Effects of thymoquinone on some cytokine levels in cerulein-induced acute pancreatitis

Year 2022, , 194 - 201, 31.08.2022

Semiha Kanaç , Ercan Keskin , Deniz Uluışık

https://doi.org/10.31797/vetbio.1063971

Cited By: 1

Abstract

In this study, it was aimed to evaluate the possible effects of thymoquinone administration on some cytokine levels in rats with experimental acute pancreatitis. No application was made the animals in group K. TQ group animals were intraperitoneally given 20 mg/kg thymoquinone daily for 9 days. In the AP group animals, acute pancreatitis was induced by intraperitoneal administration of cerulein as first dose 50 µg/kg and 2 hours later 25 µg/kg second dose on the 7th day of the study. Animals in the AP+TQ group were intraperitoneally administered 20 mg/kg thymoquinone daily for 9 days. On the 7th day of the study, after 2 hours from thymoquinone administration, acute pancreatitis was induced by intraperitoneal administration of cerulean as 50 µg/kg and 2 hours later 25 µg/kg. TNF-α, IL-6, IL-8, IL-10, AST and ALT levels were determined in the blood samples taken from all animals. In the study, TNF-α level was found to be importantly higher in the acute pancreatitis group compared to the control group, while TNF-α level was significantly lower in the acute pancreatitis group treated with thymoquinone than the acute pancreatitis group. IL-6 and IL-8 levels were higher in the acute pancreatitis group compared to the control group. IL-6 and IL-8 levels were found to be significantly lower in rats with acute pancreatitis treated with thymoquinone compared to the group with acute pancreatitis. While AST and ALT levels in the acute pancreatitis group were significantly increased when compared with the control group, both enzyme levels in the acute pancreatitis group treated with thymoquinone administration were found to be significantly lower than the rats with acute pancreatitis. In the study, the findings obtained in rats with acute pancreatitis which were pre-treated with thymoquinone can be evaluated as that thymoquinone alleviates inflammation due to pancreatitis.

Keywords

Cerulein, Cytokine, Rats, Thymoquinone

Supporting Institution

Selcuk University Scientific Research Projects Coordinatorship

Project Number

Project no: 19202064

Serulein ile Akut Pankreatit Oluşturulan Ratlara Timokinon Uygulamasının Bazı Sitokinler Üzerine Etkileri

Abstract

Çalışmada serulein ile deneysel akut pankreatit oluşturulan ratlara timokinon uygulamasının bazı sitokinler üzerine olası etkilerinin değerlendirilmesi amaçlandı. K grubundaki hayvanlara herhangi bir uygulama yapılmadı. TQ grubundaki hayvanlara 9 gün süre ile günde 20 mg/kg timokinon intraperitoneal olarak verildi. AP grubundaki hayvanlarda araştırmanın 7. gününde 50 µg/kg ve 2 saat sonra 25 µg/kg seruleinin intraperitoneal olarak uygulanmasıyla akut pankreatit oluşturuldu. AP+TQ grubundaki hayvanlara günde 20 mg/kg olmak üzere 9 gün süre ile intraperitoneal olarak timokinon uygulandı ve 7. günde timokinon uygulamasından 2 saat sonra 50 µg/kg ve bundan 2 saat sonra 25 µg/kg seruleinin intraperitoneal olarak uygulanmasıyla akut pankreatit oluşturuldu. Alınan kan örneklerinde Tümör Nekroz Faktör (TNF)-α, Interlökin (IL)-6, IL-8, IL-10, Aspartat Aminotransferaz (AST) ve Alanin Aminotransferaz (ALT) düzeyleri belirlendi. Çalışmada akut pankreatitli grubun TNF-α düzeyi kontrol grubuna göre anlamlı olarak yüksek bulunurken, timokinon uygulanan akut pankreatitli grupta TNF-α düzeyi akut pankreatitli gruba göre anlamlı olarak daha düşük bulundu. IL-6 ve IL-8 düzeyleri akut pankreatit grubunda kontrol grubuna göre yüksek bulundu. Timokinon uygulanan akut pankreatitli ratlarda IL-6 ve IL-8 düzeyleri akut pankreatitli gruba göre anlamlı oranda düşüktü. Akut pankreatitli grupta AST ve ALT düzeyleri kontrol grubuna göre önemli oranda yüksek bulunurken, akut pankreatitli ratlara timokinon uygulamasıyla her iki enzim düzeyinin akut pankreatitli gruba göre anlamlı olarak düşük olduğu belirlendi. Çalışmada timokinon ön uygulaması yapılan akut pankreatitli ratlarda elde edilen bulgular timokinonun pankreatite bağlı olarak gelişen inflamasyonu hafiflettiği şeklinde değerlendirilebilir.

Keywords

Rat, Serulein, Sitokin, Timokinon

Project Number

Project no: 19202064

References

• Abukhader, M.M. (2013). Thymoquinone in the clinical treatment of cancer: Fact or fiction? Pharmacognosy reviews, 7(14), 117-120. doi:10.4103/0973-7847.120509.
• Ahmad, A., Husain, A., Mujeeb, M., Khan, S.A., Najmi, A.K., Siddique, N.A., Damanhouri, Z.A., & Anwar, F. (2013). A review on therapeutic potential of Nigella sativa: A miracle herb. Asian Pacific Journal of Tropical Biomedicine, 3(5), 337-352. doi: 10.1016/S2221-1691(13)60075-1.
• Al Rowais, N.A. (2002). Herbal medicine in the treatment of diabetes mellitus. Saudi Medical Journal, 23(11), 1327-1331. PMID: 12506289.
• Ali, B.H., & Blunden, G. (2003). Pharmacological and toxicological properties of Nigella sativa. Phytotherapy Research, 17(4), 299-305. doi: 10.1002/ptr.1309.
• Arjumand, S., Shahzad, M., Shabbir, A., & Yousaf, M.Z. (2019). Thymoquinone attenuates rheumatoid arthritis by downregulating TLR2, TLR4, TNF-α, IL-1, and NFκB expression levels. Biomedicine Pharmacotherapy, 111, 958-963. doi: 10.1016/j.biopha.2019.01.006.
• Badr, G., Alwasel, S., Ebaid, H., Mohany, M., & Alhazza, I. (2011). Perinatal supplementation with thymoquinone improves diabetic complications and T cell immune responses in rat offspring. Cellular immunology, 267(2), 133-140. doi: 10.1016/j.cellimm.2011.01.002.
• Baggiolini, M., Walz, A., & Kunkel, S. (1989). Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. Journal of Clinical Investigation, 84(4), 1045-1049. doi: 10.1172/JCI114265.
• Banks, P.A., Bollen, T.L., Dervenis, C., Gooszen, H.G., Johnson, C.D., Sarr, M.G., Tsiotos, G.G., & Vege, S.S. (2013). Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut, 62(1), 102-111. doi: 10.1136/gutjnl-2012-302779.
• Bhatia, M., Wong, F.L., Cao, Y., Lau, H.Y., Huang, J., Puneet, P., & Chevali, L. (2005). Pathophysiology of acute pancreatitis. Pancreatology, 5(2-3), 132-144. doi: 10.1159/000085265.
• Bhatia, M., Brady, M., Shokuhi, S., Christmas, S., Neoptolemos, J.P., & Slavin, J. (2000). Inflammatory mediators in acute pancreatitis. The Journal of Pathology, 190(2), 117-125. doi: 10.1002/(SICI)1096-9896(200002)190:2<117::AID-PATH494>3.0.CO;2-K.
• Castell, J.V., Gómez-Lechón, M.J., David, M., Andus, T., Geiger, T., Trullenque, R., Fabra, R., & Heinrich, P.C. (1989). Interleukin‐6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS letters, 242(2), 237-239. doi: 10.1016/0014-5793(89)80476-4.
• Chehl, N., Chipitsyna, G., Gong, Q., Yeo, C.J., & Arafat, H.A. (2009). Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells. Hpb (Oxford), 11(5), 373-381. doi: 10.1111/j.1477-2574.2009.00059.x.
• Donaldson, K. (1998). Introduction to the healing herbs. ORL Head and Neck Nursing, 16(3), 9-16. PMID: 9814329.
• El Gazzar, M. (2007). Thymoquinone suppressses in vitro production of IL-5 and IL-13 by mast cells in response to lipopolysaccharide stimulation. Inflammation Research, 56(8), 345-351. doi: 10.1007/s00011-007-7051-0.
• Fiorentino, D.F., Zlotnik, A., Mosmann, T.R., Howard, M., & O'Garra, A. (1991). IL-10 inhibits cytokine production by activated macrophages. The Journal of Immunology, 147(11), 3815-3822. PMID: 1940369.
• Gallagher, S.F., Yang, J., Baksh, K., Haines, K., Carpenter, H., Epling-Burnette, P., Peng, Y., Norman, J., & Murr, M.M. (2004). Acute pancreatitis induces FasL gene expression and apoptosis in the liver. Journal of Surgical Research, 122(2), 201-209. doi: 10.1016/j.jss.2004.05.019.
• Galloway, S., & Kingsnorth, A. (1994). Reduction in circulating levels of CD4-positive lymphocytes in acute pancreatitis: relationship to endotoxin, interleukin 6 and disease severity. British Journal of Surgery, 81(2), 312. doi: 10.1002/bjs.1800810261.
• Geiger, T., Andus, T., Klapproth, J., Hirano, T., Kishimoto, T., & Heinrich, P.C. (1988). Induction of rat acute‐phase proteins by interleukin 6 in vivo. European Journal of Immunology, 18(5), 717-721. doi: 10.1002/eji.1830180510.
• Hack, C.E., Hart, M., Van Schijndel, R., Eerenberg, A., Nuijens, J., Thijs, L., & Aarden, L. (1992). Interleukin-8 in sepsis: relation to shock and inflammatory mediators. Infection and Immunity, 60(7), 2835-2842. doi: 10.1128/iai.60.7.2835-2842.1992.
• Hadi, V., Kheirouri, S., Alizadeh, M., Khabbazi, A., & Hosseini, H. (2016). Effects of Nigella sativa oil extract on inflammatory cytokine response and oxidative stress status in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled clinical trial. Avicenna Journal of Phytomedicine, 6(1), 34-43. PMID: 27247920.
• Jeannin, P., Delneste, Y., Gosset, P., Molet, S., Lassalle, P., Hamid, Q., Tsicopoulos, A., & Tonnel, A.B. (1994). Histamine induces interleukin-8 secretion by endothelial cells. Blood, 84(7), 2229-2233. PMID: 7919340.
• Kingsnorth, A., Galloway, S., & Formela, L. (1995). Randomized, double-blind phase II trial of Lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis. British Journal of Surgery, 82(10), 1414-1420. doi: 10.1002/bjs.1800821039.
• Kusske, A.M., Rongione, A.J., Ashley, S.W., McFadden, D.W., & Reber, H.A. (1996). Interleukin-10 prevents death in lethal necrotizing pancreatitis in mice. Surgery, 120(2), 284-289. doi: 10.1016/s0039-6060(96)80299-6.
• Lane, J.S., Todd, K.E., Gloor, B., Chandler, C.F., Kau, A.W., Ashley, S.W., Reber, H.A., & McFadden, D.W. (2001). Platelet activating factor antagonism reduces the systemic inflammatory response in a murine model of acute pancreatitis. Journal of Surgical Research, 99(2), 365-370. doi: 10.1006/jsre.2001.6206.
• Majdalawieh, A., & Ro, H.S. (2010). Regulation of IκBα function and NF-κB signaling: AEBP1 is a novel proinflammatory mediator in macrophages. Mediators of Inflammation, 2010, 823821. doi: 10.1155/2010/823821.
• Majdalawieh, A.F., & Fayyad, M.W. (2015). Immunomodulatory and anti-inflammatory action of Nigella sativa and thymoquinone: A comprehensive review. International Immunopharmacology, 28(1), 295-304. doi: 10.1016/j.intimp.2015.06.023.
• Majdalawieh, A.F., Hmaidan, R., & Carr, R.I. (2010). Nigella sativa modulates splenocyte proliferation, Th1/Th2 cytokine profile, macrophage function and NK anti-tumor activity. Journal of Ethnopharmacology, 131(2), 268-275. doi: 10.1016/j.jep.2010.06.030.
• Mahmood, M.S., Gilani, A.H., Khwaja, A., Rashid, A., & Ashfaq, M.K. (2003). The in vitro effect of aqueous extract of Nigella sativa seeds on nitric oxide production. Phytotherapy Research, 17(8), 921-924. doi: 10.1002/ptr.1251.
• McKay, C.J., Gallagher, G., Brooks, B., Imrie, C.W., & Baxter, J.N. (1996). Increased monocyte cytokine production in association with systemic complications in acute pancreatitis. British Journal of Surgery, 83(7), 919-923. doi: 10.1002/bjs.1800830712.
• Mohamed, A., Afridi, D.M., Garani, O., & Tucci, M. (2005). Thymoquinone inhibits the activation of NF-kappaB in the brain and spinal cord of experimental autoimmune encephalomyelitis. Biomedical Science Instrumentation, 41, 388-393. PMID: 15850137.
• Norman, J.G., Fink, G.W., Denham, W., Yang, J., Carter, G., Sexton, C., Falkner, J., Gower, W.R., & Franz, M.G. (1997). Tissue-specific cytokine production during experimental acute pancreatitis. A probable mechanism for distant organ dysfunction. Digestive Disease and Science, 42(8), 1783-1788. doi: 10.1023/a:1018886120711.
• Norman, J.G., Fink, G.W., & Franz, M.G. (1995). Acute pancreatitis induces intrapancreatic tumor necrosis factor gene expression. The Archives of Surgery, 130(9), 966-970. doi: 10.1001/archsurg.1995.01430090052018.
• Osman, M.O., Jacobsen, N.O., Kristensen, J.U., Deleuran, B., Gesser, B., Larsen, C.G., & Jensen, S.L. (1998). IT 9302, a synthetic interleukin-10 agonist, diminishes acute lung injury in rabbits with acute necrotizing pancreatitis. Surgery, 124(3), 584-592. PMID: 9736913.
• Pandol, S.J., Saluja, A.K., Imrie, C.W., & Banks, P.A. (2007). Acute pancreatitis: bench to the bedside. Gastroenterology, 132(3), 1127-1151. doi: 10.1053/j.gastro.2007.01.055.
• Petrov, M.S., Shanbhag, S., Chakraborty, M., Phillips, A.R., & Windsor, J.A. (2010). Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis. Gastroenterology, 139(3), 813-820. doi: 10.1053/j.gastro.2010.06.010.
• Pezzilli, R., Billi, P., Miniero, R., & Barakat, B. (1997). Serum interleukin-10 in human acute pancreatitis. Digestive Disease and Science, 42(7), 1469-1472. doi: 10.1023/a:1018814710291.
• Rahimian, R., Zirak, M.R., Seyedabadi, M., Keshavarz, M., Rashidian, A., Kazmi, S., Jafarian, A.H., Karimi, G., & Mousavizadeh, K. (2017). Protective effects of tropisetron on cerulein-induced acute pancreatitis in mice. Biomedicine Pharmacotherapy, 93, 589-595. doi: 10.1016/j.biopha.2017.06.067.
• Rahmani, A.H., Alzohairy, M.A., Khan, M.A., & Aly, S.M. (2014). Therapeutic Implications of Black Seed and Its Constituent Thymoquinone in the Prevention of Cancer through Inactivation and Activation of Molecular Pathways. Evidence-Based Complementary and Alternative Medicine, 2014, 724658. doi: 10.1155/2014/724658.
• Rongione, A.J., Kusske, A.M., Kwan, K., Ashley, S.W., Reber, H.A., & McFadden, D.W. (1997). Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology, 112(3), 960-967. doi: 10.1053/gast.1997.v112.pm9041259.
• Salem, M.L. (2005). Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. International Immunopharmacology, 5(13-14), 1749-1770. doi: 10.1016/j.intimp.2005.06.008.
• Sayed, A.A., & Morcos, M. (2007). Thymoquinone decreases AGE-induced NF-kappaB activation in proximal tubular epithelial cells. Phytotherapy Research, 21(9), 898-899. doi: 10.1002/ptr.2177.
• Schneider-Stock, R., Fakhoury, I.H., Zaki, A.M., El-Baba, C.O., & Gali-Muhtasib, H.U. (2014). Thymoquinone: fifty years of success in the battle against cancer models. Drug Discovery Today, 19(1), 18-30. doi: 10.1016/j.drudis.2013.08.021.
• Sha, H., Ma, Q., Jha, R.K., Xu, F., Wang, L., Wang, Z., Zhao, Y., & Fan, F. (2008). Resveratrol ameliorates hepatic injury via the mitochondrial pathway in rats with severe acute pancreatitis. European Journal of Pharmacology, 601(1-3), 136-142. doi: 10.1016/j.ejphar.2008.10.017.
• Shabana, A., El-Menyar, A., Asim, M., Al-Azzeh, H., & Al Thani, H. (2013). Cardiovascular benefits of black cumin (Nigella sativa). Cardiovascular Toxicology, 13(1), 9-21. doi: 10.1007/s12012-012-9181-z.
• Shimada, M., Andoh, A., Hata, K., Tasaki, K., Araki, Y., Fujiyama, Y., & Bamba, T. (2002). IL-6 secretion by human pancreatic periacinar myofibroblasts in response to inflammatory mediators. Journal of Immunology, 168(2), 861-868. doi: 10.4049/jimmunol.168.2.861.
• Stimac, D., Fisić, E., Milić, S., Bilić-Zulle, L., & Perić, R. (2006). Prognostic values of IL-6, IL-8, and IL-10 in acute pancreatitis. Journal of Clinical Gastroenterology, 40(3), 209-212. doi: 10.1097/00004836-200603000-00007.
• Vaillancourt, F., Silva, P., Shi, Q., Fahmi, H., Fernandes, J.C., & Benderdour, M. (2011). Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis. Journal of Cellular Biochemistry, 112(1), 107-117. doi: 10.1002/jcb.22884.
• Wereszczynska-Siemiatkowska, U., Dabrowski, A., Siemiatkowski, A., Mroczko, B., Laszewicz, W., & Gabryelewicz, A. (2003). Serum profiles of E-selectin, interleukin-10, and interleukin-6 and oxidative stress parameters in patients with acute pancreatitis and nonpancreatic acute abdominal pain. Pancreas, 26(2), 144-152. doi: 10.1097/00006676-200303000-00010.
• Woo, C.C., Kumar, A.P., Sethi, G., & Tan, K.H. (2012). Thymoquinone: potential cure for inflammatory disorders and cancer. Biochemical Pharmacology, 83(4), 443-451. doi: 10.1016/j.bcp.2011.09.029.
• Zhang, H., Yang, W., Li, Y., Hu, L., Dai, Y., Chen, J., Xu, S., Xu, X., & Jiang, H. (2018). Astaxanthin ameliorates cerulein-induced acute pancreatitis in mice. International Immunopharmacology, 56, 18-28. doi: 10.1016/j.intimp.2018.01.011.