Mechanism Of Sinensetin Reverses Cisplatin-induced Inflammatory Injury Of Intestinal Epithelium

Pet tumors are one of the most common diseases in veterinary practice today,affecting the quality of life of pets and even posing a serious health threat.Tumor diseases have become a major cause of death in dogs,cats and other pets.As with human tumors,animal tumors are usually intervened by surgery,radiation therapy or chemotherapy,and can also be treated by a combination of surgery combined with chemotherapy or radiation therapy.Chemotherapy,the main implementation method of tumor treatment,also faces great challenges.As the functions of natural extracts or compounds continue to be explored,more and more studies are showing their effectiveness in many diseases.In view of this,natural compounds with a range of characteristics such as safety and modulation are of great clinical interest and the role played by natural compounds in the future prevention and treatment of pet tumors is increasing.Sinensetin are natural flavonoids derived from citrus fruits with anti-inflammatory,antioxidant and antitumor properties.Although studies have demonstrated the association of flavonoids with apoptosis,autophagy and cell cycle arrest in cancer cells,little is known about the effects of flavonoids on chemotherapy induction.In contrast,natural compounds have been applied in combination with chemotherapeutic agents in clinical settings to improve efficacy or reduce adverse effects.It is worth exploring whethersinensetin play a role in reducing chemotherapy-induced pyroptosis.In this study,a mouse model of acute intestinal injury was established to evaluate the efficacy of sinensetin and the chemotherapeutic drug cisplatin.The dissection results showed no significant abnormalities in the intestinal tissues of the mice administered with sinensetin alone,while the body weight of the mice in this group was maintained at normal levels,demonstrating a high level of biosafety.The intestine of mice in the cisplatin group showed significant pathological histological changes such as intestinal hemorrhage,shortening of intestinal segments and hemorrhage,and the above changes were significantly attenuated in the sinensetin and cisplatin combination group.The results of HE staining of the above-mentioned tissues showed that sinensetin reduced the cisplatin-induced changes such as shortening of intestinal villi,reduction in number and loss of intestinal villi integrity.Immunohistochemical results showed that the cisplatin-induced neutrophil infiltration and reduction of cupped cells were also partially reversed by the effect of sinensetin.Finally,a mouse melanoma model was established,and the dissection results showed that the mean tumor volume and weight of the sinensetin and cisplatin combination group were significantly smaller than those of the other three groups,while the mean tumor volume and weight of the sinensetin alone administration group were also significantly smaller than those of the control(PBS)group.The above results demonstrate that sinensetin attenuate cisplatin-induced inflammatory bowel injury without affecting the anti-tumor effect of cisplatin in vivo,and even enhanced the anti-tumor effect with cisplatin.In the in vivo study,we first investigated the effects of sinensetin on cytotoxicity induced by the chemotherapeutic drug cisplatin and the changes in molecular markers associated with pyroptosis.After verifying the biosafety and anti-inflammatory properties of sinensetin by LDH lactate dehydrogenase release assay and real-time fluorescence quantitative PCR,mouse body weight and BCS score,the drug concentration of sinensetin for in vivo and ex vivo experiments could be selected.Subsequently,the expression of cisplatin-induced pyroptosis markers was detected by Western blotting,and the results showed that sinensetin could weaken the pyroptosis induced by cisplatin.The morphological changes of cells under microscope after drug application showed the same experimental results.Also,in the reactive oxygen species(ROS)and DNA damage associated with pyroptosis,sinensetin also attenuated the cisplatin-induced ROS surge and DNA damage.The results of the above questions will help to explore the role of natural compounds in the chemotherapeutic process of pet tumors in depth.