Protective effect of apoptosis signal-regulating kinase 1 inhibitor against mice liver injury

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• 作者：Ping He¹ ; Bo Zeng¹ ; Xiao-Li Zhang¹ ; Dian-Liang Fang¹ ; Xia-Qia Zhou² ; Ke-Qiang Wan² ; Wen-Guang Tian² ; ^{twg9366@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Apoptosis signal-regulating kinase 1 ; Acetaminophen ; Liver injury ; JNK
• 刊名：Asian Pacific Journal of Tropical Medicine
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：9
• 期：3
• 页码：283-287
• 全文大小：284 K

文摘

To explore the protective effect and its molecular mechanism of apoptosis signal-regulating kinase 1 (ASK1) inhibitor (GS-459679) on acetaminophen-induced liver injury in mice.

Methods

The model of liver injury was established by administration of acetaminophen (APAP) (300 mg/kg, i.p.) on C57BL/6 mice. Forty-eight male C57BL/6 mice were randomly divided into four groups, consisting of control group, GS group (GS-459679, 30 mg/kg, i.p.), APAP-induced group, and GS combined with APAP-induced group. For GS combined with APAP-induced group, mice were treated with GS 30 min prior to administration of APAP. After mice were euthanized at 6 h or 12 h, respectively, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed, and mRNA levels of TNF-α, IL-6 and IL-1β were tested. The activity of glutathione (GSH), oxidized GSH (GSSG) and malondialdehyde were quantified. In addition, ASK1, P-ASK1, JNK and P-JNK protein levels were tested in all groups.

Results

The ASK1 and P-ASK1 levels were up-regulated in APAP-induced group. Compared to the control group, serum levels of ALT and AST, and mRNA levels of TNF-α, IL-6 and IL-1β were increased in APAP-induced group. Meanwhile, the levels of MAD and GSSG, and the ratio of GSSG/GSH were higher and the JNK was activatedin APAP-induced group compared with that in control group. However, compared to APAP-induced group, GS combined with APAP-induced group displayed a decrease of protein expression levels of ASK1, P-ASK1 and P-JNK, a reduction of serum levels of ALT and AST, a decrease in TNF-α, IL-6 and IL-1β mRNA levels, and a low ration of GSSG/GSH.

Conclusions

GS-459679 treatment effectively down-regulates ASK1 and P-ASK1 expression. Addition of GS-459679 decreases the generation of liver metabolites and inflammatory factors, reduces oxidative stress reaction, inhibits JNK activation, and then protects the responsiveness to APAP-induced liver injury.