Protective Effect And Mechanism Of Compound SLL-1-43 On DSS-induced Acute And Chronic Ulcerative Colitis In Mice

Ulcerative Colitis(UC)is a recurrent,long-term inflammatory disease of the digestive system with the potential to develop into colorectal cancer.the pathogenesis of UC is complex,and some studies suggest that the high expression of NOX2 activates oxidative stress in the intestinal mucosa,which in turn causes damage to the intestinal barrier function and promotes the development of UC.The current drugs used for the treatment of UC are mainly aminosalicylates,glucocorticoids and immunosuppressants,which have large side effects and are likely to cause other diseases in the long term,therefore,it is necessary to explore safer,effective and less side effects drugs for the treatment of UC.The compound SLL-1-43 is a non-steroidal organoselenium compound with a novel structure.The results of previous laboratory studies at the cellular level showed that SLL-1-43 significantly inhibited the expression of inflammatory factors and inflammation-related signaling pathways in the lipopolysaccharide-induced inflammation model of RAW264.7 cells.The aim of this study was to investigate the protective effect of compound SLL-1-43 on DSS-induced acute and chronic UC mouse models at animal level and to investigate its molecular mechanism.The results of the study were as follows:1.SLL-1-43 significantly attenuates clinical signs in a mouse model of DSSinduced acute ulcerative colitisMice were given 3%DSS freely for 5 consecutive days,and acute UC mouse model was constructed.On the 5th day,the mice were given the drug intragastric for 7consecutive days.During the experimental period,the body weight of 3% DSS-induced acute UC mice was monitored and the disease activity index(DAI)was calculated at the same time every day,and the results showed that SLL-1-43 significantly improved the 3% DSS-induced acute UC in mice,alleviated the weight loss,reduced the DAI score,reduced the symptoms of shortened colon length,and reduced the ratio of colon weight to colon length,reduced the ratio of colonic weight to colonic length,and had a restorative effect on intestinal injury,and SLL-1-43 had no effect on the organ index of mice;further,Masson staining analysis,colonic crypt depth measurement,HE staining analysis,and histopathological scoring were performed on their colonic tissues,and the results showed that SLL-1-43 could significantly reduce the 3% DSS-induced acute UC The results showed that SLL-1-43 significantly reduced the area of fibrosis,increased the depth of colonic crypts,and decreased the histopathological score in the colonic tissues of mice with 3% DSS-induced acute UC.2.SLL-1-43 significantly attenuates clinical signs in a mouse model of DSSinduced chronic ulcerative colitisMice were given 2%DSS at week 1,week 4 and week 7,with normal water intake during the rest of the week,respectively.Chronic UC mouse model was constructed,and the drug was given intragastric administration at week 7 for 10 consecutive days.During the experiment,the body weight of 2%DSS induced chronic UC mice was monitored at the same time every day,and DAI was calculated every other day.The results showed that: SLL-1-43 can significantly improve chronic UC induced by2%DSS in mice,relieve weight loss,reduce DAI score,reduce the symptoms of shortened colon length,reduce the ratio of colon weight to colon length and colon weight to body weight,and have a certain easing effect on intestinal injury.In addition,it can significantly reduce the increase of spleen index in mice.Further Masson staining analysis,colonic recess depth measurement,HE staining analysis,and histopathological score were performed on the colon tissues.The results showed that SLL-1-43 could also significantly reduce the fibrosis area,increase colonic recess depth,and decrease histopathological score in 2% DSS-induced chronic UC mice.3.Molecular mechanism of SLL-1-43 protection in DSS-induced acute and chronic UC mouse modelsThe possible molecular mechanism of SLL-1-43 to attenuate DSS-induced acute and chronic UC in mice was further investigated.The colonic tissues of DSS-induced acute and chronic UC mice were stained by IHC and the expression of oxidative stressrelated proteins(gp91phox,p47 phox,NLRP3,Nrf2)and tight junction proteins(ZO-1,Occludin,Claudin 1)in the colonic tissues of the above mouse models were examined using Western Blot were examined,and the results showed that compound SLL-1-43 significantly reduced the integrated optical density of gp91 phox and the area of positive gp91 phox expression in the colon tissue of DSS-induced acute and chronic UC mice;significantly down-regulated the expression levels of gp91 phox,p47phox and NLRP3 proteins,and significantly up-regulated the expression levels of Nrf2,ZO-1,Occludin and Claudin 1 protein expression levels to alleviate the imbalance of oxidative stress,mitigate intestinal barrier damage and maintain intestinal stability in UC.In conclusion: the compound SLL-1-43 can alleviate DSS-induced weight loss in mice with acute and chronic UC,reduce DAI scores,reduce the area of fibrosis in colonic tissues,reduce histopathological scores and other clinical signs,and its molecular mechanism may be through downregulating the expression levels of gp91 phox,p47phox and NLRP3 proteins and upregulating Nrf2,ZO-1,Occludin and Claudin 1 protein expression levels to maintain intestinal oxidative stress stability and restore the intestinal mucosal barrier.The results of the current study provide new ideas for the treatment of UC and provide a feasible exploration direction for the compound SLL-1-43 to further target the treatment of UC and the development of new drugs.