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Yu X, Mankia K, Do T, Meade J. Oral Microbiome Dysbiosis and Citrullination in Rheumatoid Arthritis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1472:185-199. [PMID: 40111693 DOI: 10.1007/978-3-031-79146-8_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Rheumatoid arthritis and periodontal diseases, both characterized by chronic inflammation, share many common risk factors, sparking interest in understanding their established association. Emerging research has shed light on the link between these two diseases potentially occurring through the intricate interactions within the oral microbiome. The enrichment of pathogenic strains and species in this microbial community disrupts the delicate balance of both ecological and immunological homeostasis with the host. Particular attention has been paid to the role of key pathogens, such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, known for their immunomodulatory abilities. The generation of an autoimmune response against proteins modified by citrullination is known to be a key step in the pathogenesis of RA. Importantly, the bidirectional citrullination mediated by both host innate immune cells and oral bacteria generates citrullinated peptide neoepitopes, which may serve as potential triggers for the loss of tolerance and subsequent autoimmunity in susceptible individuals. This review highlights the importance of understanding the mechanisms through which oral microbiome dysbiosis and citrullination contribute to the onset and progression of RA. Insights into these mechanisms not only advance pathobiological understanding but also offer potential therapeutic targets. Furthermore, we discuss the potential impact of nonsurgical periodontal treatment in modifying disease progression or mitigating RA, underscoring the critical role of periodontal health in managing systemic inflammatory conditions.
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Affiliation(s)
- Xia Yu
- Division of Oral Biology, School of Dentistry, University of Leeds, Leeds, UK
| | - Kulveer Mankia
- Leeds Biomedical Centre-NIHR, Leeds, UK
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
| | - Thuy Do
- Division of Oral Biology, School of Dentistry, University of Leeds, Leeds, UK
| | - Josephine Meade
- Division of Oral Biology, School of Dentistry, University of Leeds, Leeds, UK.
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Khalid KE. Association of Hematological and Biochemical Parameters and HLA-DRB1 Alleles With Anti-cyclic Citrullinated Peptide Autoantibodies in Sudanese Rheumatic Patients. Cureus 2024; 16:e58551. [PMID: 38765443 PMCID: PMC11102094 DOI: 10.7759/cureus.58551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2024] [Indexed: 05/22/2024] Open
Abstract
Introduction Anti-citrullinated protein/peptide antibodies (ACPA) are crucial for the diagnosis and prognosis of rheumatoid arthritis (RA) and are associated with class II HLA-DRB1 alleles. The study's goal was to determine how DRB1 alleles and hematological and biochemical parameters affect ACPA production in RA patients from Sudan. Methods The study analyzed the hematological and biochemical parameters and the frequency of HLA-DRB1 alleles in 120 RA patients and 100 controls. Automated analyzers, ELISA, the latex agglutination test, and the Westergren method were utilized for hematological and biochemical testing. HLA class II alleles were genotyped using polymerase chain reaction-sequence-specific primers (PCR-SSP). The student's t-test and the chi-square (Χ2) test were employed to identify significant alterations between the examined parameters and allele frequencies. Results A total of 51.7% of 120 RA patients tested positive for ACPA (ACPA+). Among those patients, the DRB1*04 and *10 alleles were significantly more prevalent (22.2% vs. 8.9%, P = 0.048 and 23.8% vs. 8.9%, P = 0.030, respectively). RA patients had significantly higher counts of platelet count test (PLT; P = 0.011), lymphocytes (LY; P = 0.000), neutrophils (NE; P = 0.025), monocytes (MO; P = 0.000), eosinophils (EO; P = 0.000), neutrophil-to-lymphocyte ratio (NLR; P = 0.006), C-reactive protein (CRP; P = 0.000), and erythrocyte sedimentation rate (ESR; P = 0.000) than controls. Patients also showed low counts of red blood cells (RBC; P = 0.003), hemoglobin (Hb; P = 0.024), mean platelet volume (MPV; P = 0.000), and basophils (BA; P = 0.048). ACPA+ RA patients had elevated white blood cells (WBC; P = 0.046), PLT (P = 0.029), and low mean corpuscular hemoglobin concentration (MCHC; P = 0.022). The hematological and biochemical parameters of ACPA+ RA patients with the DRB1*04 or *10 alleles did not differ significantly. Conclusions We found significant differences in hematological and biochemical parameters between RA patients and controls that had nothing to do with ACPA positivity or the frequency of DRB1*04 or *10 alleles.
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Affiliation(s)
- Khalid E Khalid
- Department of Basic Medical Sciences, Faculty of Applied Medicla Sciences, Al-Baha University, Al-Baha, SAU
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Dwivedi SD, Yadav K, Bhoi A, Sahu KK, Sangwan N, Singh D, Singh MR. Targeting Pathways and Integrated Approaches to Treat Rheumatoid Arthritis. Crit Rev Ther Drug Carrier Syst 2024; 41:87-102. [PMID: 38305342 DOI: 10.1615/critrevtherdrugcarriersyst.2023044719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Rheumatoid arthritis (RA) is a chronic symmetrical systemic disorder that not only affects joints but also other organs such as heart, lungs, kidney, and liver. Approximately there is 0.5%-1% of the total population affected by RA. RA pathogenesis still remains unclear due to which its appropriate treatment is a challenge. Further, multitudes of factors have been reported to affect its progression i.e. genetic factor, environmental factor, immune factor, and oxidative factor. Therapeutic approaches available for the treatment of RA include NSAIDs, DMARDs, enzymatic, hormonal, and gene therapies. But most of them provide the symptomatic relief without treating the core of the disease. This makes it obligatory to explore and reach the molecular targets for cure and long-term relief from RA. Herein, we attempt to provide extensive overlay of the new targets for RA treatment such as signaling pathways, proteins, and receptors affecting the progression of the disease and its severity. Precise modification in these targets such as suppressing the notch signaling pathway, SIRT 3 protein, Sphingosine-1-phosphate receptor and stimulating the neuronal signals particularly efferent vagus nerve and SIRT 1 protein may offer long term relief and potentially diminish the chronicity. To target or alter the novel molecules and signaling pathway a specific delivery system is required such as liposome, nanoparticles and micelles and many more. Present review paper discusses in detail about novel targets and delivery systems for treating RA.
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Affiliation(s)
- Shradha Devi Dwivedi
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur 492 010, India
| | - Krishna Yadav
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G), 492010, India
| | - Anita Bhoi
- School of Studies in Biotechnology, Pt. Ravishankar Shukla University, Raipur 492 010, India
| | - Keshav Kant Sahu
- School of studies in biotechnology, Pt. Ravishankar Shukla University, Raipur (C.G), 492010, India
| | - Neelam Sangwan
- Department of Biochemistry, School of Interdisciplinary and Applied Sciences, Central University of Haryana, Mahendergarh, 123031, India
| | - Deependra Singh
- University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, 492010, India; National Centre for Natural Resources, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, 492010, India
| | - Manju Rawat Singh
- University Institute of pharmacy, Pt.Ravishankar Shukla University, Raipur.(C.G.) 2. National centre for natural resources, Pt. Ravishankar Shukla University, Raipur
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Blackler G, Akingbasote J, Cairns E, Howlett C, Kiser P, Barra L. The effect of HLA-DRB1*04:01 on a mouse model of atherosclerosis. J Transl Autoimmun 2023; 7:100203. [PMID: 37408614 PMCID: PMC10318502 DOI: 10.1016/j.jtauto.2023.100203] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 07/07/2023] Open
Abstract
Objectives HLA-DRB1 is associated with an increased risk of cardiovascular disease in patients with rheumatoid arthritis (RA). This study aimed to determine the effect of HLA-DRB1 on atherosclerotic cardiovascular disease (ASCVD) using a novel mouse model. Methods Mice transgenic for HLA-DRB1*04:01 (DR4tg) were crossed with low density lipoprotein receptor knock-out (Ldlr-/-) mice that develop atherosclerosis when fed a high fat, high cholesterol (HFHC) diet. Male and female DR4tgLdlr-/- (n = 48), Ldlr-/- (n = 24), DR4tg (n = 24), and C57Bl/6 (B6) background (n = 24) mice were fed HFHC or regular diet (RD) for 12 weeks. Blood samples were analyzed for serum lipoproteins using a colorimetric assay. C-reactive protein (CRP) and oxidized LDL (OxLDL) were measured using ELISA. Atherosclerosis in the aortas was assessed using the lipid stain, Sudan IV. The presence of citrulline in atherosclerotic plaque was determined by immunohistochemistry. Results Sera low-density lipoprotein cholesterol (LDL-C) levels were higher in HFHC-fed Ldlr-/- versus DR4tgLdlr-/--; p = 0.0056, but the aortic plaque burden and degree of citrullination in the plaque were similar for these two strains. The ratio of pro-atherogenic OxLDL to LDL levels was higher in DR4tgLdlr-/- than Ldlr-/-mice; p = 0.0017. All mice had an increase in CRP when fed a HFHC diet, most pronounced for DR4tgLdlr-/-; p = 0.0009. There were no significant sex differences for DR4tgLdlr-/- mice; however, male Ldlr-/- mice had worse atherosclerosis. B6 and DR4tg mice did not have significant elevations in serum cholesterol levels and did not develop atherosclerosis. Conclusions Expression of HLA-DRB1 resulted in an elevation of OxLDL and a reduction in the male bias for atherosclerosis, mimicking what is observed in RA.
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Affiliation(s)
- Garth Blackler
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - James Akingbasote
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
| | - Ewa Cairns
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Department of Medicine, Division of Rheumatology, Western University, London, Ontario, Canada
| | - Christopher Howlett
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
- Department of Pathology and Laboratory Medicine, London Health Research Centre, London, Ontario, Canada
| | - Patti Kiser
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
| | - Lillian Barra
- Department of Microbiology and Immunology, Western University, London, Ontario, Canada
- Department of Medicine, Division of Rheumatology, Western University, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
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Ali AA, Khalid KE, Hussien HM, Mohammed SE, Saeed OK. The Association of Human Leukocyte Antigen Genotyping Among Sudanese Patients With Rheumatoid Arthritis: Reference to Ethnicity. Cureus 2023; 15:e43905. [PMID: 37746389 PMCID: PMC10512431 DOI: 10.7759/cureus.43905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/22/2023] [Indexed: 09/26/2023] Open
Abstract
INTRODUCTION Human leukocyte antigens (HLA) account for up to one-half of the total genetic contribution to rheumatoid arthritis (RA) risk. The study investigated the association of HLA class II genotyping with RA susceptibility in Sudanese ethnic groups. METHODS The DRB1 and DQB1 alleles and haplotypes were determined in 122 RA patients (i.e., Gaalia = 54, Johayna = 24, Baggara = 17, Nile Nubian = 12, and others = 15) and 120 healthy controls of ethnic groups (i.e., Gaalia = 44, Johayna = 11, Baggara = 15, Nile Nubian = 9, and others = 21) using a polymerase chain reaction with sequence-specific primers method. RESULTS Susceptibility to RA was associated with a high frequency of DRB1*04 (P = 0.04), DRB1*10 (P = 0.04), and DQB1*03 (P = 2.2 x 10-8/Pc = 6.6 x 10-8) between study ethnic groups, while protective effects were shown with DRB1*07 (P = 0.01), DQB1*02 (P = 0.02), and DQB1*06 (P = 2.2 x 10-6/Pc = 6.6 x 10-6), with an inconsistent frequency between study ethnic groups. The HLA haplotypes that were high in frequency among RA ethnic groups and showed susceptibility associations were DRB1*03-DQB1*03, DRB1*04-DQB1*03, DRB1*08-DQB1*03, DRB1*13-DQB1*02, and DRB1*13-DQB1*03 (P = 0.00003/Pc = 0.0003, P = 0.0001/Pc = 0.0001, P = 0.03, P = 0.004/Pc = 0.03, and P = 3.79x10-8/Pc = 3.3x10-9, respectively). On the contrary, DRB1*03-DQB1*02, DRB1*07-DQB1*02, and DRB1*13-DQB1*06 were lower in frequency in the ethnic groups with RA and may confer protection (P = 0.004/Pc = 0.032, P = 0.002/Pc = 0.02, and P = 0.01, respectively). CONCLUSIONS Our findings indicate an association between HLA-DRB1 and DQB1 genotypes and the susceptibility to RA in the Sudanese population, with a moderate frequency between our ethnic groups.
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Affiliation(s)
- Adil A Ali
- Department of Biochemistry and Nutrition, Faculty of Medicine, University of Gezira, Wad Medani, SDN
| | - Khalid E Khalid
- Department of Basic Medical Sciences, Faculty of Applied Medical Sciences, Albaha University, Al-Baha, SAU
| | - Hajir M Hussien
- Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Gezira, Wad Medani, SDN
| | - Somaya E Mohammed
- Department of Pathology, Faculty of Medicine, University of Gezira, Wad Medani, SDN
| | - Osman K Saeed
- Department of Internal Medicine, Faculty of Medicine, University of Gezira, Wad Medani, SDN
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Ali AA, Khalid KE, Mohammed SE, Akhtar MS, Saeed OK. Association of Human Leukocyte Antigen (HLA) class II ( DRB1 and DQB1) alleles and haplotypes with Rheumatoid Arthritis in Sudanese patients. Front Immunol 2023; 14:1178546. [PMID: 37426636 PMCID: PMC10324672 DOI: 10.3389/fimmu.2023.1178546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/05/2023] [Indexed: 07/11/2023] Open
Abstract
The aim of this study was to determine the Human Leukocyte Antigen (HLA) class II (DRB1 and DQB1) alleles and haplotype frequency in Rheumatoid Arthritis (RA) in the Sudanese population. The frequency of HLA-DRB1 and -DQB1 alleles and DRB1-DQB1 haplotypes were determined in 122 RA patients and 100 controls. HLA alleles were genotyped by the polymerase chain reaction-sequence specific primers (PCR-SSP) method. In RA patients, HLA-DRB1*04 and *10 alleles were high in frequency (9.6% vs 14.2%, P = 0.038 and P = 0.042, respectively), and dependently on anti-citrullinated protein antibodies (ACPAs) seropositivity (P = 0.044 and P = 0.027, respectively). In contrast, the frequency of the HLA-DRB1*07 allele was significantly low in patients than in controls (11.7% vs 5.0%, P = 0.010). Moreover, the HLA-DQB1*03 allele was strongly associated with RA risk (42.2%, P = 2.2x10-8), whereas, HLA-DQB1*02 and *06 showed protective effects against RA (23.1% and 42.2%, P = 0.024 and P = 2.2x10-6, respectively). Five different HLA haplotypes, DRB1*03-DQB1*03 (P = 0.00003), DRB1*04-DQB1*03 (P = 0.00014), DRB1*08-DQB1*03 (P = 0.027), DRB1*13-DQB1*02 (P = 0.004), and DRB1*13-DQB1*03 (P = 3.79x10-8) were significantly associated with RA risk, while 3 protective haplotypes, DRB1*03-DQB1*02 (Pc = 0.008), DRB1*07-DQB1*02 (Pc = 0.004), and DRB1*13-DQB1*06 (Pc = 0.02) were identified. This is the first study determining the association between HLA class II alleles and haplotypes and RA risk in our population.
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Affiliation(s)
- Adil Ahmed Ali
- Department of Biochemistry and Nutrition, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
| | - Khalid Eltahir Khalid
- Department of Biochemistry and Nutrition, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
- Department of Basic Medical Sciences, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, Saudi Arabia
| | - Somaya Elhaj Mohammed
- Department of Pathology, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
| | - Mohammed Salman Akhtar
- Department of Basic Medical Sciences, Faculty of Applied Medical Sciences, Al-Baha University, Al-Baha, Saudi Arabia
| | - Osman Khalafalla Saeed
- Department of Internal Medicine, Faculty of Medicine, University of Gezira, Wad Medani, Sudan
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Anti-Arthritic Effect of the Hydroethanolic Root Extract of Psydrax subcordata in Rats. Adv Pharmacol Pharm Sci 2022; 2022:9748382. [PMID: 36061079 PMCID: PMC9433293 DOI: 10.1155/2022/9748382] [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: 05/04/2022] [Revised: 07/18/2022] [Accepted: 07/23/2022] [Indexed: 11/20/2022] Open
Abstract
Background In Ghana, decoctions of various parts of Psydrax subcordata, Bridson (Rubiaceae) are employed in the management of inflammatory conditions. However, not much scientific data is available to back such folkloric use of the plant. This study, therefore, seeks to investigate the chronic anti-inflammatory activity of hydroethanolic root extract of Psydrax subcordata (PSRE) using the adjuvant-induced arthritis model in rats. Methods Freund's adjuvant-induced arthritis model was used to assess the ameliorative effects of PSRE in chronic inflammation. The effect of PSRE on tissue and joint integrity in arthritis was also evaluated by histopathology and microscopy. The effect of PSRE on oxidative markers and serum transforming growth factor (TGF) beta 1 was also determined via chemical assays. Results Oral PSRE (30–300 mg/kg) inhibited both ipsilateral and contralateral paw arthritis when given prophylactically and therapeutically in rats. It reduced paw defect on X-ray with histologically-reduced inflammatory cells and synovial hyperplasia. Finally, PSRE significantly reduced TGF-beta 1 levels and raised antioxidants such as reduced glutathione, catalase, and superoxide dismutase levels in arthritic rats. Conclusion The findings show that hydroethanolic root extract of Psydrax subcordata possesses anti-inflammatory properties in rodents.
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Sakyi SA, Owusu‐Yeboah M, Obirikorang C, Dadzie Ephraim RK, Kwarteng A, Opoku S, Afranie BO, Senu E, Boateng AO, Boakye DK, Buckman TA, Amoani B. Profiling vitamin D, its mediators and proinflammatory cytokines in rheumatoid arthritis: A case-control study. Immun Inflamm Dis 2022; 10:e676. [PMID: 35894711 PMCID: PMC9274797 DOI: 10.1002/iid3.676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/25/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION The active form of vitamin D has immunomodulatory and anti-inflammatory effect. Vitamin D is implicated in pathogenesis of rheumatoid arthritis (RA) and its deficiency leads to increased inflammation. Moreover, its production is dependent on concentration of calcium, phosphorus, and parathyroid hormone (PTH). Cytokines mediates inflammation in RA synovium. This study evaluated vitamin D, its mediators and proinflammatory cytokines among RA patients. METHODS In a case-control study, 78 RA patients from Komfo Anokye Teaching Hospital rheumatology clinic and 60 healthy blood donors were recruited. Chemistry analyzer and enzyme-linked immunosorbent assay kits were used to measure biochemical parameters and cytokines. RESULTS We found significantly higher levels of interleukin (IL)-1β, interferon gamma (IFN-γ), and tumor necrosis factor-α (TNF-α) in RA patients compared with controls (p < .05). There was a significant positive correlation between intact parathyroid hormone (iPTH) and IL-10 (r = .30, p < .05) and a negative correlation between IL-6 (r = -0.28, p > .05), IL-1β (r = -0.25, p > .05), TNF-α (r = -0.26, p > .05), IFN-γ (r = -0.24, p > .05), and iPTH. There was a significant negative correlation between IL-1β (r = -0.33, p < .05), IFN- γ (r = -0.29, p < .05), and calcium. CONCLUSION Reduced PTH, calcium, and phosphorus is associated with higher levels of proinflammatory cytokines which may worsen RA disease condition. Vitamin D is therefore not an independent regulator of proinflammatory cytokines in RA.
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Affiliation(s)
- Samuel A. Sakyi
- Department of Molecular Medicine, School of Medicine and DentistryKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Mavis Owusu‐Yeboah
- Department of Molecular Medicine, School of Medicine and DentistryKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Christian Obirikorang
- Department of Molecular Medicine, School of Medicine and DentistryKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Richard K. Dadzie Ephraim
- Department of Medical Laboratory Sciences, Faculty of Allied HealthUniversity of Cape CoastCape CoastGhana
| | - Alexander Kwarteng
- Department of Biochemistry and BiotechnologyKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Stephen Opoku
- Department of Molecular Medicine, School of Medicine and DentistryKwame Nkrumah University of Science and TechnologyKumasiGhana
- Department of Medical Diagnostics, Faculty of Allied Health Sciences, College of Health SciencesKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Bright O. Afranie
- Department of Molecular Medicine, School of Medicine and DentistryKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Ebenezer Senu
- Department of Molecular Medicine, School of Medicine and DentistryKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Andy O. Boateng
- Department of Molecular Medicine, School of Medicine and DentistryKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Derrick K. Boakye
- Department of Medical Diagnostics, Faculty of Allied Health Sciences, College of Health SciencesKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Tonnies A. Buckman
- Department of Molecular Medicine, School of Medicine and DentistryKwame Nkrumah University of Science and TechnologyKumasiGhana
| | - Benjamin Amoani
- Department of Biomedical Science, School of Allied Health SciencesUniversity of Cape CoastCape CoastGhana
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Raad T, George E, Griffin A, Larkin L, Fraser A, Kennedy N, Tierney A. A randomised controlled trial of a Mediterranean Dietary Intervention for Adults with Rheumatoid Arthritis (MEDRA): Study protocol. Contemp Clin Trials Commun 2022; 28:100919. [PMID: 35620325 PMCID: PMC9126839 DOI: 10.1016/j.conctc.2022.100919] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 03/10/2022] [Accepted: 05/01/2022] [Indexed: 11/30/2022] Open
Abstract
Background Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis affecting 0.5-1% of the adult population worldwide. While the primary line of treatment of RA includes pharmacological therapies, people living with the condition often seek non-pharmacological therapies such as diet and exercise in an attempt to attenuate their symptoms. Established, evidence-based dietary guidelines for RA are currently lacking. The MEDRA study aims to explore the effectiveness of implementing, via telehealth, a Mediterranean type diet (MedDiet) compared to a standard healthy diet as per the Healthy Eating Guidelines (HEG) in Ireland in terms of differences in physical function and quality of life in adults with RA living in Ireland. Methods The MEDRA study is a parallel, randomised controlled trial delivered through telehealth methods. Forty-four eligible participants who have RA will be randomly allocated to either a MedDiet or HEG group for a 12 weeks intervention period. Primary outcome measures include changes in physical function and quality of life, both of which will be measured using validated questionnaires at baseline, six and twelve weeks. Both intervention arms will attend a total five teleconsultations with a Registered Dietitian (RD). The MedDiet intervention arm focuses on recommendations from the traditional Mediterranean diet and HEG intervention arm will use the dietary recommendations as currently advised in Ireland. Discussion This study will provide evidence as to whether dietary treatment of RA can improve physical function and quality of life in a small cohort of participants with RA. The results of the study will be disseminated at national scientific conferences and published in peer-reviewed journals. Ethics This protocol has been approved by the Education and Health Sciences Research Ethics Committee at the University of Limerick (2020_09_05_EHS) and by the Health Service Executive Mid-Western Regional Hospital Research Ethics Committee (REC Ref 103/19). Trial registration ClinicalTrials.gov NCT04262505. Trial registration date: April 2, 2020.
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Affiliation(s)
- Tala Raad
- Discipline of Dietetics, School of Allied Health, Faculty of Education and Health Sciences and Health Implementation Science and Technology Cluster, Health Research Institute, University of Limerick, V94 T9PX, Ireland
| | - Elena George
- Deakin University, Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Geelong, Victoria, 3220, Australia
| | - Anne Griffin
- Discipline of Dietetics, School of Allied Health, Faculty of Education and Health Sciences and Health Implementation Science and Technology Cluster, Health Research Institute, University of Limerick, V94 T9PX, Ireland
| | - Louise Larkin
- Discipline of Physiotherapy, School of Allied Health, Faculty of Education and Health Sciences, Implementation Science and Technology Centre, Health Research Institute, University of Limerick, V94 T9PX, Ireland
| | - Alexander Fraser
- Department of Rheumatology, University Hospital Limerick, Limerick, V94 T9PX, Ireland
- Graduate Entry Medical School, Faculty of Education and Health Sciences, University of Limerick, Limerick, V94 T9PX, Ireland
| | - Norelee Kennedy
- Discipline of Physiotherapy, School of Allied Health, Faculty of Education and Health Sciences, Implementation Science and Technology Centre, Health Research Institute, University of Limerick, V94 T9PX, Ireland
| | - Audrey Tierney
- Discipline of Dietetics, School of Allied Health, Faculty of Education and Health Sciences and Health Implementation Science and Technology Cluster, Health Research Institute, University of Limerick, V94 T9PX, Ireland
- School of Allied Health, Human Services and Sport, Faculty of Science and Engineering, La Trobe University, Melbourne, Vic, 3086, Australia
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Nii-Trebi NI, Matsuoka S, Kawana-Tachikawa A, Bonney EY, Abana CZ, Ofori SB, Mizutani T, Ishizaka A, Shiino T, Ohashi J, Naruse TK, Kimura A, Kiyono H, Ishikawa K, Ampofo WK, Matano T. Super high-resolution single-molecule sequence-based typing of HLA class I alleles in HIV-1 infected individuals in Ghana. PLoS One 2022; 17:e0269390. [PMID: 35653364 PMCID: PMC9162337 DOI: 10.1371/journal.pone.0269390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 05/19/2022] [Indexed: 11/18/2022] Open
Abstract
Polymorphisms in human leukocyte antigen (HLA) class I loci are known to have a great impact on disease progression in HIV-1 infection. Prevailing HIV-1 subtypes and HLA genotype distribution are different all over the world, and the HIV-1 and host HLA interaction could be specific to individual areas. Data on the HIV-1 and HLA interaction have been accumulated in HIV-1 subtype B- and C-predominant populations but not fully obtained in West Africa where HIV-1 subtype CRF02_AG is predominant. In the present study, to obtain accurate HLA typing data for analysis of HLA association with disease progression in HIV-1 infection in West African populations, HLA class I (HLA-A, -B, and -C) four-digit allele typing was performed in treatment-naïve HIV-1 infected individuals in Ghana (n = 324) by a super high-resolution single-molecule sequence-based typing (SS-SBT) using next-generation sequencing. Comparison of the SS-SBT-based data with those obtained by a conventional sequencing-based typing (SBT) revealed incorrect assignment of several alleles by SBT. Indeed, HLA-A*23:17, HLA-B*07:06, HLA-C*07:18, and HLA-C*18:02 whose allele frequencies were 2.5%, 0.9%, 4.3%, and 3.7%, respectively, were not determined by SBT. Several HLA alleles were associated with clinical markers, viral load and CD4+ T-cell count. Of note, the impact of HLA-B*57:03 and HLA-B*58:01, known as protective alleles against HIV-1 subtype B and C infection, on clinical markers was not observed in our cohort. This study for the first time presents SS-SBT-based four-digit typing data on HLA-A, -B, and -C alleles in Ghana, describing impact of HLA on viral load and CD4 count in HIV-1 infection. Accumulation of these data would facilitate high-resolution HLA genotyping, contributing to our understanding of the HIV-1 and host HLA interaction in Ghana, West Africa.
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Affiliation(s)
- Nicholas I. Nii-Trebi
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
- Department of Medical Laboratory Sciences, School of Biomedical and Allied Health Sciences, University of Ghana, Accra, Ghana
| | - Saori Matsuoka
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Ai Kawana-Tachikawa
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
- Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Evelyn Y. Bonney
- Department of Virology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Christopher Z. Abana
- Department of Virology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Sampson B. Ofori
- Department of Medicine, Koforidua Government Hospital, Eastern Region, Ghana
| | | | - Aya Ishizaka
- Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Teiichiro Shiino
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Jun Ohashi
- Department of Biological Sciences, Graduate School of Sciences, University of Tokyo, Tokyo, Japan
| | - Taeko K. Naruse
- Department of Protozoology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
- Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Akinori Kimura
- Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
- Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroshi Kiyono
- Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Future Medicine Education and Research Organization, Chiba University, Chiba, Japan
- CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, Department of Medicine, University of California San Diego, San Diego, California, United States of America
| | - Koichi Ishikawa
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - William K. Ampofo
- Department of Virology, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
- * E-mail: (WKA); (TM)
| | - Tetsuro Matano
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
- Institute of Medical Science, University of Tokyo, Tokyo, Japan
- * E-mail: (WKA); (TM)
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Sarnik J, Makowska J. Citrullination good or bad guy? Immunobiology 2022; 227:152233. [DOI: 10.1016/j.imbio.2022.152233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 04/11/2022] [Accepted: 05/21/2022] [Indexed: 11/16/2022]
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Reactivity of Rheumatoid Arthritis-Associated Citrulline-Dependent Antibodies to Epstein-Barr Virus Nuclear Antigen1-3. Antibodies (Basel) 2022; 11:antib11010020. [PMID: 35323194 PMCID: PMC8944695 DOI: 10.3390/antib11010020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/17/2022] [Accepted: 03/08/2022] [Indexed: 12/22/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic disease which causes joint inflammation and, ultimately, erosion of the underlying bone. Diagnosis of RA is based on the presence of biomarkers, such as anti-citrullinated protein antibodies (ACPA) and rheumatoid factors, along with clinical symptoms. Much evidence points to a link between the Epstein-Barr virus and RA. In this study, we analyzed ACPA reactivity to citrullinated peptides originating from Epstein-Barr nuclear antigens (EBNA1, EBNA2, and EBNA3) in order to elaborate the diagnostic potential of citrullinated EBNA peptides. Moreover, ACPA cross-reactivity to citrullinated peptides from myelin basic protein (MBP) was analyzed, as citrullinated MBP recently was described to be associated with multiple sclerosis, and some degree of sequence homology between MBP and citrullinated EBNA exists. A peptide from EBNA2, (EBNA2-A, GQGRGRWRG-Cit-GSKGRGRMH) reacted with approximately 70% of all RA sera, whereas only limited reactivity was detected to EBNA1 and EBNA3 peptides. Moreover, screening of ACPA reactivity to hybrid peptides of EBNA3-A (EPDSRDQQS-Cit-GQRRGDENRG) and EBNA2-A and peptides containing citrulline close to the N-terminal confirmed that ACPA sera contain different populations of ACPAs. No notable ACPA reactivity to MBP peptides was found, confirming that ACPAs are specific for RA, and that other factors than the presence of a central Cit-Gly motif are crucial for antibody binding. Collectively, these findings illustrate that citrullinated EBNA2 is an optimal candidate for ACPA detection, supporting current evidence that EBV is linked to RA onset.
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Marinović I, Čečuk-Jeličić E, Perković D, Marasović Krstulović D, Aljinović J, Šošo D, Škorić E, Martinović Kaliterna D. Association of HLA-DRB1 alleles with rheumatoid arthritis in Split-Dalmatia County in southern Croatia. Wien Klin Wochenschr 2022; 134:463-470. [PMID: 35238988 DOI: 10.1007/s00508-022-02010-5] [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: 09/21/2021] [Accepted: 01/26/2022] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the distribution of HLA-DRB1 alleles in patients with rheumatoid arthritis (RA) in the Sinj Region (SR) and the rest of the Split-Dalmatia County (SDC) in Croatia and to determine their relationship with disease severity. METHODS A total of 74 RA patients and 80 healthy controls from the SR, and 74 RA patients and 80 healthy controls from the rest of the SDC were genotyped using sequence-specific oligonucleotide primed PCR. High-resolution typing of HLA-DRB1*04 alleles was performed using the single specific primed polymerase chain reaction (PCR-SSP) method. Serum anti-CCP, rheumatoid factor, C‑reactive protein, and erythrocyte sedimentation rate were measured in all RA patients, whereas disease activity was assessed by DAS-28 and functional status by the Health Assessment Questionnaire Disability Index. RESULTS The HLA-DRB1*04 allele was more frequent in patients with RA from the SR than that in patients from the rest of the SDC (18.2% vs. 9.5%; P = 0.014), whereas the HLA-DRB1*15 allele was more frequent in patients with RA from the rest of the SDC than in patients from the SR (16.2% vs. 7.4%; P = 0.010). Shared epitope (SE) positive patients from the SR had significantly higher serum anti-CCP and RF antibody levels (P = 0.014 and P = 0.004, respectively), higher disease activity (P = 0.043), and worse functional status (P < 0.001), than SE-positive patients from the rest of the SDC. CONCLUSION The observed higher incidence of more severe forms of RA in the SR in comparison to the rest of the SDC might be associated with the higher incidence of HLA-DRB1*04 allele in the SR.
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Affiliation(s)
- Ivanka Marinović
- Department of Physical Medicine and Rehabilitation with Rheumatology, University Hospital of Split, Spinčićeva 1, 21000, Split, Croatia.
- Department of Health Studies, University of Split, Ruđera Boškovića 35, 21000, Split, Croatia.
| | - Esma Čečuk-Jeličić
- Department of Blood Transfusion Tissue Typing Laboratory, University Hospital of Split, Spinčićeva 1, 21000, Split, Croatia
- Department of Health Studies, University of Split, Ruđera Boškovića 35, 21000, Split, Croatia
| | - Dijana Perković
- Department of Rheumatology and Clinical Immunology, University Hospital of Split, Spinčićeva 1, 21000, Split, Croatia
- University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia
| | - Daniela Marasović Krstulović
- Department of Rheumatology and Clinical Immunology, University Hospital of Split, Spinčićeva 1, 21000, Split, Croatia
- University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia
| | - Jure Aljinović
- Department of Physical Medicine and Rehabilitation with Rheumatology, University Hospital of Split, Spinčićeva 1, 21000, Split, Croatia
- Department of Health Studies, University of Split, Ruđera Boškovića 35, 21000, Split, Croatia
| | - Daniela Šošo
- Department of Physical Medicine and Rehabilitation with Rheumatology, University Hospital of Split, Spinčićeva 1, 21000, Split, Croatia
| | - Ela Škorić
- Department of Physical Medicine and Rehabilitation with Rheumatology, University Hospital of Split, Spinčićeva 1, 21000, Split, Croatia
| | - Dušanka Martinović Kaliterna
- Department of Rheumatology and Clinical Immunology, University Hospital of Split, Spinčićeva 1, 21000, Split, Croatia
- University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia
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Albarzinji N, Ismael SA, Albustany D. Association of rheumatoid arthritis and its severity with human leukocytic antigen-DRB1 alleles in Kurdish region in North of Iraq. BMC Rheumatol 2022; 6:4. [PMID: 35016727 PMCID: PMC8753826 DOI: 10.1186/s41927-021-00229-9] [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: 04/17/2021] [Accepted: 07/30/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Rheumatoid arthritis is a complex multifactorial chronic disease, the importance of human leukocytic antigen (HLA) as a major genetic risk factor for rheumatoid arthritis was studied worldwide. The objective of this study is to identify the association of HLA-DRB1 subtypes with rheumatoid arthritis and its severity in Kurdish region. METHODS A case-control study recruited 65 rheumatoid arthritis patients and 100 healthy individuals as control group all over the Kurdistan region/Iraq. Both patient and control groups are genotyped using polymerase chain reaction with sequence specific primer. Anti-CCP antibodies were measured by ELISA test. Rheumatoid factor, C-reactive protein, and disease activity score 28 which measured by DAS-28 values were calculated. The DAS-28 was used to assess the clinical severity of the patients. RESULTS HLA-DRB1-0404 and HLA-DRB1-0405 frequencies showed a strong association with disease susceptibility (P < 0.001). The frequency of HLA-DRB1-0411 and HLA-DRB1-0413 were significantly higher in control group (P < 0.001). The frequency of rheumatoid factor and Anti-CCP were significantly higher among shared epitope-positive patients compared to shared epitope-negative patients (P < 0.001). Regarding the disease activity by DAS-28, rheumatoid arthritis patients didn't show significant difference between the shared epitope-positive and shared epitope-negative patients. CONCLUSIONS HLA-DR0404 and HLA-DR0405 alleles are related to RA, while HLA-DR1-0411 and HLA-DRB1-0413 protect against RA in the Kurdistan region in the North of Iraq.
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Li Y, Wei S, Sun Y, Zong S, Sui Y. Nanomedicine-based combination of dexamethasone palmitate and MCL-1 siRNA for synergistic therapeutic efficacy against rheumatoid arthritis. Drug Deliv Transl Res 2021; 11:2520-2529. [PMID: 34331261 DOI: 10.1007/s13346-021-01037-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2021] [Indexed: 02/08/2023]
Abstract
The main aim of this research was to design a MCL-1 siRNA and dexamethasone (DEX)-loaded folate modified poly(lactide-co-glycolide) (PLGA)-based polymeric micelles with an eventual goal to improve the therapeutic outcome in the rheumatoid arthritis (RA). Polymeric micelles encapsulating the MCL-1 siRNA and DEX was successfully developed and observed to be stable. Physicochemical characteristics such as particle size and particle morphology were ideal for the systemic administration. Folate-conjugated DEX/siRNA-loaded polymeric micelles (DS-FPM) significantly lowered the MCL-1 mRNA expression compared to either DEX/siRNA-loaded polymeric micelles (DS-PM) or free siRNA in Raw264.7 cells and macrophage cells suggesting the importance of targeted nanocarriers. Most importantly, DS-FPM exhibited a greatest decrease in the hind paw volume with lowest clinical score compared to any other treated group indicating a superior anti-inflammatory activity. DS-FPM showed significantly lower levels of the TNF-α and IL-1β compared to AIA model and free groups. The folate receptor (FR)-targeting property of DS-FPM has been demonstrated to be a promising delivery platform for the effective delivery of combination therapeutics (siRNA and DEX) toward the treatment of rheumatoid arthritis.
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Affiliation(s)
- Yanmei Li
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai, 264000, Shandong, China.
| | - Shitong Wei
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai, 264000, Shandong, China
| | - Yonghua Sun
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai, 264000, Shandong, China
| | - Shihua Zong
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai, 264000, Shandong, China
| | - Yameng Sui
- Department of Rheumatology and Immunology, Yantaishan Hospital, Yantai, 264000, Shandong, China
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Mizuno K, Ikeuchi-Takahashi Y, Hattori Y, Onishi H. Preparation and evaluation of conjugate nanogels of glycyl-prednisolone with natural anionic polysaccharides as anti-arthritic delivery systems. Drug Deliv 2021; 28:144-152. [PMID: 33372563 PMCID: PMC7782909 DOI: 10.1080/10717544.2020.1865478] [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] [Indexed: 12/28/2022] Open
Abstract
Although prednisolone (PD) is used as an anti-arthritis drug due to its rapid and strong anti-inflammatory potential, its frequent and large dosing often brings about adverse effects. Therefore, targeting therapy has attracted increasing attention to overcome such adverse effects. In the present study, nanogels (NGs) composed of macromolecule-PD conjugates were developed as a novel targeting delivery system, and their anti-inflammatory potential was examined. Conjugates were prepared by carbodiimide coupling between glycyl-prednisolone (GP) and the natural anionic polysaccharides, alginic acid (AL) and hyaluronic acid (HA). NGs were produced by the evaporation of organic solvent from the conjugate solution. The obtained NGs, named AL-GP-NG and HA-GP-NG, respectively, were examined for particle characteristics, in vitro release, pharmacokinetics, and in vivo efficacy. Both NGs were several hundred nanometers in size, had negative zeta potentials, and several % (w/w) drug contents. They released PD gradually at pH 7.4 and 6. They exhibited fairly good retention in the systemic circulation. In the efficacy examination using rats with adjuvant-induced arthritis, both NGs showed the stronger and more prolonged suppression of paw inflammation than PD alone. These suggested that the present NGs should be possibly useful as anti-arthritis targeting therapeutic systems.
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Affiliation(s)
- Kohei Mizuno
- Department of Drug Delivery Research, Hoshi University, Tokyo, Japan
| | | | - Yoshiyuki Hattori
- Department of Drug Delivery Research, Hoshi University, Tokyo, Japan
| | - Hiraku Onishi
- Department of Drug Delivery Research, Hoshi University, Tokyo, Japan
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Issilbayeva A, Kushugulova A, Meiramova A, Kozhakhmetov S, Akhmetova Z, Nurgaziyev M, Chulenbayeva L, Babenko D, Kunz J, Ainabekova B. Epidemiological Trends of Rheumatoid Arthritis and PADI4, PTPN22, and HLA-DRB9 Genes Distribution in the Kazakhstan Population. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: The prevalence of rheumatoid arthritis (RA) is 1% in the global population. The lack of epidemiological studies in developing countries makes it difficult to obtain a complete global epidemiological picture of RA. RA develops due to the interaction of multiple genetic and environmental factors, though the contribution of these factors to the various disease occurrence seen in different populations is unclear.
AIM: The aim of our study was to analyze the dynamics of the general prevalence and incidence of RA among the population of Kazakhstan in 2017–2019 as well as to investigate the three most common single-nucleotide polymorphisms (SNP) of RA in the Kazakhstan population.
METHODS: The analysis of statistical data on Form 12 “On the health of the people and the health care system” was carried out. Prevalence and incidence rates were calculated according to generally accepted rules. Demographic data for the Republic of Kazakhstan were obtained from the official website stat.gov.kz. Our study included 70 RA patients and 113 control subjects. Blood samples were collected and genotyped for peptidylarginine deiminase 4 (PADI4), protein tyrosine phosphatase 22, and human leukocyte antigen (HLA)-DRB9 SNPs by reverse transcription polymerase chain reaction.
RESULTS: The prevalence of RA in Kazakhstan in 2017–2019 was 0.36–0.38%, with an incidence rate of 0.085–0.087%, which can be comparable to data of other countries in Central Asia. The allele and genotypes frequency analyses were carried out between patients and controls. The HLA-DRB9 showed significant association of the G allele odds ratio (OR) 1.96 (95% confidence interval [CI]: 1.252–3.081), p= 0.0025 and G/G genotype OR = 3.67 (95% CI: 1.58–8.54), p = 0.00162 with RA in our sample. Strong association between anti-citrullinated protein antibody (ACPA) profile and PADI4 (OR 12.19 [95% CI: 2.19–67.94], p = 0.00115) was found.
CONCLUSION: There was an increase in RA prevalence with age among females and a higher crude prevalence and incidence of RA in the southern regions of Kazakhstan. HLA-DRB9 prevailed in Kazakhstani patients with RA, PADI4 showed association with ACPA-positive RA. Further studies on larger samples are required to confirm our obtained results.
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Nomura S, Abe M, Yamaoka M, Ito T. Effect of Cytokine Gene Polymorphisms on Eltrombopag Reactivity in Japanese Patients with Immune Thrombocytopenia. J Blood Med 2021; 12:421-429. [PMID: 34113203 PMCID: PMC8187034 DOI: 10.2147/jbm.s309680] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/10/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelet counts resulting from antiplatelet autoantibodies. Analysis of polymorphisms in cytokine-encoding genes is important for understanding the pathophysiology of ITP and selecting appropriate treatments. We investigated associations between polymorphisms in cytokine-encoding genes and responses to therapy in Japanese patients with ITP. METHODS The participants in this study comprised 153 patients with ITP and 70 healthy controls. We extracted data on sex, age, platelet counts, bleeding symptoms, and therapeutic responses, including those to prednisolone (PSL) and eltrombopag. Genomic DNA was isolated from peripheral blood and polymorphisms in TNF-α, IL-10, TGF-β1, and IFN-γ genes were analyzed using the PCR-SSP method. RESULTS Our results showed that the TGF-β1 +869 C/C genotype might be related to ITP in Japanese patients. The IL-10 -592 C/C and A/A, -819 C/C and T/T, and -1082, -819, -592 ATA/ATA genotypes might be associated with reactivity to PSL. Furthermore, the IL-10 -592 C/A -819 C/T genotypes, IL-10 ACC/ATA genotype, and TGF-β1 +869 T/T and T/C genotypes might be linked to the response to eltrombopag. CONCLUSION Our results indicate that analysis of polymorphisms in cytokine-encoding genes could aid in understanding PSL and eltrombopag responsiveness in Japanese patients with ITP.
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Affiliation(s)
- Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
| | - Misao Abe
- Division of Blood Transfusion, Kansai Medical University, Hirakata, Osaka, Japan
| | - Manabu Yamaoka
- Division of Blood Transfusion, Kansai Medical University, Hirakata, Osaka, Japan
| | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
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Wagan AA, Raheem A, Bhatti A, Zafar T. Fatigue assessment by FACIT-F scale in Pakistani cohort with Rheumatoid Arthritis (FAF-RA) study. Pak J Med Sci 2021; 37:1025-1030. [PMID: 34290777 PMCID: PMC8281179 DOI: 10.12669/pjms.37.4.3602] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/12/2020] [Accepted: 03/26/2021] [Indexed: 11/29/2022] Open
Abstract
Objective: To fine out fatigue frequency and severity by FACIT-F scale in Pakistani cohort with rheumatoid arthritis. Methods: This study was conducted at department of Medicine division of rheumatology CPMC Lahore. After the approval of IRB, 192 patients of RA were recruited. Written, informed consent was taken, demographic details were noted, patients filled the URDU version of FACIT-F (fatigue severity scale). 5-ml of blood was taken for fasting blood sugar, viral markers and ESR by a trained phlebotomist. Each individual’s disease activity was assessed by DAS-28 and FACIT-F score was calculated. Results: The Mean age (39.9±10.5) years, (71.9%) were females. Fatigue frequency was 62% (n=126), age, education, hypertension, DAS-28, exercise levels and HCV gives significant association with fatigue score. Linear regression analysis, results showed one unit increase in DAS-28 will gives 2.71 unit increases in fatigue scores(P <0.05). Conclusions: We have very high frequency of fatigue in RA, increases with disease activity & associated conditions.
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Affiliation(s)
- Abrar Ahmed Wagan
- Dr. Abrar Ahmed Wagan, MBBS, FCPS (Medicine), FCPS (Rheumatology), FACR. Assistant Professor, Indus Medical College, Tando Mohammad Khan, Pakistan
| | - Abdul Raheem
- Dr. Abdul Raheem, MBBS. Postgraduate Trainee, Central Park Medical College Lahore, Lahore, Pakistan
| | - Afra Bhatti
- Dr. Afra Bhatti, MBBS. Postgraduate Trainee, Central Park Medical College Lahore, Lahore, Pakistan
| | - Taimoor Zafar
- Dr. Taimoor Zafar, MBBS. Postgraduate Trainee, Central Park Medical College Lahore, Lahore, Pakistan
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Márquez Pete N, Pérez Ramírez C, Maldonado Montoro MDM, Martínez Martínez F, Fernández-Llimos F, Sánchez Pozo A, Ramírez Tortosa MDC, Jiménez Morales A. Association of vitamin D receptor gene polymorphisms with rheumatoid arthritis. Arch Med Sci 2021; 20:1529-1537. [PMID: 39649257 PMCID: PMC11623149 DOI: 10.5114/aoms/116606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 01/14/2020] [Indexed: 12/10/2024] Open
Abstract
Introduction Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of unknown etiology which causes progressive deterioration of the joints, leading to severe pain and functional disability. Vitamin D and its receptor (VDR) play a significant part in the onset of autoimmune diseases such as RA. The purpose of this study was to evaluate the association between VDR gene polymorphisms and risk of developing RA. Material and methods A retrospective study was performed, including 214 RA cases and 748 controls of Caucasian origin. FokI (rs2228570), BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and Cdx2 (rs11568820) gene polymorphisms were analyzed by TaqMan. Results The recessive logistic regression model showed that the VDR FokI-AA genotype was associated with lower risk of RA (p = 0.0255; OR = 0.58; 95% CI: 0.35-0.92). No other genetic polymorphism showed any association with RA in any of the models tested. Haplotype analysis revealed that the haplotypes ACGAG (p = 0.033; OR = 1.62; 95% CI: 1.04-2.53) and GTGCA (p < 0.01; OR = 2.77; 95% CI: 1.53-4.98) for BsmI, Cdx2, FokI, ApaI and TaqI were associated with higher risk of RA. Conclusions VDR FokI gene polymorphism showed a trend for risk of RA, taking into account the variables of gender, age and tobacco use, and preventing false positives. Among our patients we found no influence of VDR BsmI, TaqI, ApaI and Cdx2 on the risk of developing RA. However, haplotype analysis indicated that the haplotypes ACGAG and GTGCA were associated with higher risk of RA.
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Affiliation(s)
- Noelia Márquez Pete
- Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Granada, Spain
| | - Cristina Pérez Ramírez
- Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Granada, Spain
- Department of Social Pharmacy, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
- Department of Biochemistry, Faculty of Pharmacy, University of Granada, Granada, Spain
| | | | | | | | - Antonio Sánchez Pozo
- Department of Biochemistry, Faculty of Pharmacy, University of Granada, Granada, Spain
| | | | - Alberto Jiménez Morales
- Pharmacy Service, Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Granada, Spain
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Wang H, Ong E, Kao JY, Sun D, He Y. Reverse Microbiomics: A New Reverse Dysbiosis Analysis Strategy and Its Usage in Prediction of Autoantigens and Virulent Factors in Dysbiotic Gut Microbiomes From Rheumatoid Arthritis Patients. Front Microbiol 2021; 12:633732. [PMID: 33717026 PMCID: PMC7947680 DOI: 10.3389/fmicb.2021.633732] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 02/08/2021] [Indexed: 11/13/2022] Open
Abstract
Alterations in the gut microbiome have been associated with various human diseases. Most existing gut microbiome studies stopped at the stage of identifying microbial alterations between diseased or healthy conditions. As inspired by reverse vaccinology (RV), we developed a new strategy called Reverse Microbiomics (RM) that turns this process around: based on the identified microbial alternations, reverse-predicting the molecular mechanisms underlying the disease and microbial alternations. Our RM methodology starts by identifying significantly altered microbiota profiles, performing bioinformatics analysis on the proteomes of the microbiota identified, and finally predicting potential virulence or protective factors relevant to a microbiome-associated disease. As a use case study, this reverse methodology was applied to study the molecular pathogenesis of rheumatoid arthritis (RA), a common autoimmune and inflammatory disease. Those bacteria differentially associated with RA were first identified and annotated from published data and then modeled and classified using the Ontology of Host-Microbiome Interactions (OHMI). Our study identified 14 species increased and 9 species depleted in the gut microbiota of RA patients. Vaxign was used to comparatively analyze 15 genome sequences of the two pairs of species: Gram-negative Prevotella copri (increased) and Prevotella histicola (depleted), as well as Gram-positive Bifidobacterium dentium (increased) and Bifidobacterium bifidum (depleted). In total, 21 auto-antigens were predicted to be related to RA, and five of them were previously reported to be associated with RA with experimental evidence. Furthermore, we identified 94 potential adhesive virulence factors including 24 microbial ABC transporters. While eukaryotic ABC transporters are key RA diagnosis markers and drug targets, we identified, for the first-time, RA-associated microbial ABC transporters and provided a novel hypothesis of RA pathogenesis. Our study showed that RM, by broadening the scope of RV, is a novel and effective strategy to study from bacterial level to molecular level factors and gain further insight into how these factors possibly contribute to the development of microbial alterations under specific diseases.
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Affiliation(s)
- Haihe Wang
- Department of Pathogen Biology, Harbin Medical University (Daqing), Daqing, China.,Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Edison Ong
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, United States
| | - John Y Kao
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States
| | - Yongqun He
- Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, United States.,Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States.,Center of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States
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Shared epitope and polymorphism of MICA and NKG2D encoding genes in Greek and Polish patients with rheumatoid arthritis. Cent Eur J Immunol 2021; 46:92-98. [PMID: 33897289 PMCID: PMC8056341 DOI: 10.5114/ceji.2021.104425] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 05/26/2020] [Indexed: 12/29/2022] Open
Abstract
The present study aimed to analyse and compare the distribution of MICA (rs1051792) and NKG2D/KLRK1 (rs1154831, rs1049174, rs2255336) polymorphisms in 61 Greek and 100 Polish patients with rheumatoid arthritis in relation to the presence of the HLA-DRB1 shared epitope and clinical parameters. Genotyping of selected polymorphism was performed using real-time PCR. HLA-DRB1 shared epitope alleles segregated differently in Greek and Polish patients but in both populations were detected in over 60% of cases. The rs1051792-A variant was more common among SE-positive Polish patients (p = 0.003) while the rs1049174-G allele was more frequently observed in Greeks than in Poles (p < 0.001). Moreover, among Greek patients, the rs1051792-GG homozygotes more frequently presented with anti-CCP antibodies and rheumatoid factor (RF), while carriers of the rs1049174-G variant and rs1154831-CC homozygotes were characterized by lower disease activity scores (p < 0.05 in all cases). These results imply that, in addition to the HLA-DRB1 SE alleles, MICA and NKG2D polymorphisms may also play a role in rheumatoid arthritis.
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Cancela Díez B, Pérez-Ramírez C, Maldonado-Montoro MDM, Carrasco-Campos MI, Sánchez Martín A, Pineda Lancheros LE, Martínez-Martínez F, Calleja-Hernández MÁ, Ramírez-Tortosa MC, Jiménez-Morales A. Association between polymorphisms in the vitamin D receptor and susceptibility to multiple sclerosis. Pharmacogenet Genomics 2021; 31:40-47. [PMID: 33044390 DOI: 10.1097/fpc.0000000000000420] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Multiple sclerosis (MS) is a neurodegenerative chronic inflammatory. Mutations in the vitamin D receptor (VDR) gene can substantially affect serum vitamin D levels or alter its functionality, and can consequently increase susceptibility to developing MS. The objective of this study was to evaluate the association between polymorphisms in the VDR gene and risk of MS in a (Spanish) Caucasian population. PATIENTS AND METHODS We conducted a retrospective case-control study comprising 209 patients with relapsing-remitting multiple sclerosis (RRMS) and 836 controls of Caucasian origin from southern Spain. The ApaI (rs7975232), BsmI (rs1544410), Cdx2 (rs11568820), FokI (rs2228570), and TaqI (rs731236) gene polymorphisms were determined by allelic discrimination real-time PCR using TaqMan probes. RESULTS The recessive logical regression model, adjusted for age and sex, revealed that the TT genotype for VDR FokI (rs2228570) polymorphism was associated with higher risk of MS (P = 0.0150; OR = 1.82; 95% CI = 1.12-2.94; TT vs. CT + CC). No association between the other polymorphisms and development of MS was found in any of the models analyzed. The haplotype analysis, adjusted for age, smoking, and sex, did not find any statistically significant association between the haplotypes analyzed and risk of MS. CONCLUSIONS The VDR FokI (rs2228570) polymorphism was significantly associated with developing MS. We found no influence of the ApaI (rs7975232), BsmI (rs1544410), Cdx2 (rs11568820), FokI (rs2228570), and TaqI (rs731236) gene polymorphisms on the risk of developing MS in our patients.
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Affiliation(s)
- Bárbara Cancela Díez
- Pharmacy Service. Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Avda. Fuerzas Armadas
| | - Cristina Pérez-Ramírez
- Pharmacy Service. Pharmacogenetics Unit, University Hospital Virgen Macarena, Dr. Fedriani, Sevilla
| | | | - María Isabel Carrasco-Campos
- Pharmacy Service. Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Avda. Fuerzas Armadas
| | - Almudena Sánchez Martín
- Pharmacy Service. Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Avda. Fuerzas Armadas
| | - Laura Elena Pineda Lancheros
- Pharmacy Service. Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Avda. Fuerzas Armadas
| | - Fernando Martínez-Martínez
- Department of Pharmacy and Pharmaceutical Technology, Social and Legal Assistance Pharmacy Section, Faculty of Pharmacy
| | | | - María Carmen Ramírez-Tortosa
- Department of Biochemistry, Faculty of Pharmacy, University of Granada, Campus Universitario de Cartuja, s/n, 18071 Granada, Spain
| | - Alberto Jiménez-Morales
- Pharmacy Service. Pharmacogenetics Unit, University Hospital Virgen de las Nieves, UGC Provincial de Farmacia de Granada, Avda. Fuerzas Armadas
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24
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Singhai A, Patil UK. Amelioration of oxidative and inflammatory changes by Peganum harmala seeds in experimental arthritis. CLINICAL PHYTOSCIENCE 2021. [DOI: 10.1186/s40816-020-00243-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The present study was designed to investigate the therapeutic effects against oxidative stress and alleviative effects of Peganum harmala seeds (PH) in rats with Complete Freund’s Adjuvant (CFA) induced arthritis.
Methods
The extract was evaluated for its phytoconstituents, antiarthritic and antioxidant properties. The action of chloroform (PHC) and ethanolic (PHE) extracts of PH was evaluated in adult Lewis rats (150-200 g).with CFA induced arthritis. Arthritic rats received PH extracts 100 mg/kg orally for 28 consecutive days (Prophylactic treatment) and from 14th day of CFA injection (Therapeutic treatment).
Results
PHE significantly suppressed the arthritis severity in rats than PHC in 28 days. All complications shown significant reduction (p< 0.05) in arthritic rats including paw volume (63.09%), body weight loss, decreased locomotor activity, erythrocyte sedimentation rate and synovial/hepatic tissues lipid peroxidation and increase in cellular antioxidants superoxide dismutase (U/mg) activities and hemoglobin counts. The results showed the presence of alkaloids and flavonoids in PHE. Histology and radiographic analysis of arthritic ankle joints indicated abnormal changes. Marked reduction in inflammation and arthritic changes were observed after treatment with PHE.
Conclusion
Therefore, the investigation suggests that PHE at 100 mg/kg will be useful in the management of rheumatoid arthritis complications which may possibly be due to boosting the intracellular antioxidant defense.
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Tsujimoto S, Ozaki Y, Ito T, Nomura S. Usefulness of Cytokine Gene Polymorphisms for the Therapeutic Choice in Japanese Patients with Rheumatoid Arthritis. Int J Gen Med 2021; 14:131-139. [PMID: 33469350 PMCID: PMC7813643 DOI: 10.2147/ijgm.s287505] [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: 11/10/2020] [Accepted: 12/30/2020] [Indexed: 12/12/2022] Open
Abstract
Background Rheumatoid arthritis (RA) is characterized by systemic synovitis with bone erosion and joint cartilage degradation. Although the analysis of polymorphisms in cytokine-encoding genes is important or understanding the pathophysiology of RA and selecting appropriate treatment for it, few studies have examined such single-nucleotide polymorphisms (SNPs) specifically in Japanese patients. This study was established to investigate the associations between polymorphisms in cytokine-encoding genes, autoantibodies and therapeutic responses in Japanese RA patients. Methods The subjects in this study consisted of 100 RA patients and 50 healthy controls. We extracted data on sex, age, disease duration, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, and therapeutic responses, including to methotrexate (MTX) and biological disease-modifying antirheumatic drugs (DMARDs). Genomic DNA was isolated from peripheral blood, which was genotyped for IL-10, TNF-α, TGF-β1, and IFN-γ polymorphisms. Results Regarding IL-10 (−592 C/A and −819 C/T), significant decreases in the frequencies of the IL-10 (−592) CC genotype and (−819) CC genotype were found in RA patients compared with the levels in controls. For IFN-γ (+874 T/A), a significant decrease in the frequency of the TT genotype was found in RA patients compared with that in controls. Regarding TGF-β1 (+869 T/C), patients with positivity for anti-CCP antibody had a significantly lower frequency of the CC genotype than those with negativity for it. Furthermore, the IL-10 (−592) CC genotype and (−819) CC genotype might be related to the biological DMARD-response. Conclusion Our results suggest that the analysis of polymorphisms in cytokine-encoding genes may be useful when selecting treatment for Japanese RA patients.
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Affiliation(s)
- Saki Tsujimoto
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
| | - Yoshio Ozaki
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
| | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
| | - Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan
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Associations between cytokine gene polymorphisms and rheumatoid arthritis in Turkish population. North Clin Istanb 2020; 7:563-571. [PMID: 33381695 PMCID: PMC7754868 DOI: 10.14744/nci.2020.70845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 06/09/2020] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE: Various cytokine polymorphisms have been associated with genetic risk factors predisposing to Rheumatoid Arthritis (RA) in different populations. To predict the clinical outcome as well as response to therapy in RA, studies aimed to describe genetic markers. The present study aims to search for polymorphisms of 13 cytokine coding genes in the Eastern Black Sea Region of Turkey. METHODS: DNAs of 49 patients and 96 healthy bone marrow and kidney donors were isolated from peripheral blood samples. Genotyping was performed using the Heidelberg Cytokine Typing Tray kit. PCR products were visualized on an agarose gel, and results were analyzed using the interpretation scheme provided with the kit. Arlequin 3.5 software was used for statistical analysis. RESULTS: No positive association was found between allele frequencies and the disease. However, a negative association was found for the IL-A -889 C allele (p=0.02, OR=0.533, Wald’s 95% CI=0.318–0.893). IL-12 -1188 CC (p=0.01, OR=3.667, Wald’s 95% CI=1.246–10.786), IL-4 -1098 GT (p=0.02, OR=2.405, Wald’s 95% CI=1.129–5.125) genotypes were found positively associated with the RA, while IL-4 -590 CT (p=0.02, OR=0.422, Wald’s 95% CI=0.201–0.886) was found negatively associated with the disease. In addition, IL-6 GG haplotype was found positively associated with the RA (p=0.02, OR=1.880, Wald’s 95% CI=1.086–3.254). CONCLUSION: Our findings suggest that some polymorphisms of the IL-1A, IL-2, IL-4, IL-6 and IL-12 could be responsible for the susceptibility or protective to RA in our study population. Multi-centered and large numbers of subjects containing studies that search for cytokine polymorphisms will gather more information regarding the susceptibility to RA of Turkish patients.
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Schulz S, Zimmer P, Pütz N, Jurianz E, Schaller HG, Reichert S. rs2476601 in PTPN22 gene in rheumatoid arthritis and periodontitis-a possible interface? J Transl Med 2020; 18:389. [PMID: 33059697 PMCID: PMC7559817 DOI: 10.1186/s12967-020-02548-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) and periodontitis (PD) are proven to share common risk markers, including genetic factors. In the present study we focused on genetic variants in PTPN22 (rs2476601), PADI4 (rs2240340), CTLA4 genes (rs3087243) and its impact on RA and PD. MATERIALS AND METHODS In the study 111 RA patients and 256 systemically healthy controls were involved. A subdivision of patients and controls was carried out according the severity of periodontitis (no/level 1 PD vs. level 2 PD). RESULTS I. Evaluating the genetic impact on the occurrence of RA the T allele of rs2476601 (PTPN22) (bivariate: p < 0.001; multivariate: p = 0.018) and T allele of rs2240340 (PADI4) (bivariate: p = 0.006; multivariate: p = 0.070) were associated with an increased vulnerability to RA. II. Investigating the genetic influence on level 2 PD the T allele of rs2476601 (PTPN22) was shown to be associated with a higher susceptibility to PD within the RA group (bivariate: p = 0.043; multivariate: p = 0.024). III. The T allele of rs2476601 (PTPN22) was proven to be a significant marker of RA and level 2 PD comorbidity (bivariate: p < 0.001; multivariate: p = 0.028). CONCLUSIONS These results support the thesis that genetic variations may represent a possible link between PD and RA. The study increases knowledge about disease-specific and cross-disease genetic pattern.
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Affiliation(s)
- Susanne Schulz
- Department of Operative Dentistry and Periodontology, Martin Luther University Halle-Wittenberg, Halle, Germany.
| | - Pauline Zimmer
- Department of Operative Dentistry and Periodontology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Natalie Pütz
- Department of Operative Dentistry and Periodontology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Elisa Jurianz
- Department of Operative Dentistry and Periodontology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Hans-Günter Schaller
- Department of Operative Dentistry and Periodontology, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Stefan Reichert
- Department of Operative Dentistry and Periodontology, Martin Luther University Halle-Wittenberg, Halle, Germany
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Role of Infections in the Pathogenesis of Rheumatoid Arthritis: Focus on Mycobacteria. Microorganisms 2020; 8:microorganisms8101459. [PMID: 32977590 PMCID: PMC7598258 DOI: 10.3390/microorganisms8101459] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/17/2020] [Accepted: 09/21/2020] [Indexed: 12/16/2022] Open
Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by chronic erosive polyarthritis. A complex interaction between a favorable genetic background, and the presence of a specific immune response against a broad-spectrum of environmental factors seems to play a role in determining susceptibility to RA. Among different pathogens, mycobacteria (including Mycobacterium avium subspecies paratuberculosis, MAP), and Epstein–Barr virus (EBV), have extensively been proposed to promote specific cellular and humoral response in susceptible individuals, by activating pathways linked to RA development. In this review, we discuss the available experimental and clinical evidence on the interplay between mycobacterial and EBV infections, and the development of the immune dysregulation in RA.
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Investigating the GWAS-Implicated Loci for Rheumatoid Arthritis in the Pakistani Population. DISEASE MARKERS 2020; 2020:1910215. [PMID: 32831971 PMCID: PMC7422001 DOI: 10.1155/2020/1910215] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 07/17/2020] [Accepted: 07/23/2020] [Indexed: 12/12/2022]
Abstract
Rheumatoid arthritis (RA) is a complex and multifactorial autoimmune disorder with the involvement of multiple genetic and environmental factors. Genome-wide association studies (GWAS) have identified more than 50 RA genetic loci in European populations. Given the anticipated overlap of RA-relevant genes and pathways across different ethnic groups, we sought to replicate 58 GWAS-implicated SNPs reported in Europeans in Pakistani subjects. 1,959 unrelated subjects comprising 1,222 RA cases and 737 controls were collected from three rheumatology facilities in Pakistan. Genotyping was performed using iPLEX or TaqMan® methods. A total of 50 SNPs were included in the final association analysis after excluding those that failed assay design/run or postrun QC analysis. Fourteen SNPs (LINC00824/rs1516971, PADI4/rs2240336, CEP57/rs4409785, CTLA4/rs3087243, STAT4/rs13426947, HLA-B/MICA/rs2596565, C5orf30/rs26232, CCL21/rs951005, GATA3/rs2275806, VPS37C/rs595158, HLA-DRB1/rs660895, EOMES/rs3806624, SPRED2/rs934734, and RUNX1/rs9979383) were replicated in our Pakistani sample at false discovery rate (FDR) of <0.20 with nominal p values ranging from 4.73E-06 to 3.48E-02. Our results indicate that several RA susceptibility loci are shared between Pakistani and European populations, supporting the role of common genes/pathways.
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Wang S, Lv J, Meng S, Tang J, Nie L. Recent Advances in Nanotheranostics for Treat-to-Target of Rheumatoid Arthritis. Adv Healthc Mater 2020; 9:e1901541. [PMID: 32031759 DOI: 10.1002/adhm.201901541] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/31/2019] [Indexed: 12/16/2022]
Abstract
Early diagnosis, standardized treatment, and regular monitoring are the clinical treatment principle of rheumatoid arthritis (RA). The overarching principles and recommendations of treat-to-target (T2T) in RA advocate remission as the optimum aim, especially for patients with very early disease who are initiating therapy with anti-RA medications. However, traditional anti-RA drugs cannot selectively target the inflammatory areas and may cause serious side effects due to its short biological half-life and poor bioavailability. These limitations have significantly driven the research and application of nanomaterial-based drugs in theranostics of RA. Nanomedicines have appropriate sizes and easily modified surfaces which can enhance their biological compatibility and prolong circulation time of drug-loading systems in vivo. Traditional T2T regimens cannot evaluate the efficacy of drugs in real time, while clinical drug nanosizing can realize the integration of diagnosis and treatment of RA. This review bridges clinically proposed T2T concepts and nanomedicine in an integrated system for RA early-stage diagnosis and treatment. The most advanced progress in various nanodrug delivery systems for theranostics of RA is summarized, establishing a clear path and a new perspective for further optimization of T2T. Finally, the key facing challenges are discussed and prospects are addressed.
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Affiliation(s)
- Shasha Wang
- Hunan Key Laboratory of Biomedical Nanomaterials and DevicesHunan University of Technology Zhuzhou 412007 P. R. China
| | - Jing Lv
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnosis & Center for Molecular Imaging and Translational MedicineSchool of Public HealthXiamen University Xiamen 361102 P. R. China
| | - Shanshan Meng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnosis & Center for Molecular Imaging and Translational MedicineSchool of Public HealthXiamen University Xiamen 361102 P. R. China
| | - Jianxin Tang
- Hunan Key Laboratory of Biomedical Nanomaterials and DevicesHunan University of Technology Zhuzhou 412007 P. R. China
| | - Liming Nie
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnosis & Center for Molecular Imaging and Translational MedicineSchool of Public HealthXiamen University Xiamen 361102 P. R. China
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Cui X, Wang R, Bian P, Wu Q, Seshadri VDD, Liu L. Evaluation of antiarthritic activity of nimbolide against Freund’s adjuvant induced arthritis in rats. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:3391-3398. [PMID: 31394949 DOI: 10.1080/21691401.2019.1649269] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Xin Cui
- Department of Rheumatology and Immunology, Cangzhou Central Hospital, Cangzhou, China
| | - Ruijing Wang
- Department of Gynaecology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Peimin Bian
- Department of Medical Rehabilitation, The 5th People’s Hospital of Jinan, Jinan, China
| | - Qingke Wu
- Innoscience Research Sdn Bhd, Jalan USJ 25/1, Selangor, Malaysia
| | | | - Lun Liu
- Department of Joint Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
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Kuensaen C, Chomdej S, Kongdang P, Sirikaew N, Jaitham R, Thonghoi S, Ongchai S. LL-37 alone and in combination with IL17A enhances proinflammatory cytokine expression in parallel with hyaluronan metabolism in human synovial sarcoma cell line SW982-A step toward understanding the development of inflammatory arthritis. PLoS One 2019; 14:e0218736. [PMID: 31260471 PMCID: PMC6602187 DOI: 10.1371/journal.pone.0218736] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 06/07/2019] [Indexed: 11/22/2022] Open
Abstract
LL-37 is the only human cathelicidin-family host defense peptide and has been reported to interact with invading pathogens causing inflammation at various body sites. Recent studies showed high levels of LL-37 in the synovial-lining membrane of patients with rheumatoid arthritis, a common type of inflammatory arthritis. The present study aims to investigate the role of LL-37 on mechanisms associated with pathogenesis of inflammatory arthritis. The effects of LL-37 on the expression of proinflammatory cytokines, hyaluronan (HA) metabolism-related genes, cell death-related pathways, and cell invasion were investigated in SW982, a human synovial sarcoma cell line. Time-course measurements of proinflammatory cytokines and mediators showed that LL-37 significantly induced IL6 and IL17A mRNA levels at early time points (3–6 hr). HA-metabolism-related genes (i.e., HA synthase 2 (HAS2), HAS3, hyaluronidase 1 (HYAL1), HYAL2, and CD44) were co-expressed in parallel. In combination, LL-37 and IL17A significantly enhanced PTGS2, TNF, and HAS3 gene expression concomitantly with the elevation of their respective products, PGE2, TNF, and HA. Cell invasion rates and FN1 gene expression were also significantly enhanced. However, LL-37 alone or combined with IL17A did not affect cell mortality or cell cycle. Treatment of SW982 cells with both LL-37 and IL17A significantly enhanced IKK and p65 phosphorylation. These findings suggest that the chronic production of a high level of LL-37 may synchronize with its downstream proinflammatory cytokines, especially IL17A, contributing to the co-operative enhancement of pathogenesis mechanisms of inflammatory arthritis, such as high production of proinflammatory cytokines and mediators together with the activation of HA-metabolism-associated genes and cell invasion.
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Affiliation(s)
- Chakkrapong Kuensaen
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Siriwadee Chomdej
- Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand
| | - Patiwat Kongdang
- Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nutnicha Sirikaew
- Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Rungnaree Jaitham
- Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Supitcha Thonghoi
- Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Siriwan Ongchai
- Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- * E-mail:
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Hu L, Luo X, Zhou S, Zhu J, Xiao M, Li C, Zheng H, Qiu Q, Lai C, Liu X, Deng Y, Song Y. Neutrophil-Mediated Delivery of Dexamethasone Palmitate-Loaded Liposomes Decorated with a Sialic Acid Conjugate for Rheumatoid Arthritis Treatment. Pharm Res 2019; 36:97. [PMID: 31076925 DOI: 10.1007/s11095-019-2609-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 03/12/2019] [Indexed: 02/08/2023]
Abstract
PURPOSE The aim of this research was to design dexamethasone palmitate (DP) loaded sialic acid modified liposomes, with the eventual goal of using peripheral blood neutrophils (PBNs) that carried drug-loaded liposomes to improve the therapeutic capacity for rheumatoid arthritis (RA). METHODS A sialic acid - cholesterol conjugate (SA-CH) was synthesized and anchored on the surface of liposomal dexamethasone palmitate (DP-SAL). The physicochemical characteristics and in vitro cytotoxicity of liposomes were evaluated. Flow cytometry and confocal laser scanning microscopy were utilized to investigate the accumulation of liposomes in PBNs. The adjuvant-induced arthritis was adopted to investigate the targeting ability and anti-inflammatory effect of DP loaded liposomes. RESULTS Both DP-CL and DP-SAL existed an average size less than 200 nm with remarkably high encapsulation efficiencies more than 90%. In vitro and in vivo experiments manifested SA-modified liposomes provided a reinforced accumulation of DP in PBNs. As well, DP-SAL displayed a greater degree of accumulation in the joints and a stronger anti-inflammatory effect in terms of RA suppression. CONCLUSIONS SA-modified liposomal DP was a promising candidate for RA-targeting treatment through the neutrophil-mediated drug delivery system.
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Affiliation(s)
| | | | - Songlei Zhou
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Jingyang Zhu
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Mingyue Xiao
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Cong Li
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Huangliang Zheng
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Qiujun Qiu
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Chaoyang Lai
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Xinrong Liu
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Yihui Deng
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
| | - Yanzhi Song
- College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
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Valadbeigi S, Saghiri R, Ebrahimi-Rad M, Khatami S, Akhbari H. Adenosine Deaminase Activity and HLA-DRB as Diagnostic Markers for Rheumatoid Arthritis. Curr Rheumatol Rev 2019; 15:44-49. [PMID: 29623847 DOI: 10.2174/1573397114666180406101239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 04/03/2018] [Accepted: 04/03/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Rheumatoid Arthritis (RA) is a chronic multi systemic disorder with the unclarified ethiopathology. Although several markers have been presented for recognition of RA, but none of them has been specific. New markers such as HLA typing and activity of Adenosine Deaminase (ADA) isoenzymes could be useful and specific. OBJECTIVE The aim of this study is to evaluate the pattern of ADA isoenzymes activity and HLA typing in both RA patients and healthy cases. METHODS Blood samples were collected from 55 RA patients and 60 healthy subjects, over a period of 6 months. Levels of C-reactive Protein (CRP), Rheumatoid Factor (RF) and ADA (ADA1, ADA2, total ADA) were measured using AVITEX kit and HITACHI Auto Analyzer. In addition, HLA-DRB1*01,*04 and *10 was detected using PCR-SSP. RESULTS ADA activity, particularly ADA2 level, was significantly higher among RA group (Pv <0.05). The concentrations of tADA in patients with RF and CRP positive were significantly higher (Pv <0.05). The allele prevalence of DRB1*01 was significantly higher in RA patients (13.1%) compared with control group (5.5%, respectively) (P <0.05, Bonferroni adjustment P<0.003). Calculated sensitivity and specificity for diagnostic tests in this study are listed as: CRP (75%), RF (80%), ADA (84%) and RF (90%), ADA (83%), CRP (72%), respectively. CONCLUSION Increased tADA level and the frequency of DRB1*10 and *01 caused susceptibility to RA.
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Affiliation(s)
| | - Reza Saghiri
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | | | - Shohreh Khatami
- Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
| | - Hadi Akhbari
- Department of Rheumatology, Medical Sciences University of Birjand, Birjand, Iran
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35
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Karami J, Aslani S, Jamshidi A, Garshasbi M, Mahmoudi M. Genetic implications in the pathogenesis of rheumatoid arthritis; an updated review. Gene 2019; 702:8-16. [PMID: 30904715 DOI: 10.1016/j.gene.2019.03.033] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 03/09/2019] [Accepted: 03/17/2019] [Indexed: 01/11/2023]
Abstract
Three important factors, including genetics, environment factors and autoimmunity play a role in the pathogenesis of rheumatoid arthritis (RA). The heritability of RA has been accounted to be 50-60%, while the HLA involvement in heritability of the disease has been accounted to be 10-40%. It has been documented that shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, some HLA alleles like HLA-DRB1*13 and DRB1*15 are connected to RA susceptibility. An advanced classification of SE categorizes SE alleles into four main groups namely, S1, S2, S3D, and S3P. The S2 and S3P groups have been linked to susceptibility of seropositive RA. Various genome-wide association studies (GWAS) have discovered many susceptibility loci implicated in pathogenesis of RA. Some of the important single nucleotide polymorphisms (SNPs) linked to RA are TRAF1, STAT4, CTLA4, IRF5, CCR6, PTPN22, IL23R, and PADI4. HLA and non-HLA genes may discriminate anti-cyclic citrullinated peptide (anti-CCP) antibody-positive and anti-CCP-negative RA groups. Furthermore, risk of the disease has also been linked to environmental agents, mainly cigarette smoking. Pharmacogenomics has also confirmed SNPs or genetic patterns that might be linked to drugs responses. Different aspects of genetic involvement in the pathogenesis, etiology, and RA complications are reviewed in this article.
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Affiliation(s)
- Jafar Karami
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Saeed Aslani
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmadreza Jamshidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Garshasbi
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahdi Mahmoudi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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36
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Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study. Int J Mol Sci 2019; 20:ijms20061382. [PMID: 30893847 PMCID: PMC6471183 DOI: 10.3390/ijms20061382] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 03/13/2019] [Accepted: 03/15/2019] [Indexed: 11/17/2022] Open
Abstract
Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2–3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2–2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA.
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37
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Lallar M, Srivastava P, Rai A, Saxena D, Mandal K, Phadke SR. Cytogenetic microarray in structurally normal and abnormal foetuses: a five year experience elucidating increasing acceptance and clinical utility. J Genet 2019; 98:6. [PMID: 30945666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The aim of the present study was to evaluate the diagnostic yield of prenatal cytogenetic microarray (CMA) in structurally normal and abnormal foetuses and record the acceptance rate of CMA for prenatal diagnosis over a course of five year. In 128 structurally normal and abnormal foetuses, CMA was performed along with foetal karyotype, after exclusion of aneuploidy by quantitative fluorescence polymerase chain reaction. The microarray was able to detect the pathogenic variants in 5.5% cases; the diagnostic yield in structurally abnormal foetuses was 8.8% and 4.7% in foetuses with a high aneuploidy risk. Balanced and unbalanced translocations, and low level mosaicism were detected. Reanalysis of variants of uncertain significance identified pathogenic variant. The study shows higher diagnostic yield in structurally abnormal cases, the importance of foetal karyotype and reanalysis in microarray. The acceptance rate of prenatal CMA increased five-fold over a period of five year.
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Affiliation(s)
- Meenakshi Lallar
- Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226 014 , India.
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38
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Das S, Baruah C, Saikia AK, Tiwari D, Bose S. Genetic and expression changes in
$$\hbox {TNF-}\upalpha $$
TNF-
α
as a risk factor for rheumatoid arthritis pathogenesis in northeast India. J Genet 2019. [DOI: 10.1007/s12041-018-1054-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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39
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Damm-Ganamet KL, Arora N, Becart S, Edwards JP, Lebsack AD, McAllister HM, Nelen MI, Rao NL, Westover L, Wiener JJM, Mirzadegan T. Accelerating Lead Identification by High Throughput Virtual Screening: Prospective Case Studies from the Pharmaceutical Industry. J Chem Inf Model 2019; 59:2046-2062. [DOI: 10.1021/acs.jcim.8b00941] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
| | | | | | | | | | | | - Marina I. Nelen
- Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477, United States
| | | | - Lori Westover
- Discovery Sciences, Janssen Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477, United States
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40
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Zamanpoor M. The genetic pathogenesis, diagnosis and therapeutic insight of rheumatoid arthritis. Clin Genet 2019; 95:547-557. [PMID: 30578544 DOI: 10.1111/cge.13498] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/18/2018] [Accepted: 12/19/2018] [Indexed: 12/16/2022]
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes chronic inflammation of the joints. RA is a heterogeneous disorder caused by an abnormal autoimmune response triggered by the complex interactions of genetic and environmental factors that contribute to RA etiology. However, its underlying pathogenic mechanisms are yet to be fully understood. In this review, I provide an overview of the pathogenesis, diagnosis and therapeutic insight in the clinical management of RA in light of the recent updates to classification criteria and recent discoveries of genetic loci associated with susceptibility for RA.
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Affiliation(s)
- Mansour Zamanpoor
- Department of Biochemistry, University of Otago, Dunedin, New Zealand.,Wellington Regional Genetics Laboratory, Genetic Health Service New Zealand, Wellington Regional Hospital, Wellington, New Zealand
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41
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miR-125 regulates PI3K/Akt/mTOR signaling pathway in rheumatoid arthritis rats via PARP2. Biosci Rep 2019; 39:BSR20180890. [PMID: 30541899 PMCID: PMC6328865 DOI: 10.1042/bsr20180890] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 10/29/2018] [Accepted: 11/26/2018] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to explore miR-125 effects on rheumatoid arthritis (RA) development to provide a potential target for RA. Briefly, rat RA model was established (Model group) by injection of Freund’s Complete Adjuvant into the left hind toe. Normal rats injected with saline in the same location were set as Normal group. All rats’ secondary foot swelling degree, polyarthritis index score, spleen and thymus index were measured. Synovial tissues were subjected to Hematoxylin–Eosin (HE) staining and immunohistochemistry. Synovial cells of each group were isolated and named as Normal-C group and Model-C group, respectively. Synovial cells of Model-C group further underwent cotransfection with miR-125 mimics and PARP2-siRNA (mimics+siPARP2 group) or with miR-125 negative control (NC) and PARP2-siRNA NC (NC group). Quantitative reverse transcriptase PCR (qRT-PCR), Western blot, luciferase reporter assay, ELISA, and MTT assay were performed. As a result, compared with Normal group, rats of Model group showed significantly higher secondary foot swelling degree, polyarthritis index score, spleen and thymus index (P<0.01). Down-regulated miR-125 and up-regulated PARP2 was found in synovial tissues of Model group when compared with Normal group (P<0.01). Synovial tissues of Model-C group exhibited severe hyperplasia and inflammatory cell infiltration. Luciferase reporter assay indicated that PARP2 was directly inhibited by miR-125. Compared with NC group, cells of mimics+siPARP2 group had significantly lower IL-1β, MMP-1 and TIMP-1 levels, absorbance value, and p-PI3K, p-Akt and p-mTOR relative expression (P<0.01 or P<0.05). Thus, miR-125 might attenuate RA development by regulating PI3K/Akt/mTOR signaling pathway via directly inhibiting PARP2 expression.
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42
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Khalid S, Yousaf MJ, Rashid A, Khan SA. Gene expression of Interleukin-18 in rheumatoid arthritis patients on disease modifying anti-rheumatic drug therapy. Pak J Med Sci 2019; 35:802-806. [PMID: 31258598 PMCID: PMC6572992 DOI: 10.12669/pjms.35.3.1070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 03/01/2019] [Accepted: 03/06/2019] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND & OBJECTIVES The hallmark of rheumatoid arthritis is the inflammation that is mediated by the macrophages and monocytes that cause release of pro-inflammatory cytokines like interleukin-18. It is highly expressed in serum of patients suffering from rheumatoid arthritis and has a positive association with disease activity. The aim of this study was to analyze the gene expression of interleukin-18 in rheumatoid arthritis patients on disease modifying anti-rheumatic drug therapy. METHODS The cross sectional comparative study is conducted at Department of Biochemistry and Molecular Biology and Center for Research in Experimental and Applied Medicine (CREAM-1Lab), Army Medical College, Rawalpindi, in collaboration with Rheumatology Department, Military Hospital, Rawalpindi. Study was conducted on two groups consisting of Group-I of rheumatoid arthritis patients on diseases modifying anti-rheumatic drugs and control Group-II comprising of normal healthy individuals. Non-probability purposive sampling was done from patients and controls. The duration of study was one year i-e from November 2015 to November 2016. Relative quantification of gene expression of interleukin-18 was done by Real time PCR using ∆∆CT method. RESULTS Expression analysis for interleukin-18 showed down regulation of gene in rheumatoid arthritis patients as compared to controls. CONCLUSION Interleukin-18 gene shows down regulation in rheumatoid arthritis patients on disease modifying anti-rheumatic drugs therapy.
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Affiliation(s)
- Sabeen Khalid
- Dr. Sabeen Khalid, MBBS, MPhil. Department of Biochemistry, Aziz Fatimah Medical & Dental College, Faisalabad, Pakistan
| | - Muhammad Javad Yousaf
- Muhammad Javad Yousaf, MBBS, FCPS, MHPE. Department of Biochemistry & Molecular Biology, Army Medical College, Rawalpindi, Pakistani
| | - Amir Rashid
- Amir Rashid, MBBS, PhD. Department of Biochemistry & Molecular Biology, Army Medical College, Rawalpindi, Pakistani
| | - Saleem Ahmad Khan
- Saleem Ahmad khan, MBBS, FCPS, PhD. Department of Pathology, Army Medical College, Rawalpindi, Pakistani
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43
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Tarakji I, Habbal W, Monem F. Association Between STAT4 rs7574865 Polymorphism and Rheumatoid Arthritis: Debate Unresolved. Open Rheumatol J 2018; 12:172-178. [PMID: 30505369 PMCID: PMC6210524 DOI: 10.2174/1874312901812010172] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/28/2018] [Accepted: 10/01/2018] [Indexed: 11/22/2022] Open
Abstract
Background: STAT4 rs7574865 polymorphism has been evidently associated with susceptibility to Rheumatoid Arthritis (RA) in European and Eastern Asian populations, whereas studies in other countries reported otherwise. Objective: We investigated the distribution of STAT4 rs7574865 polymorphism in a group of Syrian RA patients. Methods: Eighty-one RA patients and forty healthy controls were enrolled and STAT4 rs7574865 was genotyped by direct sequencing. RA patients were stratified according to Anti-Citrullinated Protein Antibodies (ACPA) status for analysis. Results: Minor T allele frequencies were 30.4%, 16.7%, and 23.8% in ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls, respectively. No significant differences in STAT4 rs7574865 allele/genotype frequencies were found between ACPA-positive RA patients, ACPA-negative RA patients, and healthy controls (P>0.05). Conclusion: STAT4 rs7574865 TT genotype showed a potential impact on ACPA positivity in Syrian RA patients. However, STAT4 rs7574865 effect on RA onset and severity is minor compared to other genetic factors such as HLA-DRB1 shared epitope alleles.
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Affiliation(s)
- Iman Tarakji
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syria
| | - Wafa Habbal
- Clinical Laboratories Department, Al-Assad Hospital, Damascus University, P.O. Box 10769, Damascus, Syria
| | - Fawza Monem
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syria.,Clinical Laboratories Department, Al-Assad Hospital, Damascus University, P.O. Box 10769, Damascus, Syria
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44
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Kennedy AE, Ozbek U, Dorak MT. What has GWAS done for HLA and disease associations? Int J Immunogenet 2018; 44:195-211. [PMID: 28877428 DOI: 10.1111/iji.12332] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 06/16/2017] [Accepted: 07/20/2017] [Indexed: 12/14/2022]
Abstract
The major histocompatibility complex (MHC) is located in chromosome 6p21 and contains crucial regulators of immune response, including human leucocyte antigen (HLA) genes, alongside other genes with nonimmunological roles. More recently, a repertoire of noncoding RNA genes, including expressed pseudogenes, has also been identified. The MHC is the most gene dense and most polymorphic part of the human genome. The region exhibits haplotype-specific linkage disequilibrium patterns, contains the strongest cis- and trans-eQTLs/meQTLs in the genome and is known as a hot spot for disease associations. Another layer of complexity is provided to the region by the extreme structural variation and copy number variations. While the HLA-B gene has the highest number of alleles, the HLA-DR/DQ subregion is structurally most variable and shows the highest number of disease associations. Reliance on a single reference sequence has complicated the design, execution and analysis of GWAS for the MHC region and not infrequently, the MHC region has even been excluded from the analysis of GWAS data. Here, we contrast features of the MHC region with the rest of the genome and highlight its complexities, including its functional polymorphisms beyond those determined by single nucleotide polymorphisms or single amino acid residues. One of the several issues with customary GWAS analysis is that it does not address this additional layer of polymorphisms unique to the MHC region. We highlight alternative approaches that may assist with the analysis of GWAS data from the MHC region and unravel associations with all functional polymorphisms beyond single SNPs. We suggest that despite already showing the highest number of disease associations, the true extent of the involvement of the MHC region in disease genetics may not have been uncovered.
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Affiliation(s)
- A E Kennedy
- Center for Research Strategy, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - U Ozbek
- Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - M T Dorak
- Head of School of Life Sciences, Pharmacy and Chemistry, Kingston University London, Kingston-upon-Thames, UK
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Transcriptional signature associated with early rheumatoid arthritis and healthy individuals at high risk to develop the disease. PLoS One 2018; 13:e0194205. [PMID: 29584756 PMCID: PMC5870959 DOI: 10.1371/journal.pone.0194205] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 02/27/2018] [Indexed: 12/17/2022] Open
Abstract
Background Little is known regarding the mechanisms underlying the loss of tolerance in the early and preclinical stages of autoimmune diseases. The aim of this work was to identify the transcriptional profile and signaling pathways associated to non-treated early rheumatoid arthritis (RA) and subjects at high risk. Several biomarker candidates for early RA are proposed. Methods Whole blood total RNA was obtained from non-treated early RA patients with <1 year of evolution as well as from healthy first-degree relatives of patients with RA (FDR) classified as ACCP+ and ACCP- according to their antibodies serum levels against cyclic citrullinated peptides. Complementary RNA (cRNA) was synthetized and hybridized to high-density microarrays. Data was analyzed in Genespring Software and functional categories were assigned to a specific transcriptome identified in subjects with RA and FDR ACCP positive. Specific signaling pathways for genes associated to RA were identified. Gene expression was evaluated by qPCR. Receiver operating characteristic (ROC) analysis was used to evaluate these genes as biomarkers. Results A characteristic transcriptome of 551 induced genes and 4,402 repressed genes were identified in early RA patients. Bioinformatics analysis of the data identified a specific transcriptome in RA patients. Moreover, some overlapped transcriptional profiles between patients with RA and ACCP+ were identified, suggesting an up-regulated distinctive transcriptome from the preclinical stages up to progression to an early RA state. A total of 203 pathways have up-regulated genes that are shared between RA and ACCP+. Some of these genes show potential to be used as progression biomarkers for early RA with area under the curve of ROC > 0.92. These genes come from several functional categories associated to inflammation, Wnt signaling and type I interferon pathways. Conclusion The presence of a specific transcriptome in whole blood of RA patients suggests the activation of a specific inflammatory transcriptional signature in early RA development. The set of overexpressed genes in early RA patients that are shared with ACCP+ subjects but not with ACCP- subjects, can represent a transcriptional signature involved with the transition of a preclinical to a clinical RA stage. Some of these particular up-regulated and down-regulated genes are related to inflammatory processes and could be considered as biomarker candidates for disease progression in subjects at risk to develop RA.
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Lashkari M, Noori A, Oveisi S, Kheirkhah M. Association of serum testosterone and dehydroepiandrosterone sulfate with rheumatoid arthritis: a case control study. Electron Physician 2018; 10:6500-6505. [PMID: 29765575 PMCID: PMC5942571 DOI: 10.19082/6500] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 10/25/2017] [Indexed: 12/15/2022] Open
Abstract
Background It is supposed that hypoandrogenism may be involved in the pathogenesis of rheumatoid arthritis (RA). Testosterone and dehydroepiandrosterone sulfate (DHEAs) levels decrease in body fluids of patients with RA. Objective The aim of this study was to determine the association of serum testosterone and DHEAs with RA. Methods This case-control study was conducted on 59 patients with RA and 61 healthy gender- and age-matched controls at Qazvin University of Medical Sciences, Qazvin, Iran, in 2014. Serum free testosterone and DHEAs levels were measured and compared between two groups. Serum testosterone levels lower than 0.029 ng/ml in females and 2.49 ng/ml in males were considered as abnormal. DHEAs levels lower than 18.9 μg/dl in females and 88.9 μg/dl in males were considered as abnormal. Data were analyzed using independent sample T-test, Chi-square test, and logistic regression analysis by SPSS software, version 19. Results The mean testosterone level in females of the control group was significantly higher than females in the case group. The mean DHEAs in the control group was significantly higher than the case group. Abnormal testosterone and DHEAs level in the case group was significantly higher than the control group. Logistic regression analysis showed independent association only between DHEAs levels and RA, after adjusting for age and gender (OR: 0.966, 95% CI: 0.953–0.979; p<0.001). Conclusion With regard to the results, abnormal testosterone and DHEAs level in patients with RA was significantly higher than the control group. This shows the anti-inflammatory effects of gonadal and adrenal androgens in RA.
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Affiliation(s)
- Mahin Lashkari
- M.D., Rheumatologist, Assistant Professor, Metabolic Diseases Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Akram Noori
- M.D., Rheumatologist, Assistant Professor, Metabolic Diseases Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sonia Oveisi
- M.D., MPH, Ph.D. of Maternal and Child Health, Associate Professor, Metabolic Diseases Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohammadreza Kheirkhah
- M.D., Pathologist, Metabolic Diseases Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
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47
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Zhang N, Zhang ZM, Wang XF. Correlation analysis between peripheral blood basophils and disease activity in patients with rheumatoid arthritis. EUR J INFLAMM 2018. [DOI: 10.1177/1721727x17751810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
This study set out to investigate the number and the activation of peripheral blood basophils, and the correlation analysis between peripheral blood basophils and disease activity in patients with rheumatoid arthritis (RA). It was determined whether these indices could be used as a monitoring index of RA activation and thereby provide a new disease assessment method for RA. Using flow cytometry, the number and activation level of peripheral blood basophils were determined in RA patients compared with healthy donors. General clinical data were collected and laboratory indices of RA patients were analyzed. A correlation between the number and the activation of basophils was determined using the Disease Activity Score 28 (DAS28), anti-cyclic citrullinated peptide (CCP), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).The absolute count and percentage of peripheral blood basophils in RA patients were significantly lower than that of controls (absolute count P = 0.033, percentage P = 0.047). However, the activation level of basophils was significantly higher than that in controls ( P = 0.034). In addition, the activation level of basophils showed statistically significant differences in disease groups with different activities ( P = 0.011, P = 0.037, and P = 0.002). With an increasing DAS28 score, the number of peripheral blood basophils was shown to decrease while activation level increased. The absolute count and activation level of basophils in RA patients and normal controls on receiver operator characteristic (ROC) curves were (area under the curve (AUC) = 0.676, P = 0.025; AUC = 0.694, P = 0.014), respectively, which were statistically significant in differentiating RA patients from controls. The activation level of basophils was positively correlated with CCP ( P < 0.001, r = 0.831), was positively correlated with CRP ( P = 0.001, r = 0.588). These data are correlated with disease activity assessment and can be used as an early monitoring index of RA activity. Therefore, these studies provide a new basis for evaluation of clinical disease activity in RA patients.
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Affiliation(s)
- Na Zhang
- Department of Rheumatology, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Ze-Ming Zhang
- Department of Rheumatology, Shengjing Hospital of China Medical University, Shenyang, P.R. China
| | - Xiao-Fei Wang
- Department of Rheumatology, Shengjing Hospital of China Medical University, Shenyang, P.R. China
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Arshad M, Bhatti A, John P, Jalil F, Borghese F, Kawalkowska JZ, Williams RO, Clanchy FIL. T cell activation Rho GTPase activating protein (TAGAP) is upregulated in clinical and experimental arthritis. Cytokine 2017; 104:130-135. [PMID: 29017772 DOI: 10.1016/j.cyto.2017.10.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 09/11/2017] [Accepted: 10/02/2017] [Indexed: 12/15/2022]
Abstract
Genome-wide association studies have identified various susceptibility variants and loci associated with incidence of rheumatoid arthritis (RA) in different populations. One of these is T cell activation Rho GTPase activating protein (TAGAP). The present study sought to measure the expression of TAGAP in RA patients, CD4+ T cells subsets from healthy humans and in mice with collagen-induced arthritis. Peripheral blood mononuclear cells (PBMC) from RA patients and tissues of arthritic mice at different stages of the disease were used for the evaluation of TAGAP mRNA expression. Increased TAGAP expression was observed in RA patients compared to healthy controls, and there were differences in the expression level of TAGAP in the tissues of mice with experimental arthritis. Gene expression in CD4+ T cells from healthy humans was greatest 4 h after activation and protein expression was greatest after 24 h. The expression of TAGAP was not correlated with CD4+ lymphocyte subsets which were enriched for functionally defined subsets (Th17, Treg, Th1), further indicating its utility as an indicator of lymphocyte activation. These findings indicate that increased TAGAP expression is a distinguishing feature of inflammatory disease and further highlight the role of TAGAP in RA susceptibility.
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Affiliation(s)
- Maria Arshad
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences & Technology, Islamabad, Pakistan
| | - Attya Bhatti
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences & Technology, Islamabad, Pakistan
| | - Peter John
- Atta-ur-Rahman School of Applied Biosciences, National University of Sciences & Technology, Islamabad, Pakistan
| | - Fazal Jalil
- Department of Biotechnology, Abdul Wali Khan University Mardan, Pakistan
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Pan T, Cheng TF, Jia YR, Li P, Li F. Anti-rheumatoid arthritis effects of traditional Chinese herb couple in adjuvant-induced arthritis in rats. JOURNAL OF ETHNOPHARMACOLOGY 2017; 205:1-7. [PMID: 28457902 DOI: 10.1016/j.jep.2017.04.020] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 04/12/2017] [Accepted: 04/16/2017] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Clematis chinensis Osbeck / Notopterygium incisum Ting ex H, T-Chang (CN) is a traditional Chinese herb couple with prominent efficacy. The herb couple has been commonly used for clinical treatment of arthralgia syndrome ("Bi Zheng" in Chinese) for centuries in China, including rheumatic arthritis, osteoarthritis and gout in modern medicine. AIM OF THE STUDY To evaluate the anti-arthritic effect of CN herb couple in a rat model of rheumatoid arthritis (RA). MATERIALS AND METHODS Rats were divided randomly into six groups with eight each. Adjuvant-induced arthritis (AIA) model was established by intradermal injection of complete Freund's adjuvant (CFA). Rats were treated orally with different dosages of CN (0.7g/kg, 2.1g/kg, 6.3g/kg) from day 16 till day 40. Ibuprofen (50.4mg/kg) served as a positive control. Spontaneous activity, body weight, paw swelling, and arthritis index (AI) were monitored throughout drug treatment. Then serum levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) were determined by enzyme linked immunosorbent assay (ELISA) kits. In addition, histopathological examination and immunohistochemistry were used to assess the severity of arthritis. RESULTS Three dosage of CN significantly ameliorated symptoms of RA via increasing body weight as well as reducing paw swelling (at dose of 6.3g/kg, p<0.01) in AIA rats. An extremely significant reduction of AI (p<0.001) was also observed with treatment of CN (6.3g/kg) compared with model group. In parallel, treatment of CN significantly down-regulated levels of TNF-α, IL-6, and VEGF both in serum (p<0.01) and in joint synovial compared with model rats. And histopathology revealed noticeable reduction in synovial hyperplasia, cartilage damage, and inflammatory infiltration by CN treatment, especially at dose of 6.3g/kg. CONCLUSIONS To conclude, all results suggest that CN possesses evident anti-arthritic effects in AIA rats.
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Affiliation(s)
- Ting Pan
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Tao-Fang Cheng
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China
| | - Yu-Ran Jia
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
| | - Fei Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
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Mateen S, Moin S, Shahzad S, Khan AQ. Level of inflammatory cytokines in rheumatoid arthritis patients: Correlation with 25-hydroxy vitamin D and reactive oxygen species. PLoS One 2017; 12:e0178879. [PMID: 28594861 PMCID: PMC5464597 DOI: 10.1371/journal.pone.0178879] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 05/20/2017] [Indexed: 02/07/2023] Open
Abstract
Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder. Reactive oxygen species (ROS) and pro-inflammatory cytokines have been believed to be involved in the etiopathogenesis of the disease. The aim of the study was to determine the correlation of inflammatory cytokines with 25-hydroxy vitamin D and ROS. Methods 100 RA patients and 50 healthy age and sex matched individuals were included in the study. Patients were further divided on the basis of presence or absence of rheumatoid factor and disease severity. Serum 25-hydroxy vitamin D levels were monitored by chemiluminescent immunoassay. 10% hematocrit was used to detect the level of ROS by spectro fluorometer. The levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10 and IL-17) were determined in plasma by ELISA. Results The level of 25-hydroxy vitamin D was found to be decreased in RA patients in comparison to the control group. However the level of ROS and inflammatory cytokines were found to be elevated in RA patients in comparison with the healthy controls, with the increase being more pronounced in seropositive and RA patients having high disease severity. Inflammatory cytokines showed negative correlation with 25-hydroxy vitamin D and positive correlation with ROS. Conclusion This study for the first time shows the association of inflammatory cytokines with 25-hydroxy vitamin D and ROS in RA patients. The results suggest that 25-hydroxy vitamin D being an immune modulator is decreased in the serum of RA patients. Further ROS and cytokines play an important role in the pathogenesis of RA and are responsible for increasing the severity of disease.
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Affiliation(s)
- Somaiya Mateen
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Shagufta Moin
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
- * E-mail:
| | - Sumayya Shahzad
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Abdul Qayyum Khan
- Department of Orthopaedic Surgery, Faculty of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
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