The Radiation Protective Effects Of Novel Compound XH-103 In Mice

Background:With the continuous development of nuclear technology applications,the probability of receiving nuclear radiation is also increasing.Radiation can cause many types of acute and chronic radiation sickness.Small intestine is one of the tissues that are extremely sensitive to radiation.Radiation-induced intestinal injury is one of the side effects of patients receiving radiotherapy,which seriously affects the quality of life of patients,and there is currently no effective treatment drugs and methods.This project intends to synthesize a novel compound XH-103 and carry out its protective effect and study the mechanism or pathway on intestinal radiation damage in mice.Methods:Using the natural antioxidant quercetin as a lead compound and changing its molecular structure,the aminothiol analog was bonded to it through a linker to maintain the efficacy of the aminothiol and the safety of the natural antioxidant,respectively,and a novel compound XH-103 was synthesized.C57BL/6 male mice were randomly divided into control group,irradiation group and XH-103 irradiation group.The mice in the control group and irradiation group were treated with corresponding solvent 1 hour before irradiation,and the mice in the IR+103 group were intragastrically administered with XH-103 compound(100 mg/kg,200 mg/kg,400 mg/kg).The control mice were treated with sham irradiation,and the mice in IR group and IR+103 group were exposed to 9.0 Gy total body irradiation.Then the average survival days and survival rate of the mice were observed for 15 days.The mice were then subjected to whole body irradiation with 11.0 Gy y-ray,and the dose of XH-103 was 200 mg/kg.The average survival days and survival rate of the mice were observed for 15 days.Mice were sacrificed 3 days after 9.0 Gy total body irradiation,and the effects of XH-103 on the organ index of heart,spleen,liver and thymus after irradiation were observed.Paraffin sections of liver tissue were subjected to H&E staining.The liver tissue was homogenized and the expression of GSH,MDA,SOD,etc.was detected.The duodenum,jejunum and ileum were taken for H&E staining.The number of small intestinal crypts was counted,and the crypt-villi structure of the small intestine was observed.The expression of Villi,Lgr5,Ki67 and Lysozyme in the small intestine was observed by immunohistochemistry.TUNEL staining was used to detect the apoptosis of small intestinal tissues,and immunofluorescence was used to study the expression of apoptosis protein caspase-8 and capase-9 in the intestines.The expression of yH2AX and P53 protein in small intestine was also detected by immunofluorescence.The expression of Bax protein was detected by Western blot.Statistical comparisons were performed using the LSD-t test for comparison between groups.Results:In the 9.0Gy survival rate experiment,the average survival days of the irradiated group and the irradiated group were 4.9d and 6.3d,9.2d,7.7d(P<0.05),respectively.The survival rate of the XH-103-treated group was higher than that of the irradiation group(P<0.005).In the 11.0Gy survival rate experiment,the average survival days of the irradiated group and the IR+103 group were 4.0d and 6.0d,respectively(P<0.05),and the survival rate of the IR+103 group was higher than that of the irradiated group(P<0.05).After 3 days of 9.0Gy irradiation,the organ coefficient of the XH-103 treated group was higher than that of the irradiated group.and the difference of thymus coefficient was statistically significant(P<0.05).Compared with the control group,liver injury in the irradiation group included unclear structure of the hepatic lobule,disordered hepatoc\te arrangement,hepatic sinus stricture and hepatocyte enlargement,and XH-103 had some relief to liver damage.Compared with the irradiated group,the GSH content in the liver tissue of the IR+103 group increased,and the MDA level decreased(P<0.05).Compared with the control group,the small intestine tissue structure was obviously damaged in the irradiated group,the number of crypts was reduced,and the length of the villus was shortened.Compared with the irradiated group,the small intestine structure of the XH-103 treated mice was significantly improved,and the number of crypts was increased.The length of the villi became longer(P<0.05).Compared with the irradiated group,the number of Lgr5 stem cells in the small intestine crypt was increased in the IR+103 group,and the number of Ki67 positive cells was also increased,the number of Paneth cells increased,the expression of p53 decreased,and the number of apoptosis decreased.Sexual differences(p<0.05).Conclusions:The results showed that the novel compound XH-103 can i:prove the survival rate of mice.XH-103 can effectively inhibit the apoptosis of mice small intestinal crypt cells after irradiation,and XH-103 improved the proliferation and differentiation ability of mouse crypt cells.Further studies have found that XH-103 can reduce the expression of caspase8,caspase9,Bax and other apoptotic proteins of the small intestine.XH-103 reduced DNA damage and the expression of p53.In conclusion,the novel compound XH-103 may protect against intestinal radiation damage in mice by inhibiting p53-apoptosis pathway and DNA damage.