Diosmetin Ameliorated Acetaminophen-induced Hepatotoxicity via Activating Nrf2 /ARE Signaling Pathway
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Abstract:
In order to examine the protective effect of diosmetin against acetaminophen-induced hepatotoxicity in vitro and vivo, Human non-tumor hepatic cells LO2 were pretreated with either vehicle or Dios (15, 30 μM), for 6h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male C57BL/6J mice were randomly divided into control group, APAP group, low dose Dios group (30 mg/kg) and high dose Dios group (60 mg/kg). Each group included 10 mice. The mice were treated with different doses of diosmetin once daily for consecutive 7 days. At the end of the experiment, acetaminophen (300 mg/kg) was given intragastrically to induce liver injury in all groups except for the control group. Twenty-four hours later, the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) were detected. The contents of glutathione (GSH) and malondiadehyde (MDA) in liver tissue homogenates were measured through commercial kits. HE staining was performed to observe pathologic changes of the liver. The protein expression of Nrf2 was detected by Western blotting and the mRNA expressions of Nqo1, G6pdx, SOD2 was tested by quantitative real-time PCR. The results showed that in LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by Dios pretreatment. Compared with the model group, the serum activities of ALT and AST as well as MDA content remarkably decreased by the administration of diosmetin (60 mg/kg), while GSH contents were elevated in liver tissues; Nrf2 protein expression in the nucleus as well as mRNA expressions of Nqo1, G6pdx, SOD2 increased. High-dose diosmetin can inhibit acetaminophen-induced hepatotoxicity, and the mechanism may be associated with the activation of Nrf2 /ARE signaling pathway.
