| Objective:Chemotherapy is an effective method for the treatment of tumors in clinical practice.However,a large number of studies have shown that the use of chemotherapeutic drugs has great toxic and side effects on patients.The liver,as the main drug metabolism organ,is highly vulnerable to chemotherapy drugs,which not only limits the application the chemotherapy drugs but also seriously affecting the quality of life of patients,may even lead to the death of patients directly.Therefore,finding effective drugs to alleviate liver injury caused by chemotherapy is the focus of current clinical research.Radix Glycyrrhiza is a dry root and rhizome of the leguminous Glycyrrhiza glabra L.,Glycyrrhiza uralensis Fisch.and Glycyrrhiza inflata Bat.Radix Glycyrrhiza plays a role in detoxification and reconciling various medicines in the traditional Chinese medicine group.Magnesium isoglycyrrhizinate is a structural modification of the radix glycyrrhiza extract-glycyrrhetinic acid.Currently,it has been reported in clinical studies that magnesium isoglycyrrhizinate(MgIG)has a very good effect in reducing liver injury caused by chemotherapy,and has the advantage of synergistic and detoxification compared with other hepatoprotective drugs,but the specific mechanism is still unclear.FOLFOX model of liver damage in tumor-bearing mice was established in this study to clarify the potential pathway and mechanism of MgIG in hepatic injury induced by chemotherapy,and provide a solid research basis for clinical application.Methods:1.This study first adopted evidence-based literature analysis method to collect clinically randomized controlled trials of MgIG for treatment of liver cancer caused by anti-tumor chemotherapy drugs.Meta-analysis was performed using RevMan 5.3 software.The effects of MgIG on liver injury caused by different chemotherapy regimens were analyzed and representative liver injury chemotherapy regimen was constructed to construct a liver injury model of tumor-bearing mice,and the effects of MgIG on liver injury induced by chemotherapy and its effect on tumor treatment were preliminarily verified.2.Immunohistochemistry,Masson staining,PCR,flow cytometry,Western blotting and other methods were used to detect the effects of MgIG on liver fibrosis,primary hepatocyte cycle,oxidative stress level and the changes of related regulatory proteins.3.Using MgIG and 18α-glycyrrhetinic acid as detection components,the primary nucleus,mitochondria and mitochondrial cytoplasm were extracted by separating primary hepatocytes,HPLC-MS/MS was used to qualitatively detect the cytoplasm of mitochondria removed from the nucleus of primary hepatocytes and the levels of MgIG and 18α-glycyrrhetinic acid in mitochondria.Construction of fluorescently labeled 18α-glycyrrhetinic acid(FI-C2)was used to investigate the subcellular distribution of MgIG after in vitro metabolism.4.The mechanism of mitochondrial ultrastructural observation,mitochondrial proteomics and lipid metabolism in liver tissue was studied to investigate the mechanism of MgIG in reducing liver injury induced by FOLFOX in mice.Based on the structural characteristics of MgIG and its metabolite 18α-glycyrrhetinic acid,which in the previous research results,the potential target and biological regulation process were analyzed to find out the mechanism of MgIG on inhibiting liver injury induced by FOLFOX.5.The mouse liver injury model was constructed by administering oxaliplatin,5-fluorouracil or FOLFOX,and the difference in liver damage was evaluated by observation of liver histopathology and mitochondrial ultrastructure.The intervention effect and mechanism verification of oxaliplatin-induced liver injury model of tumor-bearing mice to observe MgIG were constructed.Results:1.Meta-analysis showed that MgIG has a preventive effect on liver damage caused by FOLFOX,and has better curative effect than other commonly used hepatoprotective drugs.Moreover,prophylactic administration of MgIG can reduce liver injury induced by FOLFOX in tumor-bearing mice and it does not affect the therapeutic effect of FOLFOX on tumor.2.MgIG can significantly inhibit FOLFOX-induced liver fibrosis in mice,affect P21-mediated cell cycle,reduce FOLFOX-induced primary hepatocyte oxidative stress,and inhibit VEGF-mediated JNK activation and expression of MMP9.3.The concentration of MgIG and its metabolite 18α-glycyrrhetinic acid in mitochondria increased significantly compared with the concentration in the nucleus,and 18α-glycyrrhetinic acid were mainly distributed in the mitochondria of hepatic stellate cells in vitro.4.Connexin Cx43 may be the key to inhibit liver injury induced by FOLFOX by MgIG.5.Oxaliplatin is a major factor in liver damage induced by FOLFOX in mice,and MgIG can inhibit oxaliplatin-induced liver injury in tumor-bearing mice.The mechanism is related to the abnormality of mitochondrial Cx43 MgIG attenuate oxaliplatin-induced and the abnormality of Cx43 in nucleus,MgIG can reduce the activation of hepatic stellate cells by reducing Cx43 in the nucleus of hepatic stellate cells,decreasing N-cadeherin,ROS production and abnormal inhibiting mitochondrial membrane potential.Conclusions:1.MgIG prophylaxis significantly reduced FOLFOX-induced liver damage in multiple pathways.2.MgIG attenuated FOLFOX-induced hepatocyte cell cycle arrest,hepatocyte oxidative stress levels,liver fibrosis,and inhibition of VEGF-A-mediated JNK activation and MMP-9 expression.3.MgIG is metabolized as 18-glycyrrhetinie acid in vivo and aggregates in mitochondria4.Connexin Cx43 may be the key to inhibition of FOLFOX-induced hepatic injury in tumor-bearing mice by MgIG.5.Oxaliplatin is a key factor in liver injury induced by FOLFOX,and prophylactic administration of MgIG can significantly reduce liver damage caused by oxaliplatin.6.MgIG can inhibit the expression of Cx43 in the nucleus of hepatic stellate cells,which reduce the level of N-cadeherin,to relieve the activation of hepatic stellate cells. |
PDF Full Text Request