Schisandrin A suppresses lipopolysaccharide-induced inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-κB, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling

摘要

Schisandrin?A is a bioactive lignan occurring in the fruits of plants of the Schisandra genus that have traditionally been used in Korea for treating various inflammatory diseases. Although the anti-inflammatory and antioxidant effects of lignan analogues similar to schisandrin?A have been reported, the underlying molecular mechanisms have remained elusive. In the present study, schisandrin?A significantly suppressed the lipopolysaccharide?(LPS)-induced production of the key pro-inflammatory mediators nitric oxide?(NO) and prostaglandin?E2 by suppressing the expression of inducible NO synthase and cyclooxygenase-2 at the mRNA and protein levels in RAW?264.7?macrophages. Furthermore, schisandrin?A was demonstrated to reduce the LPS-induced secretion of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β; this was accompanied by a simultaneous decrease in the respective mRNA and protein levels in the macrophages. In addition, the LPS- induced translocation of nuclear factor-κB (NF-κB), as well as activation of mitogen-activated protein kinases (MAPKs) and phosphatidylinositol?3 kinase?(PI3K)/Akt pathways were inhibited by schisandrin?A. Furthermore, schisandrin?A significantly diminished the LPS-stimulated accumulation of intracellular reactive oxygen species, and effectively enhanced the expression of NF erythroid?2-related factor?2?(Nrf2) and heme oxygenase-1?(HO-1). These results suggested that schisandrin?A has a protective effect against LPS-induced inflammatory and oxidative responses in RAW?264.7 cells by inhibiting the NF-κB, MAPK and PI3K/Akt pathways; these effects are mediated, at least in part, by the activation of the Nrf2/HO-1 pathway. Based on these results, it is concluded that schisandrin?A may have therapeutic potential for treating inflammatory and oxidative disorders caused by over-activation of macrophages.