Antioxidant Effects of Pioglitazone and Interleukin-1 receptor-associated kinase inhibitor on Oxidative Stress Indices in obese C57BL/6J Mice

Background: Pioglitazone possesses antioxidant properties, whereas the antioxidant effects of IRAKi (Interleukin-1 receptorassociated kinase inhibitor; an anti-inflammatory agent) remain less established. Therefore, we investigated the antioxidant properties of IRAKi and pioglitazone in the liver of obese C57BL/6J mice. Methods: Thirty-five mice were randomly assigned to five groups (n=7); Control, high-fat diet (HFD), HFD-IRAKi, HFD-pioglitazone (PIO), and HFD-IRAKi-PIO. After 12 weeks on an HFD, IRAKi (2 mg/kg, intraperitoneally, three times a week) and pioglitazone (10 mg/kg, orally, daily) were administered for two weeks. The expression levels of Superoxide dismutase (SOD) and glutathione peroxidase (GPx) genes were evaluated through Real-time PCR analysis. Malondialdehyde (MDA), SOD, total antioxidant status (TAS), GPx, and total oxidant status (TOS) levels were quantified. Results: HFD increased oxidative stress. IRAKi and pioglitazone, administered separately, increased SOD and TAS while reducing MDA and TOS compared to the HFD group. However, neither treatment significantly altered GPx activity. The combination of IRAKi and pioglitazone exhibited superior antioxidant effects compared to their separate administrations. Specifically, the combined treatment improved both GPx and SOD levels as well as their gene expression. Conclusion: Our findings demonstrate the antioxidative effects of IRAKi and pioglitazone in C57BL/6J mice. Notably, their combination produced additive effects, enhancing the antioxidant defense system in the liver. These results suggest that IRAKi and pioglitazone, when used together, may serve as a promising therapeutic approach for managing oxidative stress in liver disease. By providing a dual mechanism of action, this combination highlights its potential for broader clinical applications in chronic disease management.