Effects of silymarin as adjuvant drug on serum levels of CTRP3, anti-cyclic citrullinated peptide (CCP), and high-sensitivity C-reactive protein (hs-CRP) in rheumatoid arthritis patients

Document Type : Original article

Authors

1 Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran

2 Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

3 Regenerative Medicine Research Center (RMRC), Kermanshah University of Medical Sciences, Iran Medical Sciences

4 Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Kermanshah, Iran

5 Department of Internal Medicine, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran

Abstract

Silymarin is known for its anti-inflammatory and antioxidant properties. We investigated these effects on serum levels of CTRP3, Anti-CCP, and hs-CRP in individuals with Rheumatoid arthritis (RA). In this study, 42 individuals with RA were recruited and their serum specimens were collected, serum levels of hs-CRP, AntiCCP antibodies, and CTRP3 were measured using ELISA. DNA was extracted and investigated for the existence of possible new mutations in the gene encoding CTRP3 using the PCR technique; the desired fragments were then amplified and sequenced. Another blood sample was collected from the case group after taking livergol for three months (3 doses of 140 mg/day) and the tests were repeated. Anti-CCP Abs levels in the postintervention responding group decreased compared to preintervention (p<0.001) while in the non-responding group, the levels increased after the intervention compared to the levels before the intervention (p=0.019). Additionally, CTRP3 levels in the responding group increased postintervention (p=0.003), however, in the non-responding group the levels decreased postintervention when compared to preintervention (p=0.02). The responding group had significantly lower levels of hs-CRP when compared to that of preintervention (p=0.005) whereas the non-responding group had significantly higher levels of postintervention (p<0.001). Moreover, the results of sequencings of exon 6 on CTRP3 gene showed the presence of mutations in exon 6 (position 215:C>T, 338:G>A, 359:A>C, and 153:T>C). Silymarin could be used as an adjuvant in the treatment of rheumatoid arthritis.

Keywords


  1. Mueller AL, Payandeh Z, Mohammadkhani N, Mubarak SMH, Zakeri A, Alagheband Bahrami A, Brockmueller A, Shakibaei M. Recent advances in understanding the pathogenesis of rheumatoid arthritis: New treatment strategies. Cells 2021;10:3017.
  2. Venetsanopoulou AI, Alamanos Y, Voulgari PV, Drosos AA. Epidemiology of rheumatoid arthritis: genetic and environmental influences. Expert Rev Clin Immunol 2022;18:923-931.
  3. Elieh Ali Komi D, Grauwet K. Role of mast cells in regulation of T cell responses in experimental and clinical settings. Clin Rev Allergy Immunol 2018;54:432-445.
  4. Sparks JA. Rheumatoid Arthritis. Ann Intern Med 2019;170;ITC1-ITC16
  5. Pope JE, Choy EH. C-reactive protein and implications in rheumatoid arthritis and associated comorbidities. Semin Arthritis Rheum 2021;51:219-229.
  6. Kim KW, Kim BM, Moon HW, Lee SH, Kim HR. Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis. Arthritis Res Ther 2015;17:41.
  7. Ali AM, Rostam HM, Fatah MH, Noori CM, Ali KM, Tawfeeq HM. Serum troponin, D-dimer, and CRP level in severe coronavirus (COVID-19) patients. Immun Inflamm Dis 2022;10:e582.
  8. Elieh Ali Komi D, Rahimi Y, Asghari R, Jafari R, Rasouli J, Mohebalizadeh M, Abbasi A, Nejadrahim R, Rezazadeh F, Shafiei-Irannejad V. Investigation of the molecular mechanism of coagulopathy in severe and critical patients iith COVID-19. Front Immunol 2021;12: 762782.
  9. Puszczewicz M, Iwaszkiewicz C. Role of anti-citrullinated protein antibodies in diagnosis and prognosis of rheumatoid arthritis. Arch Med Sci 2011;7:189-194.
  10. Hasegawa N, Fujie S, Horii N, Uchida M, Kurihara T, Sanada K, Hamaoka T, Iemitsu M. Aerobic exercise training-induced changes in serum C1q/TNF-related protein levels are associated with reduced arterial stiffness in middle-aged and older adults. Am J Physiol Regul Integr Comp Physiol 2018;314:R94-R101.
  11. Trier NH, Houen G. Epitope specificity of anti-citrullinated protein antibodies. Antibodies (Basel) 2017;6:5.
  12. Elieh Ali Komi D, Shafaghat F, Christian M. Crosstalk between mast cells and adipocytes in physiologic and pathologic conditions. Clin Rev Allergy Immunol 2020;58:388-400
  13. Schäffler A, Buechler C. CTRP family: linking immunity to metabolism. Trends Endocrinol Metab 2012;23:194-204
  14. Kopp A, Bala M, Buechler C, Falk W, Gross P, Neumeier M, Schölmerich J, Schäffler A. C1q/TNF-related protein-3 represents a novel and endogenous lipopolysaccharide antagonist of the adipose tissue. Endocrinology 2010;151:5267-5278.
  15. Masoodian SM, Toolabi K, Omidifar A, Zabihi H, Rahimipour A, Shanaki M. Increased mRNA expression of CTRP3 and CTRP9 in adipose tissue from obese women: is it linked to obesity-related parameters and mRNA expression of inflammatory cytokines? Rep Biochem Mol Biol 2020;9:71-81
  16. Fadaei R, Moradi N, Baratchian M, Aghajani H, Malek M, Fazaeli AA, Fallah S. Association of C1q/TNF-related protein-3 (CTRP3) and CTRP13 serum levels with coronary artery disease in subjects with and without type 2 diabetes mellitus. PLoS One 2016;11:e0168773.
  17. Zhang J, Zhang B, Cheng Y, Xu J. Low serum CTRP3 levels are associated with nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Cytokine 2018; 106:131-135.
  18. Wagner RM, Sivagnanam K, Clark WA, Peterson JM. Divergent relationship of circulating CTRP3 levels between obesity and gender: a cross-sectional study. PeerJ 2016,4:e2573.
  19. Peterson JM, Wei Z, Wong GW. C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output. J Biol Chem 2010;285:39691-39701.
  20. Navabi SM, Elieh-Ali-Komi D, Afshari D, Goudarzi F, Mohammadi-Noori E, Heydari K, Heydarpour F, Kiani A. Adjunctive silymarin supplementation and its effects on disease severity, oxidative stress, and inflammation in patients with Alzheimer's disease. Nutr Neurosci 2024;14:1-11
  21. El-Lakkany NM, Hammam OA, El-Maadawy WH, Badawy AA, Ain-Shoka AA, Ebeid FA. Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schisto-somicide praziquantel against Schistosoma mansoni-induced liver fibrosis. Parasit Vectors 2012;5:9.
  22. Ferraz AC, Almeida LT, da Silva Caetano CC, da Silva Menegatto MB, Souza Lima RL, de Senna JPN, de Oliveira Cardoso JM, Perucci LO, Talvani A, Geraldo de Lima W, de Mello Silva B, Barbosa Reis A, de Magalhães JC, Lopes de Brito Magalhães C. Hepatoprotective, antioxidant, anti-inflammatory and antiviral activities of silymarin against mayaro virus infection. Antiviral Res 2021;194:105168.
  23. Aliyari M, Elieh Ali Komi D, Kiani A, Moradi M, Tanhapour M, Rahimi Z, Mozafari H, Mohammadi-Noori E, Pourmotabbed T, Vaisi-Raygani A, Bahrehmand F. The role of caveolin-1 and endothelial nitric oxide synthase polymorphisms in susceptibility to prostate cancer. Int J Exp Pathol 2021;102:260-267
  24. Amiri M, Elieh Ali Komi D, Vaisi-Raygani A, Kiani A, Moradi M, Aliyari M, Rahimi Z, Mohammadi-Noori E, Bashiri H. Association between vitamin D binding protein gene polymorphism (rs7041), vitamin D receptor, and 25-hydroxyvitamin D serum levels with prostate cancer in Kurdish population in west of Iran. Pathol Oncol Res 2022;28:1610246.
  25. Mohammadi-Noori E, Salehi N, Mozafari H, Elieh Ali Komi D, Saidi M, Bahrehmand F, Vaisi-Raygani A, Elahirad S, Moini A. Kiani A. Association of AHSG gene polymorphisms with serum Fetuin-A levels in individuals with cardiovascular calcification in west of Iran. Mol Biol Rep 2020;47:1809-1820
  26. Vanni A, Mazzoni A, Semeraro R, Capone M, Maschmeyer P, Lamacchia G, Salvati L, Carnasciali A, Farahvachi P, Giani T, Simonini G, Filocamo G, Romano M, Liotta F, Mashreghi MF, Cosmi L, Cimaz R, Magi A, Maggi L, Annunziato F. Clonally expanded PD-1-expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients. Eur J Immunol 2023;53:e2250162
  27. Brown P, Pratt AG, Hyrich KL. Therapeutic advances in rheumatoid arthritis. BMJ 2024; 384:e070856.
  28. Finckh A, Gilbert B, Hodkinson B, Bae SC, Thomas R, Deane KD, Alpizar-Rodriguez D, Lauper K. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol 2022;18:591-602.
  29. Mostmans Y, De Smedt K, Richert B, Elieh Ali Komi D, Maurer M, Michel O. Markers for the involvement of endothelial cells and the coagulation system in chronic urticaria: A systematic review. Allergy 2021;76:2998-3016.
  30. Ullah I, Awan HA., Aamir A, Diwan MN, de Filippis R, Awan S, Irfan M, Fornaro M, Ventriglio A, Vellante F, Pettorruso M, Martinotti G, Di Giannantonio M, De Berardis D. Role and perspectives of inflammation and C-reactive protein (CRP) in psychosis: An economic and widespread tool for assessing the disease. Int J Mol Sci 2021;22:13032.
  31. Shokri-Mashhadi N, Moradi S, Heidari Z, Saadat S. Association of circulating C-reactive protein and high-sensitivity C-reactive protein with components of sarcopenia: A systematic review and meta-analysis of observational studies. Exp Gerontol 2021;150:111330.
  32. Guo B, Zhuang T, Xu F, Lin X, Li F, Shan SK, Wu F, Zhong JY, Wang Y, Zheng MH, Xu QS, Ehsan UMH, Yuan LQ. New insights into implications of CTRP3 in obesity, metabolic dysfunction, and cardiovascular diseases: Potential of therapeutic interventions. Front Physiol 2020;11:570270.
  33. Papadopoulos NG, Tsiaousis GZ, Pavlitou-Tsiontsi A, Giannakou A, Galanopoulou VK. Does the presence of anti-CCP autoantibodies and their serum levels influence the severity and activity in rheumatoid arthritis patients?. Clin Rev Allergy Immunol 2008;34:11-15.
  34. Weigert J, Neumeier M, Schäffler A, Fleck M, Schölmerich J, Schütz C, Buechler C. The adiponectin paralog CORS-26 has anti-inflammatory properties and is produced by human monocytic cells. FEBS Lett 2005;579:5565-5570.
  35. Kay J, Upchurch KS. ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford) 2012;51:vi5-vi9.
  36. Ebrahimpour Koujan S, Gargari BP, Mobasseri M, Valizadeh H, Asghari-Jafarabadi M. Effects of Silybum marianum (L.) Gaertn. (silymarin) extract supplementation on antioxidant status and hs-CRP in patients with type 2 diabetes mellitus: a randomized, triple-blind, placebo-controlled clinical trial. Phytomedicine 2015;22:290-296.
  37. Hussain SA, Mortada AH, Jasim NA, Gorial FI. Silibinin improves the effects of methotrexate in patients with active rheumatoid arthritis: Pilot clinical study. Oman Med J 2016;31:263-269
  38. Elgarf AT, Mahdy MM, Sabri NA. Effect of silymarin supplementation on glycemic control, lipid profile and insulin resistance in patients with type 2 diabetes mellitus. Int J Adv Res 2015;3:812-821.
  39. Giuseppe D, Angelaq D'A, Davide R, Pamela M. Effects of a combination of berberis aristata, silybum marianum and monacolin on lipid profile in subjects at low cardiovascular risk; A double-blind, randomized, placebo-controlled trial. Int J Mol Sci 2017;18:343.