上调 Nrf2/P62/Keap1 涉及甘草酸单铵盐和盐酸半胱氨酸联合 CCl 诱导的抗纤维化作用。

Up-regulation of Nrf2/P62/Keap1 involves in the anti-fibrotic effect of combination of monoammonium glycyrrhizinate and cysteine hydrochloride induced by CCl.

机构信息

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

Shanxi Key Laboratory of Chinese Medicine Encephalopathy, Shanxi University of Chinese Medicine, Taiyuan, 030024, China.

出版信息

Eur J Pharmacol. 2021 Dec 15;913:174628. doi: 10.1016/j.ejphar.2021.174628. Epub 2021 Nov 11.

DOI:10.1016/j.ejphar.2021.174628

PMID:34774851

Abstract

Combination of monoammonium glycyrrhizinate and cysteine hydrochloride (MG-CH) has been used in the treatment of chronic liver disease for decades, however, its mechanism is still unclear. Our previous studies showed that MG-CH confers the optimal therapeutic effect at the ratio of 2:1 to against acute liver damage. In this study, it was used to investigate the anti-fibrotic effect induced by CCl. The results showed that injection of MG-CH produced anti-fibrotic effect ranged from 30 mg/kg to 60 mg/kg, evidenced by decreased the collagens deposition and inhibited the production of hydroxyproline. Mechanism study found that Nrf2/ARE signaling pathway was activated by MG-CH, whereas loss of hepatocytic Nrf2 abolished its anti-fibrotic effect significantly. Furthermore, it was demonstrated that MG-CH is a non-canonical NRF2 inducer, which promoted the autophagy activity and release the Nrf2 from keap 1 by promoting the phosphorylation of p62 at Ser351. Knockdown of p62 abolished the enhancement of nuclear accumulation of Nrf2 by MG-CH. All of these results suggested that up-regulation of Nrf2/P62/Keap1 involves in the anti-fibrotic effect of MG-CH, which provide a rational explanation for the usage of MG-CH in the treatment of fibrosis.

摘要

单体铵甘草酸和盐酸半胱氨酸（MG-CH）的组合已在慢性肝病的治疗中使用了几十年，但作用机制仍不清楚。我们之前的研究表明，MG-CH 在 2:1 的比例下对急性肝损伤具有最佳的治疗效果。在这项研究中，我们用它来研究 MG-CH 对 CCl 诱导的抗纤维化作用。结果表明，注射 MG-CH 产生的抗纤维化作用范围为 30mg/kg 至 60mg/kg，表现为胶原沉积减少，羟脯氨酸生成受到抑制。机制研究发现，MG-CH 激活了 Nrf2/ARE 信号通路，而肝细胞 Nrf2 的缺失则显著消除了其抗纤维化作用。此外，研究表明，MG-CH 是一种非经典的 NRF2 诱导剂，通过促进 p62 在 Ser351 的磷酸化，促进自噬活性并将 Nrf2 从 Keap1 中释放出来。p62 的敲低消除了 MG-CH 对 Nrf2 核积累的增强作用。所有这些结果表明，Nrf2/P62/Keap1 的上调参与了 MG-CH 的抗纤维化作用，为 MG-CH 在纤维化治疗中的应用提供了合理的解释。