Oroxyloside ameliorates acetaminophen-induced hepatotoxicity by inhibiting JNK related apoptosis and necroptosis

Oroxyloside is a natural flavonoid isolated from Scutellaria baicalensis Georgi (Lamiaceae) which is a Chinese herb widely used for liver diseases. However, its mechanisms on protecting against drug induced liver injury has not been investigated yet. To investigate the protecting effects and the primary mechanisms of oroxyloside on acetaminophen (APAP)-induced liver injury. After a 12 h fasting period with free access to water, C57BL/6 mice were injected with APAP (300 mg/kg) intragastrically (i.g.) and 1 h later with oroxyloside (100 mg/kg, i.g.). When mice sacrificed, blood samples were collected from fundus venous plexus and liver tissues were collected. In addition, cells were incubated with 10 mM APAP alone and 10 mM APAP combined with 100 μM oroxyloside for 24 h. ELISA, TUNEL assay, qRT-PCR et al. were used to assess the effect of oroxyloside on ameliorating APAP-induced hepatotoxicity in vitro and in vivo. Western bolt and immunohistochemistry were used in the signaling pathway analysis. Oroxyloside administration significantly decreased the accumulations of CYP2E1, CYP1A2, IL-6, IL-1β, ALT and AST induced by APAP in vivo. In addition, oroxyloside inhibited the APAP-induced JNK related apoptosis by enhancing the antioxidant defenses, reversing ER-stress and keeping the mito-balance of liver cells in vivo and in vitro. Furthermore, oroxyloside protected the liver cells from necroptosis by affecting JNK pathway. Oroxyloside acted as a protective agent against APAP-induced liver injury through inhibiting JNK-related apoptosis and necroptosis. [Display omitted]