Cao Yuzhu, Xia Yawen, Wang Yufei, Shi Hang, Wu Yuanyuan, Lu Yin
School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
J Clin Transl Hepatol. 2023 Jun 28;11(3):584-594. doi: 10.14218/JCTH.2022.00048. Epub 2022 Dec 5.
Oxaliplatin is widely used in cancer chemotherapy with adverse effects such as liver toxicity. Magnesium isoglycyrrhizinate (MgIG) has hepatoprotective effects, but the underlying mechanism remains elusive. The study's aim was to investigate the mechanism underlying the hepatoprotective effects of MgIG against oxaliplatin-induced liver injury.
A xenografted colorectal cancer mouse model was established with MC38 cells. Mice were given oxaliplatin (6 mg/kg/week) for 5 weeks to mimic oxaliplatin-induced liver injury . LX-2 human hepatic stellate cell s(HSCs) were employed for studies. Serological tests, hematoxylin and eosin staining, oil red O staining and transmission electron microscopy were used for histopathological examinations. Real-time PCR, western blotting, immunofluorescence and immunohistochemical staining were used to determine Cx43 mRNA or protein levels. Flow cytometry was used to assay reactive oxygen species (ROS) and mitochondrial membrane. Short hairpin RNA targeting Cx43 was lentivirally transduced in LX-2 cells. Ultra-high performance liquid chromatography-tandem mass spectrometry was used to determine MgIG and metabolite concentration.
MgIG (40 mg/kg/day) treatment significantly reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels in the mouse model, and alleviated liver pathological changes, including necrosis, sinusoidal expansion, mitochondrial damage, and fibrosis. MgIG reduced the abnormal expression of Cx43 in the mitochondria and nuclei of HSCs. MgIG inhibited the activation of HSCs via reducing ROS generation, mitochondrial dysfunction, and N-cadherin transcription. MgIG's inhibition of HSCs activation was abolished after knockdown of Cx43 in LX-2 cells.
Cx43 mediated MgIG's hepatoprotective effects against oxaliplatin-induced toxicity.
奥沙利铂广泛应用于癌症化疗，但具有肝毒性等不良反应。异甘草酸镁（MgIG）具有肝脏保护作用，但其潜在机制仍不清楚。本研究旨在探讨MgIG对奥沙利铂诱导的肝损伤的肝脏保护作用机制。
用MC38细胞建立异种移植结直肠癌小鼠模型。小鼠接受奥沙利铂（6mg/kg/周）治疗5周以模拟奥沙利铂诱导的肝损伤。使用LX-2人肝星状细胞（HSCs）进行研究。采用血清学检测、苏木精-伊红染色、油红O染色和透射电子显微镜进行组织病理学检查。采用实时定量PCR、蛋白质印迹法、免疫荧光和免疫组织化学染色来测定Cx43 mRNA或蛋白水平。采用流式细胞术检测活性氧（ROS）和线粒体膜。将靶向Cx43的短发夹RNA慢病毒转导至LX-2细胞中。采用超高效液相色谱-串联质谱法测定MgIG及其代谢物浓度。
MgIG（40mg/kg/天）治疗显著降低了小鼠模型中的血清天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平，并减轻了肝脏病理变化，包括坏死、肝血窦扩张、线粒体损伤和纤维化。MgIG降低了HSCs线粒体和细胞核中Cx43的异常表达。MgIG通过减少ROS生成、线粒体功能障碍和N-钙黏蛋白转录来抑制HSCs的激活。在LX-2细胞中敲低Cx43后，MgIG对HSCs激活的抑制作用被消除。
Cx43介导了MgIG对奥沙利铂诱导的毒性的肝脏保护作用。
