| Chronic atrophic gastritis(CAG)is a common disease of the digestive system characterized by the decrease of the natural glands of the gastric mucosa,accompanied by intestinal metaplasia and dysplasia.It goes through the process of precancerous lesion of gastric cancer without intervention,which may lead to the risk trend of gastric cancer.Therefore,the early diagnosis and intervention of chronic atrophic gastritis and precancerous lesion of gastric cancer can block its development to gastric cancer and play a positive role in the prevention and control of gastric cancer.A number of studies have shown that traditional Chinese medicine has a good effect in treating chronic atrophic gastritis and precancerous lesions by syndrome differentiation.Profound studies on syndromes related to this disease will help to explore the key pathogenesis and establish the core target of clinical treatment,thus laying a clinical theoretical foundation for the development of treatment principles and methods.Based on the long-term clinical and experimental studies,our research group believed that the pathogenesis of pregastric cancer was caused by qi-deficiency and toxin and blood stasis.Therefore,the method of supplementing qi,removing blood stasis and detoxifying toxin was proposed as the basic treatment for precancerous lesions,and its effectiveness in reversing precancerous lesions was confirmed by clinical observation and animal experiments.This study was mainly divided into two parts:clinical study and experimental study.The clinical study established a database based on cross-sectional collection of related information of patients with chronic atrophic gastritis,and used data mining method to explore the hidden laws of distribution of syndrome elements of chronic atrophic gastritis,correlation among syndrome elements,and combination of four diagnosis information,etc.After extracting the key syndrome elements,we evaluated their important role in this disease from the aspects of clinical symptom degree,pathological signs and psychosocial function,and provide the theoretical basis for the establishment of the core treatment principle of this disease.Based on preliminary clinical observation and animal experiments,the experimental study was to verify the intervention of the Yiqi Huayu Jiedu principle for Xiaopi granules on general situation,macroscopic characterization and pathological changes of gastric mucosa and to investigate the mechanism to reverse the protein signaling axis of precancerous lesions at the molecular level.I.Clinical studyObjective:Based on data mining,to explore the correlation law of syndrome elements of chronic atrophic gastritis,and to study the influence of key syndrome elements in this disease.Methods:Clinical data of four TCM diagnosis,gastroscopy and pathological examination of patients with chronic atrophic gastritis were collected to construct a database of chronic atrophic gastritis.Factor analysis,correspondence analysis,hidden structure model,association rule algorithm and data mining method based on neural network modeling were used to analyze the distribution of chronic atrophic gastritis syndrome elements,the correlation among syndrome elements,the core symptoms of chronic atrophic gastritis and the correlation between important pathological changes and syndrome elements.After extracting the key syndrome elements,the clinical symptoms,pathological signs and psychological-social functions were used to explain their influence,and the core pathogenesis and treatment methods of the disease were established.Results:i.A study on the distribution of chronic atrophic gastritis syndrome elements based on data mining(1)Factor analysis showed that the syndrome elements of chronic atrophic gastritis included qi deficiency,dampness,heat,blood stasis,qi stagnation,Yin deficiency and Yang deficiency.The distribution of syndrome elements is at least in sequence:dampness>qi stagnation>heat>blood stasis>qi deficiency>Yin deficiency>Yang deficienc(P<0.05).(2)According to the corresponding analysis,there were higher correlations between qi deficiency and qi stagnation,qi deficiency and Yang deficiency,dampness and heat,blood stasis and qi stagnation,blood stasis and Yang deficiency,qi stagnation and Yang deficiency.(3)According to the analysis of association rules,the core four-diagnosis information of chronic atrophic gastritis obtained from 59 four-diagnosis information items with a frequency of more than 10%through Apriori algorithm was 12,including stomach-tingling,halitosis,poor appetite and foreign body sensation in pharynx,covering syndrome elements blood stasis,heat,dampness,qi stagnation,Yang deficiency and qi deficiency.(4)The syndrome elements extracted from the hidden structure model analysis showed that the syndrome elements of chronic atrophic gastritis included qi deficiency,dampness,heat,blood stasis,qi stagnation and Yang deficiency.(5)Neural network analysis predicted that dampness,blood stasis and qi deficiency had a significant influence on the major pathological changes of dysplasia.ii.Discussion on the influence of dampness and blood stasis as the important syndrome elements of chronic atrophic gastritis(1)In the distribution of gastric mucosa pathology,syndrome factor dampness was positively correlated with Hp infection(P<0.05)and blood stasis was positively correlated with dysplasia(P<0.05).(2)In terms of the pathological score distribution of gastric mucosa,there were statistical differences in the Hp score and the pathological total score among the four groups(P<0.05).(3)In terms of symptom score distribution,there were statistical differences in main symptom score and total symptom score among the four groups(P<0.05).(4)On the score distribution of chronic gastritis PRO scale,there were statistical differences in the physiological field score and the total PRO score among the four groups(P<0.05).There was no significant difference in independence,psychology,social environment and quality of life scores between the groups(P>0.05).(5)There were significant statistical differences in the distribution of cases at different stages of disease(P<0.05).The number of cases in the pure stasis group from atrophy stage to dysplasia stage showed an increasing trend,while the number of pure dampness group showed a decreasing trend,and the number of cases of non-dampness non-stasis group and dampness with stasis group were basically the same.But there was no correlation between the group and the course of disease(P>0.05)?(6)The score of dysplasia has a great influence on the prediction of the dampness.The degree of dysplasia is lighter,then the possibility of dampness is greater.Dysplasia score,intestinal metaplasia score and activity score have a great influence on the prediction of blood stasis.The degree of dysplasia is serious and the degree of intestinal metaplasia is relatively light,the possibility of blood stasis is greater.Conclusion:The syndrome elements of chronic atrophic gastritis are mainly qi deficiency,dampness,heat,blood stasis,qi stagnation,Yin deficiency and Yang deficiency.Qi deficiency is the basic syndrome elements throughout the course of the disease.Dampness and blood stasis play an important role in the severity and progress of the disease.In view of the core pathogenesis of qi deficiency and toxin-stasis transformation,the Yiqi Huayu Jiedu principle reflects the inclusion of key syndrome elements targets of chronic atrophic gastritis and precancerous lesions,providing a syndrome basis for its clinical efficacy in reversing precancerous lesions and preventing gastric cancer.?.Experimental studyObjective:To establish the animal model of gastric precancerous lesion in rats,to explore the intervention for general conditons,pathological changes in rats with PLGC under the treatment of Xiaopi granule,to further investigate the effects of Yiqi Huayu Jiedu principle on miR-21-PTEN-PI3K/AKT signaling pathway in rats with precancerous lesions.Methods:70 Wistar male rats were randomly divided into model group(60 rats)and blank group(10 rats).The blank group rats were given standard diet of SPF animals until the end of the experiment.Three factors were used to make model of precancerous lesions of gastric cancer for the making model group rats,mainly by 200mg/L MNNG,5mL/kg,1 time/d,assisted by 0.05%for drinking water and 0.03%ranitidine in feed.After the model was succeeded on the 44th weekend,residual 41 rats in the making model group were randomly divided into model groups(14 rats),vatacoenayme groups(14 rats)and Xiaopi granules groups(13 rats).Each group was liven the corresponding medicine once daily:3 mL/kg saline for the model group,2mL/kg vatacoenayme suspension liquid(0.3g/kg vatacoenayme)for the vatacoenayme group and 3mL/kg herbal solution(containing 9g/kg crude drug).All the rats were sacrificed after treatment for 12 weeks.The method of RT-PCR and ELISA were used for detecting gene miR-21,PTEN and protein expression of PI3K,AKT in rats of all groups.The pathological changes were observed with light microscope.Results:i.Experimental study on intervention of PLGC rats by Yiqi Huayu Jiedu principle(1)At the modeling stage,the general condition and characterization of rats in the model group were significantly worse than that in the blank group.At the intervention stage,the macroscopical characterization of the rats in Xiaopi granule group and vatacoenayme group was better than that in the model group,especially in Xiaopi granule group,but the macroscopical characterization of the model group was not improved obviously.(2)At the modeling stage,the rats in the model group showed that gastric mucosa atrophy occurred at the 34th week of the experiment,dysplasia tended to be at the 38th week of the experiment,and dysplasia occurred at the 44th week of the experiment.At the intervention stage,there were statistically significant differences in gastric mucosal thickness,mucosal muscularis thickness and ratio between groups(P<0.05).The changes of gastric mucosa in different groups were statistically different(P<0.05).The gastric mucosa of the rats in the model group continued to atrophy,accompanied by dysplasia.The pathological changes of the rats in the Xiaopi granule group were significantly better than those in the model group(P<0.05),which was mainly reflected in the improvement of chronic inflammation and dysplasia.There was no significant difference in the pathological changes of the vatacoenayme compared with the model group(P>0.05).(3)After intervention,there was a strong positive correlation between the characterization scores and the total pathological scores(P<0.05).ii.Experimental study on axis intervention of miR-21-PTEN-PI3K/AKT signaling pathway in PLGC rats by Yiqi Huayu Jiedu principle(1)The expression levels of miR-21,PTEN gene,AKT protein and PI3K protein in each group were statistically different(P<0.05).Compared with each group,the expression of miR-21 was the highest in the model group,followed by the vatacoenayme group,and the lowest in Xiaopi granule group.Compared with each group,the expression of PTEN gene in Xiaopi granule group was the highest,followed by the blank group and the lowest in the model group.Compared with each group,the expression of AKT and PI3K protein was the highest in the model group,followed by the vatacoenayme group,and the lowest in the blank group.(2)miR-21 was negatively correlated with PTEN gene expression(P<0.05)and was positively correlated with the expression of PI3K and AKT(P<0.05).PTEN gene expression was negatively correlated with PI3K expression(P<0.05).PI3K protein was positively correlated with AKT protein expression(P<0.05).(3)The results of multiple linear regression analysis indicated that there was a strong correlation between the total pathological score and the expression of PI3K protein in rats.Conclusion:Xiaopi granules made by Yiqi Huayu Jiedu principl can effectively improve the general condition and macroscopic characterization of the rats with precancerous lesions,reverse the pathological changes of precancerous lesions,and block the occurrence of gastric cancer.Xiaopi granules can regulate PTEN gene by inhibiting the abnormal expression of miR-21,so as to intervene in the PI3K/AKT signaling pathway to reverse the occurrence of pregastric cancer,which may be one of its effective mechanisms for the prevention and treatment of gastric cancer. |
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