Exploration of the intestinal flora to reveal the important contribution of Radix Astragali to Huangqi Jianzhong Tang in treating chronic atrophic gastritis rats.

Radix Astragali (Huangqi in Chinese, HQ) is a commonly used Chinese herbal medicine for thousands of years. In this study, A classic prescription Huangqi Jianzhong tang (HQJZ) was selected to evaluate the important effect of HQ on rats with chronic atrophic gastritis (CAG) from the perspective of intestinal flora in cecal contents samples. Traditional pharmacological indicators, including weight change, pathological examination and biochemical indicators showed that HQ exerted favorable contribution to HQJZ against CAG, where the efficiencies of HQ and HQJZ were better than HY (HQJZ prepared without HQ). An accurate strategy was adopted to screen out the differential metabolites in the metabolomis analysis of intestinal flora in cecal contents samples based on the optimal screening factors, including VIP (importance of variables in projection), FC (fold change), AUROC (area under the receiver operating characteristic curve) and -ln(p-value), which were evaluated based on their interpreting, grouping, and predicting abilities of the performed orthogonal partial least-squares-discriminate analysis (OPLS-DA) models. Ten altered differential metabolites were obtained and associated with the intestinal flora, which HQ exerted the important metabolic contributions to HQJZ. The efficacy on the diversity of intestinal flora and their correlations with the altered metabolites further showed the important role of HQ in HQJZ composition. This work provided valuable approach for looking for potential biomarkers associated with metabolomics research with more accuracy, and provided new insights into the mechanisms to explain the efficacy of HQ contributing to HQJZ formula.

Clinical Effect of Jianpi Huoxue Prescription Combined with Acupuncture on Chronic Atrophic Gastritis with Gastric Blood Stasis and Its Impact on Inflammatory Indicators and Gastric Mucosal Function / 中国实验方剂学杂志

ObjectiveTo explore the application effect of Jianpi Huoxue prescription combined with acupuncture in patients with chronic atrophic gastritis （CAG） of gastric blood stasis type. MethodA total of 86 patients with CAG admitted to Wuhan First Hospital from November 2021 to March 2023 were selected and randomly divided into two groups. The control group was treated with conventional Western medicine， while the observation group was treated with Jianpi Huoxue prescription combined with acupuncture. The clinical efficacy， traditional Chinese medicine （TCM） syndrome score， pathological score， negative conversion rate of Helicobacter pylori （Hp）， inflammatory indicators ［neutrophils/lymphocytes （NLR） and interleukin （IL）-1β］， changes in levels of gastric protease （PG） Ⅰ， PG Ⅰ/PG Ⅱ， and gastrin-17 （G-17）， and drug safety during treatment were observed after treatment in both groups. ResultAfter treatment， the total effective rate of the observation group ［95.35% （41/43）］ was significantly better than that of the control group ［79.07% （34/43）］， and the difference was statistically significant （χ2=5.108， P<0.05）. After treatment， the scores of the primary and secondary TCM syndromes in the observation group and the control group were significantly decreased （P<0.05）. After treatment， the scores of primary and secondary TCM syndromes in the observation group were significantly lower than those in the control group （P<0.05）. After treatment， the pathological scores of gastric mucosa atrophy， activity， chronic inflammation， intestinal metaplasia， and dysplasia were significantly lower in the observation group and control group （P<0.05）. After treatment， the pathological scores of gastric mucosa atrophy， activity， chronic inflammation， intestinal metaplasia， and dysplasia in the observation group were significantly lower than those in the control group （P<0.05）. After treatment， the Hp conversion rate in the observation group was significantly increased compared with the control group （P<0.05）. After treatment， the levels of inflammatory indicators NLR and IL-1β in the observation group and control group were significantly lower （P<0.05）， and the levels of inflammatory indicators NLR and IL-1β in the observation group were significantly lower than those in the control group （P<0.05）. After treatment， the levels of PGI and PGⅠ/PGⅡ in the observation group and control group were significantly higher （P<0.05）， and the levels of PGI and PGⅠ/PGⅡ in the observation group were significantly higher than those in the control group （P<0.05）. After treatment， the G-17 level of the observation group and the control group was different at different time points （P<0.05）， and the G-17 level of the observation group was higher at different time points than that of the control group （P<0.05）. The G-17 level of the observation group had an increasing trend compared with the control group （P<0.05）. There was no significant difference in the risk of adverse reactions between the two groups. ConclusionThe combination of Jianpi Huoxue prescription and acupuncture can effectively alleviate symptoms， increase Hp negative conversion rate， inhibit inflammation， and regulate PG and G-17 levels in CAG patients， thus controlling or even reversing gastric mucosal atrophy and reducing the probability of its progression to gastric cancer.

Mechanistic insights into the ameliorative effects of Xianglianhuazhuo formula on chronic atrophic gastritis through ferroptosis mediated by YY1/miR-320a/TFRC signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xianglianhuazhuo formula (XLHZ) has a potential therapeutic effect on chronic atrophic gastritis (CAG). However, the specific molecular mechanism remains unclear. AIM OF THE STUDY: To evaluate the effect of XLHZ on CAG in vitro and in vivo and its potential mechanisms. METHODS: A rat model of CAG was established using a composite modeling method, and the pathological changes and ultrastructure of gastric mucosa were observed. YY1/miR-320a/TFRC and ferroptosis-related molecules were detected. An MNNG-induced gastric epithelial cell model was established in vitro to evaluate the inhibitory effect of XLHZ on cell ferroptosis by observing cell proliferation, migration, invasion, apoptosis, and molecules related to ferroptosis. The specific mechanism of action of XLHZ in treating CAG was elucidated by silencing or overexpression of targets. RESULTS: In vivo experiments showed that XLHZ could improve the pathological status and ultrastructure of gastric mucosa and inhibit ferroptosis by regulating the YY1/miR-320a/TFRC signaling pathway. The results in vitro demonstrated that transfection of miR-320a mimics inhibited cell proliferation, migration, and invasion while promoting cell apoptosis. MiR-320a targeted TFRC and inhibited ferroptosis. Overexpression of TFRC reversed the inhibitory effect of miR-320a overexpression on cell proliferation. The effect of XLHZ was consistent with that of miR-320a. YY1 targeted miR-320a, and its overexpression promoted ferroptosis. CONCLUSION: XLHZ inhibited ferroptosis by regulating the YY1/miR-320a/TFRC signaling pathway, ultimately impeding the progression of CAG.

Explore the active ingredients and potential mechanisms of JianPi QingRe HuaYu Methods in the treatment of gastric inflammation-cancer transformation by network pharmacology and experimental validation.

BACKGROUND: JianPi QingRe HuaYu Methods (JQH) have been long used to treat chronic atrophic gastritis (CAG) and precancerous lesions of gastric cancer (PLGC). However, whether JQH can inhibit the transformation of gastritis to gastric cancer (GC) remains unclear. METHODS: Herein, we first retrieved the active ingredients and targets of JQH from the TCMSP database and the targets related to the gastric inflammation-cancer transformation from public databases. Differentially expressed genes (DEGs) related to gastric inflammation-cancer transformation were identified from the Gene Expression Omnibus (GEO) database. Then, we obtained the potential therapeutic targets of JQH in treating gastric inflammation-cancer transformation by intersecting drugs and disease targets. The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses of the potential therapeutic targets were conducted using R software. Next, we conducted molecular docking and in vitro experiments to validate our results. RESULTS: We obtained 214 potential therapeutic targets of JQH by intersecting drugs and disease targets. We found that the potential mechanisms of JQH in treating gastric inflammation-cancer transformation might be related to JAK-STAT, Wnt, p53 and VEGF signaling pathways. The molecular docking indicated that quercetin, as the main active ingredient of JQH, might inhibit gastric inflammation-cancer transformation by binding with specific receptors. Our experimental results showed that quercetin inhibited cells proliferation (P < 0.001), promoted cell apoptosis (P < 0.001), reduced the secretion of pro-inflammatory cytokines (P < 0.001) and promoted the secretion of anti-inflammatory cytokines (P < 0.001) in MNNG-induced GES-1 cells. Furthermore, quercetin inhibited cells proliferation (P < 0.001) and reduced mRNA and protein level of markers of PLGC (P < 0.001) in CDCA-induced GES-1 cells. CONCLUSION: These results provide the material basis and regulatory mechanisms of JQH in treating gastric inflammation-cancer transformation.

Integrating metabolomics, 16S rRNA sequencing, network pharmacology, and metorigin to explore the mechanism of Cinnamomi Cortex in treating chronic atrophic gastritis rats.

BACKGROUND: Cinnamomi cortex called as Rougui (RG) in Chinese was a widely used food-medicine homology. RG has the potential to treat chronic atrophic gastritis (CAG), a disease with widespread impact in the Chinese population. PURPOSE: This study aimed to explore its mechanism against CAG based on amalgamated strategies. METHODS: Network pharmacology was used to predict the potential effective components and the core targets of RG against CAG based on the comprehensive chemical characterization using UHPLC-Q/TOF MS (ultra high performance liquid chromatogramphy-quadrupole/time-of-flight mass spectrometry). The CAG animals model were further used to validate its pharmacodynamics, of which gut microbiota of caecal contents were analyzed by integrating metabolomics, 16S rRNA sequencing, Metorigin metabolite traceability analysis and molecular docking to explore its action mechanism. RESULTS: Network pharmacology firstly predicted the efficacy of RG was attributed to four effective components and seven targets. Metabolomics of caecal contents in CAG rats revealed primary bile acid biosynthesis was its targeted metabolic pathway associated with the metabolism of gut microbiota coupled with Metorigin traceability analysis. 16S rRNA sequencing showed that RG treated CAG by regulating the imbalance of gut microbiota. Molecular docking further confirmed that the effective components of RG could intervene with potential targets, metorigin analysis pathway, and key enzymes of gut microbiota metabolic pathways. CONCLUSION: Our results proved that RG exerted favorable effect on CAG. The four active ingredients (quercetin, kaempferol, oleic acid, and (-)-epicatechin) of RG were the key to exert drug effect, which could targeted the core target of CAG, primary bile acid biosynthesis and intestinal flora metabolic pathways.

Amalgamated Pharmacoinformatics Study to Investigate the Mechanism of Xiao Jianzhong Tang against Chronic Atrophic Gastritis.

BACKGROUND: Traditional Chinese medicine (TCM) Xiaojianzhong Tang (XJZ) has a favorable efficacy in the treatment of chronic atrophic gastritis (CAG). However, its pharmacological mechanism has not been fully explained. OBJECTIVE: The purpose of this study was to find the potential mechanism of XJZ in the treatment of CAG using pharmacocoinformatics approaches. METHODS: Network pharmacology was used to screen out the key compounds and key targets, MODELLER and GNNRefine were used to repair and refine proteins, Autodock vina was employed to perform molecular docking, ΔLin_F9XGB was used to score the docking results, and Gromacs was used to perform molecular dynamics simulations (MD). RESULTS: Kaempferol, licochalcone A, and naringenin, were obtained as key compounds, while AKT1, MAPK1, MAPK14, RELA, STAT1, and STAT3 were acquired as key targets. Among docking results, 12 complexes scored greater than five. They were run for 50ns MD. The free binding energy of AKT1-licochalcone A and MAPK1-licochalcone A was less than -15 kcal/mol and AKT1-naringenin and STAT3-licochalcone A was less than -9 kcal/mol. These complexes were crucial in XJZ treating CAG. CONCLUSION: Our findings suggest that licochalcone A could act on AKT1, MAPK1, and STAT3, and naringenin could act on AKT1 to play the potential therapeutic effect on CAG. The work also provides a powerful approach to interpreting the complex mechanism of TCM through the amalgamation of network pharmacology, deep learning-based protein refinement, molecular docking, machine learning-based binding affinity estimation, MD simulations, and MM-PBSA-based estimation of binding free energy.

Weierning, a Chinese patent medicine, improves chronic atrophic gastritis with intestinal metaplasia.

ETHNOPHARMACOLOGICAL RELEVANCE: Weierning tablet (WEN) is a traditional Chinese patent medicine widely used in clinical for chronic atrophic gastritis (CAG) therapy for years. However, the underlying mechanisms of WEN on anti-CAG are still unveiled. AIM OF THE STUDY: The present study aimed to elucidate the characteristic function of WEN on anti-CAG and to illuminate its potential mechanism. METHODS: The CAG model was established by gavage rats with a modeling solution (consisting of 2% sodium salicylate and 30% alcohol) with irregular diets and free access to 0.1% ammonia solution for two months on end. An enzyme-linked immunosorbent assay was used to measure the serum levels of gastrin, pepsinogen, and inflammatory cytokines. qRT-PCR was applied to measure mRNA expressions of IL-6, IL-18, IL-10, TNF-α, and γ-IFN in gastric tissue. Pathological changes and the ultrastructure of gastric mucosa were examined by hematoxylin and eosin staining and transmission electron microscopy, respectively. AB-PAS staining was applied to observe the intestinal metaplasia of gastric mucosa. Immunohistochemistry and Western blot were used to measure the expression levels of mitochondria apoptosis-related proteins and Hedgehog pathway-related proteins in gastric tissues. Expressions of Cdx2 and Muc2 protein were determined by immunofluorescent staining. RESULTS: WEN could dose-dependently lower the serum level of IL-1ß and the mRNA expressions of IL-6, IL-8, IL-10, TNF-α, and γ-IFN in gastric tissue. Also, WEN significantly alleviated the collagen deposition in gastric submucosa, regulated the expressions of Bax, Cleaved-caspase9, Bcl2, and Cytochrome c to reduce the apoptosis of gastric mucosa epithelial cells, and maintained the integrity of the gastric mucosal barrier. Moreover, WEN could reduce protein expressions of Cdx2, Muc2, Shh, Gli1, and Smo, and reverse intestinal metaplasia of gastric mucosa to block the progress of CAG. CONCLUSION: This study demonstrated a positive effect of WEN on improving CAG and reverse intestinal metaplasia. These functions were related to the suppression of gastric mucosal cells' apoptosis and the inhibition of Hedgehog pathways' activation.

Analysis of the relationship between oipA, babA2, babB genotypes and helicobacter pylori-related gastric precancerous lesions.

OBJECTIVE: To investigate the distribution of helicobacter pylori-related genotypes of oipA, babA2, and babB in patients with gastrointestinal diseases. Methods: The retrospective study was conducted at the Jiamusi College, Heilongjiang University of Traditional Chinese Medicine, Harbin, China, and comprised data from February 2017 to May 2020 of patients of either gender 20-80 years who underwent gastroscopy. An instrument based on polymerase chain reaction was used to amplify oipA, babA2 and babB genes, and their distribution in terms of gender, age and pathological types was analysed. RESULTS: Among the 116 patients, 52(44.8%) had oipA genotype, 48(41.2%) babA2, and 72 (62.1%) babB, respectively, and the size of amplified products of 486bp, 219bp and 362bp, respectively. The infection rate of oipA and babB genotypes was highest [26(50.0%) and 31(43.1%)]in those aged 61-80 years, and lowest [9(17.3%) and 15(20.8%)]in those aged 20-40 years. The infection rate of babA2 genotype was highest [23(47.9%)] in those aged 41-60 years, and lowest [12(25.0%)] in those aged 61-80 years. Male patients were under a higher [28(53.9%) and 26(54.2%)] rate of infection with oipA and babA2, and female patients has a higher [40(55.6%)] rate of infection with babB. Among Hp-infected patients with digestive diseases, babB genotype was mainly found in patients with chronic superficial gastritis[17(58.6%)], duodenal ulcer[17(85.0%)], chronic atrophic gastritis[19(59.4%)] and gastric ulcer[16(72.7%)], while oipA genotype was mainly found in patients with gastric cancer[8(61.5%)]. CONCLUSIONS: Chronic superficial gastritis, duodenal ulcer, chronic atrophic gastritis, and gastric ulcer may have a close bearing on babB genotype infection, while oipA genotype infection may be associated with gastric cancer.

Bile acid metabolism involved into the therapeutic action of Xiaojianzhong Tang via gut microbiota to treat chronic atrophic gastritis in rats.

BACKGROUND: As a classical traditional Chinese medicine (TCM), Xiaojianzhong Tang (XJZ) is effective in treating chronic atrophic gastritis (CAG). However, the pharmacological mechanism of XJZ has not been fully explained. PURPOSE: The purpose of this study was to investigate the mechanism of XJZ against CAG rats via gut microbiome using a multi-omics approach. METHODS: The rat cecal contents were analyzed through the integration of an untargeted metabolomic approach based on ultra-high performance liquid chromatography coupled with the quadrupole-time of flight mass spectrometry (UHPLC-QTOF-MS) and 16S rRNA gene sequencing. Finally, the interaction of differential metabolites with bile acid (BA)-related targets was verified by molecular docking. RESULTS: A new strategy was adopted to screen out the differential metabolites based on the comprehensive evaluation of VIP, |log2(FC)|, -ln(p-value) and ǀp(corr)ǀ. As results, XJZ showed favor regulations on the screened metabolites, cholic acid, deoxycholic acid, glycoursodeoxycholic acid, taurochenodesoxycholic acid, docosahexaenoic acid and L-isoleucine. The 16S rRNA gene sequencing analysis showed that XJZ could regulate gut microbiota disturbances in CAG rats, especially bile acid (BA) metabolism-related bacteria (Butyricimonas, Desulfovibrio, Bacteroides, Parabacteroides, Acetobacter and Alistipes). Molecular docking further showed that the differential metabolites regulated by XJZ had a good docking effect on BA-related targets. CONCLUSION: The current work indicated that XJZ's therapeutic action was strongly linked to BA-related microorganisms and metabolic processes. These findings provided new insights into the effects of XJZ for the treatment of CAG.

Exploring the effect of Weifuchun capsule on the toll-like receptor pathway mediated HES6 and immune regulation against chronic atrophic gastritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Weifuchun capsule (WFC) is a traditional Chinese patent medicine for chronic atrophic gastritis (CAG) in clinic. However, the mechanism of action of WFC for CAG still remains unclear due to its complex composition. AIM OF THE STUDY: The study was projected to uncover the mechanism of action of WFC and the corresponding pharmacodynamic substance of WFC against CAG as well as providing a standard example for the research of traditional Chinese medicine (TCM) from the perspective of the network and the system. MATERIALS AND METHODS: We identified the compounds of WFC through LC-MS/MS analysis and performed a systematic network targets analysis for WFC in the treatment of CAG which thoroughly described the mechanism of action of WFC for CAG. Based on analysis integrating omics data and algorithms, we focused on the specific immune regulatory role of WFC in the treatment of CAG, especially on a hub pathway, Toll-like receptor signaling pathway and thus deciphered the role of WFC in immune regulation, anti-inflammation and mediation of HES6. In experiments part, MNNG-GES-1-cell line and rat models were used to validate our findings. RESULTS: In this study, compounds of WFC are identified through LC‒MS/MS and network target analysis is performed to dissect the specific immunoregulatory effect as well as mediation of HES6, a newly discovered biomolecule related to gastritis carcinoma progression, of WFC on CAG through the Toll-like receptor signaling pathway. Based on cell line and rat models, we verify the mechanism of action of WFC for CAG in inhibiting inflammatory cytokines, regulating immune cells like T cells and macrophages, related genes including TLR2 and CD14. It is also validated that WFC inhibits the expression of HES6 (P < 0.05). CONCLUSION: Based on the combination of computational strategy and experiments, our study offers a comprehensive analysis to reveal the role of WFC in regulating immune response, inhibiting inflammation in the treatment of CAG, and provides a standard example for the research of TCM from the perspective of the network and the system.

Relationship Between NLRP3 Inflammatory Corpuscles and Chronic Atrophic Gastritis Based on "Spleen-mitochondrion Correlation" / 中国实验方剂学杂志

Chronic atrophic gastritis （CAG） is a common and intractable disease in the digestive system characterized by the reduction or disappearance of gastric mucosal glands. The intestinal metaplasia or dysplasia in CAG is called precancerous lesion， which greatly increases the risk of cancerization. Dysactivation of nucleotide-binding oligomerization domain-like receptor protein 3 （NLRP3） inflammatory corpuscles can release a large number of inflammatory factors， induce inflammatory cascade reactions， and participate in the process of many diseases. As reported， the dysactivation of NLRP3 inflammatory corpuscles can cause long-term chronic inflammatory infiltration of gastric mucosa and induce the development of CAG. Mitochondrial dysfunction plays an important role in the activation of NLRP3 inflammatory corpuscles. The accumulation of reactive oxygen species （ROS） produced by mitochondrial dysfunction is the key to activating NLRP3 inflammatory corpuscles. Professor LIU Youzhang put forward the theory of "spleen-mitochondrion correlation"， which holds that the spleen mainly transports water and grains， generates qi and blood， transports nutrients to the whole body， and supplies energy and materials needed by the body. Adenosine triphosphate （ATP） generated by mitochondria through the circulation of tricarboxylic acid is the main energy source of the human body. The view that both of them serve as human energy processing plants coincides in terms of physiology. Pathologically， spleen deficiency is associated with mitochondrial oxidative phosphorylation dysfunction. Pathological products such as dampness， turbidity， phlegm， and blood stasis due to failure in transportation because of spleen deficiency are consistent with metabolites generated by mitochondrial dysfunction. Based on the theory of "spleen-mitochondrion correlation"， this study discussed the pathogenesis of CAG in traditional Chinese medicine （TCM）， analyzed the relationship between NLRP3 inflammatory corpuscles and the pathogenesis of CAG， and proposed that the activation of NLRP3 inflammatory corpuscles by mitochondrial dysfunction was the modern biological basis of the pathogenesis of spleen deficiency in CAG. The spleen-strengthening method may be related to improving the mitochondrial function and inflammatory response of patients with CAG and alleviating the damage of gastric mucosa， providing a new idea for TCM in the prevention and treatment of CAG.

Traditional Chinese Medicine Treats Chronic Atrophic Gastritis via Multiple Pathways / 中国实验方剂学杂志

ObjectiveTo mine the compatibility rules of patented traditional Chinese medicine (TCM) compound prescriptions for treating chronic atrophic gastritis (CAG) by systems pharmacology and molecular docking methods, and predict the targets and molecular mechanisms of Chinese medicinals with different efficacy in the treatment of CAG. MethodThe TCM compound prescriptions for treating CAG were extracted from the patent system of the China National Intellectual Property Administration. The active components and targets of the prescriptions were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Traditional Chinese Medicine Integrative Database (TCMID), and UniProt. The candidate targets and pathways of CAG were obtained from GeneCards, DisGeNet, Online Mendelian Inheritance in Man (OMIM), MalaCards, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome. The gene ontology (GO) functional annotation and KEGG pathway enrichment were realized by R Studio 4.1.2. STRING11.0 was employed to build the protein-protein interaction (PPI) network, and AutoDock Vina 4.2.6 was used for the docking between key targets and components. ResultA total of 228 TCM compound prescriptions for treating CAG were extracted. The medicinals used in these prescriptions mainly had warm or cold nature, bitter or sweet taste, tropism to the spleen, stomach, and liver meridians, and the efficacy of tonifying Qi, regulating Qi movement, clearing heat, and activating and toniying blood. The prescriptions mainly treated CAG via p53, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), forkhead box protein O (FoxO), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1 (HIF-1) signaling pathways. Molecular docking results confirmed that the active components in the prescriptions had docking activities with key receptor proteins. ConclusionThis study preliminarily analyzed the compatibility rules of TCM compound prescriptions in the treatment of CAG. The medicinals with different efficacy treat CAG by regulating cell proliferation, apoptosis, and oxidative stress response, preventing carcinogen production, promoting gastric acid secretion, and improving local microcirculation in a multi-target, multi-pathway, multi-link manner. The findings facilitate the research on the TCM treatment of CAG.

Transformation of Chronic Atrophic Gastritis into Gastric Cancer and Prevention and Treatment： Based on Spleen Deficiency and Pathogen Stagnation / 中国实验方剂学杂志

Gastric ''inflammation-cancer'' transformation stars from inflammation and ends as gastric cancer （GC）， and the pathogenesis is still unclear. In China， GC features high morbidity and mortality and poor prognosis， influencing the quality of life and physical and mental health of patients. Therefore， it is of great significance to construct the prevention and treatment system for GC. Chronic atrophic gastritis （CAG） plays a key role in the occurrence， development， and outcome of gastric ''inflammation-cancer'' transformation. Modern therapies for CAG generally aim at eliminating causes and alleviating clinical symptoms， which show satisfactory short-term efficacy， but the reverse and recurrence are common. Based on the holistic view， syndrome differentiation-based treatment， and the ''inflammation-cancer'' transformation in modern medicine， traditional Chinese medicine emphasizes both prevention and treatment， with individualized therapies for CAG and GC to control the transformation. According to the pathogenesis of CAG-asthenia in origin and sthenia in superficiality and deficiency-excess in complexity， this study proposed the theory of spleen deficiency and pathogen stagnation in CAG， and believed spleen deficiency， pathogen， and stagnation are respectively the root cause of， the main factor of， and the key to ''inflammation-cancer'' transformation， respectively. Spleen deficiency and pathogen stagnation are closely related to the process of the transformation. For the treatment， the spleen-invigorating and pathogen-eliminating method should be used for invigorating the spleen to consolidate original Qi， improve the blood supply in stomach， and regulate immunity， and eliminating the pathogen to relieve stagnation， reduce the occurrence of non-controllable inflammation， and improve inflammatory micro-environment. As a result， the gastric inflammation is controlled at the early stage and the gastric ''inflammation-cancer'' transformation is blocked. The gastric mucosal lesions are blocked， delayed， or even reversed. This study provides a new idea in clinical diagnosis and treatment of CAG and in the prevention of GC.

Medicine for chronic atrophic gastritis: a systematic review, meta- and network pharmacology analysis.

PURPOSE: The aim of this study is to determine the effectiveness and reliability of adding traditional Chinese medicine (TCM) in the clinical intervention and explore mechanisms of action for chronic atrophic gastritis (CAG) through meta- and network pharmacology analysis (NPAs). METHODS: A predefined search strategy was used to retrieve literature from PubMed, Embase database, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wan Fang Data and China Science and Technology Journal Database (VIP). After applying inclusion and exclusion criteria, a total of 12 randomized controlled trials (RCTs) were included for meta-analysis to provide clinical evidence of the intervention effects. A network meta-analysis using Bayesian networks was conducted to observe the relative effects of different intervention measures and possible ranking of effects. The composition of the TCM formulation in the experimental group was analysed, and association rule mining was performed to identify hub herbal medicines. Target genes for CAG were searched in GeneCards, Online Mendelian Inheritance in Man, PharmGKB, Therapeutic Target Database and DrugBank. A regulatory network was constructed to connect the target genes with active ingredients of the hub herbal medicines. Enrichment analyses were performed using the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to examine the central targets from a comprehensive viewpoint. Protein-protein interaction networks (PPINs) were constructed to identify hub genes and conduct molecular docking with differentially expressed genes (DEGs) and corresponding active molecules. RESULTS: A total of 1140 participants from 12 RCTs were included in the statistical analysis, confirming that the experimental group receiving the addition of TCM intervention had better clinical efficacy. Seven hub TCMs (Paeonia lactiflora, Atractylodes macrocephala, Pinellia ternata, Citrus reticulata, Codonopsis pilosula, Salvia miltiorrhiza and Coptis chinensis) were identified through association rule analysis of all included TCMs. Thirteen hub genes (CDKN1A, CASP3, STAT1, TP53, JUN, MAPK1, STAT3, MAPK3, MYC, HIF1A, FOS, MAPK14 and AKT1) were obtained from 90 gene PPINs. Differential gene expression analysis between the disease and normal gastric tissue identified MAPK1 and MAPK3 as the significant genes. Molecular docking analysis revealed that naringenin, luteolin and quercetin were the main active compounds with good binding activities to the two hub targets. GO analysis demonstrated the function of the targets in protein binding, while KEGG analysis indicated their involvement in important pathways related to cancer. CONCLUSIONS: The results of a meta-analysis of 12 RCTs indicate that TCM intervention can improve the clinical treatment efficacy of CAG. NPAs identified seven hub TCM and 13 target genes associated with their actions, while bioinformatics analysis identified two DEGs between normal and CAG gastric tissues. Finally, molecular docking was employed to reveal the mechanism of action of the active molecules in TCM on the DEGs. These findings not only reveal the mechanisms of action of the active components of the TCMs, but also provide support for the development of new drugs, ultimately blocking the progression from chronic gastritis to gastric cancer.

Jian-Pi-Yi-Qi-Fang ameliorates chronic atrophic gastritis in rats through promoting the proliferation and differentiation of gastric stem cells.

Background: Jian-Pi-Yi-Qi-Fang (JPYQF) is a traditional Chinese medicine (TCM) herbal formula for treating chronic atrophic gastritis (CAG) in the clinic; however, its related mechanism remains unclear. The purpose of this study was to explore the potential mechanisms of JPYQF in treating CAG by examining proteins and genes related to the proliferation and differentiation of gastric stem cells and Wnt signaling. Methods: A CAG model was established in Sprague-Dawley (SD) rats which were induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and ranitidine. We randomly divided 25 CAG rats into 5 groups: the model group, positive drug group, low-dose group of JPYQF (JPYQF-L), middle-dose group of JPYQF (JPYQF-M), and high-dose group of JPYQF (JPYQF-H), with 5 rats of the same age classified into the control group. The body weight of rats was measured and their gastric morphology was visually assessed. Furthermore, pathological analysis of rat gastric tissue was performed. The expression levels of proteins and genes associated with the proliferation and differentiation of gastric stem cells and Wnt signaling were measured via immunohistochemistry and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Results: Compared with the model group, treatment with JPYQF increased the body weight of the rats, and relieved the gastric atrophy and inflammation. Compared with the control group, the protein and messenger RNA (mRNA) expression levels of gastric stem cell proliferation and differentiation markers Lgr5, Sox2, Ki67, PCNA, Muc5AC, and Wnt signaling initiator Wnt3A and enhancer R-spondin-1 (Rspo1) were decreased in the model group. Treatment with JPYQF increased the protein and mRNA expression levels of these markers. Conclusions: The Wnt signaling of CAG rats may be in a low activation state, which inhibits the proliferation and differentiation of gastric stem cells, so that gland cells cannot be replenished in time to repair the damaged gastric mucosa. The TCM formula JPYQF could enhance Wnt signaling to promote the restricted proliferation and normal differentiation of gastric stem cells, thereby improving gastric mucosal atrophy in CAG rats, which provides a novel and robust theoretical basis for CAG treatment.

[Effect of modified Danggui Shaoyao Powder on SOCS3/TLR4 signaling pathway in rats with chronic atrophic gastritis].

This study aims to investigate the effect of modified Danggui Shaoyao Powder on the suppressor of cytokine signaling 3(SOCS3)/Toll-like receptor 4(TLR4) signaling pathway in gastric tissue of rats with chronic atrophic gastritis(CAG).Sixty SPF-grade SD rats were randomly assigned into the normal group, model group, Moluo Pills group, and high-, medium-, and low-dose groups of modified Danggui Shaoyao Powder.The rats in other groups except the normal group were treated with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) to establish the CAG model.After 12 weeks of modeling, the rats in each group were administrated with corresponding drugs by gavage for 8 weeks.After the last administration, the histopathological changes of rat gastric mucosa were observed via hematoxylin-eosin(HE) staining.The serum levels of IL-6, TNF-α, and CRP were determined by enzyme-linked immunosorbent assay(ELISA).The mRNA levels of SOCS3 and TLR4 were determined by real-time PCR.The protein levels of SOCS3, TLR4, JAK2, p-JAK2, STAT3, and p-STAT3 in rat gastric tissue were measured by Western blot.Immunohistochemical method was employed to determine the protein levels of NF-κB, MyD88, NLRP3, Bcl-2, Bax, and Bad in rat gastric tissue.The results showed that modified Danggui Shaoyao Powder alleviated gastric mucosal atrophy of rats, significantly lowered the levels of IL-6, TNF-α, and CRP in rat serum, up-regulated the mRNA level of SOCS3, and down-regulated the mRNA level of TLR4 in rat gastric tissue.Furthermore, modified Danggui Shaoyao Powder up-regulated the protein level of SOCS3, down-regulated the protein levels of TLR4, p-JAK2, p-STAT3, NF-κB, MyD88, NLRP3, Bax, and Bad, and promoted the expression of Bcl-2 protein.Therefore, modified Danggui Shaoyao Powder may mitigate the gastric mucosal atrophy of rats by regulating the SOCS3/TLR4 signaling pathway.

Effects of Granule Dendrobii on chronic atrophic gastritis induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

BACKGROUND: Dendrobium officinale is an herb of Traditional Chinese Medicine (TCM) commonly used for treating stomach diseases. One formula of Granule Dendrobii (GD) consists of Dendrobium officinale and American Ginseng (Radix Panacis quinquefolii), and is a potent TCM product in China. Whether treatment with GD can promote gastric acid secretion and alleviate gastric gland atrophy in chronic atrophic gastritis (CAG) requires verification. AIM: To determine the effect of GD treatment on CAG and its potential cellular mechanism. METHODS: A CAG model was induced by feeding rats N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 12 wk. After oral administration of low, moderate, and high doses of GD in CAG rats for 8 wk, its effects on body weight, gastric mucosa histology, mucosal atrophy, intestinal metaplasia, immunohistochemical staining of proliferating cell nuclear antigen (PCNA) and B-cell lymphoma-2, and hemoglobin and red blood cells were examined. RESULTS: The body weights of MNNG-induced CAG model rats before treatment (143.5 ± 14.26 g) were significantly lower than that of healthy rats (220.2 ± 31.20 g, P < 0.01). At the 8th week of treatment, the body weights of rats in the low-, moderate-, and high-dose groups of GD (220.1 ± 36.62 g) were significantly higher than those in the untreated group (173.3 ± 28.09 g, all P < 0.01). The level of inflammation in gastric tissue of the high-dose group (1.68 ± 0.54) was significantly reduced (P < 0.01) compared with that of the untreated group (3.00 ± 0.00, P < 0.05). The number and thickness of gastric glands in the high-dose group (31.50 ± 6.07/mm, 306.4 ± 49.32 µm) were significantly higher than those in the untreated group (26.86 ± 6.41/mm, 244.3 ± 51.82 µm, respectively, P < 0.01 and P < 0.05), indicating improved atrophy of gastric mucosa. The areas of intestinal metaplasia were significantly lower in the high-dose group (1.74% ± 1.13%), medium-dose group (1.81% ± 0.66%) and low-dose group (2.36% ± 1.08%) than in the untreated group (3.91% ± 0.96%, all P < 0.01). The expression of PCNA in high-dose group was significantly reduced compared with that in untreated group (P < 0.01). Hemoglobin level in the high-dose group (145.3 ± 5.90 g/L), medium-dose group (139.3 ± 5.71 g/L) and low-dose group (137.5 ± 7.56 g/L) was markedly increased compared with the untreated group (132.1 ± 7.76 g/L; P < 0.01 or P < 0.05). CONCLUSION: Treatment with GD for 8 wk demonstrate that GD is effective in the treatment of CAG in the MNNG model by improving the histopathology of gastric mucosa, reversing gastric atrophy and intestinal metaplasia, and alleviating gastric inflammation.

Regulatory effect of traditional Chinese medicines on signaling pathways of process from chronic atrophic gastritis to gastric cancer.

Chronic atrophic gastritis (CAG), a common disease of digestive system, is an extremely important cause of gastric cancer (GC). The occurrence and development of CAG involves the abnormality of multiple signaling pathways. Traditional Chinese medicines (TCMs) has the advantages of mild action, multi-target and small adverse reaction, etc., which broadens the way for the treatment of the disease, and TCMs can play a therapeutic role by regulating multiple signaling pathways. In this review, based on the related experiments of TCMs and Chinese herbal compounds in recent years, the related literatures were searched and 10 kinds of signaling pathways involved were summarized, in order to provide a reference for further research on reversing or delaying the progress of CAG and preventing gastric cancer.

Integrated pharmacokinetics of Huangqi Jianzhong Tang in normal and chronic atrophic gastritis rats.

Huangqi Jianzhong Tang (HQJZ) is a famous traditional Chinese medicine formula widely used in the treatment of gastrointestinal diseases in China. In this study, an ultra-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) was used to study the pharmacokinetics of 12 prototypical components and one metabolite in HQJZ in normal and chronic atrophic gastritis rats. The results showed that the area under the concentration-time curve and peak concentration of most flavonoids and flavonoid glycosides were decreased, and the half-life and mean residence time were significantly increased, which indicated that the absorption of drugs in disease was decreased less and for longer in vivo. Then, an integrated pharmacokinetic study was carried out using the pharmacokinetic parameter model integration of each component. The results showed that the absorption of drugs in vivo with disease was reduced, and the absorption speed of flavonoids and flavonoid glycosides was accelerated. This study will provide the basis for the clinical medication safety of HQJZ.

Use of folic acid supplementation to halt and even reverse the progression of gastric precancerous conditions: a meta-analysis.

BACKGROUND: Current data indicate that supplements such as folic acid and vitamin B may be beneficial in halting and even reversing atrophic gastritis, intestinal metaplasia and intraepithelial neoplasia, generally referred to as gastric precancerous conditions(GPC). However, there is no Meta-analysis article to evaluate the prevention and treatment of folic acid in the gastric precancerous conditions. We therefore conducted a meta-analysis to confirm the efficacy of folic acid in treating GPC. METHODS: Using a systematic review method, consider randomized controlled trials (RCT), including clinical trial reports, unpublished clinical trial data, and conference papers. The search time was been set from the database's establishment to June 2, 2021. The language was not limited, using PubMed, SinoMed, Lancet, Web of Science, CNKI, Cochrane, Ovid, Science Direct, Embase, and EBSCO databases. Data were extracted using a pre-designed extraction tool and analysis was undertaken using RevMan5.2.Besides,we use Origin software to construct the Time-dose interval analysis. RESULTS: Of the 225 records identified, 13 studies involving 1252 patients (including 11 clinical controlled trials, 1 conference paper report and 1 unpublished research report) met the inclusion conditions. Folic acid dose maintained at 20-30 mg / d for 3-6 months may be beneficial to pathological changes of GPC. Moreover, in the 3 month treatment of 5 trials, the effect was more obvious when the folic acid dose was maintained at 30 mg / d. In the 7 trials, the symptom ineffective rate of GPC treated with folic acid was 32% (RR:0.32, 95% confidence interval CI:0.21-0.48), which was combined using a fixed analysis model; The effect of folic acid on gastric mucosal atrophy in 5 trials (RR: 1.61, 95%CI 1.07-2.41). The changes of folic acid on intestinal metaplasia in the 2 experiments (RR: 1.77, 95% CI: 1.32-2.37).The 2 results are combined using a fixed analytical model. However, the subgroup analysis of 9 trials revealed no significant effectiveness of symptom. CONCLUSIONS: Our research showed that folic acid supplementation brings benefits in preventing and even reversing the progression of GPC in the stomach, and provided evidence for its potential clinical use in management of GPC. REGISTRATION: The logn number of our Meta-anlysis on PROSPERO is CRD420223062.