Quercetin 3-O-rutinoside prevents radiation induced oxidative damage and inflammation by coordinated regulation of Nrf2/ NF-κB/ NLRP3- inflammasome signaling in gastrointestine

Irradiation causes extensive alteration in the cellular homeostasis leading to severe organ damage and dysfunction. The lack of understanding of the mechanism conferring radioprotection is often considered a major limitation in the development of agents that suppress the damaging effects of radiation. In this study, we demonstrate that Quercetin 3-O-rutinoside (Q-3-R), a flavonoid, can significantly protect the gastrointestine against gamma radiation induced damage. Q-3-R (10 mg/kg body weight) treated C57BL/6 mice were investigated for anti-oxidant status, regulations of critical targets of Nrf2, NF-κB signaling and the inflammasome complex in the irradiated intestine. Prophylactic administration of Q-3-R stabilized radiation induced reactive oxygen species, maintained total antioxidant and glutathione levels in the intestine. Q-3-R pretreatment activated Nrf2, supported its nuclear translocation and upregulated cytoprotective proteins, HO-1, thioredoxin1, GST and GCLC. The key inflammatory mediator, NF-kB p65 was found down-regulated in Q-3-R treated jejunum. NF-kB p65 downregulation caused suppression of genes of the inflammasome complex, pro-inflammatory cytokine (IL-6 and TNF-α) expression and myeloperoxidase activity. ML385, a specific Nrf2 inhibitor that, when used at a concentration of 30 mg/kg prevented Q-3-R mediated activation of Nrf2 and upregulated NF-kB, suggesting that Q-3-R mediates protection against radiation primarily via Nrf2 activation. Q-3-R also prevented intestinal apoptosis by inhibiting mitochondrial translocation of cytochrome c into the cytosol and subsequent activation of caspase-3. Molecular docking studies confirmed the interactions of Q-3-R with key antioxidant and anti-inflammatory proteins. The findings suggest that Q-3-R effectively coordinated the regulation of cellular anti-oxidant and inflammatory response, thereby minimizing apoptotic event in the irradiated intestine.