immunofluorescence assays were performed to examine immune cell recruitment in the affected joints. Human MH7A synoviocytes were stimulated with tumour necrosis factor (TNF)-α and incubated with FTY720. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) mRNA and protein expression were evaluated using RT-PCR and enzyme-linked immunosorbent assay, respectively. Signal transduction pathway protein expression was measured by Western blotting. Nuclear translocation of nuclear factor (NF)-κB was also analyzed by fluorescence microscopy. Results In vivo experiments showed that FTY720 inhibited the recruitment of CD4+ lymphocytes in the affected joints of CIA mice. FTY720 reduced the secretion of IL-1β, IL-6, and IL-8 from TNF-α-stimulated MH7A cells in a dose-dependent manner. FTY720 also inhibited TNF-α-induced phosphorylation of NF-κBp65 and IκBα, as well as NF-κBp65 nuclear translocation, in a dose- and time-dependent manner. Interestingly, FTY720 blocked PI3K/Akt, the upstream targets of the NF-κB pathway. Conclusion Our findings demonstrated that oral administration of FTY720 exerted beneficial effects in CIA mice by inhibiting CD4+ T lymphocyte recruitment to the affected joints. Our data also indicated that FTY720 inhibited TNF-α-induced inflammation by suppressing the AKT/PI3K/NF-κB pathway in MH7A cells.
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Affiliation(s)
- Chao Zhu
- Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, People's Republic of China.,NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Department of Orthopedics, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, People's Republic of China.,Orthopaedic Research Institution of Hebei Province, Shijiazhuang, People's Republic of China
| | - Shuang Wen
- Department of Immunology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Junyong Li
- Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, People's Republic of China.,NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Orthopaedic Research Institution of Hebei Province, Shijiazhuang, People's Republic of China
| | - Hongyu Meng
- Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, People's Republic of China.,NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Orthopaedic Research Institution of Hebei Province, Shijiazhuang, People's Republic of China
| | - Junzhe Zhang
- Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, People's Republic of China.,NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Orthopaedic Research Institution of Hebei Province, Shijiazhuang, People's Republic of China
| | - Kuo Zhao
- Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, People's Republic of China.,NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Orthopaedic Research Institution of Hebei Province, Shijiazhuang, People's Republic of China
| | - Ling Wang
- Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, People's Republic of China.,NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Orthopaedic Research Institution of Hebei Province, Shijiazhuang, People's Republic of China
| | - Yingze Zhang
- Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, People's Republic of China.,NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.,Orthopaedic Research Institution of Hebei Province, Shijiazhuang, People's Republic of China.,Chinese Academy of Engineering, Beijing, People's Republic of China
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29
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Ciechomska M, Wojtas B, Bonek K, Roszkowski L, Gluszko P, Benes V, Maslinski W. Comprehensive microRNA and transcriptomic profiling of rheumatoid arthritis monocytes: role of microRNA-146b in proinflammatory progression. Rheumatology (Oxford) 2021; 60:5424-5435. [PMID: 34009317 DOI: 10.1093/rheumatology/keab407] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/19/2021] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE To explore global miRNA and transcriptomic profiling of monocytes from rheumatoid arthritis (RA) patients compared with healthy controls (HC) to predict which aberrantly expressed microRNA (miRNA) can negatively modulate inflammatory molecules. METHODS Using next generation sequencing (NGS), we have performed simultaneous global analysis of miRNA (miRNA-seq) and transcriptome (RNA-seq) of monocytes from RA patients, HC. Global analysis of miRNA of systemic sclerosis (SSc) monocytes was also performed. Following differential analysis and negative correlation, miRNA-RNA pairs were selected. RESULTS We found that 20 specific miRNA candidates are predicted to silence inflammatory mediators, out of 191 significantly changed miRNAs in RA monocytes. Based on the highest scoring in terms of negative correlation (r=-0.97, p= 1.75e-07, FDR = 0.04) and the number of seeds in miRNA responsible for negative regulation, we selected miRNA-146b and its target gene anti-inflammatory retinoic acid receptor alpha (RARA). Similarly, to NGS, qPCR analysis also confirmed negative correlation between miRNA-146b and RARA expression (r= -0.45, p= 0.04,). Additionally, miRNA-146b expression in RA monocytes significantly correlated with clinical parameters including disease activity score-28 for RA with c-reactive protein (DAS28-CRP) and erythrocyte sedimentation rate (DAS28-ESR). Whereas overexpression of miRNA-146b was able to functionally reduce RARA expression in THP-1 monocytic cell line. Finally, circulating miRNA-146b expression in sera and synovial fluids was significantly elevated in RA patients. CONCLUSIONS Overall, in this study we have identified a new miRNA-146b candidate which is predicted to negatively regulate anti-inflammatory RARA transcript, whereas circulating miRNA-146b level can be used as a biomarker predicting proinflammatory RA progression and disease activity.
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Affiliation(s)
- Marzena Ciechomska
- National Institute of Geriatrics Rheumatology and Rehabilitation, Warsaw, Poland
| | - Bartosz Wojtas
- Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Krzysztof Bonek
- National Institute of Geriatrics Rheumatology and Rehabilitation, Warsaw, Poland
| | - Leszek Roszkowski
- National Institute of Geriatrics Rheumatology and Rehabilitation, Warsaw, Poland
| | - Piotr Gluszko
- National Institute of Geriatrics Rheumatology and Rehabilitation, Warsaw, Poland
| | - Vladimir Benes
- European Molecular Biology Laboratory, Heidelberg, Germany
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Liu F, Liang Y, Zhao Y, Chen L, Wang X, Zhang C. Meta-analysis of association of microRNAs genetic variants with susceptibility to rheumatoid arthritis and systemic lupus erythematosus. Medicine (Baltimore) 2021; 100:e25689. [PMID: 33907143 PMCID: PMC8084041 DOI: 10.1097/md.0000000000025689] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 02/28/2021] [Accepted: 04/07/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND An increasing body of studies has investigated that genetic polymorphisms in microRNA (miRNA) may be related to susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, some results remain controversial. Thus, a meta-analysis was embarked on assessing whether some miRNA polymorphisms are associated with the risk of RA and SLE. METHODS Relevant studies were acquired on PubMed, Web of Science, Cochrane Library, CNKI, and Embase electronic databases from inception to December 2019. The strength of the association of miRNA polymorphisms with the risk of RA and SLE was assessed by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Eligible 20 articles (36 studies) involving 5 miRNAs were enrolled in the meta-analysis. For RA, the polled result showed that there was no significant relationship between miR-146a rs2910164 and RA, but subgroup analysis based on ethnicity demonstrated that CC genotype may be a genetic protect factor for RA in Caucasians (CC vs CG+GG, OR = 0.825, 95% CI: 0.684-0.996, Pz = .045, Ph = .166). Besides, statistical significance of miR-499 rs3746444 (T/C) with susceptibility to RA was observed as well in the overall population, and the association was only significant in Caucasians but not Asians. For SLE, the associations of miR-146a rs2431697 T allele/T-carrier with increased risk of SLE were observed. CONCLUSIONS Our results highlight that miR-499 rs3746444 may contribute to RA susceptibility, particularly in Caucasians. In addition, CC genotype in miR-146a rs2910164 may act as a protector of RA in Caucasians. For SLE, miR-146a rs2431697 (C/T) is most likely to the increased the risk of SLE. These findings do not support the genetic association between miR-196a2 rs11614913 and RA/SLE susceptibility, as well as the association of miR-146a rs2910164, miR-146a rs57095329, miR-499 rs3746444 with SLE.
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Affiliation(s)
- Fengzhen Liu
- Department of Ultrasound, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Yahang Liang
- Department of General Surgery, Qilu Hospital, Cheeloo College of Medical, Shandong University, Jinan, Shandong, China
| | - Yu Zhao
- Department of Ultrasound, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Lili Chen
- Department of Ultrasound, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Xiaolin Wang
- Department of Ultrasound, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
| | - Chunquan Zhang
- Department of Ultrasound, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi
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31
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Khan MS, Rahman B, Haq TU, Jalil F, Khan BM, Maodaa SN, Al-Farraj SA, El-Serehy HA, Shah AA. Deciphering the Variants Located in the MIR196A2, MIR146A, and MIR423 with Type-2 Diabetes Mellitus in Pakistani Population. Genes (Basel) 2021; 12:genes12050664. [PMID: 33925232 PMCID: PMC8146332 DOI: 10.3390/genes12050664] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/07/2021] [Accepted: 04/09/2021] [Indexed: 12/22/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNA molecules that control the post-transcriptional gene expression. They play a pivotal role in the regulation of important physiological processes. Variations in miRNA genes coding for mature miRNA sequences have been implicated in several diseases. However, the association of variants in miRNAs genes with Type 2 Diabetes Mellitus (T2DM) in the Pakistani population is rarely reported. Therefore, the current study was designed to investigate the association of rs11614913 T/C (MIR196A2), rs2910164 G/C (MIR146A), and rs6505162 C/A (MIR423) in clinicopathological proven T2DM patients and gender-matched healthy controls. The tetra-primer amplification refractory mutation system-polymerase chain (ARMS-PCR) reaction method was used to determine the genotypes and to establish the association of each variant with T2DM through inherited models. In conclusion, the present study showed that variants rs11614913 T/C and rs2910164 G/C were linked with the risk of T2DM. The data suggested that rs11614913 T/C and rs2910164 G/C could be considered as novel risk factors in the pathogenesis of T2DM in the Pakistani population.
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Affiliation(s)
- Muhammad Sohail Khan
- Department of Biotechnology, University of Malakand, Chakdara 18800, Pakistan; (M.S.K.); (B.R.); (T.U.H.)
| | - Bashir Rahman
- Department of Biotechnology, University of Malakand, Chakdara 18800, Pakistan; (M.S.K.); (B.R.); (T.U.H.)
| | - Taqweem Ul Haq
- Department of Biotechnology, University of Malakand, Chakdara 18800, Pakistan; (M.S.K.); (B.R.); (T.U.H.)
| | - Fazal Jalil
- Department of Biotechnology, Abdul Wali Khan University Mardan (AWKUM), Mardan 23200, Pakistan;
| | - Bilal Muhammad Khan
- University Institute of Biochemistry and Biotechnology, Pir Mehr Ali Shah Arid Agriculture University, Rawalpindi 46300, Pakistan;
- National Center of Industrial Biotechnology, Pir Mehr Ali Shah Arid Agriculture University, Rawalpindi 46300, Pakistan
| | - Saleh N. Maodaa
- Department of Zoology, College of Science, King Saud University, Riyadh l1451, Saudi Arabia; (S.N.M.); (S.A.A.-F.); (H.A.E.-S.)
| | - Saleh A. Al-Farraj
- Department of Zoology, College of Science, King Saud University, Riyadh l1451, Saudi Arabia; (S.N.M.); (S.A.A.-F.); (H.A.E.-S.)
| | - Hamed A. El-Serehy
- Department of Zoology, College of Science, King Saud University, Riyadh l1451, Saudi Arabia; (S.N.M.); (S.A.A.-F.); (H.A.E.-S.)
| | - Aftab Ali Shah
- Department of Biotechnology, University of Malakand, Chakdara 18800, Pakistan; (M.S.K.); (B.R.); (T.U.H.)
- Correspondence:
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Wielinska J, Bogunia-Kubik K. miRNAs as potential biomarkers of treatment outcome in rheumatoid arthritis and ankylosing spondylitis. Pharmacogenomics 2021; 22:291-301. [PMID: 33769067 DOI: 10.2217/pgs-2020-0148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Common autoimmune, inflammatory rheumatic diseases including rheumatoid arthritis and ankylosing spondylitis can lead to structural and functional disability, an increase in mortality and a decrease in the quality of a patient's life. To date, the core of available therapy consists of nonsteroidal anti-inflammatory drugs, glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs, like methotrexate. Nowadays, biological therapy including anti-TNF, IL-6 and IL-1 inhibitors, as well as antibodies targeting IL-17 and Janus kinase inhibitors have been found to be helpful in the management of rheumatic conditions. The review provides a summary of the current therapy strategies with a focus on miRNA, which is considered to be a potential biomarker and possible answer to the challenges in the prediction of treatment outcome in patients with rheumatoid arthritis and ankylosing spondylitis.
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Affiliation(s)
- Joanna Wielinska
- Laboratory of Clinical Immunogenetics & Pharmacogenetics, Hirszfeld Institute of Immunology & Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114 Wroclaw, Poland
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics & Pharmacogenetics, Hirszfeld Institute of Immunology & Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114 Wroclaw, Poland
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Cunningham CC, Wade S, Floudas A, Orr C, McGarry T, Wade S, Cregan S, Fearon U, Veale DJ. Serum miRNA Signature in Rheumatoid Arthritis and "At-Risk Individuals". Front Immunol 2021; 12:633201. [PMID: 33746971 PMCID: PMC7966707 DOI: 10.3389/fimmu.2021.633201] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/11/2021] [Indexed: 12/15/2022] Open
Abstract
Background MicroRNAs (miRNAs) are small non-coding RNAs which have been implicated as potential biomarkers or therapeutic targets in autoimmune diseases. This study examines circulatory miRNAs in RA patients and further investigates if a serum miRNA signature precedes clinical manifestations of disease in arthralgia or “at-risk individuals”. Methods Serum was collected from HC subjects (N = 20), RA patients (N = 50), and arthralgia subjects (N = 10), in addition to a subgroup of the RA patients post-methotrexate (MTX) (N = 18). The FirePlex miRNA Immunology-V2 panel was selected for multiplex analysis of 68 miRNAs in each sample. DNA intelligent analysis (DIANA)-mirPath and Ingenuity Pathway Analysis (IPA) software were used to predict pathways targeted by the dysregulated miRNAs. Results 8 miRNA (miR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p, miR-339-5p, let-7i-5p) were significantly elevated in RA serum compared to HC (all p < 0.01) and 1 miRNA (miR-17-5p) was significantly lower in RA (p < 0.01). High specificity and sensitivity were determined by receiver operating characteristic (ROC) curve analysis. Both miR-339-5p and let-7i-5p were significantly reduced post-MTX (both p < 0.01). MiR-126-3p, let-7d-5p, miR-431-3p, miR-221-3p, miR-24-3p, miR-130a-3p were also significantly elevated in subjects “at risk” of developing RA (all p < 0.05) compared to HC. IPA analysis of this miRNA signature identified downstream targets including key transcription factors NF-κB, STAT-1, STAT-3, cytokines IL-1β, TNF-α, and matrix-metalloproteases all importantly associated with RA pathogenesis. Conclusion This study identified six miRNAs that are altered in both RA and “at-risk individuals,” which potentially regulate key downstream pathways involved in regulating inflammation. These may have potential as predictive signature for disease onset and early progression.
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Affiliation(s)
- Clare C Cunningham
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland.,EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
| | - Sarah Wade
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland.,EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
| | - Achilleas Floudas
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland.,EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
| | - Carl Orr
- EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
| | - Trudy McGarry
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland.,EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
| | - Siobhan Wade
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland.,EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
| | - Sian Cregan
- EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
| | - Ursula Fearon
- Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland.,EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
| | - Douglas J Veale
- EUropean League Against Rheumatism (EULAR) Centre of Excellence, Centre for Arthritis & Rheumatic Diseases, University College Dublin, Dublin, Ireland
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Shi C, Rattray M, Barton A, Bowes J, Orozco G. Using functional genomics to advance the understanding of psoriatic arthritis. Rheumatology (Oxford) 2021; 59:3137-3146. [PMID: 32778885 PMCID: PMC7590405 DOI: 10.1093/rheumatology/keaa283] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/17/2020] [Accepted: 04/28/2020] [Indexed: 01/03/2023] Open
Abstract
Psoriatic arthritis (PsA) is a complex disease where susceptibility is determined by genetic and environmental risk factors. Clinically, PsA involves inflammation of the joints and the skin, and, if left untreated, results in irreversible joint damage. There is currently no cure and the few treatments available to alleviate symptoms do not work in all patients. Over the past decade, genome-wide association studies (GWAS) have uncovered a large number of disease-associated loci but translating these findings into functional mechanisms and novel targets for therapeutic use is not straightforward. Most variants have been predicted to affect primarily long-range regulatory regions such as enhancers. There is now compelling evidence to support the use of chromatin conformation analysis methods to discover novel genes that can be affected by disease-associated variants. Here, we will review the studies published in the field that have given us a novel understanding of gene regulation in the context of functional genomics and how this relates to the study of PsA and its underlying disease mechanism.
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Affiliation(s)
- Chenfu Shi
- Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, Centre for Genetics and Genomics Versus Arthritis
| | - Magnus Rattray
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester.,NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre
| | - Anne Barton
- Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, Centre for Genetics and Genomics Versus Arthritis.,NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre.,Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - John Bowes
- Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, Centre for Genetics and Genomics Versus Arthritis.,NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre
| | - Gisela Orozco
- Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, Centre for Genetics and Genomics Versus Arthritis.,NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre.,Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Bonek K, Roszkowski L, Massalska M, Maslinski W, Ciechomska M. Biologic Drugs for Rheumatoid Arthritis in the Context of Biosimilars, Genetics, Epigenetics and COVID-19 Treatment. Cells 2021; 10:323. [PMID: 33557301 PMCID: PMC7914976 DOI: 10.3390/cells10020323] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/24/2021] [Accepted: 01/30/2021] [Indexed: 01/08/2023] Open
Abstract
Rheumatoid arthritis (RA) affects around 1.2% of the adult population. RA is one of the main reasons for work disability and premature retirement, thus substantially increasing social and economic burden. Biological disease-modifying antirheumatic drugs (bDMARDs) were shown to be an effective therapy especially in those rheumatoid arthritis (RA) patients, who did not adequately respond to conventional synthetic DMARD therapy. However, despite the proven efficacy, the high cost of the therapy resulted in limitation of the widespread use and unequal access to the care. The introduction of biosimilars, which are much cheaper relative to original drugs, may facilitate the achievement of the therapy by a much broader spectrum of patients. In this review we present the properties of original biologic agents based on cytokine-targeted (blockers of TNF, IL-6, IL-1, GM-CSF) and cell-targeted therapies (aimed to inhibit T cells and B cells properties) as well as biosimilars used in rheumatology. We also analyze the latest update of bDMARDs' possible influence on DNA methylation, miRNA expression and histone modification in RA patients, what might be the important factors toward precise and personalized RA treatment. In addition, during the COVID-19 outbreak, we discuss the usage of biologicals in context of effective and safe COVID-19 treatment. Therefore, early diagnosing along with therapeutic intervention based on personalized drugs targeting disease-specific genes is still needed to relieve symptoms and to improve the quality of life of RA patients.
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Affiliation(s)
- Krzysztof Bonek
- Department of Rheumatology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (K.B.); (L.R.)
| | - Leszek Roszkowski
- Department of Rheumatology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (K.B.); (L.R.)
| | - Magdalena Massalska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (M.M.); (W.M.)
| | - Wlodzimierz Maslinski
- Department of Pathophysiology and Immunology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (M.M.); (W.M.)
| | - Marzena Ciechomska
- Department of Pathophysiology and Immunology, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-635 Warsaw, Poland; (M.M.); (W.M.)
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NFKB1 promoter -94 insertion/deletion ATTG polymorphism (rs28362491) is associated with severity and disease progression of rheumatoid arthritis through interleukin-6 levels modulation in Egyptian patients. Clin Rheumatol 2021; 40:2927-2937. [PMID: 33459954 DOI: 10.1007/s10067-021-05584-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/30/2020] [Accepted: 01/10/2021] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Rheumatoid arthritis (RA) is an inflammatory autoimmune disorder, which can cause progressive and functional disability. Previous data suggests that some inflammatory cytokines are dysregulated in patients with RA. Polymorphisms in the NFKB1 gene were studied in different populations with RA. Specific studies showed that the NFKB1 promoter -94ins/delATTG (rs28362491) polymorphism appears to be correlated with alterations in the IL-6 expression and may lead to disease development. We aimed to evaluate the association between the NFKB1 -94ins/delATTG polymorphism and biochemical, and clinical markers for severity of RA in Egyptian patients. METHODS Study subjects included 196 RA patients from the Egyptian population. NFKB1 -94ins/delATTG polymorphism was genotyped by real-time PCR using the TaqMan assay. Concentrations of plasma IL-6 were assessed using the ELISA method. RESULTS The frequencies of (del/del + ins/del) genotype in cases with erosive arthritis were significantly increased as compared to cases with non-erosive arthritis (63.0% vs. 47.7%, OR = 1.86, 95% CI: 1.05-3.30, p: 0.043). Carriers of del allele had high activity and severity markers compared with those of ins/ins genotype. The del allele was significantly associated with higher IL-6 levels in a dose-dependent manner. Plasma levels of IL-6 were significantly higher in the del/del (41.4 ± 16.2 pg/ml) and ins/del (19.1 ± 12.4 pg/ml) genotype when compared with the ins/ins genotype (11.4 ± 4.21 pg/ml). In a multivariate analysis of variance, including confounding factors associated with higher IL-6 levels (RF, disease duration, and DAS28), the NFKB1 -94ins/delATTG polymorphism retained its role. Logistic regression analyses revealed that high IL-6 plasma levels independently associated with an increased risk of presenting erosive RA, while -94ins/delATTG polymorphism has no direct association with the progression of erosive arthritis. CONCLUSION Our data indicate that the NFKB1 -94ins/delATTG polymorphism contributes to the severity and progression of RA through IL-6 levels modulation in Egyptian patients. Key Points • Carriers of del allele had high activity and severity markers compared with those of ins/ins genotype. • In RA patients, the del allele was significantly associated with higher IL-6 levels in a dose-dependent manner. • IL-6 plasma levels are independently associated with an increased risk of presenting erosive arthritis. • The NFKB1 -94ins/delATTG polymorphism contributes to the severity and progression of RA through IL-6 levels modulation in Egyptian patients.
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Chen W, Ji L, Wei Z, Yang C, Chang S, Zhang Y, Nie K, Jiang L, Deng Y. miR-146a-3p suppressed the differentiation of hAMSCs into Schwann cells via inhibiting the expression of ERBB2. Cell Tissue Res 2021; 384:99-112. [PMID: 33447879 PMCID: PMC8016804 DOI: 10.1007/s00441-020-03320-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 10/12/2020] [Indexed: 02/07/2023]
Abstract
Human amniotic mesenchymal stem cells (hAMSCs) can be differentiated into Schwann-cell-like cells (SCLCs) in vitro. However, the underlying mechanism of cell differentiation remains unclear. In this study, we explored the phenotype and multipotency of hAMSCs, which were differentiated into SCLCs, and the expression of nerve repair-related Schwann markers, such as S100 calcium binding protein B (S-100), TNF receptor superfamily member 1B (P75), and glial fibrillary acidic protein (GFAP) were observed to be significantly increased. The secreted functional neurotrophic factors, like brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), were determined and also increased with the differentiation time. Moreover, miR-146a-3p, which significantly decreased during the differentiation of hAMSCs into SCLCs, was selected by miRNA-sequence analysis. Further molecular mechanism studies showed that Erb-B2 receptor tyrosine kinase 2 (ERBB2) was an effective target of miR-146a-3p and that miR-146a-3p down-regulated ERBB2 expression by binding to the 3'-UTR of ERBB2. The expression of miR-146a-3p markedly decreased, while the mRNA levels of ERBB2 increased with the differentiation time. The results showed that down-regulating miR-146a-3p could promote SC lineage differentiation and suggested that miR-146a-3p negatively regulated the Schwann-like phenotype differentiation of hAMSCs by targeting ERBB2. The results will be helpful to establish a deeper understanding of the underlying mechanisms and find novel strategies for cell therapy.
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Affiliation(s)
- Wei Chen
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China
| | - Linlin Ji
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China
| | - Zairong Wei
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China.
| | - Chenglan Yang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China
| | - Shusen Chang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China
| | - Yucheng Zhang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China
| | - Kaiyu Nie
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China
| | - Lingli Jiang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China
| | - Yurong Deng
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical College, 149 Dalian Road, Guizhou, Zunyi, China
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Qiu M, Li T, Wang B, Gong H, Huang T. miR-146a-5p Regulated Cell Proliferation and Apoptosis by Targeting SMAD3 and SMAD4. Protein Pept Lett 2020; 27:411-418. [PMID: 31544687 PMCID: PMC7460735 DOI: 10.2174/0929866526666190911142926] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 05/06/2019] [Accepted: 06/24/2019] [Indexed: 12/19/2022]
Abstract
Background: microRNAs (miRNAs) are a small, endogenous non-coding RNAs that are involved in post-transcriptional gene regulation of many biological processes, including embryo implantation and placental development. In our previous study, miR-146a-5p was found expressed higher in the serum exosomes of pregnant sows than non-pregnant. The research on miR-146a-5p has been mainly related to human diseases, but there are few studies on its effects on the reproduction of sows in early pregnancy. Objective: In this article, our motivation is to study the role of miR-146a-5p in the early pregnancy of sows on the cell proliferetion and apoptosis by targeting SMAD3 and SMAD4. Methods: Bioinformatics software was used to identify the target genes of miR-146a-5p. The wild-type and mutant-type recombinant plasmids of dual-luciferase reporter with 3'-UTR of Smad3 or 3'-UTR of Smad4 were constructed, and co-transfected in porcine kidney cell (PK-15 cell) with miR-146a-5p mimic, mimic-NC(M-NC), inhibitor and inhibitor-NC(IN-NC), then dual-luciferase activity analysis, qRT-PCR and Western blot were performed to verify the target genes. After the transfection of BeWo choriocarcinoma cell (BeWo cell) with miR-146a-5p mimic, M-NC, inhibitor and IN-NC, the mRNA expression of Caspase-3, BAX and Bcl-2 was measured using qRT-PCR, and the cell proliferation was measured using CCK-8 kit. Results: The luciferase, mRNA and protein expression of Smad3 in PK-15 cells treated by Smad3-3'-UTR-W co-transfected with miR-146a-5p mimic were significantly lower than that with miR-146a-5p M-NC, and the results of Smad4 were similar to Smad3, but the protein expression had a trend to lower in mimic group. The expression level of Bcl-2 in the miR-146a-5p mimic group was significantly lower than that in the miR-146a-5p M-NC group, but the expression pattern of Caspase-3 was just opposite. The mimic of miR-146a-5p reduced the proliferation of BeWo cells, however the inhibitor increased. Conclusion: Smad3 and Smad4 are the direct target genes of miR-146a-5p. The expression of Smad3 and Smad4 were affected by the mimic and inhibitor of miR-146a-5p. miR-146a-5p affects cell apoptosis and proliferation by regulating their target genes. This study provided new data to understand the regulation mechanism of early pregnancy in sows.
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Affiliation(s)
- Meiyu Qiu
- College of Animal Science and Technology, Shihezi University, Shihezi 832000, China.,Institute of Biotechnology, Xinjiang Academy of Animal Science, Urumqi 830000, China
| | - Tao Li
- College of Animal Science and Technology, Shihezi University, Shihezi 832000, China.,Animal Husbandry General Station of Yili Prefecture, Yili 835000, China
| | - Binhu Wang
- College of Animal Science and Technology, Shihezi University, Shihezi 832000, China
| | - Hongbin Gong
- College of Animal Science and Technology, Shihezi University, Shihezi 832000, China
| | - Tao Huang
- College of Animal Science and Technology, Shihezi University, Shihezi 832000, China
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39
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Culibrk RA, Hahn MS. The Role of Chronic Inflammatory Bone and Joint Disorders in the Pathogenesis and Progression of Alzheimer's Disease. Front Aging Neurosci 2020; 12:583884. [PMID: 33364931 PMCID: PMC7750365 DOI: 10.3389/fnagi.2020.583884] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/06/2020] [Indexed: 12/12/2022] Open
Abstract
Late-onset Alzheimer's Disease (LOAD) is a devastating neurodegenerative disorder that causes significant cognitive debilitation in tens of millions of patients worldwide. Throughout disease progression, abnormal secretase activity results in the aberrant cleavage and subsequent aggregation of neurotoxic Aβ plaques in the cerebral extracellular space and hyperphosphorylation and destabilization of structural tau proteins surrounding neuronal microtubules. Both pathologies ultimately incite the propagation of a disease-associated subset of microglia-the principle immune cells of the brain-characterized by preferentially pro-inflammatory cytokine secretion and inhibited AD substrate uptake capacity, which further contribute to neuronal degeneration. For decades, chronic neuroinflammation has been identified as one of the cardinal pathophysiological driving features of AD; however, despite a number of works postulating the underlying mechanisms of inflammation-mediated neurodegeneration, its pathogenesis and relation to the inception of cognitive impairment remain obscure. Moreover, the limited clinical success of treatments targeting specific pathological features in the central nervous system (CNS) illustrates the need to investigate alternative, more holistic approaches for ameliorating AD outcomes. Accumulating evidence suggests significant interplay between peripheral immune activity and blood-brain barrier permeability, microglial activation and proliferation, and AD-related cognitive decline. In this work, we review a narrow but significant subset of chronic peripheral inflammatory conditions, describe how these pathologies are associated with the preponderance of neuroinflammation, and posit that we may exploit peripheral immune processes to design interventional, preventative therapies for LOAD. We then provide a comprehensive overview of notable treatment paradigms that have demonstrated considerable merit toward treating these disorders.
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Affiliation(s)
| | - Mariah S. Hahn
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States
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40
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Le CT, Nguyen TL, Nguyen TD, Nguyen TA. Human disease-associated single nucleotide polymorphism changes the orientation of DROSHA on pri-mir-146a. RNA (NEW YORK, N.Y.) 2020; 26:1777-1786. [PMID: 32994184 PMCID: PMC7668254 DOI: 10.1261/rna.077487.120] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 09/25/2020] [Indexed: 06/04/2023]
Abstract
The Microprocessor complex of DROSHA and DGCR8 initiates the biosynthesis of microRNAs (miRNAs) by processing primary miRNAs (pri-miRNAs). The Microprocessor can be oriented on pri-miRNAs in opposite directions to generate productive and unproductive cleavages at their basal and apical junctions, respectively. However, only the productive cleavage gives rise to miRNAs. A single nucleotide polymorphism (SNP, rs2910164) in pri-mir-146a is associated with various human diseases. Although this SNP was found to reduce the expression of miRNA, it is still not known if it affects the activity of the Microprocessor directly, and how it functions. In this study, we revealed that the SNP creates an unexpected mGHG motif at the apical junction of pri-mir-146a. This mGHG motif interacts with the double-stranded RNA-binding domain (dsRBD) of DROSHA, switching its orientation on pri-mir-146a from the basal to the apical junction. As a result, the SNP facilitates Microprocessor to cleave SNP-pri-mir-146a at its unproductive sites. Our findings help to elucidate the molecular mechanism that explains how the disease-associated SNP modulates the biogenesis of pri-mir-146a and thereby affects its cellular functions.
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Affiliation(s)
- Cong Truc Le
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Thuy Linh Nguyen
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Trung Duc Nguyen
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Tuan Anh Nguyen
- Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China
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41
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Mignot S, Cagnard N, Albaud B, Bally C, Siavellis J, Hermine O, Frenzel L. Unique inflammatory signature in haemophilic arthropathy: miRNA changes due to interaction between blood and fibroblast-like synoviocytes. J Cell Mol Med 2020; 24:14453-14466. [PMID: 33159500 PMCID: PMC7753994 DOI: 10.1111/jcmm.16068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 10/15/2020] [Accepted: 10/16/2020] [Indexed: 11/19/2022] Open
Abstract
In haemophilia, the recurrence of hemarthrosis leads to irreversible arthropathy termed haemophilic arthropathy (HA). However, HA is a unique form of arthropathy in which resident cells, such as fibroblast‐like synoviocytes (FLS), come into direct contact with blood. Therefore, we hypothesized that FLS in HA could have a unique inflammatory signature as a consequence of their contact with blood. We demonstrated with ELISA and ELISPOT analyses that HA‐FLS expressed a unique profile of cytokine secretion, which differed from that of non‐HA‐FLS, mainly consisting of cytokines involved in innate immunity. We showed that unstable cytokine mRNAs were involved in this process, especially through miRNA complexes as confirmed by DICER silencing. A miRNOME analysis revealed that 30 miRNAs were expressed differently between HA and non‐HA‐FLS, with most miRNAs involved in inflammatory control pathways or described in certain inflammatory diseases, such as rheumatoid arthritis or lupus. Analysis of transcriptomic networks, impacted by these miRNAs, revealed that protein processes and inflammatory pathways were particularly targeted in LPS‐induced FLS, and in particular vascularization and osteoarticular modulation pathways in steady‐state FLS. Our study demonstrates that the presence of blood in contact with FLS may induce durable miRNA changes that likely participate in HA pathophysiology.
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Affiliation(s)
- Sandra Mignot
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris Descartes - Sorbonne Paris Cité University, Labex GR-Ex, Imagine Institute, Inserm U1163, Paris, France
| | | | | | - Cécile Bally
- Hematology unit care - hemophilia Center - Necker Hospital, Paris, France
| | - Justine Siavellis
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris Descartes - Sorbonne Paris Cité University, Labex GR-Ex, Imagine Institute, Inserm U1163, Paris, France
| | - Olivier Hermine
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris Descartes - Sorbonne Paris Cité University, Labex GR-Ex, Imagine Institute, Inserm U1163, Paris, France.,Hematology unit care - hemophilia Center - Necker Hospital, Paris, France.,Faculté de médecine Paris-Descartes, Paris, France
| | - Laurent Frenzel
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Paris Descartes - Sorbonne Paris Cité University, Labex GR-Ex, Imagine Institute, Inserm U1163, Paris, France.,Hematology unit care - hemophilia Center - Necker Hospital, Paris, France.,Faculté de médecine Paris-Descartes, Paris, France
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Taheri M, Eghtedarian R, Dinger ME, Ghafouri-Fard S. Dysregulation of non-coding RNAs in Rheumatoid arthritis. Biomed Pharmacother 2020; 130:110617. [DOI: 10.1016/j.biopha.2020.110617] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/26/2020] [Accepted: 08/02/2020] [Indexed: 02/07/2023] Open
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Liu X, Liu B, Li R, Wang F, Wang N, Zhang M, Bai Y, Wu J, Liu L, Han D, Li Z, Feng B, Zhou G, Wang S, Zeng L, Miao J, Yao Y, Liang B, Huang L, Wang Q, Wu Y. miR-146a-5p Plays an Oncogenic Role in NSCLC via Suppression of TRAF6. Front Cell Dev Biol 2020; 8:847. [PMID: 33015045 PMCID: PMC7493784 DOI: 10.3389/fcell.2020.00847] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most deadly cancer in the world due to its often delayed diagnosis. Identification of biomarkers with high sensitivity, specificity, and accessibility for early detection, such as circulating microRNAs, is therefore of utmost importance. In the present study, we identified a significantly higher expression of miR-146a-5p in the serum and tissue samples of NSCLC patients than that of the healthy controls. In parallel, miR-146a-5p was also highly expressed in three human NSCLC adenocarcinoma-cell lines (A549, H1299, and H1975) compared to the human bronchial epithelium cell line (HBE). By dual-luciferase reporter assay and manipulation of the expressions of miR-146a-5p and its target gene, tumor necrosis factor receptor-associated factor 6 (TRAF6), we showed that the functional effects of miR-146a-5p on NSCLC cell survival and migration were mediated by direct binding to and suppression of TRAF6. Overexpression of TRAF6 sufficiently reversed miR-146a-5p-induced cancer cell proliferation, migration, and apoptosis resistance. Our data implied that miR-146a-5p/TRAF6/NF-κB-p65 axis could be a promising diagnostic marker and a therapeutic target for NSCLC.
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Affiliation(s)
- Xiangdong Liu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Bo Liu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Ruihua Li
- Department of Clinical Laboratory, Second Affiliated Hospital of Dalian Medical University, Liaoning, China
| | - Fei Wang
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Ning Wang
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Maihe Zhang
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Yang Bai
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Liaoning, China
| | - Jin Wu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Liping Liu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Dongyu Han
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Zhiguang Li
- Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian, China
| | - Bin Feng
- Department of Biotechnology, Dalian Medical University, Dalian, China
| | - Guangbiao Zhou
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Shujing Wang
- Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China.,Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, China
| | - Li Zeng
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China
| | - Jian Miao
- Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Liaoning, China
| | - Yiqun Yao
- Department of Thyroid and Breast Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Bin Liang
- School of Life Sciences, Yunnan University, Kunming, China
| | - Lin Huang
- Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China.,Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Qi Wang
- Department of Respiratory Medicine, Second Affiliated Hospital of Dalian Medical University, Liaoning, China
| | - Yingjie Wu
- Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian, China.,National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, China.,Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, Dalian, China.,Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, United States.,Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Mortazavi-Jahromi SS, Aslani M, Mirshafiey A. A comprehensive review on miR-146a molecular mechanisms in a wide spectrum of immune and non-immune inflammatory diseases. Immunol Lett 2020; 227:8-27. [PMID: 32810557 DOI: 10.1016/j.imlet.2020.07.008] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/10/2020] [Accepted: 07/21/2020] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are single-strand endogenous and non-coding RNA molecules with a length of about 22 nucleotides, which regulate genes expression, through modulating the translation and stability of their target mRNAs. miR-146a is one of the most studied miRNAs, due to its central role in immune system homeostasis and control of the innate and acquired immune responses. Accordingly, abnormal expression or function of miR-146a results in the incidence and progression of immune and non-immune inflammatory diseases. Its deregulated expression pattern and inefficient function have been reported in a wide spectrum of these illnesses. Based on the existing evidence, this miRNA qualifies as an ideal biomarker for diagnosis, prognosis, and activity evaluation of immune and non-immune inflammatory disorders. Moreover, much attention has recently been paid to therapeutic potential of miR-146a and several researchers have assessed the effects of different drugs on expression and function of this miRNA at diverse experimental, animal, besides human levels, reporting motivating results in the treatment of the diseases. Here, in this comprehensive review, we provide an overview of miR-146a role in the pathogenesis and progression of several immune and non-immune inflammatory diseases such as Rheumatoid arthritis, Systemic lupus erythematosus, Inflammatory bowel disease, Multiple sclerosis, Psoriasis, Graves' disease, Atherosclerosis, Hepatitis, Chronic obstructive pulmonary disease, etc., discuss about its eligibility for being a desirable biomarker for these disorders, and also highlight its therapeutic potential. Understanding these mechanisms underlies the selecting and designing the proper therapeutic targets and medications, which eventually facilitate the treatment process.
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Affiliation(s)
| | - Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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Mortazavi-Jahromi SS, Ahmadzadeh A, Rezaieyazdi Z, Aslani M, Omidian S, Mirshafiey A. The role of β-d-mannuronic acid, as a new non-steroidal anti-inflammatory drug on expression of miR-146a, IRAK1, TRAF6, NF-κB and pro-inflammatory cytokines following a clinical trial in rheumatoid arthritis patients. Immunopharmacol Immunotoxicol 2020; 42:228-236. [DOI: 10.1080/08923973.2020.1742734] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
| | - Arman Ahmadzadeh
- Department of Rheumatology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Rezaieyazdi
- Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Aslani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Saiedeh Omidian
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Mirshafiey
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Zhao J, Chen B, Peng X, Wang C, Wang K, Han F, Xu J. Quercetin suppresses migration and invasion by targeting miR-146a/GATA6 axis in fibroblast-like synoviocytes of rheumatoid arthritis. Immunopharmacol Immunotoxicol 2020; 42:221-227. [PMID: 32216502 DOI: 10.1080/08923973.2020.1742732] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background: Rheumatoid arthritis (RA) is a systematic autoimmune disease which may lead to joint dysfunction and disability. Aberrant migration and invasion of fibroblast-like synoviocytes (FLSs) is one of the most predominant etiopathogenesis of RA. Quercetin is a bioflavonoid which is implicated in the development of RA, yet its role in regulating the migration and invasion of FLSs is still elusive. The aim of this study is to investigate the impact of quercetin treatment on migration and invasion of FLSs and the underlying mechanism.Methods: Capacity of migration and invasion of FLSs were assessed using transwell assay. Immunofluorescence assay was used to determine the expression of F-actin. The RNA levels of miR-146a and GATA transcription factor 6 (GATA6) were measured using quantitative real-time PCR. Western blot was used to examine the protein level of GATA6. The correlation between miR-146a and GATA6 was validated using luciferase reporter assay.Results: Transwell assay revealed that the migration and invasion of FLSs were significantly inhibited after quercetin treatment, which was also proved by decreased expression of F-actin. The RNA level of miR-146a was decreased in RA tissues and was negatively related to the expression of GATA transcription factor 6 (GATA6). Quercetin treatment elevated the RNA level of miR-146a, but suppressed the expression of GATA6 in FLSs. Further luciferase reporter assay validated that GATA6 is a downstream target of miR-146a. Besides, miR-146a inhibited the migration and invasion of FLSs, and further GATA6 over-expression abrogated the miR-146a-induced inhibition. In addition, specific anti-miR-146a inhibitor abolished quercetin-mediated suppression of migration and invasion of FLSs.Conclusion: Our study suggested that quercetin suppresses the migration and invasion of FLSs via regulating the miR-146a/GATA6 axis.
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Affiliation(s)
- Jinying Zhao
- Department of Rheumatism and Immunology, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Bo Chen
- Department of Emergency, The 940th Hospital of Joint logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Xiaodong Peng
- Department of Pharmacology, Ningxia Medical University, Ningxia Hui Autonomous Region, Yinchuan, China
| | - Chunyu Wang
- Department of Rheumatism and Immunology, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Kejing Wang
- Department of Rheumatism and Immunology, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Fengxia Han
- Department of Rheumatism and Immunology, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
| | - Jin Xu
- Department of Rheumatism and Immunology, The 940th Hospital of Joint Logistics Support Force of People's Liberation Army, Lanzhou, China
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Papathanasiou I, Mourmoura E, Balis C, Tsezou A. Impact of miR-SNP rs2910164 on miR-146a expression in osteoarthritic chondrocytes. Adv Med Sci 2020; 65:78-85. [PMID: 31918067 DOI: 10.1016/j.advms.2019.12.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 04/04/2019] [Accepted: 12/15/2019] [Indexed: 12/17/2022]
Abstract
PURPOSE MiR-146a acts as a negative inflammatory mediator in different diseases and has been implicated in osteoarthritis (OA) pathogenesis. In our study, we investigated the association between miR-SNP rs2910164 and OA susceptibility and its role on the expression of miR-146a, inflammatory and catabolic mediators in osteoarthritic chondrocytes. MATERIALS AND METHODS Genetic association analysis was performed in 1688 knee OA patients and healthy individuals of Greek origin. Genomic DNA was extracted from blood and genotyped for rs2910164 (G > C) using Restriction-Fragment Length Polymorphism (RFLP). Total RNA was extracted from chondrocytes of 18 OA patients and miR-146a, IL-1 Receptor-Associated Kinase 1 (IRAK-1), TNF Receptor-Associated Factor 6 (TRAF-6), A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS-5), Matrix Metalloproteinase-13 (MMP-13), Interleukin-6 (IL-6), Interleukin-1 Beta (IL-1β) and Tumor Necrosis Factor-Alpha (TNF-α) expression was evaluated using quantitative Real-Time PCR (qRT-PCR). RESULTS OA patients carrying rs2910164-GC and CC genotypes did not have an increased risk for OA development compared to GG genotype carriers. MiR-146a expression in OA chondrocytes was significantly lower in patients with rs2910164-GC genotype than in the GG carriers. OA patients carrying the rs2910164-GC genotype in their chondrocytes exhibited increased IRAK-1, TRAF-6, MMP-13, IL-1β and IL-6 expression levels compared with rs2910164-GG carriers. CONCLUSION We demonstrate, for the first time, that miR-SNP rs2910164 in miR-146a gene is associated with reduced miR-146a and increased inflammatory and catabolic mediators' expression in OA chondrocytes. Our data imply that genetic variations in miRNAs linked to OA pathogenesis may regulate their expression levels, suggesting new therapeutic strategies for patients with cartilage diseases.
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Gomes da Silva IIF, Lima CAD, Monteiro MLA, Barboza DASP, Rushansky E, Mariano MHQDA, Sandrin-Garcia P, de Souza PRE, Maia MDMD. IL1β, IL18, NFKB1 and IFNG gene interactions are associated with severity of rheumatoid arthritis: A pilot study. Autoimmunity 2020; 53:95-101. [PMID: 31992083 DOI: 10.1080/08916934.2019.1710831] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease which can lead to progressive and functional disability. Literature data suggest that some inflammatory proteins are dysregulated in RA patients and its genetic polymorphisms may contribute to the aetiology and pathogenesis of disease in different ethnic groups. Polymorphisms in IL1β, IL18, NFKB1 and IFNG genes were studied in different populations with RA, but the analysis indicated contradictory results. Thereby, we hypothesised that polymorphisms in these genes could have a combined effect on susceptibility to and severity of disease. We evaluated the +3953 C/T IL1β (rs1143634), -137 G/C IL18 (rs187238), -94 ins/del ATTG NFKB1 (rs28362491) and +874 T/A IFNG (rs2430561) polymorphisms in the northeastern Brazilian population. Peripheral blood samples were collected and DNA extraction was conducted. The polymorphisms were evaluated by RFLP and ARMS-PCR. An association was observed in rs1143634 which showed a protective effect against development of RA in carriers of the T allele (OR = 0.58; 95% CI 0.36-0.92; p = .020). In addition, we found an association among genotypes of the rs1143634 with the HAQ index (p = .021) and rs2430561 with DAS28 (p = .029) and CDAI (p = .029). In relation to combined effects of these SNPs (C/C to rs1143634, G/G to rs187238, I/I to rs28362491 and AA to rs2430561) we found a significant association with decreased functional disability (HAQ index p < .001) and ESR (p = .034), indicating a lower disease activity in carriers of these genotypes. GLM analysis confirmed these associations (HAQ (F = 5.497; p < .001) and ESR (F = 2.727; p = .032)). Our analysis indicated that in the studied population +3953 C/T IL-1β (rs1143634), -137 G/C IL-18 (rs187238), -94 ins/del ATTG NFKB1 (rs28362491) and +874 T/A IFNG (rs2430561) polymorphisms can together contribute to RA severity although they do not individually influence the disease.
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Affiliation(s)
| | - Camilla Albertina Dantas Lima
- Laboratory of Immunopathology Keizo Asami, Recife, Brazil.,Department of Oceanography, Federal University of Pernambuco, Recife, Brazil
| | | | | | - Eliezer Rushansky
- Division of Clinical Rheumatology, University of Pernambuco, Recife, Brazil
| | | | - Paula Sandrin-Garcia
- Department of Genetics, Federal University of Pernambuco, Recife, Brazil.,Laboratory of Immunopathology Keizo Asami, Recife, Brazil
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Zhang L, Wu H, Zhao M, Lu Q. Identifying the differentially expressed microRNAs in autoimmunity: A systemic review and meta-analysis. Autoimmunity 2020; 53:122-136. [DOI: 10.1080/08916934.2019.1710135] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Lian Zhang
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Central South University, Changsha, China
| | - Haijing Wu
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Central South University, Changsha, China
| | - Ming Zhao
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Central South University, Changsha, China
| | - Qianjin Lu
- Hunan Key Laboratory of Medical Epigenomics, Department of Dermatology, Central South University, Changsha, China
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Mossallam GI, Fattah RA, Mahmoud HK. Nuclear factor-κB1 and MicroRNA-146a polymorphisms and risk of acute graft versus host disease post allogeneic stem cell transplantation. Immunobiology 2019; 225:151876. [PMID: 31813598 DOI: 10.1016/j.imbio.2019.11.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 11/18/2019] [Accepted: 11/26/2019] [Indexed: 12/22/2022]
Abstract
Acute graft-versus-host disease (aGVHD) is a severe inflammatory complication of haematopoeitic stem cell transplantation. The nuclear factor- Kappa Beta (NF-κB) signaling pathway regulates T cell activation. The NF-κB controls the expression of microRNA-146a (miR-146a) that in turn regulates NF-κB activation through a negative feedback loop. We aim to analyze the association between NF-κB1 encoding p50 (rs28362491, -94 in.ertion/deletion ATTG) and miR-146a (rs2910164, G > C) polymorphisms and risk of aGVHD. Genotyping was performed for 135 HLA-matched donors using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP).The incidence of aGVHD grades II-IV was 24/135 (17.8 %). NF-κB1 genotype and cytomegalovirus infection were significantly associated with risk of aGVHD II-IV (p = 0.022, HR = 3.17, 95 % CI:1.18-8.51 and p = 0.048, HR = 2.56, 95 % CI:1.01-6.52, respectively). In multivariate analysis, NF-κB1homozygous deletion/deletion genotype was the only independent risk factor associated with aGVHD II-IV (p = 0.013, HR = 3.50, 95 % CI:1.30-9.44). No significant association could be observed between miR-146a polymorphism and aGVHD. Combined NF-κB1 and miR146a genotype analysis warrants investigation in a larger cohort. Our preliminary data do not support the association between miR146a and aGVHD, but suggest an association between NF-κB1 and risk of aGVHD that may pave the way for the development of a novel targeted therapy if proved in a larger cohort.
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Affiliation(s)
- Ghada I Mossallam
- Bone Marrow Transplantation Laboratory Unit, National Cancer Institute, Cairo University, Cairo, Egypt.
| | - Raafat Abdel Fattah
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt Bone Marrow Transplantation Unit, Nasser Institute Hospital for Research and Treatment, Cairo, Egypt
| | - Hossam K Mahmoud
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt Bone Marrow Transplantation Unit, Nasser Institute Hospital for Research and Treatment, Cairo, Egypt
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