Sphingosine-1-phosphate signal transducer and activator of transcription 3 signaling pathway contributes to baicalein-mediated inhibition of dextran sulfate sodium-induced experimental colitis in mice

Background:Baicalein has been shown to have anti-inflammatory and anti-tumor activities.However,the mechanisms underlying its anti-inflammatory effect on colitis remain unclear.Methods:A dextran sodium sulfate(DSS)-induced model of acute colitis was established in BALB/c mice(6-8 weeks old,weighing 18-22 g).Six groups of mice received:(1)water for 10 days(control),n=6;(2)DSS 4%solution in the drinking water for 7 days,followed by normal water for 3 days,n=7;(3),(4),and(5)as for group 2 plus baicalein(10,20,40 mg/kg)administered once daily starting on day 1,n=6;and(6)as for(2)plus 5-aminosalicylic acid(50 mg/kg)administered once daily starting on day 1,n=6.Body weights,stool consistency,and hematochezia were recorded,and the severity of colitis was evaluated using a disease activity index.On day 11,the mice were euthanized,and organs and blood were collected for analysis.Serum inflammatory factors were detected by enzyme-linked immunosorbent assay;CD11b-positive cells were analyzed by immunofluorescence microscopy;expression of retinoic-acid-receptor-related orphan nuclear receptor gamma,sphingosine kinase 1(SPHK1),and phosphorylated signal transducer and activator of transcription 3(p-STAT3)was detected by immunohistochemistry;and expression of nucleotide-binding oligomerization domain 2(NOD2),SPHK1,sphingosine 1-phosphate receptor 1(S1PR1),total STAT3,and p-STAT3 were detected by western blotting analysis.Inter-group differences were compared using Student’s t test.Results:Baicalein treatment dose-dependently reduced DSS-induced weight loss(P<0.01 or P<0.05),splenomegaly(P<0.01),and colonic damage,as reflected by amelioration of diarrhea,rectal bleeding,and colonic ulceration,congestion,edema(shown as colon length,P<0.05 or P<0.01),and inflammatory cell infiltration.Baicalein also significantly decreased the levels of inflammatory mediators in the serum(P<0.01)and colon,and significantly inhibited expression of NOD2 SPHK1,S1PR1,and p-STAT3 in the colon(P<0.05).Conclusions:Baicalein treatment ameliorated colitis in mice by inhibiting S1P-STAT3 signaling,suggesting that this flavonoid might be beneficial in the treatment of colitis.