Investigation of The Effect Of Thymoquinone On Liver Tissue DNA Damage and Molecular Pathways in Glucocorticoid-induced Insulin Resistance

Abstract

Objective: This study investigates the role of various compounds in the prevention or repair of tissue damage associated with insulin resistance at the molecular level. It aims to evaluate the effects of thymoquinone (TK), the principal active compound of Nigella sativa known for its numerous beneficial effects, on DNA damage and some molecular pathways in experimental insulin resistance. Methods: The insulin resistance model was induced using glucocotiocoids. A total of 40 Wistar-Albino rats were utilized, comprising 7 in the control (C) group, 7 in the insulin resistance (IR) group, 7 receiving TK, 7 protection with TK (TKIR), and undergoing treatment with TK (IRTK) and 5 for tretament control with insulin resistance plus metformin (IM) groups. Expression levels of metabolic genes (antioxidant: Gpx, Sod; necrotic: Rip1, Rip3; autophagic: Atg3, Atg5; apoptotic: Caspase 3, Caspase 8, Caspase 9; DNA repair: KU70, KU80, TP53) in liver tissue were determined using Real time qPCR. Differences between groups were assessed by comparing fold changes in expression against the control group. Statistical analysis was performed using SPSS. Results: The expression levels of DNA repair and damage genes KU70 and KU80 increased in the groups receiving TK. The TP53 gene exhibited a significant increase in the IR group but decreased in the TK treatment group. Apoptotic Caspase 8 gene expression was elevated in the IR group and reduced in the TK groups, while no significant differences were observed for Caspase 3 and Caspase 9 expression. No significant differences were noted in antioxidant gene expression (Gpx1, Sod1) among the groups. Autophagic Atg5, and necrotic Rip1 and Rip3 gene expressions increased in the IR group but decreased in the TK groups. Conclusion: The results suggest that TK may reduce insulin resistance, improve glucose tolerance, and support pancreatic β-cell functions through mechanism including enhancing DNA repair via KU70 and KU80, upregulating antiapoptotic genes, and inhibiting autophagic and necrotic pathways. These results could provide valuable insights into the biochemical basis for the hepatoprotective effects of TK in the treatment and prevention of insulin resistance-related complications. © This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.