| 1.Background and ObjectiveUlcerative Colitis(UC),one of the two primary forms of idiopathic inflammatory bowel disease(IBD),remains enigmatic from the standpoint of etiopathogenesis.There has been significant progress in recent years in China.Presentation is usually with chronic watery or bloody diarrhoea,slimy rectal discharge and abdominal pain and tenesmus.The severity of these symptoms depends on the extent of the colitis.Extra-intestinal manifestations of ulcerative colitis include arthritis(predominantly in the large joints,hips and knees).The development of carcinoma within the colon of the patient with ulcerative colitis is related to the duration of disease.The causes of UC probably involve interaction with many factors. Environmental,micro organic,potential genetic and immunologic factors are thought to contribute to the pathogenesis of ulcerative colitis in animal models and human disease. Recently,salazosulfamide,azathioprine and corticosteroid treatment are the most widely used in western medical management of ulcerative colitis,which would lead to some side effects and uncomfortable prostecdtive efficacy.The development of potent biological therapies have focus attention,but the long-term safety of biologicals and the ability of these novel and often expensive therapies to alter the natural history of the disease are still unclear.UC is classified to dysentery and decanta etc.according to symptoms in TCM.The controversy of etiopathogenisis,pathogenesis and pattern of syndrome is still on.In our opinion,the pathogenesis is splenic asthenia,humid heat and blood stasis,which result in asthenia in origin and asthenia in superficiality.UC is an coldheat complex disorder affecting the colon.Spleen,stomach,liver and kidney all play their vital roles according to TCM.For the past few years,clinical researches about Chinese herbal treating UC have shown satisfactory therapeutic effect,which has caught more attention.However,as the number of potential treatment expands,unanswered questions remain regarding optimal treatment strategies.In this study,we summarize the laws of clinical medication of UC by means papers review.For further study,we deeply investigate the mechanism of the prescriptions in IL-4/STAT6 signal pathway and evaluate their therapeutic effect.We expect to propose the targets of Chinese medicine and new methods to treat UC by TCM,in order to offer the objective evidence of TCM treating UC.2.MethodIn this study,we summarize frequently effective traditional Chinese drug and prescription for Ulcerative Colitis as well as to sum up clinical classification and regularity of compatibility though analysis of clinical data by means of Cluster analysis.Black plum pill uniting Decoction of Four Mild Drugs and Black plum pill are involved as experiment treatment.According to the result of literature study,we confirm experiment treating prescriptions, which are Black plum pill(BPP) and Black plum pill uniting Decoction of Four Mild Drugs (BUF).TNBS/ethanol model is adopted and evaluated.We perform experiments on SD rats. Rats are divided into five groups randomly,which includes control,model,SASP,BPP and BUF group.The therapeutic effect is evaluated according to tests of disease activity index (DAI),colon mucosa damage index(CMDI) and pathomorphological survey.On the basis of passed study,four key factors in IL-4/STAT6 signal pathway,including IL-4,STAT6,SOCS1 and eotaxin,are involved.We deeply investigate the regulation mechanism of Black plum pill and its addition to UC on IL-4/STAT6 signal pathway.ELISA is used to detect the content of IL-4 in serum,and immunohistochemistry method is used to detect the expression of STAT6, SOCS1 and eotaxin in colon of rats.3.ResultThe demonstration of Black plum pill and its additionThe data of lecture study suggests that the main pathogenesis of UC is spleen-asthenia with excessive damp,cold-heat complex,and the foundational prescription is Black plum pill uniting Decoction of Four Mild Drugs.Black plum pill(BPP) and Decoction of Four Mild Drugs are respective representative medicine of cold-heat complex and deficiency of spleen-QI.The two formulas are reviewed and analyzed in the angle of TCM and modern medicine.The protective effect of Black plum pill and its addition to UC induced by TNBSThe data indicates that DAI and CMDI of model group rise dramatically compared to control group,which suggests that reproduction of model is successful.DAI and CMDI of BPP and BUF groups are sharp lower than ones of model group,which suggests the obvious prevention function of Black plum pill and its addition.However compared to BPP,BUF cannot enhance its protective function.The impact of Black plum pill and its addition to UC on IL-4/STAT6 signal pathwayThe data indicates that the content of IL-4 in serum and the expression of STAT6 and eotaxin in colon show degression with SOCS1 up-regulation in BPP group,which have significant statistics difference.While in BUF group,the expression of STAT6,SOCS1 and eotaxin in colon show the same change as ones in BPP group,but the content of IL-4 in serum doesn't down regulate as dramatically as one in BPP group.4.ConclusionWe put forward the following presumption:The balance of Th1/Th2 in affection colon mucosa of UC is destroyed,which lead to IL-4 over-expression and becoming proinflammatory factor.Accordingly,STAT6 are over activated,translocate and accumulate in the nucleus,where they regulate gene expression,hke eotanxin.Eaotaxin are activated and then attract eosinophils towards inflammation location. On the other hand,the expression of SOCS 1 is inhibited,which is one of Negative regulation factors of STAT6.It makes imflammation more serious.Black plum pill and its addition exert the treatment through restraining over-expression of IL-4,STAT6 and eotaxin and enhancing expression of SOCS1.SASP have function on regulating expression of STAT6,SOCS1 and eotaxin in involved colon,but its effect doesn't involve IL-4.The results suggest that Black plum pill and its addition have regulationg on IL-4/STAT6 signal pathway and BPP have more effect on IL-4 in serum than BUF.However,the evidences cannot demonstrate the targets of the two formulas have obvious statistic difference,which is not consistent with literature study results.We need further study.The main pathogenesis of UC is splenic asthenia and humid heat.The study suggests that BPP and BUF have comfortable and therapeutic action on UC rats introduced by TNBS.BPP which aim at wanning middle energizer to dispel cold and expelling dampness and heat and BUF with additional effect of nourishing qi to invigorate spleen,both can regulate IL-4/STAT6 signal pathway through multi-targets.However,our study doesn't demonstrate that BUF has better therapeutical effect than BPP on UC rats introduced by TNBS.It emphasize that Chinese herbal has advantages in signal nets regulation.We expect these mechanisms can be further studied. |
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