| Summary: | Background: 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. Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.
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