The Situation of Chemokine Ligands and Receptors Gene Expression, Following the Oral Administration of Drug Mannuronic Acid in Rheumatoid Arthritis Patients

Author(s): Mona Aslani, Arman Ahmadzadeh*, Zahra Rezaieyazdi, Seyed S. Mortazavi-Jahromi, Anis Barati, Mostafa Hosseini, Abbas Mirshafiey*

Journal Name: Recent Patents on Inflammation & Allergy Drug Discovery
Continued as Recent Advances in Inflammation & Allergy Drug Discovery

Volume 14 , Issue 1 , 2020


Background: Regarding the leukocytes infiltration into the synovium of Rheumatoid Arthritis (RA) patients is mostly mediated by chemokine ligands and receptors, and following the efficient and motivating results of international Phase III clinical trial of β-D-Mannuronic acid (M2000) patented EP067919 (2017), as a novel anti-inflammatory drug, in patients with RA, the present research was designed.

Objectives: This study aimed to assess the oral administration effects of this new drug on gene expression of some chemokine receptors and ligands, including CXCR4, CXCR3, CCR2, CCR5 and CCL2/MCP-1 in PBMCs of patients with active form of RA.

Methods: Twelve patients suffering from RA, with inadequate response to conventional drugs were selected (Clinical trial identifier IRCT2017100213739N10) and 1000mg/day of M2000 was orally administrated to them for 12 weeks. The mRNA expression of target molecules was then evaluated in PBMCs of the patients before and after treatment with M2000 using real-time PCR and was compared to healthy controls. Patents related to this study were also reviewed.

Results: The results showed that M2000 was able to significantly down-regulate the mRNA expression of CXCR4, CCR2 and CCL2/MCP-1 in the PBMCs of the RA patients. It should be noted that the gene expression situation of the target molecules was in coordinate with the clinical and paraclinical assessments in the patients.

Conclusion: Taken together, the results of this investigation revealed the part of molecular and immunological mechanisms of drug Mannuronic acid (M2000) in the treatment of RA, based on chemokine ligands and receptors mediated processes.

Keywords: Chemokine, Clinical trial, DMARDs, Mannuronic acid, M2000, NSAIDs.

Mo W-X, Yin S-S, Chen H, et al. Zhou C, Zhou J-X, Zhao L-D, et al.Chemotaxis of Vδ2 T cells to the joints contributes to the pathogenesis of rheumatoid arthritis. Ann Rheum Dis 2017; 76(12): 2075-84.
[] [PMID: 28866647]
Okamoto H. Molecular aspects of rheumatoid arthritis: chemokines, environmental factors and transcription factors. FEBS J 2008; 275(18): 4447-7.
[] [PMID: 18662306]
Okamoto H, Cujec TP, Yamanaka H, Kamatani N. Molecular aspects of rheumatoid arthritis: role of transcription factors. FEBS J 2008; 275(18): 4463-70.
[] [PMID: 18662303]
Zwerina J, Redlich K, Schett G, Smolen JS. Pathogenesis of rheumatoid arthritis: targeting cytokines. Ann N Y Acad Sci 2005; 1051(1): 716-29.
[] [PMID: 16127012]
Ota Y, Niiro H, Ota S-I, Ueki N, Tsuzuki H, Nakayama T, et al. Generation mechanism of RANKL+ effector memory B cells: Relevance to the pathogenesis of rheumatoid arthritis. Arthritis Res Ther 2016. 6 18:67.
Wasserman A. Rheumatoid arthritis: Common questions about diagnosis and management. Am Fam Physician 2018; 97(7): 455-62.
Leclerc P. Characterization of the PGE2 pathway in arthritis and inflammation: mPGES-1 as a therapeutic target. PhD Dissertation, From the Rheumatology Research Unit Department of Medicine Karolinska Institute, Stockholm, Sweden, June 2013.
Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol 2017; 31(1): 3-18.
[] [PMID: 29221595]
Korczowska I. Rheumatoid arthritis susceptibility genes: An overview. World J Orthop 2014; 5(4): 544-9.
[] [PMID: 25232530]
Fodil M, Benzaoui A, Zemani-Fodil F, et al. Association of PTPN22 (rs2476601) and STAT4 (rs7574865) polymorphisms with Rheumatoid Arthritis in the Western Algerian population. Acta Reumatol Port 2015; 40(1): 56-62.
[PMID: 25351936]
Zhang L, Yu M, Deng J, et al. Chemokine signaling pathway involved in CCL2 expression in patients with rheumatoid arthritis. Yonsei Med J 2015; 56(4): 1134-42.
[] [PMID: 26069140]
Szekanecz Z, Kim J, Koch AE. Chemokines and chemokine receptors in rheumatoid arthritis. Semin Immunol 2003; 15(1): 15-21.
[] [PMID: 12495637]
Szekanecz Z, Vegvari A, Szabo Z, Koch AE. Chemokines and chemokine receptors in arthritis. Front Biosci (Schol Ed) 2010; 2(2): 153-67.
[] [PMID: 20036936]
Redlich K, Hayer S, Ricci R, et al. Osteoclasts are essential for TNF-α-mediated joint destruction. J Clin Invest 2002; 110(10): 1419-27.
[] [PMID: 12438440]
Gouwy M, Struyf S, Noppen S, et al. Synergy between coproduced CC and CXC chemokines in monocyte chemotaxis through receptor-mediated events. Mol Pharmacol 2008; 74(2): 485-95.
[] [PMID: 18469140]
Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu Rev Immunol 2014; 32: 659-702.
[] [PMID: 24655300]
Nanki T, Takada K, Komano Y, et al. Chemokine receptor expression and functional effects of chemokines on B cells: implication in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther 2009; 11(5): R149.
[] [PMID: 19804625]
Gouwy M, Struyf S, Berghmans N, Vanormelingen C, Schols D, Van Damme J. CXCR4 and CCR5 ligands cooperate in monocyte and lymphocyte migration and in inhibition of dual-tropic (R5/X4) HIV-1 infection. Eur J Immunol 2011; 41(4): 963-73.
[] [PMID: 21381021]
Nevius E, Gomes AC, Pereira JP. Inflammatory cell migration in rheumatoid arthritis: A comprehensive review. Clin Rev Allergy Immunol 2016; 51(1): 59-78.
[] [PMID: 26511861]
Choi J, Selmi C, Leung PS, Kenny TP, Roskams T, Gershwin ME. Chemokine and chemokine receptors in autoimmunity: the case of primary biliary cholangitis. Expert Rev Clin Immunol 2016; 12(6): 661-72.
[] [PMID: 26821815]
Björkander S, Heidari-Hamedani G, Bremme K, Gunnarsson I, Holmlund U. Peripheral monocyte expression of the chemokine receptors CCR2, CCR5 and CXCR3 is altered at parturition in healthy women and in women with systemic lupus erythematosus. Scand J Immunol 2013; 77(3): 200-12.
[] [PMID: 23298254]
Antonelli A, Ferrari SM, Giuggioli D, Ferrannini E, Ferri C, Fallahi P. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev 2014; 13(3): 272-80.
[] [PMID: 24189283]
Lebre MC, Vergunst CE, Choi IY, et al. Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis. PLoS One 2011; 6(7)e21772
[] [PMID: 21747955]
Kumase F, Takeuchi K, Morizane Y, et al. AMPK-activated protein kinase suppresses CCR2 expression by inhibiting the NF-κB pathway in RAW264. 7 macrophages. PLoS One 2016; 11(1)e0147279
[] [PMID: 26799633]
Rossol M, Pierer M, Arnold S, et al. Negative association of the chemokine receptor CCR5 d32 polymorphism with systemic inflammatory response, extra-articular symptoms and joint erosion in rheumatoid arthritis. Arthritis Res Ther 2009; 11(3): R91.
[] [PMID: 19538721]
Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 2009; 29(6): 313-26.
[] [PMID: 19441883]
Frodsham M, Penton JA. Methotrexate formulation.WO2016067024 (2016).
Mensonides-Harsema M, Bialleck S. Sulfasalazine salts, production processes and uses. WO2019101903 (2019).
Gupton BF, Ahmad S, Mangunuru HPR, Telang NS. Highyielding continuous flow synthesis of antimalarial drug hydroxychloroquine.WO2019165337 (2019).
Flemming J, Peters H, Brandt A, Will H, Mensonides-Harsema M. High-yielding continuous flow synthesis of antimalarial drug hydroxychloroquine. WO2014096464 (2014).
Reiner G, Reiner A. Diclofenac formulations and methods of use.US20170319484 (2017).
Andrew B. Piroxicam transdermal composition to treat plantar fasciitis. US20140371211 (2014)
Kiel JS, Bryant TJ, Levasseur RG, Thomas HG, Parks CR. Liquid formulations of celecoxib for oral administration.WO2016196085 (2016).
Sirihorachai R, Rosar P. Modified release formulation of naproxen sodium. WO2017062027 (2017).
Asotra S, Gao S, Yacobi A. Oral suspension of prednisolone acetate. US20130143853 (2013).
Kreyenborg C, Meimberg E, Tissen C, Bannefeld KH. Compositions comprising dexamethasone. US20190183907 (2019).
Mirshafiey A. Pharmaceutical use of beta-D-mannuronic acid.EP067919 (2017).
Ahmadi H, Jamshidi AR, Gharibdoost F, et al. A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of β-D-mannuronic acid in rheumatoid arthritis patients. Inflammopharmacology 2018; 26(3): 737-45.
[] [PMID: 29696564]
Mirshafiey A, Cuzzocrea S, Rehm B, Mazzon E, Saadat F, Sotoude M. Treatment of experimental arthritis with M2000, a novel designed non-steroidal anti-inflammatory drug. Scand J Immunol 2005; 61(5): 435-41.
[] [PMID: 15882435]
Mortazavi-Jahromi SS, Jamshidi MM, Farazmand A, Aghazadeh Z, Yousefi M, Mirshafiey A. Pharmacological effects of β-d-mannuronic acid (M2000) on miR-146a, IRAK1, TRAF6 and NF-κB gene expression, as target molecules in inflammatory reactions. Pharmacol Rep 2017; 69(3): 479-84.
[] [PMID: 28324845]
Rezaieyazdi Z, Farooqi A, Soleymani-Salehabadi H, et al. International multicenter randomized, placebo-controlled phase III clinical trial of β-D-mannuronic acid in rheumatoid arthritis patients. Inflammopharmacology 2019; 27(5): 911-21.
[] [PMID: 30604197]
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62(9): 2569-81.
[] [PMID: 20872595]
Fattahi MJ, Abdollahi M, Agha Mohammadi A, et al. Preclinical assessment of β-d-mannuronic acid (M2000) as a non-steroidal anti-inflammatory drug. Immunopharmacol Immunotoxicol 2015; 37(6): 535-40.
[] [PMID: 26584020]
Mortazavi-Jahromi SS, Alizadeh S, Javanbakht MH, Mirshafiey A. Anti-diabetic effect of β-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property on insulin production, blood glucose, and inflammatory markers in the experimental diabetes model. Arch Physiol Biochem 2019; 125(5): 435-40.
[] [PMID: 29882437]
Fattahi MJ, Jamshidi AR, Mahmoudi M, et al. Evaluation of the efficacy and safety of β-d-mannuronic acid in patients with ankylosing spondylitis: A 12-week randomized, placebo-controlled, phase I/II clinical trial. Int Immunopharmacol 2018; 54: 112-7.
[] [PMID: 29127910]
Ho CY, Wong CK, Li EK, Tam LS, Lam CW. Suppressive effect of combination treatment of leflunomide and methotrexate on chemokine expression in patients with rheumatoid arthritis. Clin Exp Immunol 2003; 133(1): 132-8.
[] [PMID: 12823287]
Ellingsen T, Hornung N, Møller BK, Poulsen JH, Stengaard-Pedersen K. Differential effect of methotrexate on the increased CCR2 density on circulating CD4 T lymphocytes and monocytes in active chronic rheumatoid arthritis, with a down regulation only on monocytes in responders. Ann Rheum Dis 2007; 66(2): 151-7.
[] [PMID: 16905577]
Liang L, Hu D, Liu W, Williams JP, Okunieff P, Ding I. Celecoxib reduces skin damage after radiation: selective reduction of chemokine and receptor mRNA expression in irradiated skin but not in irradiated mammary tumor. Am J Clin Oncol 2003; 26(4): S114-21.
[] [PMID: 12902868]
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365(23): 2205-19.
[] [PMID: 22150039]
Nanki T, Hayashida K, El-Gabalawy HS, et al. Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. J Immunol 2000; 165(11): 6590-8.
[] [PMID: 11086103]

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 29 March, 2020
Page: [69 - 77]
Pages: 9
DOI: 10.2174/1872213X13666191114111822

Article Metrics

PDF: 12