| Background and aims:Functional dyspepsia(FD)is a common functional gastrointestinal disorder and accounts for a significant proportion of patients seen in the internal medicine department.The direct and indirect economic burden caused by FD is huge and has considerable negative impact on productivity.The main pharmacotherapeutic options include acid suppression,prokinetic drugs,anti-anxiety medications and antidepressants,all of which have limited effects.The treatment of FD with anxiety and depression is especially a huge problem.Many studies have suggested the potential effectiveness of Chinese herbal medicine(CHM)in the treatment of FD,but effectiveness of CHM on the treatment of FD with anxiety and depression has little scientific evidence.Previous studies had shown that Jianpiliqi formula can improve the dyspepsia sympotoms in patients with FD.It is necessary to explore the effect of Jianpiliqi formula on FD with anxiety and depression.Functional dyspepsia is a heterogeneous disorder.The underlying pathogenesis is complicated and largely unknown.Potential causes are visceral hypersensitivity,decreased gastric compliance and abnormal gastric motility.It was proposed all the sympotoms are come from stomach,but recent studies have shown that duodenal barrier function is impaired and hypersensitivity is present in the duodenum of FD patients.CHM has demonstrated dramatic therapeutic effects in the treatment of FD,while the mechanisms are not clear.In preliminary experiments,we found that Jianpiliqi formula can improve visceral hypersensitivity,decreased gastric compliance and abnormal gastric motility and promote secretin of serotonin and prostaglandin E2.In order to explore different targets and mechanisms of Jianpiliqi formula,the major goal of the current proposal is to delineate Jianpiliqi formula could promote HC03-secretion via IRBIT and restore the duodenal barrier function.Clincial trial:Method:60 patients with anxiety-depression and FD of spleen-deficiency and qi-stagnation syndrome were randomly assigned to groups given the Jianpiliqi formulaor placebo in a 1:1 ratio.The trial included a 4-week treatment period and a 4-week follow-up period.The primary outcomes were dyspepsia symptom scores,measured by the total dyspepsia symptoms scale at weeks 0,1,2,3,4 and 8.The secondary outcome were TCM syndrome scores,Hamilton Anxiety Scale(HAMA)scoresand Hamilton Depression Scale(HAMD)scores.TheTCM syndrome scoreswere measured by the TCM syndrome scale at weeks 0,1,2,3,4 and 8.HAMA and HAMD were measured at weeks 0,4 and 8.Results:?On aspect of total dyspepsia symptoms:After 4-week treatment,total dyspepsia symptoms scores of the two groups were 3.63± 1.81 and 5.27±1.80(P=0.001).At follow-up,total dyspepsia symptoms scores of the two groups were 4.30±2.02 and 6.30±2.31(P=0.001).?On aspect of TCM syndrome:After 4-week treatment,TCM syndrome scores of the two groups were 8.37±2.06and 10.90±2.60(P=0.000).At follow-up,TCM syndrome scores of the two groups were 8.70±2.70 and 10.03±2.79(P=0.065).?On aspect of HAMA:After 4-week treatment,HAMA scores of the two groups were 4.60±2.34 and 6.23±2.95(P=0.021).At follow-up,HAMA scores of the two groups were 4.67±2.26 and 6.70±3.41(P=0.009).?On aspect of HAMD:After 4-week treatment,HAMD scores of the two groups were 6.90±2.55 and 5.07±1.82(P=0.002).At follow-up,HAMD scores of the two groups were 7.57±1.68 and 6.57±1.41(P=0.254).Conclusion:Jianpiliqi formula appeared to offer symptomatic and mental improvement in patients with anxiety-depression and FD of spleen-deficiency and qi-stagnation syndrome.Experiment:Method:FD was induced by stimulating rats via tail clamping.FD rats were randomly divided into two groups,which received saline or the Jianpiliqi formula for 7 days.Caco-2 cells were used as an in vitro model.Result:We found that Jianpiliqi formula downgraded gastric sensitivity and upgraded gastric compliance and upgraded duodenal PH.ELISA assay showed that Jianpiliqi formula induced the secretion of 5-hydroxytryptamine(5-HT)and prostaglandin E2(PGE2).Because recent evidence points to an important role of duodenal hypersensitivity to gastric acid in the pathogenesis of FD,we determined the expression level of Na+/HCO3-co-transporter(NBCe1-B),a basolateral membrane transporter that mediates the influx of Na+and HCO3-,in duodenal epithelial cells of healthy and FD rats.Interestingly,the membrane expression level of NBCe1-B was significantly decreased in FD rats compared to healthy rats as indicated by immunofluorescence staining.In contrast,Jianpiliqi formula treatment restored normal expression of NBCe1-B at the basolateral membrane compartments of duodenal epithelial cells.By using Caco-2 cells,we observed that 5-HT(1 ?M)and PGE2(2 uM)co-treatment for 30 min induced an increase in the interaction between IRBIT and NBCe1-B proteins.The stimulatory effect was abolished by pre-treatment with Go6850,inhibitors of protein kinase C(PKC),respectively,suggesting that 5-HT and PGE2 regulate IRBIT-NBCe1-B binding dependent on the activation of PKC.Conclusion:Jianpiliqi formula up-regulates NBCe1-B expression and increases the secretion of 5-HT and PGE2 in the duodenum of a rat model of FD.5-HT and PGE2 induce synergistic activation of IRBIT-NBCe1-Binteraction,which leads to an increase in NBCe1-B activity.Our findings suggest that the therapeutic effects of Jianpiliqi formula on FD are at least partially through improved acid neutralization via increased NBCe1-B expression and HCO3-influx in duodenum epithelial cells. |
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