Journal of Inflammation Research (Jul 2021)
Fisetin Ameliorates the Inflammation and Oxidative Stress in Lipopolysaccharide-Induced Endometritis
Abstract
Kangfeng Jiang,1,2,* Jing Yang,3,* Guanhong Xue,1,* Ailing Dai,4 Haichong Wu1 1Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, People’s Republic of China; 2Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yunnan Agricultural University, Kunming, Yunnan, 650201, People’s Republic of China; 3State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, 430070, People’s Republic of China; 4College of Life Sciences of Longyan University, Longyan, 364012, Fujian, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haichong Wu Tel +86 571-88982091Email [email protected]: Fisetin is a natural flavone of polyphenol, which widely exists in many fruits and vegetables and has many pharmacological activities. However, the mechanism involved remains largely unknown. Here, we investigate the mechanisms of fisetin on the inflammatory response and oxidative stress in LPS-induced endometritis model and bovine endometrial epithelial cell line (BEND).Methods: The function of fisetin was analyzed by network pharmacology. Effects of increasing doses of fisetin on inflammation and oxidative stress are studied in BALB/c mice with LPS-induced endometritis. The underlying mechanisms of antioxidant activity of fisetin were further explored in LPS-stimulated BEND cells.Results: The results showed that fisetin significantly alleviated LPS-induced inflammatory injury and oxidative stress both in vivo and in vitro. Further studies found that fisetin greatly inhibited the LPS stimulated TLR4 expression and nuclear translocation of nuclear factor-κB (NF-κB), thus reducing the pro-inflammatory mediators secretion. Silencing TLR4 reduced LPS-induced inflammatory responses. Moreover, we observed that fisetin evidently decreased ROS production but activated Nrf2/HO-1 pathway in LPS-stimulated BEND cells. To further explore the role of Nrf2 in fisetin-induced HO-1 protein expression, the specific siRNA was used to silence Nrf2 expression. Silencing Nrf2 abrogated the inhibitory effects of fisetin on LPS-induced pro-inflammatory cytokines TNF-α, IL-1β secretion, NADPH oxidase-4 (Nox4) and ROS production.Conclusion: In conclusion, fisetin effectively protected against LPS-induced oxidative stress and inflammatory responses which may be closely correlated to inhibition of TLR4-mediated ROS/NF-κB and activation of the Nrf2/HO-1 pathway.Keywords: fisetin, endometritis, inflammation, oxidative stress, TLR4/Nrf2
