| BackgroundChronic atrophic gastritis（CAG）is characterized by abdominal pain,feelings of fullness,belching and loss of appetite,and is often accompanied by intestinal metaplasia and atypical hyperplasia or intraepithelial neoplasia.It is a major precancerous lesion of gastric cancer.The treatment of CAG patients is an important step.Currently,chemical drugs are often used for intervention,but the single drug does not work for all the symptoms,and long-term use is accompanied by obvious adverse reactions.The classic prescription Banxia Xiexin decoction originated from Treatise on Cold Damage and Miscellaneous Diseases.It is widely used in the clinical treatment of CAG.The herbal formula pays attention to the application of herbs containing cold and warm,pungent and bitter,resist Xie and replenishesOi.In recent years,there have been a number of systematic reviews or meta-analyses on Banxia Xiexin decoction treating CAG,but there is still a lack of methodological quality and evidence quality analysis for the systematic reviews,to some extent which affects the correct implementation of clinical practice.Based on the current clinical evidence,the systematic reviews of Banxia Xiexin decoction for CAG have showed that the formula could improve the comprehensive effect of gastroscope and pathology,increase the helicobacter pylori（HP）negative conversion ratio,immunological indexes and so on.On the other hand,the clinical evidence on incidence of gastric cancer and the quality of life is limited However,the endpoint outcome incidence of gastric cancer often requires long-term observation and follow-up with large samples and multiple centers,which is difficult to obtain in the majority of researches.CAG is a chronic inflammation of gastric mucosa caused by various etiologies and the patients’ conditions are difficult to be healed,which brine great inconvenience forthe life and work.Currentlv.there are relatively few studies on the quality of life in the clinical research of Banxia Xiexin decoction for CAG.At the same time,there is lack of a randomized,double-blind.placebo-controlled clinical trial design to confirm its absolute effect.Chinese herbal formula is characterized by multi-component,multiple targets and overall synergy.Traditional pharmacology research method has certain limitation.Network pharmacology method emphasizes the characteristics that drug effect has the effect for disease network.The idea is consistent with the effect of TCM compound.It can predict the key targets in the process of disease regulation and it provides a new strategy for the mechanism research of TCM compound.On the basis of the excellent clinical efficacy,the pharmacodynamic effect of Banxia Xiexin decoction has been preliminarily confirmed.Nevertheless,it is particularly important to further explain the mechanism of the herbal formula in the treatment of CAG from the molecular level and explore the key effect targets in this process.The network pharmacology research method is applied to study the mechanism of Banxia Xiexin decoction treating CAG,and its mechanism is widely clarified.This research has positive instructive significance and necessity for the clinical application,and can provide important reference for further experimental research.Objective2.1 To evaluate the currently completed systematic review of Banxia Xiexin decoction treating CAG,and analyze the methodological quality of the systematic evaluation and the reliability of the conclusion,in order to provide the evidence for clinical practice and research.2.2 To observe the clinical efficacy of the classic herbal formula Banxia Xiexin decoction on quality of life and TCM symptoms of CAG patients,and monitor the safety of Banxia Xiexin decoction in the treatment of CAG.2.3 To explore the potential molecular mechanism of Banxia Xiexin decoction for CAG,so as to provide reference for animal experiments and cell experiments in verifyingthe action mechanism.Methods3.1 Overview of systematic reviews of Banxia Xiexin decoction treating chronic atrophic gastritisPubMed,EMBASE,Cochrane library,CNKI,Wanfang,VIP,CBM Chinese and English database were applied to screen the literature.The combination of subject words and free words were used and the search was from their inception through March 15,2019 with no language restrictions.Two researchers independently searched and selected the literature,extracted the data.The systematic review measurement tool "assessment of multiple systematic reviews"（AMSTAR）was further used to evaluate the methodological quality of the existing system review of Banxia Xiexin decoction for CAG.The Grading of Recommendations Assessment.Development and Evaluation system（GRADE）was applied to evaluate the quality of evidence for outcome measures.According to the data characteristics,the data were analyzed via descriptive analysis methods3.2 Clinical research of Banxia Xiexin decoction treating chronic atrophic gastritis on improvement of quality of life and TCM symptomsA prospective,randomized,placebo-controlled clinical trial was designed and the inclusion and exclusion criteria were established.Forty patients with CAG were randomized into two groups,and health education was implemented for the all patients.The experimental group and the control group were treated with Banxia Xiexin decoction and placebo respectively.The course of treatment was 2 months.Quality of life,and TCM symptoms（epigastric dull pain or swelling pain,fullness,noise in the stomach,fatigue and weakness,and loss of appetite）and the safety were evaluated.This clinical efficacy and safety evaluation of Banxia Xiexin decoction in treating CAG will provide a new evidence for the clinical application.3.3 Network pharmacology study on the mechanism of Banxiaxiexin decoction treating chronic atrophic gastritisAccording to the theory of TCM,the classic prescription Banxia Xiexin decoctionfor CAG was used as the research object.The network pharmacology research method was used to predict the drug target,network construction and analysis,and to construct the“Banxia Xiexin decoction containing TCM-candidate targets molecular network" and "Banxia Xiexin decoction candidate targets-CAG-related molecular network”.Targets interaction network was established based on protein interaction network PPI databaseand the data were extracted for CAG-candidate-targets of Banxia Xiexin decoction.Finally,on the basis of the GO function analysis and KEGG pathway enrichment analysis,combined with the human disease database MalaCards and literature research,we obtained the possible biological pathways and processes of Banxia Xiexin decoction for CAG to explorepreliminary the molecular effect mechanism.Results4.1 Overv iew of systematic reviews of Banxia Xiexin decoction treating chronic atrophic gastritisAccording to the inclusion and exclusion criteria of the study,six systematic reviews or meta-analyses of Banxia Xiexin decoction treating CAG,which were published from 2013 to 2019.The interventions were Banxia Xiexin decoction or the modified Banxia Xiexin decoction.The control was positive drug control,such as vitacoenzyme tablets,anti-HP triple or quadruple therapy,Chinese patent medicine weifuchun etc.However,there had no placebo control clinical trials.Most of the studies took clinical effectiveness as the mainindex for evaluation,and calculation of effective rate was usually based on the improvement of clinical symptoms and signs and the improvement of gastroscopy and pathological efficacy.Four studies used the Cochrane bias risk assessment tool to evaluate methodological quality,and two studies used the Jadad scale for methodological quality evaluation.According to the eleven items of the AMSTAR scale,the methodological quality of the systematic review was evaluated.One review scored nine points and was judged as high quality.four reviews scored six points and were judged as medium quality,while the last one scored five points and was judged to be of low quality.Although the systematic review reported that Banxia Xiexin decoction alone or in combination with conventional drugs treating CAG had positive results in improving the incidence of gastric cancer,gastroscopy and/or pathological efficacy.HP negative conversion rate,gastrin and other laboratory indicators,TCM symptom scores,clinical total effective rate.Additionally,fewer adverse reactions were found.The quality of the evidence for each outcome was evaluated by the GRADE grading system and the results showed that the quality of the evidence was low or extremely low.Based on the analysis of existing research results,using the critical outcome indicators（gastric cancer incidence,gastroscopy and/or pathological efficacy）as the criteria for the quality of evidence,we found the overall evidence quality level of the classic herbal formulaBanxia Xiexin decoction for CAG outcomes should be low quality.4.2 Clinical research of Banxia Xiexin decoction treating chronic atrophic gastritis on improvement of quality of life and TCM symptomsAll the patients completed two months of treatment.there was no withdraw aland lost to follow-up.So the final sample size included in the statistical analysis was 40 cases.There were slightly more women than men in the two groups.The mean age of the patients in the experimental group was（54.68 ± 10.24）years,and the mean duration of disease was（3.45±2.58）years.The mean age of the control group was（55.19±9.56）years,and the mean disease duration was（3.23±2.31）years.The basic characteristics such as gender,age distribution and disease duration were comparable.For the quality of life measured by SF-12,Banxia Xiexin decoction remarkably increased physical component summary（PCS）score and mental health component（MCS）score compared with placebo（P<001～0.05）.In addition,Banxia Xiexin decoction was superior to the control group in relieving TCM symptomsepigastric dull pain or swelling pain,fullness,fatigue and weakness,and loss of appetite（P<0.01～0.05）via the rank sum test.However,there was no statistically significant difference between the two groups in alleviating noise in the stomach（P>0.05）.During the two months’ treatment and visit,one subject in each group reported the aggravation of stomach pain but the symptoms quicklydisappeared and did not stop taking the drug.The clinician determined that the symptom may be not related to the drug,so it was considered to be the adverse event.The subjects did not experience other discomfortsymptoms and no serious adverse events occurred during the study.4.3 Network pharmacology study on the mechanism of Banxiaxiexin decoction treating chronic atrophic gastritisA total of 420 chemical constituents of the seven kinds of Chinese traditional medicine of Banxia Xiexin decoction were collected,including 41 kinds of Pinellia ternata constituents,14 kinds of Rhizoma coptidis constituents,54 kinds of Astragalus membranaceus constituents,68 kinds of Codonopsis pilosula constituents,38 kinds of dried ginger constituents,133 kinds of licorice constituents,and 72 species of jujube constituents.The similarity score of the Chinese medicine compound was set to>0.9 and 1228 predicted targets were obtained.Based on the PPI interaction database,a network of potential targets of Banxia Xiexin decoction and disease targets was constructed,and 454 Chinese medicine and disease-related Hub nodes were screened according to the conditions.The relevant pathways mainly included chemokine signal transduction pathway,immune system,gap junction,epithelial signal transduction in HP infection,and T cell receptor signaling pathway,endocrine system and other pathways.At the same time,the human disease database MalaCards analysis showed that the most relevant signal transduction pathway to CAG was IL-17 family signaling pathway（Score=12.14）using atrophic gastritis as a search term.Based on the literature analysis,it was found that IL-17/ERK signaling pathway was involved in the regulation of inflammatory gene expression,and phosphorylation of ERK protein was an important link.Overall,the network pharmacology,human disease database MalaCards and literature analysis results suggested that the mechanism of Banxia Xiexin decoction was likely to regulate the MAPK cascade reaction through immunoregulatory factors such as IL-17,further promote the downstream ERK signaling pathway and affect the phosphorylation level of ERK proteinin inflammatory expression.Conclusion5.1 Clinical evaluation methodological researchBased on the analysis of the existing systematicreview,Banxia Xiexin decoction has significant clinical effect in treating CAG compared with the conventional western medicine or frequently-used Chinese patent medicine.The herbal formula can improve the gastroscope and/or pathological curative effect,HPnegative conversion ratioand immunological indexes.Banxia Xiexin decoction plus conventional western medicine not only improve gastroscope and/or pathological curative effect,increase HP negative conversion rate,but can significantly improve gastrin compared with conventional western medicine.In the aspect of safety,the adverse reaction of Banxia Xiexin decoction for CAG is relatively few.However,the methodological quality of the included systematic review and the level of evidence quality of the outcome are low.There is lack of high-quality clinical studies to provide the available evidence.Clinicians should carefully use existing evidence in the practice5.2 Clinical researchCompared to the placebo after two consecutive month treatment.Banxia Xiexin decoction can significantly improve the quality of life,and alleviate the clinical symptoms of the CAG patients including epigastric dull pain or swelling pain.fullness,fatigue and weakness,and loss of appetite based on the health education.No adverse reactions were found.In view of this,the formula is a safe and effective treatment approach in treating CAG,which is worthy of clinical popularization and application.CAG is the key step in the transformation processfrom inflammation to carcinoma,so this study provides a new evidence for the treatment of CAG via Banxia Xiexin decoction.5.3 Network pharmacology researchThe network pharmacology research suggested that the effect of Banxia Xiexin decoction for CAG was related to the expression of autoimmune factors,MAPK cascade reaction,and HP-infected epithelial cells signal transduction and so on.Analysis the MalaCards human disease database and the related literature,IL-17/ERK signaling pathway is very crucial in the CAG inflammationfrom the perspective of inflammation in the signal transduction.Phosphorylation of ERK protein,IL-17 and ERK1/2 may be as potential targets to study the action mechanism of Banxia Xiexin decoction in the treatment of CAG.This study will provide a reference for animal experiments and cell experiments.Innovation6.1 The overview of systematic reviews method is applied to evaluate the methodological quality for the systematic review of Banxia Xiexin decoction in treating CAG,and the quality of evidence for the treatment outcome is summarized via the GRADE tool.6.2 The clinical efficacy and safety of Banxia Xiexin decoction in the treatment of CAGare observed by the prospective,randomized,double-blind,placebo-controlled trial design.And quality of life and TCM symptomsare evaluated.6.3 Based on the network pharmacology research,human disease database MalaCards and related literature analysis,ERK protein phosphorylation,IL-17 and ERK1/2 are used as potential targets for CAG treated byBanxia Xiexin decoction,which isone of the possibleaction mechanismsto study the classic prescription in improving CAG from the perspective of anti-inflammatory. |
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