Cantharidin Causes The Target Organs Of Acute Poisoning Injury In Mice And Its Related Mechanisms

Background:Initial liver cancer is one of the malignant tumors that threaten human health.At present,drugs for the treatment of liver cancer still use Solafini as the first choice drug,and its toxic and side effects are relatively strong.It is essential to look for a new type of treatment for liver cancer.Targeted drugs have always been the direction and goal of scientific researchers.Cantharidin(CTD)drugs have different anti-cancer effects on different tumors.They were discovered by Chinese scholars early in the last century and found that they have a greater killing effect on liver cancer cells.However,in clinical practice,the effects of cantharidinoids are greatly limited due to its strong toxic and side effects.Therefore,CTD drug toxicity study is very important to solve the clinical side effects of CTD.Looking for a combination of drugs and methods that can reduce the side effects of cantharidin is also of great significance.Objective:To establish an acute toxicity model of CTD-induced mice in this study,and to compare the injury status of various organs after administration in order to determine the acute toxic dose of CTD toxic target organs.The key toxic target organs were used as research objects to investigate the mechanism of cantharidin damage in the mice.Method:1.Comparing the survival of different doses of mice at different times,to explore the best dose and the best time for mice and establish an acute toxicity model in mice2.Comparing the same dose,the mouse organ damage at different time points initially determine the toxicity of targeted organs in mice.3.To ensure the target organs by comparing the more comprehensive biochemical indicators and pathological changes of different tissues obtained at the same time point at the same dose.4.Detecting the Polarization of Mouse Heart by Detecting Electrocardiogram in Mice5.Detecting the concentration of superoxide dismutase(SOD)and malondialdehyde(MDA)in the blood of mice to investigate whether the CTD injury is related to the redox reaction in mice.6.Succinic acid dehydrogenase staining of myocardial cells to investigate whether CTD injury is related to the tricarboxylic acid cycle in mouse myocardial mitochondria7.Through the myocardial tissue immunohistochemistry on the expression of NF-kb explore the appearance of inflammatory response in the mouse myocardium.Result:1.The median lethal dose of CTD in mice given by gastric administration is about 2 mg/kg.When administered at 3 mg/kg,it is suitable for studies at different time points.The total lethal dose is about 4 mg/kg.2.There was no obvious pathological changes in intestinal and kidney within 8 hours after administration of 3 mg/kg CTD.Liver tissue showed pathological changes around 4 h,since it returned to normal after 8 h.There was no significant increase in related biochemical indicators.The pathological section of the heart showed that as time went by,the damage of myocardial tissue in mice became heavier and the inflammatory cells infiltrated on the outer membrane.3.After 4 mg/kg CTD was given to the mice for 3 hours,liver function-related biochemical markers such as alanine aminotransferase(ALT),aspartate aminotransferase(AST),and renal function-related index urea nitrogen(BUN)were elevated in the CTD group.Compared with the control group,difference of the index was significant(P<0.05).In the administration group,the concentrations of creatine kinase(CK)and lactate dehydrogenase(LDH)were significantly different from those in the control group(P<0.01),and the blood concentration of troponin(Tnnil)increased significantly.HE staining showed that the pathological lesions of liver,kidney and intestine of CTD-intoxicated mice were relatively mild or no obvious damage;severe inflammatory cell infiltration appeared on the outer membrane of heart tissue,and the structure of myocardial cells was disordered.4.Electrocardiogram results showed that the ECG of CTD-intoxicated mice had a significant J-point upward shift,and the mean heart rate was slower than that of normal mice.5.Serum SOD,MDA values have increased,compared with the control group,the difference was statistically significant(P<0.05).6.Succinate dehydrogenase staining showed that mice in the CTD group had a large area of shallow staining,and their succinate dehydrogenase activity was decreased.7.Immunohistochemistry results showed that the NF-kB partial overexpression of the myocardial cell outer membrane was observed.Conclusion:1.The main toxic target organ under the acute toxicity does of cantharidin in mouse is the heart.2.The acute poisoning mechanism of cantharidin may be related to the decrease of redox capacity of myocardial cells and the mitochondrial tricarboxylic acid cycle in mouse.