Thymoquinone restores liver fibrosis and improves oxidative stress status in a lipopolysaccharide-induced inflammation model in rats

Document Type: Original Research Article

Authors

1 Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Neurocognitive Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Departments of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Neurogenic Inflammation Research Center, Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective: Liver fibrosis is the primary sign of chronic liver injury induced by various causes. Thymoquinone (TQ) is the major ingredient of Nigella sativa with several beneficial effects on the body. In the present study, we aimed to investigate the effect of TQ on liver fibrosis in a lipopolysaccharide (LPS)-induced inflammation in male rats.
Materials and methods: Fifty male Wistar rats were randomly divided into five groups (n=10 in each group) as follow: (1) control; (2) LPS (1 mg/kg/day; i.p); (3) LPS+TQ 2 mg/kg/day (i.p) (LPs+TQ2); (4) LPS+TQ 5 mg/kg/day (LPS+TQ5); (5) LPS+ TQ 10 mg/kg/day (LPS+ TQ10). After three weeks, blood samples were taken for evaluation of liver function tests. Then, the livers were harvested for histological evaluation of fibrosis and collagen content and measurement of oxidative stress markers including malondialdehyde (MDA), total thiol groups, superoxide dismutase (SOD) and catalase activity in tissue homogenates.
Results: LPS group showed higher levels of fibrosis and collagen content stained by Masson’s trichrome in liver tissue with impaired liver function test and increased oxidative stress markers (p<0.05). Treatment by TQ restored liver fibrosis, improved liver function tests and increased the levels of anti-oxidative enzymes (SOD and catalase), while reduced MDA concentration (p<0.05).
Conclusion: Treatment by TQ restores inflammation-induced liver fibrosis possibly through affecting oxidative stress status. It seems that administration of TQ can be considered as a part of liver fibrosis management.

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Alsaif MA. 2007. Effect of thymoquinone on ethanol-induced hepatotoxicity in Wistar rats. J Med Sci, 7:1164-1170.

Amin B, Hosseinzadeh H. 2016. Black cumin (Nigella sativa) and its active constituent, thymoquinone: an overview on the analgesic and anti-inflammatory effects. Planta Medica, 82:8-16.

Awad AS, Al Haleem ENA, El-Bakly WM, Sherief MA. 2016. Thymoquinone alleviates nonalcoholic fatty liver disease in rats via suppression of oxidative stress, inflammation, apoptosis. Naunyn Schmiedebergs Arch Pharmacol, 389:381-391.

Bai T, Lian L-H, Wu Y-L, Wan Y, Nan J-X. 2013. Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells. Int immunopharmacol, 15:275-281.

Bataller R, Brenner DA. 2005. Liver fibrosis. J Clin Invest, 115:209-218.

Beheshti F, Hosseini M, Shafei MN, Soukhtanloo M, Ghasemi S, Vafaee F, Zarepoor L. 2016. The effects of Nigella sativa extract on hypothyroidism-associated learning and memory impairment during neonatal and juvenile growth in rats. Nutritional neuroscience:1-11.

Ceccarelli S, Panera N, Mina M, Gnani D, De Stefanis C, Crudele A, Rychlicki C, Petrini S, Bruscalupi G, Agostinelli L. 2015. LPS-induced TNF-factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease. Oncotarget, 6:41434-41452.

Darakhshan S, Pour AB, Colagar AH, Sisakhtnezhad S. 2015. Thymoquinone and its therapeutic potentials. Pharmacol Res, 95:138-158.

Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. 1994. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology, 19:1513-1520.

Friedman SL. 2000. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem, 275:2247-2250.

Friedman SL. 2008. Mechanisms of hepatic fibrogenesis. Gastroenterology, 134:1655-1669.

Gholamnezhad Z, Havakhah S, Boskabady MH. 2016. Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: A review. J Ethnopharmacol, 190:372-386.

Harry D, Anand R, Holt S, Davies S, Marley R, Fernando B, Goodier D, Moore K. 1999. Increased sensitivity to endotoxemia in the bile duct–ligated cirrhotic rat. Hepatology, 30:1198-1205.

Hassanein KM, Al-Emam A, Radad K. 2016. Prophylactic effects of thymoquinone against carbon tetrachloride-induced hepatic damage in Sprague-Dawley rats. J Appl Pharm Sci, 6:167-171.

Karaa A, Thompson KJ, McKillop IH, Clemens MG, Schrum LW. 2008. S-adenosyl-L-methionine attenuates oxidative stress and hepatic stellate cell activation in an ethanol-LPS-induced fibrotic rat model. Shock, 30:197-205.

Koyama I, Matsunaga T, Harada T, Hokari S, Komoda T. 2002. Alkaline phosphatases reduce toxicity of lipopolysaccharides in vivo and in vitro through dephosphorylation. Clin Biochem, 35:455-461.

Liver EAFTSOT. 2012. EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol, 56:908-943.

Nagi MN, Al-Shabanah OA, Hafez MM, Sayed-Ahmed MM. 2011. Thymoquinone supplementation attenuates cyclophosphamide-induced cardiotoxicity in rats. J Biochem Mol Toxicol, 25:135-142.

Oguz S, Kanter M, Erboga M, Erenoglu C. 2012. Protective effects of thymoquinone against cholestatic oxidative stress and hepatic damage after biliary obstruction in rats. J Mol Histol, 43:151-159.

Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. 2003. Toll‐like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology, 37:1043-1055.

Poynard T1, Lebray P, Ingiliz P, Varaut A, Varsat B, Ngo Y, Norha P, Munteanu M, Drane F, Messous D, Bismut FI, Carrau JP, Massard J, Ratziu V, Giordanella JP. 2010. Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest). BMC Gastroenterol, 22;10:40.

Rockey DC, Friedman SL. 2012. Hepatic fibrosis and cirrhosis. Zakim and Boyer’s hepatology, 6th edn Elsevier Saunders, Philadelphia:64-85.

Sánchez-Valle V, C Chavez-Tapia N, Uribe M, Méndez-Sánchez N. 2012. Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem, 19:4850-4860.

Schwabe RF, Seki E, Brenner DA. 2006. Toll-like receptor signaling in the liver. Gastroenterology, 130:1886-1900.

Tsochatzis EA, Bosch J, Burroughs AK. 2014. Liver cirrhosis. Lancet, 383:1749-1761.

Woo CC, Kumar AP, Sethi G, Tan KH. 2012. Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem Pharmacol, 83:443-451.