Dihydroquercetin (DHQ) ameliorated concanavalin A-induced mouse experimental fulminant hepatitis and enhanced HO-1 expression through MAPK/Nrf2 antioxidant pathway in RAW cells

作者：Zhao, Mingyi; Chen, Jiajie; Zhu, Ping; Fujino, Masayuki; Takahara, Terumi; Toyama, Sumika; Tomita, Amy; Zhao, Lingling; Yang, Zuocheng; Hei, Mingyan; Zhong, Liang^*; Zhuang, Jian; Kimura, Shuichi; Li, Xiao-Kang

来源：International Immunopharmacology, 2015, 28(2): 938-944.

DOI：10.1016/j.intimp.2015.04.032

• Antioxidant
• ConA
• DHQ
• Hepatitis
• Mitogen-activated protein kinases
• HO-1
• Nrf2

Autoimmune hepatitis represents a ubiquitous human health problem and has a poor prognosis. Dihydroquercetin (DHQ), a well-known antioxidant, significantly inhibits fulminant hepatitis through antioxidant and anti-inflammation mechanisms. In this study, we show that administration of DHQ ameliorated concanavalin A (ConA)-induced mouse liver injury by increasing the survival rate, reducing the serum ALT and AST level, preventing histopathological injuries and decreasing pro-inflammatory cytokine mRNA expression in hepatic tissue. As macrophages/Kupffer cells in oxidative stress and pro-inflammatory mediators play an important role in the pathogenesis of immune-mediated hepatitis, we further exposed mouse RAW264 macrophage cell lines to ConA in vitro and found that DHQ significantly inhibited mRNA expression and secretion of IFN-gamma and TNF-alpha in cell culture supernatant. In addition, DHQ significantly enhanced heme oxygenase-1 (HO-1) expression in a dose-and time-dependent manner via increased Nrf2 expression in cytoplasm and nuclear translocation. Furthermore, DHQ enhanced phosphorylation of three members of the mitogen-activated protein kinase (MAPK) family, and cell treatment with MEK/ERK (PD98059), p38 (SE203580) and JNK (SP600125) inhibitors reduced DHQ-induced HO-1 expression. These results indicate that DHQ possesses hepatoprotective properties against ConA-induced liver injury, which are attributed to its ability to scavenge oxidative stress and to inhibit the release of inflammatory mediators via upregulation of HO-1 activity through the MAPK/Nrf2 signaling pathway in macrophages/Kupffer cells.

• 出版日期2015-10
• 单位复旦大学; 广东省心血管病研究所; 中南大学; 广东省人民医院