| Background:Gastric cancer is a common cancer in the alimentary system.Its incidence rate and cancer mortality is the second place among the world's incidence rate and cancer mortality,so it has became a serious threat to human health.Because we don' t know its pathogen and pathogenesis,we could not prevent the disease according to the pathogenesis.Gastric mucosa cancerization always go though long precancerous phase.The pathological changes had shown the general trend that from chronic superficial gastritis to chronic atrophia gastritis,then intestines epidermis vegetates and atypical hyperplasia.The intestines epidermis vegetate and atypical hyperplasia were named as gastric precancerous lesion.So preventing and treating gastric precancerous lesions is the key of the secondary prevention. If we can diagnose and treat the disease in the gastric precancerous stage, cancer mortality should be decline greatly.Chinese medcine demonstrates advantages in preventing and treating precancerous lesions.According to the theory of Traditional Chinese Medicine(TCM) which spleen and stomach are the postnatal base and the sources for the production and transformation of qi and blood,Professor Liu Youzhang created the TCM compound formula named as WeiYanIHao(WYIH) after the long-term clinical practice.Preliminary clinical researches have shown that WYIH have significant curative effect on the chronic atrophic gastritis patients with weakness of the spleen and the stomach. Preliminary animal experiment have shown that WYIH have significant curative effect on the CAG model rats,as well as reverse intestines epidermis vegetate to some extent.The purpose of this research is to study the possible mechanism.In recent years,several studies have shown that Matrix metalloproteinase(MMPs) can be expressed excessively in gastric cancer.MMPs are endogenic proteolytic enzyme,Which participate in tissue reconstruct,cell proliferation,malignant cell infiltration,and metastasis by means of degrading extracellular matrix,regulating cell adhesion,and promoting vascularization,et al.As the important members of MMPs famility,MMP-7 and MMP-9 had been proved that their excessive expression and increasing activity are connected closely with tumorous growing,immersion,and transferring. Previous researches have shown that the expressions of MMP-7,9 in gastric precancerous lesions are higher than those expressions in the chronic gestritis tissue.Are the control mechanisms that the WYIH formula treat the gastric precancerous lesion related to MMP-7,9? These will be the focus of the experiment.Objective:According to the clinical research,we will draw out an impersonal and fair conclusion on WYIH clinical effects.The animal experiment which provide theoretical basis for clinical working is to explore the possible mechanism of WYIH formula on treatment of gastric precancerous lesions by means of studying the expression of MMPs with the molecular biology techniques and immunohistochemistry technique.Methods:1.Animal experiment:84 rats were randomly divided into six groups:model group,normal group,large dose WYIH group,medium dose WYIH group,small dose WYIH group,and WeiMeiSu(WMS) group.Each groups had 12 rats,but model group had 24 rats.Normal group was given normal water,diet and the same volume of 0.9%saline.Other groups freely drank 50μg/mL N-methyl-N'-nitro-nitrosoguanidine (MNNG) solution,without other water during the produced animal model phase;and were drunk with ranitidine hydrochloride at 0.03g/kg one time a day;and were given hunger-satiety disorders(animals were fed with adequate food for 2 days and not given food for 1 day).A total of 20 weeks were spent for produced animal model.After the animal model was successfully produced,WYIH large,medium and small dose group were given WYIH separately in the dose of 2.16g/(kg·d),1.08g/(kg·d),0.54g/(kg·d).WMS group was given WMS decoction in the dose of 0.86g/(kg·d).Normal group and model group were given 0.9%saline in the dose of 0.18g/(kg·d).At the end of the 3 months experiment,the general state of rats' health and histopathological examination of stomach were observed,as well as the expression and activity of MMP-7,MMP-9 of gastric tissue were observed by the three methods of immunohistochemistry,gelatin zymography and polymerase chain reaction technique.2.Clinical observations:30 cases were selected and randomly divided into two groups:WYIH group and WMS group.Before and after the treatment,the clinical symptoms and drug safety were compared to know the effect of WYIH by the table of TCM symptom schedule.Results:1.Animal experiment:The abnormalities of the rat' s gastric mucosa included gland atrophy, intestinal metaplasia,and atypical hyperplasia,which shown the animal model was successfully produced.After the treatment of WYIH and WMS,these histological abnormalities were lessened.Compared with model group,on the expression of MMP-7 in gastric tissue, normal group was statistically significant(P=0.000);large dose WYIH group, medium dose WYIH group,small dose WYIH group and WMS group were statistically significant(P=0.000,P=0.000,P=0.005,P=0.032).There were not significant differences between large dose WYIH group,medium dose WYIH group and small dose WYIH group.There were significant differences between medium dose WYIH group and WMS group(P=0.032);but there were no differences between large dose WYIH group,small dose WYIH group and WMS group(P=0.093,P=0.466).Compared with model group,normal group were statistically significant on the expression of MMP-9 in gastric tissue(P=0.001);large dose WYIH group, medium dose WYIH group,small dose WYIH group and WMS group were statistically significant(P=0.002,P=0.000,P=0.002,P=0.012).There were not significant differences between large dose WYIH group,medium dose WYIH group,small dose WYIH group and WMS group.There were significant differences among each group for the activity of MMP-7 in gastric tissue(P=0.000).From the mean rank trend,the activity of MMP-7 of model group was higher than others groups,and the activity of MMP-7 of normal group was lowest in the groups.The activity of MMP-7 of medium dose WYIH group was lower than large dose WYIH group,small dose WYIH group and WMS group.There were significant differences among each group for the activity of MMP-9 in gastric tissue(P=-0.000).From the mean rank trend,the activity of MMP-9 of model group was higher than others groups,and the activity of MMP-9 of normal group was lowest in the groups.The activity of MMP-9 of medium dose WYIH group was lower than large dose WYIH group,small dose WYIH group and WMS group. There are significant differences among each of group for the expression of MMP-7mRNA in gastric tissue(P<0.05).From the mean rank trend,the expression of MMP-7 of model group was higher than normal group,and large dose WYIH group,medium dose WYIH group,small dose WYIH group and WMS group were lower than model group on the expression of MMP-7.There are significant differences among each of group for the expression of MMP-9mRNA in gastric tissue(P<0.05).From the mean rank trend,the expression of MMP-9 mRNA of model group was higher than normal group,and large dose WYIH group,medium dose WYIH group,small dose WYIH group and WMS group were lower than model group on the expression of MMP-9mRNA.2.Clinical observations:The differences among sex,age and course of disease were not significant between WYIH group and WMS group(P>0.05).So these two groups are comparable. There were no differences of clinical symptoms by estimating table of TCM symptom schedule before treatment(P>0.05).The differences of stuffiness and fullness,stomachpain,dry mouth and thirst,belching and acid regurgitation,sloppy stool between the WYIH group and WMS group after treatment were significant(P<0.05).No difference of poor appetite and lack of strength between WYIH and WMS were found.The Differences of the items of TCM symptom schedule table were significant before and after treating with WYIH or WMS(P<0.05).WYIH and WMS can improve TCM symptoms such as stomachpain, belching and acid regurgitation,dry mouth and thirst,sloppy stool.The effect of WYIH was better than WMS.There was no difference in stuffiness and fullness, torpid intake and lack of strength between WYIH and WMS.The clinical curative effect of TCM between WYIH group and WMS group is significant(P=0.045),WYIH can improve symptom of TCM better than WMS.Conclusion:1.WYIH can improve general situation of rats,and treat and reverse the chronic inflammation of gastric mucosa,glands atrophy,and intestinal metaplasia. WYIH can improve the abnormal ultrastructure of gastric precancerous lesions rats.2.WYIH can decrease the expression and activity of MMP-7 and MMP-9 in gastric tissue of gastric precancerous lesions rats,as well as WYIH can decrease the expression of MMP-7mRNA and MMP-9mRNk.These maybe the possible mechanism of WYIH formula on treatment of gastric precancerous lesions 3.Both WYIH and WMS can improve the clinical symptoms of patient.The clinical curative effect of TCM between WYIH group and WMS group is significant,WYIH can improve symptom of TCM better than WMS. |
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