Genkwanin Alleviates Mitochondrial Dysfunction and Oxidative Stress in a Murine Model of Experimental Colitis: The Participation of Sirt1.

Genkwanin is a biologically active O-methylated flavone extracted from Daphne genkwa. An increasing number of studies have described the modulatory effects of genkwanin on human diseases, including antitumor, anti-inflammatory, and antioxidant activities. However, little is known about whether genkwanin might be a therapeutic agent for inflammatory bowel disease or its possible underlying mechanisms.Forty C57BL/6 male mice were orally administered dextran sulfate sodium (DSS) to generate the colitis model, and genkwanin was orally administered at the indicated concentrations. Body weight, disease activity index, colon length, and H&E staining were used to evaluate colitis. Oxidative stress and antioxidant levels were measured by detecting ROS generation and malondialdehyde, superoxide dismutase and glutathione levels. The levels of proinflammatory cytokines (TNF-α, IL-1β, IFNγ and IL-6) were measured using ELISAs. Cell viability was determined using the CCK-8 assay. Mitochondrial function was evaluated by measuring the oxygen consumption rate, mtDNA content, and activities of electron transfer chain (ETC) complexes I, II, and IV. The expression of SIRT1, Nrf2 and its target genes was determined using qRT-PCR and western blotting. SIRT1 was depleted by lentivirus-mediated knockdown.In this study, oral administration of genkwanin alleviated colitis induced by oral administration of DSS in mice, as evidenced by reduced weight loss, colon length shortening and histopathology scores. Furthermore, genkwanin relieved oxidative stress and reduced the production of proinflammatory cytokines. In vitro assays revealed that genkwanin administration inhibited reactive oxygen species (ROS) production and improved mitochondrial function in human intestinal epithelial cells. Genkwanin also upregulated the expression of SIRT1, and lentivirus-mediated SIRT1 knockdown partially abrogated the protective effect of genkwanin on oxidative stress and mitochondrial dysfunction.Findings from our murine model and cell culture experiments provide a promising basis for genkwanin to be studied as a treatment for IBD in clinical trials.