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.
Highlights
Inflammation is one of the major pathogenic events in a variety of diseases in which macrophages play crucial roles [1]
We further verified the effect of 7-DGD on HO-1 protein expression in RAW264.7 with LPS stimulation, and the results revealed that 7-DGD could strongly facilitate HO-1 expression in a dose-dependent manner in RAW 264.7 with LPS stimulation (Figure 4D–4E), indicating that suppression of macrophage activation induced by 7-DGD relies on the up-regulation of the www.impactjournals.com/oncotarget
An increasing number of reports have indicated that inflammatory responses are a common pathogenesis of a variety of diseases [23], in which macrophages function as critical participants in inflammatory and autoimmune processes
Summary
Inflammation is one of the major pathogenic events in a variety of diseases in which macrophages play crucial roles [1]. Free Nrf accumulates in the cytosol, and translocates to the nucleus where it binds to the ARE [8], activating the transcription of chemopreventive genes, including UDPglucuronosyltransferases (UGTs), detoxifying enzymes NAD(P)H, dehydrogenases (NQOs), and HO-1 [9, 10]. It has been well-known that phosphorylation of Nrf at tyrosine 568 is attributed to the nuclear export of Nrf. We for the first time determined the antiinflammatory effect and elucidated underlying mechanism of 7-DGD in vivo and in vitro
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
