Improvement Effect of Sofalcone on Alleviates Nonsteroidal Anti-inflammatory Drug-induced Small Intestinal Mucosal Injury in Rats by RIPK1/RIPK3/MLKL Signaling Pathway
10.3870/j.issn.1004-0781.2025.06.003
- VernacularTitle:索法酮通过RIPK1/RIPK3/MLKL信号通路改善非甾体抗炎药诱导的大鼠小肠黏膜损伤
- Author:
Jie TAN
1
;
Yuping CAO
;
Junxian WANG
;
Si CHEN
Author Information
1. 中国科学技术大学附属第一医院(安徽省立医院)消化内科,合肥 230000
- Publication Type:Journal Article
- Keywords:
Sofalcone;
Nonsteroidal anti-inflammatory drugs(NSAIDs);
Small intestinal injury;
RIPK1/RIPK3/MLKL signaling pathway
- From:
Herald of Medicine
2025;44(6):854-861
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the protective effects and possible mechanisms of sofalcone on small intestinal mucosal damage induced by nonsteroidal anti-inflammatory drugs(NSAIDs)in rats.Methods In the first group of animal experiments,rats were randomly divided into five groups:normal control group,diclofenac group(diclofenac 7.5 mg·kg-1),and sofalcone high-doses groups(sofalcone 10 mg·kg-1+diclofenac 7.5 mg·kg-1),sofalcone medium-doses groups(sofalcone 5 mg·kg-1+diclofenac 7.5 mg·kg-1),and sofalcone low-doses groups(sofalcone 2 mg·kg-1+diclofenac 7.5 mg·kg-1).Each group received daily gavage for seven days.Serum D-lactate levels were measured,and histological damage to the small intestine was assessed through HE staining and pathological scoring.In the second group,rats were separated into three groups:normal control group,diclofenac group(diclofenac 7.5 mg·kg-1),and sofalcone group(sofalcone 2 mg·kg-1+diclofenac 7.5 mg·kg-1).Concurrently,the rats'body mass,24-hour diet,and water intake were monitored.Additionally,serum levels of pro-inflammatory cytokines such as IL-6,IFN-γ,TNF-α,inflammatory markers CRP and D-lactate,as well as measurements of tissue reactive oxygen species(ROS),lactate dehydrogenase(LDH),and mitochondrial membrane potential were conducted using appropriate kits.Western blotting was applied to assess the expression levels of intercellular junction proteins(Occludin,Claudin-1,α-Catenin),programmed necrosis pathway-associated proteins including receptor-interacting protein kinase 1(RIPK1),RIPK3,and mixed lineage kinase domain-like pseudokinase(MLKL)along with p-MLKL.Results In the first experiment,the diclofenac group exhibited significant histological damage to the small intestine,with elevated levels of D-lactic acid and pathological scores compared to the normal control group(P<0.01).Following intervention with sofalcone,both the histological damage and the levels of D-lactic acid and pathological scores in the small intestine were notably reduced(P<0.05 or P<0.01).However,there was no substantial difference in pathological scores among different doses of sofaclone groups(P>0.05).In the second experiment,compared with normal control group,rats in the diclofenac group showed decreased body mass,24-hour average diet and water intake,along with elevated levels of IL-6,IFN-γ,TNF-α,CRP,D-lactic acid,tissue ROS,LDH activity,RIPK1,RIPK3,and p-MLKL/MLKL protein expression levels,as well as mitochondrial membrane potential(P<0.05 or P<0.01).Moreover,Occludin,Claudin-1,and α-Catenin protein expression levels were reduced(P<0.05 or P<0.01).Following sofalcone intervention,the previously mentioned parameters were reversed(P<0.05 or P<0.01).Notably,there was no statistically significant difference observed in the reduction of RIPK1 protein expression(P>0.05).Conclusions Sofalcone reduces NSAID-induced small intestinal mucosal injury in rats by inhibiting the RIPK1/RIPK3/MLKL-dependent programmed necrosis pathway.
