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The Role of MIF in Hepatic Function, Oxidative Stress, and Inflammation in Thioacetamide-induced Liver Injury in Mice: Protective Effects of Betaine

Author(s):

Dušan Vukićević, Branislav Rovčanin, Kristina Gopčević, Sanja Stanković, Danijela Vučević, Bojan Jorgačević, Dušan Mladenović, Milena Vesković, Janko Samardžić, Rada Ješić and Tatjana Radosavljević*   Pages 1 - 19 ( 19 )

Abstract:


Background: Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that contributes to the inflammatory response to chemical liver injury. This cytokine exhibits pro- and anti-inflammatory effects depending on etiology and stage of liver disease.

Objective: Our study aimed to investigate the role of MIF in oxidative stress and the inflammation in the liver, and modulatory effects of betaine on MIF in thioacetamide (TAA)-induced chronic hepatic damage in mice.

Methods: The experiment was performed on wild type and knockout MIF-/- C57BL/6 mice. They were divided into groups: Control; Bet-group, received betaine (2% wt/v dissolved in drinking water); MIF-/- mice group; MIF-/-+Bet; TAA-group, received of TAA (200 mg/kg b.w.), intraperitoneally, 3x/week/8 weeks); TAA+Bet; MIF-/-+TAA, and MIF-/-+TAA+Bet. In TAA- and Bet-treated groups, animals received in the same previous doses. After eight weeks of treatment, blood samples were collected for biochemical analysis and liver specimens were prepared for assessment the parameters of oxidative stress and inflammation.

Results: In MIF-/-mice, TAA reduced transaminases, -glutamyltranspeptidase, bilirubin, malondaldehyde (MDA), oxidative protein products (AOPP), total oxidant status (TOS), C-reactive protein (CRP), IL-6, IFN- , and increased of thiols and total antioxidant status (TAS). Betain attenuates mechanism of MIF-mediated effects in TAA-induced liver injury, reducing transaminases, -glutamyltranspeptidase, bilirubin, MDA, AOPP, TOS, CRP, IL-6, IFN-g and increasing thiols.

Conclusion: MIF is mediator in hepatotoxic, pro-oxidative and proinfammatory effects of TAA-induced liver injury. MIFtargeted therapy could potentially mitigate the oxidative stress and inflammation in the liver, but the exact mechanism of its action requires further investigation. Betaine increases antioxidative defense and attenuates hepatotoxic effects of MIF, suggesting that betaine can be used for the prevention and treatment of liver damage.

Keywords:

Thioacetamide, liver damage, inflammation, Macrophage migration inhibitory factor, betaine, mice

Affiliation:

Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, Center for Endocrine Surgery, Clinical Center of Serbia, Belgrade, Institute of Chemistry in Medicine "Prof. Dr. Petar Matavulj", Faculty of Medicine, University of Belgrade, Belgrade, Centre of Medical Biochemistry, Clinical Centre of Serbia, Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade, Institute of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Institute of Digestive Diseases, Clinical Centre of Serbia, Belgrade, Institute of Pathophysiology ''Ljubodrag Buba Mihailović'', Faculty of Medicine, University of Belgrade



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