The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources, 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, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, The SATCM Key Laboratory for New Resources, Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Eur J Pharmacol. 2020 Sep 15;883:173286. doi: 10.1016/j.ejphar.2020.173286. Epub 2020 Jun 27.
Acetaminophen (APAP)-induced acute liver failure is a serious clinic issue. Our previous study showed that chlorogenic acid (CGA) alleviated APAP-induced liver inflammatory injury, but its concrete mechanism is still not clear. This study aims to elucidate the engaged mechanism involved in the CGA-provided alleviation on APAP-induced liver inflammation. CGA reduced the increased hepatic infiltration of immune cells and the elevated serum contents of high mobility group box 1 (HMGB1) and heat shock protein 60 (HSP60) in mice treated with APAP. CGA decreased the enhanced hepatic mRNA expression of some pro-inflammatory molecules in mice treated with APAP and in RAW264.7 cells stimulated with HMGB1 or HSP60. CGA attenuated liver mitochondrial injury, rescued the decreased lon protease homolog (Lon) protein expression, and reduced mitochondrial HSP60 release in mice treated with APAP. Moreover, the CGA-provided alleviation on APAP-induced liver inflammatory injury was diminished in mice treated with anti-HSP60 antibody. Further results showed that the CGA-provided alleviation on APAP-induced liver inflammation was also diminished in nuclear factor erythroid 2-related factor 2 (Nrf2) knock-out mice. Meanwhile, the CGA-provided reduce on serum HSP60 content and restore of mitochondrial Lon protein expression were all diminished in Nrf2 knock-out mice treated with APAP. In conclusion, our study revealed that CGA alleviated APAP-induced liver inflammatory injury initiated by HSP60 or HMGB1, and Nrf2 was critical for regulating the mitochondrial HSP60 release via rescuing the reduced mitochondrial Lon protein expression.
对乙酰氨基酚（APAP）诱导的急性肝衰竭是一个严重的临床问题。我们之前的研究表明，绿原酸（CGA）减轻了 APAP 诱导的肝炎症损伤，但具体机制尚不清楚。本研究旨在阐明 CGA 减轻 APAP 诱导的肝炎症中涉及的相关机制。CGA 减少了 APAP 处理小鼠肝脏中免疫细胞的浸润增加和高迁移率族蛋白 1（HMGB1）和热休克蛋白 60（HSP60）的血清含量升高。CGA 降低了 APAP 处理小鼠和用 HMGB1 或 HSP60 刺激的 RAW264.7 细胞中某些促炎分子的肝 mRNA 表达增强。CGA 减轻了 APAP 处理小鼠的肝线粒体损伤，挽救了降低的 lon 蛋白酶同源物（Lon）蛋白表达，并减少了线粒体 HSP60 的释放。此外，在用抗 HSP60 抗体处理的小鼠中，CGA 对 APAP 诱导的肝炎症损伤的缓解作用减弱。进一步的结果表明，在核因子红细胞 2 相关因子 2（Nrf2）敲除小鼠中，CGA 对 APAP 诱导的肝炎症的缓解作用也减弱。同时，在 Nrf2 敲除小鼠中，用 APAP 处理后，CGA 降低血清 HSP60 含量和恢复线粒体 Lon 蛋白表达的作用均减弱。总之，本研究表明，CGA 减轻了 HSP60 或 HMGB1 引发的 APAP 诱导的肝炎症损伤，Nrf2 通过挽救减少的线粒体 Lon 蛋白表达来调节线粒体 HSP60 的释放。
