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

// Jian-Yu Chen 1 , Guo-Yuan Zhu 1 , Xiao-Hui Su 1 , Rui Wang 1 , Juan Liu 1 , Kangsheng Liao 1 , Rutong Ren 1 , Ting Li 1 and Liang Liu 1 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China Correspondence to: Ting Li, email: tli@must.edu.mo Liang Liu, email: lliu@must.edu.mo Keywords: 7-deacetylgedunin, anti-inflammation, Keap1, Nrf2, HO-1 Received: April 12, 2017 Accepted: June 11, 2017 Published: July 05, 2017 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.