Studies On The Anti-inflammatory And Antitumor Of Evodiamine In Ulcerative Colitis And Colitis-associated Colorectal Cancer

Inflammatory bowel disease（IBD）is a chronic bowel disease that includes ulcerative colitis（UC）and Crohn’s disease（CD）,which is considered colorectal cancer（Colorectal cancer,CRC）.The clinical symptoms of colitis are abdominal pain,diarrhea,and gastrointestinal bleeding.Colorectal cancer is the third most common cancer in the world,with the second highest mortality rate.Currently,IBD is closely related to CRC.Persistent inflammation activates the proliferation and apoptosis of premalignant cells,which further promotes the development and progression of tumors.Evodiamine（Evo）is an alkaloid that is mainly extracted from the rutaeaceae plant Evodiamine.Evodia has anti-diarrheal,anti-emetic,choleretic,anti-ulcer,and anti-tumor activities.In this study,we explored the effect of Evo on SW480 cells and Caco-2 cells in vitro,and explored the effect and preliminary mechanism of Evo on DSC-induced UC mice and C57BL/6-Apc^MinC/Gpt mice with spontaneous colorectal cancer.（1）By exploring the effect of Evo on DSS-induced UC mice,it was found that Evo inhibited weight loss in UC mice,reduced DAI scores,and promoted colonic length recovery.Pathological analysis showed that Evo improved colonic mucosa exfoliation,crypt loss,inflammatory infiltration of mucosa and submucosa in UC mice.At the same time,it inhibited the expression of pro-inflammatory factors such as IL-1β,IL-2,IL-6,IL-8 and TNF-αin UC mice,and promoted the expression of anti-inflammatory factor such as IL-10.By western blot analysis,Evo regulated NF-κB-related signaling pathways to regulate inflammatory factors and thus treat ulcerative colitis.（2）By exploring the effects of Evo on SW480 cells and Caco-2 cells,it was found that that Evo significantly inhibited cell viability,regulated the cell cycle and promote damaged to mitochondrial membrane potential,and accumulated intracellular ROS to achieve apoptosis in colorectal cancer cells.（3）To investigate the effect of Evo on spontaneous colorectal cancer C57BL/6-ApcMinC/Gpt mice,we found that Evo could inhibit the weight loss of CRC mice,reduce the mortality,and inhibit the size and number of tumors in the colorectum of CRC mice.Histopathological analysis showed that hepatocyte vacuoles around the central vein of the hepatic lobules were degenerate in CRC mice,and there were no significant lesions in the spleen and kidney.However,Evo reduced the liver and kidney of CRC mice by organ index measurement.Evo inhibited the expression of IL-1β,IL-2,IL-6,Il-17,IL-22,MMP-2,MMP-9 and TNF-αin CRC mice,and increased the levels of IL-4,IL-15 and IL-18 in CRC mice.Thus,the anti-colorectal cancer effect of Evo was achieved by regulating the NF-κB/STAT3 signaling pathway.In summary,our research shows that Evo could regulate NF-κB-related signaling pathways and inflammatory factors to achieve relief of ulcerative colitis and colitis-related colorectal cancer symptoms.This also provided a data basis for Evo to become an anti-colitis and anti-tumor drug.