Antioxidant properties of 5-hydroxy-4-phenyl-butenolide via activation of Nrf2/ARE signaling pathway

• Published in: Food and chemical toxicology Vol. 107; no. Pt A; pp. 129 - 137
• Main Authors: Tabei, Yosuke, Murotomi, Kazutoshi, Umeno, Aya, Horie, Masanori, Tsujino, Yoshio, Masutani, Bumbu, Yoshida, Yasukazu, Nakajima, Yoshihiro
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2017
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - pharmacology; 5-Hydroxy-4-phenyl-butenolide; Animals; Antioxidant Response Elements - drug effects; Antioxidants - pharmacology; Cell Death - drug effects; Cytoprotective effect; DNA Damage - drug effects; Female; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hydrogen Peroxide - metabolism; Mice; Mice, Inbred ICR; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2/ARE signaling pathway; Oxidative stress; Oxidative Stress - drug effects; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Oxidative stress; MI-MAC; Reactive oxygen species; AAPH; HO-1; H2O2; SLG; DMEM; Nrf2; FBS; 5-Hydroxy-4-phenyl-butenolide; SLR3; GSH; 5H4PB; GSSG; DAPI; SOD; Nrf2/ARE signaling pathway; Cytoprotective effect; GPx; PPARγ; DCFH-DA; ARE; Trolox; CAT; ROS; TK; Keap1
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2017.06.039

5-Hydroxy-4-phenyl-butenolide (5H4PB) is a bioactive compound with antifungal and anti-obesity properties. Although it has recently been shown that 5H4PB activates peroxisome proliferator-activated receptor-gamma (PPARγ), the effect of 5H4PB on intracellular signaling pathways has not been clarified. In this study, we found that 5H4PB activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, which plays an important role in cellular defense against oxidative stress, and the subsequent upregulation of ARE-dependent cytoprotective genes, including the heme oxygenase-1, catalase, and superoxide dismutase genes, without exhibiting cytotoxicity. In addition, 5H4PB significantly attenuated intracellular ROS generation, glutathione oxidation, and DNA damage induced by hydrogen peroxide (H2O2) exposure in mouse fibroblast cells. Furthermore, we demonstrated that pretreatment with 5H4PB confers a significant cytoprotective effect against H2O2-induced cell death in mouse cultured fibroblasts and primary hepatocytes. Thus, our study demonstrated that 5H4PB enhanced cellular resistance to oxidative damage via activation of the Nrf2/ARE signaling pathway. [Display omitted] •5H4PB activates the Nrf2/ARE signaling pathway.•5H4PB increases the expression levels of antioxidant genes.•5H4PB reduces oxidative stress.•5H4PB protects against hydrogen peroxide-induced cell death.