Huang Zhenlin, Sheng Yuchen, Chen Minwei, Hao Zhanxia, Hu Feifei, Ji Lili
The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Toxicol Appl Pharmacol. 2018 Sep 15;355:18-27. doi: 10.1016/j.taap.2018.06.014. Epub 2018 Jun 15.
Hepatic sinusoidal obstruction syndrome (HSOS) is a serious and life-threatening liver disease. Liquiritigenin (LG) and liquiritin (LQ) are natural flavonoids distributed in Glycyrrhizae Radix et Rhizoma (Gan-cao). This study aims to investigate the protective effect and mechanism of LG and LQ against monocrotaline (MCT)-induced HSOS. Results of serum alanine/aspartate aminotransferases (ALT/AST) activities, liver histological evaluation and scanning electron microscope observation, and hepatic metalloproteinase-9 (MMP-9) expression demonstrated that LG and LQ both alleviated HSOS induced by MCT in rats. Results of hepatic reactive oxygen species (ROS), malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), oxidized glutathione (GSSG) and reduced glutathione (GSH) contents, glutathione reductase (GR) and superoxide dismutase (SOD) activities showed that LG and LQ attenuated MCT-induced liver oxidative stress injury. Furthermore, LG and LQ were found to promote Nrf2 nuclear translocation and lead to the increased expression of Nrf2 downstream antioxidative genes. Molecule docking analysis indicated the potential interaction of LG and LQ with Nrf2 binding site in the kelch-like ECH-associated protein-1 (Keap1) protein. Finally, Nrf2 knock-out mice were used. The results showed that LG and LQ both alleviated MCT-induced HSOS in wild-type mice, but such protection was totally diminished in Nrf2 knock-out mice. In conclusion, our study revealed that LG and LQ alleviated MCT-induced HSOS by inducing the activation of hepatic Nrf2 antioxidative defense system.
肝窦阻塞综合征（HSOS）是一种严重的、危及生命的肝脏疾病。甘草苷（LG）和甘草素（LQ）是分布于甘草中的天然黄酮类化合物。本研究旨在探讨LG和LQ对野百合碱（MCT）诱导的HSOS的保护作用及其机制。血清丙氨酸/天冬氨酸转氨酶（ALT/AST）活性、肝脏组织学评估、扫描电子显微镜观察以及肝脏金属蛋白酶-9（MMP-9）表达的结果表明，LG和LQ均可减轻MCT诱导的大鼠HSOS。肝脏活性氧（ROS）、丙二醛（MDA）、4-羟基壬烯醛（4-HNE）、氧化型谷胱甘肽（GSSG）和还原型谷胱甘肽（GSH）含量以及谷胱甘肽还原酶（GR）和超氧化物歧化酶（SOD）活性的结果显示，LG和LQ可减轻MCT诱导的肝脏氧化应激损伤。此外，发现LG和LQ可促进Nrf2核转位并导致Nrf2下游抗氧化基因表达增加。分子对接分析表明LG和LQ与kelch样ECH相关蛋白-1（Keap1）蛋白中的Nrf2结合位点存在潜在相互作用。最后，使用了Nrf2基因敲除小鼠。结果显示，LG和LQ均可减轻野生型小鼠中MCT诱导的HSOS，但在Nrf2基因敲除小鼠中这种保护作用完全消失。总之，我们的数据表明LG和LQ通过诱导肝脏Nrf2抗氧化防御系统的激活来减轻MCT诱导的HSOS。
