The Inhibiting Effect And Mechanism Of JQ-1 On The Hepatic Granuloma And Fibrosis Of Mice Infected With Schistosoma Japonicum

Objective Schistosomiasis is a serious parasitic disease.Although there are many studies on the liver damage caused by Schistosoma japonicum,the mechanism of liver fibrosis caused by schistosomiasis remains to be understood.JQ-1 is a small-molecule inhibitor,which has achieved good results in anti-tumor efficacy and has a good effect in inhibiting inflammation.We mainly want to study whether JQ-1 can treat hepatic fibrosis caused by schistosomiasis and explore possible new mechanisms.Methods C67 / BL6 mice were infected with 18 ± 2 cercariae and divided into experimental group and control group with 8 in each group.For the granuloma model,two groups of mice were injected intraperitoneally with JQ-1(experimental group,50 mg/kg/d)and 10% ?-cyclodextrin(control group)at the 4th week for 2 weeks.24 h after dosing was sacrificed.HE staining was used to detect the size of liver granuloma in mice;liver transaminases were detected;q PCR was used to quantitatively detect related inflammatory factors.For the fibrotic model,we administered oral praziquantel to the mice on the 6th week,and then injected the mice with JQ-1(experimental 50 mg/kg/d)and 10% ?-cyclodextrin(control)in the 7th week for 2 weeks and sacrificed 24 h after the last dose.Liver fibrosis area was detected by Sirius red staining;Liver biochemical indicators were tested with kits;expression of liver ?-SMA and collagen m RNA was detected by q PCR;some liver sent to the company for m RNA sequencing analysis;q PCR verification of m RNA sequencing results.In cytology experiments,JS-1 cells were treated with JQ-1(500 n M),and the activity,proliferation,apoptosis,and senescence of the cells were detected using the corresponding kits;and the ?-SMA and collagen m RNA expressions of the cells were evaluated.The amount of p-STAT3 protein was detected by Western-blot.Results In the model of hepatic granuloma,the area of hepatic granuloma in JQ-1 treatment group was significantly reduced and the degree of hepatic granuloma was significantly reduced.Through the quantitative analysis of relevant inflammatory factors,JQ-1 can reduce the expression of related inflammatory cytokines;liver fibrosis model,JQ-1 treatment group liver fibrosis area was significantly reduced,liver function-related testing has also been significantly improved,Quantitative analysis of ?-SMA and collagen m RNAs showed that JQ-1 treatment can inhibit the activation of stellate cells in the liver and reduce the expression of collagen.The sequencing results of the sentinel m RNA showed that there were 350 differentially expressed genes after JQ-1 treatment,of which 164 genes were up-regulated and 186 genes were down-regulated.As can be seen from the GO analysis,JQ-1 can influence the expression of a broad spectrum of biological processes and cellular components that are known to play a key role in the transdifferentiation of HSCs into myofibroblasts and hepatic fibrosis.These components include extracellular regions,extracellular matrix,extracellular regions,receptor activity,regulated ion transport,lipid metabolism,and integration pathways.KEGG analysis shows that highly enriched metabolic pathways are mainly concentrated on six aspects of biodegradation and metabolism of xenobiotics,lipid metabolism,metabolism of cancer,cofactors and vitamins,endocrine and metabolic diseases,and carbohydrate metabolism.The identification of sequencing results by q PCR showed some consistency,indicating that the reliability of sequencing was high;cytological studies showed that JS-1 treatment of mouse hepatic stellate cell line JS-1 could inhibit its increment,but to JS-1 activity,aging,and apoptosis have no effect.The expression of p-STAT3 protein was detected by Western-blot.The results showed that JQ-1 could inhibit the expression of p-STAT3.Conclusion It can alleviate liver granuloma and fibrosis caused by infection with Schistosoma japonicum.In the early stage of schistosome infection,it mainly relieves granulomatous symptoms by inhibiting the expression of various proinflammatory factors.In the treatment of fibrosis in the late stage of infection,it can inhibit the phosphorylation of STAT3 in the JAK2/STAT3 pathway and thereby inhibit the activation of hepatic stellate cells,leading to a reduction in the degree of fibrosis.