5-7-dihydroxy-6-methoxy-2-phenylchromen-4-one and Liver-Failure--Acute

Oroxylin A, a natural flavonoid isolated from Scutellariae baicalensis, has been reported to possess a wide spectrum of pharmacologic activities. However, the effects of oroxylin A on liver injury are poor understood. The purpose of this study was to investigate the effects of oroxylin A on acute liver injury in mice induced by lipopolysaccharide and/or D-galactosamine (LPS and/or D-GalN).. Mice acute liver injury model was induced by LPS (50 μg/kg) and/or GalN (800 mg/kg). Serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-α levels, hepatic tissue histology, malondialdehyde content, and myeloperoxidase activity were analyzed. Meanwhile, nuclear factor kappa B (NF-κB), heme oxygenase-1 (HO-1), and nuclear factor erythroid2-related factor 2 (Nrf2) expression were detected by Western blotting.. The results showed that oroxylin A dose-dependently inhibited LPS and/or GalN-induced serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-α levels. Hepatic malondialdehyde content and myeloperoxidase activity were also suppressed by oroxylin A. We also found that oroxylin A inhibited LPS and/or GalN-induced toll like receptor 4 (TLR4) expression and NF-κB activation. In addition, oroxylin A upregulated the expression of Nrf2 and HO-1 in a dose-dependent manner.. In conclusion, oroxylin A protected against LPS and/or GalN-induced liver injury through activating Nrf2 and inhibiting TLR4 signaling pathway.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Flavonoids; Galactosamine; Lipopolysaccharides; Liver; Liver Failure, Acute; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Peroxidase; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Based on the previous research that oroxylin A can suppress inflammation, we investigated the hepatoprotective role of oroxylin A against CCl₄-induced liver damage in mice and then studied the possible alteration of the activities of cytokine signaling participating in liver regeneration. Wild type (WT) mice were orally administrated with oroxylin A (60 mg/kg) for 4 days after CCl₄ injection, the anti-inflammatory effects of oroxylin A were assessed directly by hepatic histology and indirectly by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Albumin. Proliferating cell nuclear antigen (PCNA) staining was performed to evaluate the role of oroxylin A in promoting hepatocyte proliferation. Serum IL-1β, TNF-α, IL-6 and IL-1Ra levels were measured by enzyme-linked immunosorbent assay (ELISA) and liver HGF, EGF, TNF-α, IL-6, IL-1Ra and IL-1β gene expression was determined by quantitative real-time PCR. The data indicated that the IL-6 and TNF-α mRNA of oroxylin A administered group significantly increased higher than the control within 12 hours after CCl4 treatment. Meanwhile, oroxylin A significantly enhanced the expression of IL-1Ra at the early phase, which indicated that oroxylin A could facilitate the initiating events in liver regeneration by increasing IL-1Ra which acts as an Acute-Phase Protein (APP). In addition, a lethal CCl₄-induced acute liver failure model offers a survival benefit in oroxylin A treated WT mice. However, oroxylin A could not significantly improve the percent survival of IL-1RI⁻/⁻ mice with a lethal CCl₄-induced acute liver failure.. Our study confirmed that oroxylin A could strongly promote liver structural remodeling and functional recovery through IL-1Ra/IL-1RI signaling pathway. All these results support the possibility of oroxylin A being a therapeutic candidate for acute liver injury.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Carbon Tetrachloride; Cell Proliferation; Flavonoids; Gene Expression Regulation; Interleukins; Liver; Liver Failure, Acute; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; NAD(P)H Dehydrogenase (Quinone); Serum Albumin; Tumor Necrosis Factor-alpha