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Echinacea alkamides induce heme oxygenase-1 expression and prevent lipopolysaccharide/D-galactosamine induced acute hepatic injury
Alkamides, the major lipophilic constituents of E. purpurea, have been claimed for various bioactivities. Heme oxygenase-1 (HO-1) is one of the significant inducible enzymes preventing inflammatory events and a potential therapeutic target for hepatoprotection. We report here that isomeric dodeca-2E,4E,8Z,10Z(E)-tetraenoic acid isobutylamides (8/9), the major alkamides of E. purpurea, could significantly induce heme oxygenase-1 protein expression in murine macrophages and hepatocytes. The inhibition of HO-1 activity or carbon monoxide scavenger significantly reversed the inhibitory effect of alkamides 8/9 on LPS-induced TNF-α production, indicating the anti-inflammatory effect of alkamides 8/9. Moreover, alkamides 8/9 treatment increased JNK phosphorylation, c-jun protein expression and phosphorylation, and AP-1 binding activity in RAW264.7 cells. RAW264.7 cells pretreated with a specific inhibitor SP600125 for JNK activity could significantly attenuate the c-jun phosphorylation and HO-1 protein expression. The alkamides 8/9-induced HO-1 expression was observed partly due to the induction of oxidative stress via JNK-PI3K signaling cascade, as HO-1 expression was reversed in RAW264.7 cells pretreated with antioxidant N-acetylcystein and PI3K inhibitor LY294002. The LPS/D-GalN-induced fulminate hepatitis in a mouse model further demonstrated the hepatoprotective effect of alkamides 8/9 in vivo. Alkamides 8/9 could markedly suppress serum aminotransferases activities, TNF-α production, and cleaved form of caspase-3 in mouse liver. Taken together, this study demonstrates that alkamides 8/9 exert a cytoprotecive effect by mainly up-regulating JNK-mediated c-jun and HO-1 expression in turn preventing liver injury induced by LPS/D-GalN. This is the first report providing new insights of Echinacea alkamides as hepatoprotective agents.