7-deacetylgedunin suppresses inflammatory responses through activation of Keap1/Nrf2/HO-1 signaling

Abstract

Macrophages play a critical role in a variety of inflammatory diseases. Activation of Keap1/Nrf2/HO-1 signaling results in inactivation of macrophages and amelioration of inflammatory and autoimmune conditions. Hence, discovery for the activators of Keap1/Nrf2/HO-1 signaling has become a promising strategy for treatment inflammatory diseases. In the current study, the anti-inflammatory potential of 7-deacetylgedunin (7-DGD), a limonin chemical isolated from the fruits of Toona sinensis (A. Juss.) Roem, was intensively examined in vivo and in vitro for the first time. Results showed that 7-DGD alleviated mice mortality induced by LPS. Mechanistic study showed that 7-DGD suppressed macrophage proliferation via induction of cell arrest at the G0/G1 phase. Furthermore, 7-DGD inhibited iNOS expression, which is correlated with the increases of NQO1, HO-1 and UGT1A1 mRNA expression as well as HO-1 protein expression level in the cells. More importantly, 7-DGD markedly decreased Keap1 expression, promoted p62 expression, and facilitated Nrf2 translocation and localization in the nucleus of macrophages, and in turn up-regulates these anti-oxidant enzymes expression, eventually mediated anti-inflammatory effect. Collectively, 7-DGD suppresses inflammation in vivo and in vitro, indicating that the compound is valuable for further investigation as an anti-inflammatory agent in future.