Background: PGZ, a peroxisome proliferator-activated receptor γ agonist, possesses anti-inflammatory and antioxidant actions. The current study investigated an alternative molecular target of pioglitazone (PGZ) to protect against inflammatory bowel disease development.

Methods: Rats were allocated into 4 groups: normal control (NC), acetic acid (AA), PGZ (25 mg/kg intraperitoneal (i.p) and PGZ+ EX527 (a sirtuin1 inhibitor) (5mg/kg, i.p) groups.

Results: PGZ attenuated ulcerative colitis severity evident by decreased disease activity index, colon weight/ length ratio, gross damage, histological disruption and meyloperoxidase activity. PGZ suppressed oxidative stress by inhibition of lipid peroxidation and nitrite/nitrate content and enhancing glutathione level and antioxidant enzyme activities. PGZ reduction of colon injury was accompanied by suppressed inflammatory response as evidenced by decreased pro-inflammatory cytokines and IFN-γ- inducible protein 10 (CXCL 10) with restored interleukin-10. PGZ repaired the mucosal barrier integrity evident by increased claudin1expression. PGZ upregulated mRNA and protein expressions of SIRT1 (Silent information regulator 2 homologue 1) and p-IκBα (phosphorylated inhibitor kappa B-alpha) protein expression. PGZ downregulated NOX4 (nicotinamide adenine dinucleatide phosphate oxidase 4), TLR4 (toll like receptor4), IKKβ kinase and p65 subunit mRNA expressions. Additionally, in RAW264.7 cells, PGZ suppressed protein expressions of H3K9ac (histone H3 lysine acetylation), NOX4 and inducible nitric oxide synthase, upregulated SIRT1 and arginase-1protein expressions. EX527 co-treatment reversed all effects of PGZ.

Conclusion: Our findings indicated the beneficial effects of PGZ in UC via modulation of SIRT1/NOX4 signaling besides suppression of TLR4/NF-κB cascades and M1-M2 macrophage polarization.