Antiinflammatory and antioxidant effects of gemcitabine in collagen-induced arthritis model

Antiinflammatory and antioxidant effects of gemcitabine in collagen-induced arthritis model

Background/aim: Gemcitabine (GEM) has antiproliferative effects on lymphocytes, which are potent pathogenic actors of rheumatoid arthritis (RA). The aim of the study was to investigate the therapeutic potential of GEM on collagen-induced arthritis (CIA). Materials and methods: Arthritis was induced by the intradermal injection of chicken type II collagen with incomplete Freund s adjuvant into albino Wistar rats. Doses of 5 and 20 mg/kg GEM were administered twice a week after the 14th day, which marked the onset the arthritis. Serum IL-17, TNF-α, malondialdehyde, catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels and tissue heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) levels were analyzed. Results: Histopathologically prevalent inflammation and cartilage/bone destruction were observed in the arthritis group. Moreover, in the arthritis group serum IL-17, TNF-α, and malondialdehyde levels were significantly increased while catalase, SOD, GPx, HO-1, and Nrf2 levels were significantly decreased. However, in the GEM-treated groups, decreased TNF-α, IL-17, and malondialdehyde levels; increased SOD, catalase, GPx, Nrf2, and HO-1 levels; and ameliorated perisynovial inflammation and cartilage/bone destruction were observed. Conclusion: GEM suppresses cytokine levels and enhances antioxidant activity. It also prevents cartilage/bone destruction in the CIA model. GEM may be a viable candidate for research into the treatment of RA.

___

  • 1. Weyand CM, Fujii H, Shao L, Goronzy JJ. Rejuvenating the immune system in rheumatoid arthritis. Nat Rev Rheumatol 2009; 5: 583-588.
  • 2. Moura RA, Graca L, Fonseca JE. To B or not to B the conductor of rheumatoid arthritis orchestra. Clin Rev Allergy Immunol 2012; 43: 281-291.
  • 3. Yang Z, Matteson EL, Goronzy JJ, Weyand CM. T-cell metabolism in autoimmune disease. Arthritis Res 2015; 17: 29.
  • 4. Zhang L, Yu M, Deng J, Lv X, Liu J, Xiao Y, Yang W, Zhang Y, Li C. Chemokine signaling pathway involved in CCL2 expression in patients with rheumatoid arthritis. Yonsei Med J 2015; 56: 1134-1142.
  • 5. Gizinski AM, Fox DA. T cell subsets and their role in the pathogenesis of rheumatic disease. Curr Opin Rheumatol 2014; 26: 204-210.
  • 6. Centola M, Cavet G, Shen Y, Ramanujan S, Knowlton N, Swan KA, Turner M, Sutton C, Smith DR, Haney DJ et al. Development of a multi-biomarker disease activity test for rheumatoid arthritis. PLoS One 2013; 8: e60635.
  • 7. Hitchon CA, El-Gabalawy HS. Oxidation in rheumatoid arthritis. Arthritis Res Ther 2004; 6: 265-278.
  • 8. Halliwell B, Hoult JR, Blake DR. Oxidants, inflammation, and anti-inflammatory drugs. FASEB J 1988; 2: 2867-2873.
  • 9. Ahmed SM, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta 2017; 1863: 585-597.
  • 10. Kim MK, Jeon YK, Woo JK, Choi Y, Choi DH, Kim YH, Kim CW. The C-terminal region of Bfl-1 sensitizes non-small cell lung cancer to gemcitabine-induced apoptosis by suppressing NF-κB activity and down-regulating Bfl-1. Mol Cancer 2011; 10: 98.
  • 11. Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res 2002; 62: 2353-2358.
  • 12. Trentham DE, Townes AS, Kang AH. Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med 1977; 146: 857-868.
  • 13. Seelig MH, Leible M, Sänger J, Berger MR. Chemoembolization of rat liver metastasis with microspheres and gemcitabine followed by evaluation of tumor cell load by chemiluminescence. Oncol Rep 2004; 11: 1107-1113.
  • 14. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275.
  • 15. Larsson P, Kleinau S, Holmdahl R, Klareskog L. Homologous type II collagen-induced arthritis in rats. Characterization of the disease and demonstration of clinically distinct forms of arthritis in two strains of rats after immunization with the same collagen preparation. Arthritis Rheum 1990; 33: 693-701.
  • 16. Barsante MM, Roffê E, Yokoro CM, Tafuri WL, Souza DG, Pinho V, Castro MS, Teixeira MM. Anti-inflammatory and analgesic effects of atorvastatin in a rat model of adjuvantinduced arthritis. Eur J Pharmacol 2005; 516: 282-289.
  • 17. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Eng J Med 2011; 365: 2205-2219.
  • 18. Holmdahl R, Malmstrom V, Burkhardt H. Autoimmune priming, tissue attack and chronic inflammation-the three stages of rheumatoid arthritis. Eur J Immunol 2014; 44: 1593- 1599.
  • 19. Plate JM, Plate AE, Shott S, Bograd S, Harris JE. Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother 2005; 54: 915- 925.
  • 20. Baird AM, Dockry E, Daly A, Stack E, Doherty DG, O’Byrne KJ, Gray SG. IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer. Front Oncol 2013; 3: 162.
  • 21. Landi D, Santini D, Vincenzi B, La Cesa A, Dianzani C, Tonini G. Dramatic improvement of psoriasis with gemcitabine monotherapy. Br J Dermatol 2003; 149: 1306-1307.
  • 22. Niimoto T, Nakasa T, Ishikawa M, Okuhara A, Izumi B, Deie M, Suzuki O, Adachi N, Ochi M. MicroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients. BMC Musculoskelet Disord 2010; 11: 209.
  • 23. Koenders MI, Marijnissen RJ, Devesa I, Lubberts E, Joosten LA, Roth J, van Lent PL, van de Loo FA, van den Berg WB. Tumor necrosis factor-interleukin-17 interplay induces S100A8, interleukin-1β, and matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis: rationale for combination treatment during arthritis. Arthritis Rheum 2011; 63: 2329-2339.
  • 24. Stamp LK, James MJ, Cleland LG. Interleukin-17: the missing link between T-cell accumulation and effector cell actions in rheumatoid arthritis? Immunol Cell Biol 2004; 82: 1-9.
  • 25. Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S, Saito S, Inoue K, Kamatani N, Gillespie MT et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999; 103: 1345-1352.
  • 26. Lubberts E, van den Bersselaar L, Oppers-Walgreen B, Schwarzenberger P, Coenen-de Roo CJ, Kolls JK, Joosten LA, van den Berg WB. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol 2003; 170: 2655-2662.
  • 27. Cope AP, Aderka D, Doherty M, Engelmann H, Gibbons D, Jones AC, Brennan FM, Maini RN, Wallach D, Feldmann M. Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases. Arthritis Rheum 1992; 35: 1160-1169.
  • 28. Girotti AW. Lipid hydroperoxide generation, turnover, and effector action in biological systems. J Lipid Res 1998; 39: 1529- 1542.
  • 29. Çimen MY, Çimen ÖB, Kaçmaz M, Öztürk HS, Yorgancioğlu R, Durak İ. Oxidant/antioxidant status of the erythrocytes from patients with rheumatoid arthritis. Clin Rheumatol 2000; 19: 275-277.
  • 30. Nivsarkar M. Improvement in circulating superoxide dismutase levels: role of nonsteroidal anti-inflammatory drugs in rheumatoid arthritis. Biochem Biophys Res Commun 2000; 270: 714-716.
  • 31. Afonso V, Champy R, Mitrovic D, Collin P, Lomri A.. Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine 2007; 74: 324-329.
  • 32. Iyama S, Okamoto T, Sato T, Yamauchi N, Sato Y, Sasaki K, Takahashi M, Tanaka M, Adachi T, Kogawa K et al. Treatment of murine collagen-induced arthritis by ex vivo extracellular superoxide dismutase gene transfer. Arthritis Rheum 2001; 44: 2160-2167.
  • 33. Jaswal S, Mehta HC, Sood AK, Kaur J. Antioxidant status in rheumatoid arthritis and role of antioxidant therapy. Clin Chim Acta 2003; 338: 123-129.
  • 34. Baskol G, Demir H, Baskol M, Kilic E, Ates F, Kocer D, Muhtaroglu S. Assessment of paraoxonase 1 activity and malondialdehyde levels in patients with rheumatoid arthritis. Clin Biochem 2005; 38: 951-955.
  • 35. Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 2014; 39: 199-218.
  • 36. Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S et al. Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 2011; 70: 844- 850.
  • 37. Maicas N, Ferrándiz ML, Brines R, Ibáñez L, Cuadrado A, Koenders MI, van den Berg WB, Alcaraz MJ. Deficiency of Nrf2 accelerates the effector phase of arthritis and aggravates joint disease. Antioxid Redox Signal 2011; 15: 889-901.
  • 38. Duong HQ, Yi YW, Kang HJ, Hong YB, Tang W, Wang A, Seong YS, Bae I. Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int J Oncol 2014; 44: 959-969.
Turkish Journal of Medical Sciences-Cover
  • ISSN: 1300-0144
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: TÜBİTAK
Sayıdaki Diğer Makaleler

Effects of Artcure Diffusional Patch application on pain and functional status in lumbar disc herniation patients: a prospective randomized controlled study

Mehmet Atıf Erol AKSEKİLİ, Mahmut UĞURLU, Halil KARA, Berat Meryem ALKAN, Ceyhun ÇAĞLAR

Neslihan Hacer Dikmenoğlu FALKMARKEN, Okan ARIHAN, Alper Bektaş İSKİT

What is the rectal colonization rate of carbapenem-resistant Enterobacteriaceae (CRE)-infected patients? What is the decolonization rate of CRE-colonized patients in the hospital?

Fatma Feriha ÇİLLİ, Oğuz Reşat SİPAHİ, Sercan ULUSOY, Nilay KORKMAZ, Mehmet Ali ÖZİNEL, Münevver KAYIN, Demet DİKİŞ, Nilgün Deniz KÜÇÜKLER, Nurhayat KEPELİ, Behiye ULUSOY, Şükran AKŞİT BARIK, Bilgin ARDA, Ayşe UYAN

Comparative analysis of selected cagPAI genes and different vacA genotypes in Iranian and Turkish H. pylori-positive patients suffering from gastric adenocarcinoma and active chronic gastritis

Figen DORAN, Fatih KÖKSAL, Maryam YAASI, Suna KIZILYILDIRIM, Mohammad HOSSEIN SOMI, Amirtaher EFTEKHARSADAT, Mahsa ESMAEILLOU, Başak BEDİR, Ali BAHADORI

Possible triggering factors and comorbidities in newly diagnosed autoimmune bullous diseases

Özlem ÖZBAĞÇIVAN, Sevgi AKARSU, Şebnem AKTAN, Necla DOLAŞ

The evaluation of cervical spinal angle in patients with acute and chronic neck pain

Aliye TOSUN, Ümit Seçil DEMİRDAL, Ayhan AŞKIN, Korhan Barış BAYRAM, Emel ATAR, Çiğdem ARİFOĞLU KARAMAN, Ece GÜVENDİ

Negin NAGHDI, Masood GHANE

Serum ischemic modified albumin (IMA) concentration and IMA/albumin ratio in patients with hepatitis B-related chronic liver diseases

Mehmet ASIL, Murat BIYIK, Saliha UYSAL, Hüseyin ATASEVEN, Ramazan DERTLİ, Ali DEMİR, Fatma YAVUZ, Hakkı POLAT

Risk factors associated with poor outcome in diabetic foot ulcer patients

Saira SALEEM, Nazim HAYAT, Irshad AHMED, Tanvir AHMED, Abdul Gaffar REHAN

Fatma Feriha ÇİLLİ, Bilgin ARDA, AYŞE UYAN, Münevver KAYIN, Demet DİKİŞ, Nilay KORKMAZ, Nilgün Deniz KÜÇÜKLER, NURHAYAT KEPELİ, Behiye ULUSOY, ŞÜKRAN AKŞİT BARIK, Mehmet Ali ÖZİNEL, Sercan ULUSOY, OĞUZ REŞAT SİPAHİ