Manpixiao Decoction Halted the Malignant Transformation of Precancerous Lesions of Gastric Cancer: From Network Prediction to In-Vivo Verification.

Manpixiao decoction (MPX), a traditional Chinese medicine formula, is mainly used to improve the gastric mucosal pathology and stomach discomfort in patients with gastric precancerous lesions. Precancerous lesion of gastric cancer (PLGC) refers to intestinal metaplasia and/or dysplasia based on gastric mucosal atrophy. Effective prevention and treatment of PLGC is of great significance to reduce the incidence of gastric cancer. Because of the complexity of the etiology and pathogenesis of PLGC, there is no unified and effective treatment plan in western medicine. In recent years, traditional Chinese medicine has shown obvious advantages in the treatment of PLGC and the prevention of its further progression to gastric cancer, relying on its multi-approach and multi-target comprehensive intervention characteristics. This study is designed to examine the protective effect of MPX against PLGC and further to reveal the engaged mechanism via integrating network pharmacology and in vivo experimental evidence. Network pharmacology results demonstrated that inflammation, immune responses, and angiogenesis might be associated with the efficacy of MPX in the treatment of PLGC, in which the PI3K-Akt, cellular senescence, P53 and protein processing in endoplasmic reticulum were involved. Then, we established a rat model of PLGC using a combination of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium salicylate, irregular fasting, and ranitidine, and observed the effects after MPX treatment. Our result showed that MPX improved the pathological condition of gastric mucosa in PLGC rats and reduced the incidence of gastric cancer. Next, the analysis of serum inflammatory cytokines showed that MPX reduced the inflammation-related cytokines (such as IL-1α, IL-7, CSF-1, and CSF-3) in the serum. Additionally, MPX also had a regulation effect on the "protein/protein phosphorylation-signaling pathway" network in the core region of the PLGC rats. It is showed that MPX can inhibit the phosphorylation of PI3K-AKT, and downregulates the EGFR, ß-catenin, and N-cadherin protein levels. These results indicate that MPX halted the PLGC progression through inhibiting EGFR-PI3K-AKT related epithelial-mesenchymal transition process.

Medicinal herbs for the treatment of anxiety: A systematic review and network meta-analysis.

BACKGROUND: Anxiety disorder is a common psychiatric illness. Medicinal herbs have become a field of interest in the treatment of anxiety. This study aimed to evaluate and compare the efficacy and acceptability of all possible medicinal herbs for the treatment of anxiety. METHODS: A Bayesian network meta-analysis was conducted for adults with diagnosed or subthreshold anxiety in randomized controlled trials identified in PubMed, EMBASE, the Cochrane Library, and Web of Science, searched between Jan 1, 1987, and Dec 31, 2021. The outcomes included efficacy (measured by endpoint Hamilton Anxiety Scale [HAMA] Scores) and acceptability (discontinuation by ineffectiveness, worsening of the symptoms, or adverse events). RESULTS: A total of 29 trials were reviewed, comparing 12 medicinal herbs. Silexan (mean difference [MD]: -3.84, 95% credible interval [CrI]: -6.31 to -1.34) displayed a significant effect on anxiety, and possibly benefitted the treatment of depression (standard mean difference [SMD]: -0.37, 95% confidence interval [CI]: -0.53 to -0.20) and insomnia (SMD: -0.48, 95% CI: -0.76 to -0.21). Kava was found to be an effective anxiolytic (MD: -2.46, 95% CrI: -4.47 to -0.32) but possibly ineffective in patients with generalized anxiety disorder (MD: -0.17, 95% CrI: -2.55 to -1.97). Ginkgo biloba (MD: -4.63, 95% CrI: -9.01 to -0.23) and Withania somnifera (MD: -4.90, 95% CrI: -9.70 to -0.17) were efficacious, as measured by HAMA scores but the trials were limited by their small sample sizes. Galphimia glauca (MD: -1.23, 95% CrI: -4.68 to 2.23) and Manasamitravn Vataka (MD: -1.35, 95% CrI: -7.39 to 4.68) exhibited the same anxiolytic effect as standard treatments, but both were absent from trials that were rated low risk, highlighting that confidence in their ability to provide an anxiolytic effect requires additional study. Conversely, although Passionflower (MD: -4.20, 95% CrI: -8.82 to 0.16) and Saffron (MD: -2.71, 95% CrI: -6.06 to 0.57) did not reduce HAMA scores significantly in the summary network, both were worthy of further study because of support from separate networks. There was insufficient evidence to confirm the effectiveness of Valerian (MD: 0.95, 95% CrI: -6.57 to 8.42) in standard-controlled estimation or the ineffectiveness of Chamomile (MD: 0.54, 95% CrI: -5.13 to 6.25) compared with a placebo for anxiety. Gamisoyo-san (MD: -0.98, 95% CrI: -6.48 to 4.54) and L-theanine (MD: -0.49, 95% CrI: -6.54 to 5.57) did not outperform a placebo for the treatment of anxiety in terms of statistical certainty. All medicinal herbs were well-tolerated and exhibited a good safety profile compared with control groups. When all herbs were compared, there was no statistical evidence to suggest any comparison significantly reduced HAMA scores except Ginkgo biloba vs Kava (MD: -4.41, 95% CrI: -8.32 to -0.35), although Ginkgo biloba was ranked as worst due to its poor tolerability. CONCLUSION: Medicinal herbs may be promising for the treatment of anxiety. However, these results should be considered preliminary because of the unconvincing sample sizes, together with the potential effectiveness of placebos.

Gut Microbial Dysbiosis and Changes in Fecal Metabolic Phenotype in Precancerous Lesions of Gastric Cancer Induced With N-Methyl-N'-Nitro-N-Nitrosoguanidine, Sodium Salicylate, Ranitidine, and Irregular Diet.

Background and Aims: Precancerous lesions of gastric cancer (PLGC) are the most important pathological phase with increased risk of gastric cancer (GC) and encompass the key stage in which the occurrence of GC can be prevented. In this study, we found that the gut microbiome changed significantly during the process of malignant transformation from chronic gastritis to GC in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) multiple factors-induced rat model. Accumulating evidence has shown that alterations in gut microbiota and metabolism are potentially linked to chronic inflammation and cancer of the gastrointestinal tract. However, the correlation of gut microbiota and metabolites, inflammatory factors, and the potential mechanism in the formation of PLGC have not yet been revealed. Methods: In this study, multiple factors including MNNG, sodium salicylate drinking, ranitidine feed, and irregular diet were used to establish a PLGC rat model. The pathological state of the gastric mucosa of rats was identified through HE staining and the main inflammatory cytokine levels in the serum were detected by the Luminex liquid suspension chip (Wayen Biotechnologies, Shanghai, China). The microbial composition and metabolites in the stool samples were tested by using 16S ribosomal RNA (rRNA) gene sequencing and non-targeted metabolomics. The correlation analysis of gut microbiota and inflammatory cytokines in the serum and gut microbiota and differential metabolites in feces was performed to clarify their biological function. Results: The results showed that compared to the control group, the gastric mucosa of the model rats had obvious morphological and pathological malignant changes and the serum levels of inflammatory cytokines including interleukin-1ß (IL-1ß), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and macrophage colony-stimulating factor (M-CSF) increased significantly, while the level of chemokine (C-X-C motif) ligand 1 (CXCL1) in serum reduced significantly. There were significant differences in the composition of the gut microbiota and fecal metabolic profiles between the model and control rats. Among them, Lactobacillus and Bifidobacterium increased significantly, while Turicibacter, Romboutsia, Ruminococcaceae_UCG-014, Ruminococcaceae_UCG-005, and Ruminococcus_1 reduced significantly in the model rats compared to the control rats. The metabolites related to the lipid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathway have also undergone significant changes. In addition, there was a significant correlation between the changes of the differential inflammatory cytokines in the serum, fecal metabolic phenotypes, and gut microbial dysbiosis in model rats. Conclusion: The activation of the inflammatory response, disturbance of the gut microbiota, and changes in the fecal metabolic phenotype could be closely related to the occurrence of PLGC. This study provides a new idea to reveal the mechanism of risk factors of chronic gastritis and GC from the perspective of inflammation-immune homeostasis, gut microbiota, and metabolic function balance.

Erianin, the main active ingredient of Dendrobium chrysotoxum Lindl, inhibits precancerous lesions of gastric cancer (PLGC) through suppression of the HRAS-PI3K-AKT signaling pathway as revealed by network pharmacology and in vitro experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium chrysotoxum Lindl, a well-known traditional Chinese medicinal herb used in the treatment of gastric disease, is distinguished as the first of the "nine immortal grasses". Dendrobium chrysotoxum Lindl and the traditional Chinese medicine prescriptions containing Dendrobium chrysotoxum Lindl are often prescribed clinically to treat chronic gastritis and precancerous lesions of gastric cancer (PLGC), showing favorable clinical effects and medicinal value in the prevention of gastric cancer. However, the effective ingredients and pharmacological mechanisms through which Dendrobium chrysotoxum Lindl prevents and treats PLGC have not been adequately identified or interpreted. AIM OF THE STUDY: The present study aimed to evaluate the effective ingredients and pharmacological mechanisms of Dendrobium chrysotoxum Lindl in the prevention and treatment of PLGC using network pharmacology. In addition, in vitro verification was performed to evaluate the mechanism of action of Erianin, the main active ingredient in Dendrobium chrysotoxum Lindl, providing experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl in the treatment of PLGC. MATERIALS AND METHODS: Using network pharmacology methods, the main ingredients in Dendrobium chrysotoxum Lindl were screened from the ETCM, BATMAN-TCM, and TCMID databases, and their potential targets were predicted using the Swiss Target Prediction platform. The targets related to PLGC were retrieved through the GeneCard database, and the targets common to the main ingredients of Dendrobium chrysotoxum Lindl and PLGC were analyzed. The protein-protein interaction (PPI) network was obtained via the STRING database and analyzed visually using Cytoscape 3.7.2. The underlying mechanisms of the common targets identified through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were analyzed using DAVID online. The "component-target-pathway" networks of Dendrobium chrysotoxum Lindl and Erianin were visually constructed by Cytoscape 3.7.2. The biological activity evaluation of Erianin's effect on PLGC was carried out using MC cell lines, the PLGC cell model established using MNNG to induce damage in normal gastric mucosal epithelial cell (GES-1). After the intervention of different concentrations of Erianin, MC cell viability was explored using the MTT assays, cell migration was determined by wound healing assays, the cell cycle and apoptosis were analyzed using flow cytometry, and the expression levels of related proteins and their phosphorylation in the HRAS-PI3K-AKT signaling pathway were detected by Western blot. RESULTS: The "component-target-pathway" network constructed in this study showed 37 active ingredients from Dendrobium chrysotoxum Lindl and 142 overlapping targets related to both Dendrobium chrysotoxum Lindl and PLGC. The targets were associated with a variety of cancer-related signaling pathways, including Pathways in cancer, PI3K-Akt signaling pathway, Rap1 signaling pathway, Focal adhesion, Ras signaling pathway, and MAPK signaling pathway. Notably, the network showed that Erianin, the primary active ingredient from Dendrobium chrysotoxum Lindl and the component associated with the most targets, could regulate Pathways in cancer, PI3K-AKT signaling pathway, Focal adhesion, Rap1 signaling pathway, cell cycle, and RAS signaling pathway in the treatment of PLGC. Verification through in vitro experiments found that Erianin can significantly inhibit MC cell viability, inhibit cell migration, block the cell cycle in the G2/M phase, and induce cell apoptosis in a dose-dependent manner. The results of the Western blot experiment further showed that Erianin can significantly decrease the protein expression levels of HRAS, AKT, p-AKT, MDM2, Cyclin D1, and p-Gsk3ß, and increase the protein expression level of p21, which suggests that Erianin can treat PLGC by regulating the HRAS-PI3K-AKT signaling pathway. CONCLUSION: This study explained the positive characteristics of multi-component, multi-target, and multi-approach intervention with Dendrobium chrysotoxum Lindl in the treatment of PLGC. Our results suggest that Erianin may be a promising candidate in the development of prevention and treatment methods for PLGC. This study provided experimental evidence for the clinical use of Dendrobium chrysotoxum Lindl to treat PLGC and prevent gastric cancer.

The mechanisms of action of WeiChang'An Pill (WCAP) treat diarrhoea-predominant irritable bowel syndrome (IBS-D) using network pharmacology approach and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: WeiChang'An Pill (WCAP) is used in Traditional Chinese Medicine (TCM) to clinically treat diarrhoea-predominant irritable bowel syndrome (IBS-D); however, the underlying pharmacological mechanisms are unclear to date. AIM OF THE STUDY: To explore the mechanism underlying the therapeutic action of WCAP in IBS-D using a network pharmacology approach and in vivo experiments. MATERIALS AND METHODS: The active compounds of WCAP were selected from the TCM Systems Pharmacology Database and TCM Integrated Database, and the potential targets were identified using the Swiss Target Prediction and Similarity Ensemble Approach (SEA) databases. The targets related to IBS-D were mined from the Therapeutic Target Database (TTD), National Center for Biotechnology Information Search database (NCBI), DrugBank database, and DisGeNET database. The intersecting protein-protein interactions (PPIs) of the drug-disease crossover genes were analysed, and the central PPI network was constructed using the String database, version 11.0, and Cytoscape version 3.7.2. Following Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway analyses, the gene-pathway network was constructed for identifying the key target genes and pathways. Based on the results and existing evidence, it was selected the cyclic adenosine monophosphate (cAMP) signalling pathway for further validation using in vivo experiments. RESULTS: A total of 872 targets were identified from the 77 active compounds in WCAP, which shared 78 targets that were predicted to be related to IBS-D. Twenty-one core targets were identified from the PPI network, which was constructed from the common targets. The results of enrichment analysis revealed that HRT2B, ADRA1A, ADRA1D, and CHRM2 could be the key targets of WCAP in IBS-D, and 11 signalling pathways, including the neuroactive ligand-receptor interaction, calcium signalling, and cAMP signalling pathways, were identified as crucial for the therapeutic activity of WCAP in IBS-D. We also identified the possibility of several interactions and crosstalk between the different pathways. Subsequent molecular biology experiments revealed that the expression levels of cAMP, phospho-(Ser/Thr) protein kinase A substrates (p-PKA), 5-hydroxytryptamine, and proteins in the cAMP signalling pathway, including G protein-coupled receptor (GPCR), adenylyl cyclase 5 (AC5), and cAMP-response element binding protein (CREB), were significantly upregulated in rat models of IBS-D following treatment with WCAP (P < 0.05). However, a reverse trend was observed in the expression of nuclear factor kappa-B (NF-κB) (P < 0.05), which could be attributed to the low-grade inflammation that occurs in IBS-D. CONCLUSION: We demonstrated that WCAP may alleviate the symptoms of diarrhoea and visceral sensitivity in IBS-D by regulating the cAMP signalling pathway.

Potential effect of Maxing Shigan decoction against coronavirus disease 2019 (COVID-19) revealed by network pharmacology and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Since the occurrence of coronavirus disease 2019 (COVID-19) in Wuhan, China in December 2019, COVID-19 has been quickly spreading out to other provinces and countries. Considering that traditional Chinese medicine (TCM) played an important role during outbreak of SARS and H1N1, finding potential alternative approaches for COVID-19 treatment is necessary before vaccines are developed. According to previous studies, Maxing Shigan decoction (MXSGD) present a prominent antivirus effect and is often used to treat pulmonary diseases. Furthermore, we collected 115 open prescriptions for COVID-19 therapy from the National Health Commission, State Administration of TCM and other organizations, MXSGD was identified as the key formula. However, the underlying molecular mechanism of MXSGD against COVID-19 is still unknown. AIM OF THE STUDY: The present study aimed to evaluate the therapeutic mechanism of MXSGD against COVID-19 by network pharmacology and in vitro experiment verification, and screen the potential components which could bind to key targets of COVID-19 via molecular docking method. MATERIALS AND METHODS: Multiple open-source databases related to TCM or compounds were employed to screen active ingredients and potential targets of MXSGD. Network pharmacology analysis methods were used to initially predict the antivirus and anti-inflammatory effects of MXSGD against COVID-19. IL-6 induced rat lung epithelial type Ⅱ cells (RLE-6TN) damage was established to explore the anti-inflammatory damage activity of MXSGD. After MXSGD intervention, the expression level of related proteins and their phosphorylation in the IL-6 mediated JAK-STAT signaling pathway were detected by Western blot. Molecular docking technique was used to further identify the potential substances which could bind to three key targets (ACE2, Mpro and RdRp) of COVID-19. RESULTS: In this study, 105 active ingredients and 1025 candidate targets were selected for MXSGD, 83 overlapping targets related to MXSGD and COVID-19 were identified, and the protein-protein interaction (PPI) network of MXSGD against COVID-19 was constructed. According to the results of biological enrichment analysis, 63 significant KEGG pathways were enriched, and most of them were related to signal transduction, immune system and virus infection. Furthermore, according the relationship between signal pathways, we confirmed MXSGD could effectively inhibit IL-6 mediated JAK-STAT signal pathway related protein expression level, decreased the protein expression levels of p-JAK2, p-STAT3, Bax and Caspase 3, and increased the protein expression level of Bcl-2, thereby inhibiting RLE-6TN cells damage. In addition, according to the LibDock scores screening results, the components with strong potential affinity (Top 10) with ACE2, Mpro and RdRp are mainly from glycyrrhiza uralensis (Chinese name: Gancao) and semen armeniacae amarum (Chinese name: Kuxingren). Among them, amygdalin was selected as the optimal candidate component bind to all three key targets, and euchrenone, glycyrrhizin, and glycyrol also exhibited superior affinity interactions with ACE2, Mpro and RdRp, respectively. CONCLUSION: This work explained the positive characteristics of multi-component, multi-target, and multi-approach intervention with MXSGD in combating COVID-19, and preliminary revealed the antiviral and anti-inflammatory pharmacodynamic substances and mechanism of MXSGD, which might provide insights into the vital role of TCM in the prevention and treatment of COVID-19.

Association of Symptoms with Eating Habits and Food Preferences in Chronic Gastritis Patients: A Cross-Sectional Study.

PURPOSE: There is a lack of research on the relationship between symptoms and dietary factors of chronic gastritis (CG) patients, and the contribution of dietary management in relieving symptoms of CG patients has not attracted enough attention. This study aimed to identify the associations between different symptoms and dietary factors. Patients and Methods. All CG patients in this cross-sectional study were recruited from 3 hospitals in Beijing, China, from October 2015 to January 2016. Association Rule Mining analysis was performed to identify the correlations between gastrointestinal symptoms and dietary factors (including eating habits and food preferences), and subgroup analysis focused on gender differences. RESULTS: The majority of patients (58.17%) reported that their symptoms were related to dietary factors. About 53% reported that they had the habit of "eating too fast," followed by "irregular mealtimes" (29.66%) and "eating leftover food" (28.14%). Sweets (27.57%), spicy foods (25.10%), and meat (24.33%) were the most popular among all participants. Stomachache and gastric distention were the most common symptoms and were both associated with irregular mealtimes, irregular meal sizes, eating out in restaurants, meats, barbecue, fried foods, sour foods, sweets, snacks, and salty foods (support >0.05 and lift >1.0). Their most strongly associated factors were irregular meal sizes, barbecues, and snacks (lift >1.2). In addition, irregular mealtimes, salty foods, and sweet foods may be important diet factors influencing the symptoms in CG patients (support >0.05 and lift >1.0), as they were associated with almost all dyspeptic symptoms in the whole group and subgroup analyses. Furthermore, alcohol, barbecue, and spicy foods were associated with almost all symptoms for males (support >0.05 and lift >1.0), but sweets were the only dietary factor associated with all symptoms for females (support >0.05 and lift >1.0). CONCLUSION: This study has provided new data for the association of symptoms with eating habits and food preferences in CG patients. The role of individual daily management schemes, such as dietary or lifestyle programs, needs more attention.

Celastrol inhibits ezrin-mediated migration of hepatocellular carcinoma cells.

Progression of hepatocellular carcinoma involves multiple genetic and epigenetic alterations that promote cancer invasion and metastasis. Our recent study revealed that hyperphosphorylation of ezrin promotes intrahepatic metastasis in vivo and cell migration in vitro. Celastrol is a natural product from traditional Chinese medicine which has been used in treating liver cancer. However, the mechanism of action underlying celastrol treatment was less clear. Here we show that ROCK2 is a novel target of celastrol and inhibition of ROCK2 suppresses elicited ezrin activation and liver cancer cell migration. Using cell monolayer wound healing, we carried out a phenotype-based screen of natural products and discovered the efficacy of celastrol in inhibiting cell migration. The molecular target of celastrol was identified as ROCK2 using celastrol affinity pull-down assay. Our molecular docking analyses indicated celastrol binds to the active site of ROCK2 kinase. Mechanistically, celastrol inhibits the ROCK2-mediated phosphorylation of ezrin at Thr567 which harnesses liver cancer cell migration. Our findings suggest that targeting ROCK2-ezrin signaling is a potential therapeutic niche for celastrol-based intervention of cancer progression in hepatocellular carcinoma.

Meta-Analysis of Paclitaxel-Based Chemotherapy Combined With Traditional Chinese Medicines for Gastric Cancer Treatment.

This study aimed to compare the efficacy and safety of traditional Chinese medicines (TCMs) combined with paclitaxel-based chemotherapy and paclitaxel-based chemotherapy alone for gastric cancer treatment. Literature searches (up to September 25, 2019) were performed using the Cochrane Library, EMBASE, PubMed, Chinese Science and Technology Journals (CQVIP), Wanfang, and China Academic Journals (CNKI) databases. Data from 14 randomized controlled trials (RCTs), with 1,109 participants, were included. The results indicated that, compared with paclitaxel-based chemotherapy alone, the combination of TCMs and paclitaxel-based chemotherapy significantly improved the tumor response rate (TRR; RR: 1.39; 95% CI: 1.24-1.57; p < 0.001, I 2 = 12%), increased the quality of life based on the Karnofsky Performance Scale score (RR: 1.53; 95% CI: 1.19-1.96; p < 0.001, I 2 = 0%), and reduced the side effects, such as neutropenia (RR: 0.68; 95% CI: 0.55-0.84; p < 0.001, I 2 = 44%), leukopenia (RR: 0.69; 95% CI: 0.54-0.90; p < 0.01, I 2 = 40%), thrombocytopenia (RR: 0.66; 95% CI: 0.46-0.96; p < 0.05, I 2 = 32%), and nausea and vomiting (RR: 0.50; 95% CI: 0.32-0.80; p < 0.01, I 2 = 85%). Hepatic dysfunction (RR: 0.63; 95% CI: 0.33-1.20; p = 0.16, I 2 = 0%), neurotoxicity (RR: 0.64; 95% CI: 0.26-1.55; p = 0.32, I 2 = 0%), and anemia (RR: 0.65; 95% CI: 0.40-1.04; p = 0.07, I 2 = 0%) were similar between the two groups. Evidence from the meta-analysis suggested that compared with paclitaxel-based chemotherapy alone, the combination of TCMs and paclitaxel-based chemotherapy may increase the TRR, improve quality of life, and reduce multiple chemotherapy-related side effects in gastric cancer patients. Additional rigorously designed large RCTs are required to confirm the efficacy and safety of this treatment.

Dysbiosis of gut microbiota is associated with gastric carcinogenesis in rats.

OBJECTIVES: Although many studies have examined changes in gut microbiota composition in gastric carcinogenesis to clarify the mechanism of action of anticancer drugs, it is unclear whether animal models of gastric carcinogenesis adequately reflect the disease in humans. METHODS: To address this issue, the present study investigated changes in the gut microbiome profile of a rat model of gastric carcinogenesis established using a combination of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), sodium salicylate, irregular fasting, and ranitidine. The rats were divided into control (Normal), chronic non-atrophic gastritis (CNAG), chronic atrophic gastritis (CAG), precancerous lesion of gastric cancer (PLGC), and gastric cancer (GC) groups according to histopathological features. Gut microbiome in gastric carcinogenesis profiling was performed by 16S rRNA gene sequencing of rat feces samples. RESULTS: We found that gut bacterial species richness increased whereas species diversity decreased during gastric carcinogenesis, with the most significant changes detected in the PLGC group. Gut microbiota community composition differed across groups, with the greatest similarities observed between CNAG and CAG groups and between PLGC and GC groups. There were significant differences in taxonomic representation at the phylum level: the PLGC group had the highest ratio of Firmicutes/Bacteroidetes whereas the GC group had the highest abundance of Proteobacteria and Actinobacteria. CONCLUSIONS: These results indicate that changes in the gut microbiome in a rat model of MNNG-induced gastric carcinogenesis are similar to those observed in humans, thus providing a useful tool for evaluating the efficacy and mechanism of action of novel monotherapies or drug combinations for the treatment of gastric carcinogenesis.

Index-based dietary patterns in relation to gastric cancer risk: a systematic review and meta-analysis.

Dietary indices are widely used in diet quality measurement, and the index-based dietary patterns are related to gastric cancer risk. To evaluate the relationship between different kinds of index-based dietary patterns and gastric cancer risk, we systematically searched four English-language databases and four Chinese-language databases. The quality of studies was assessed by the Newcastle­Ottawa Scale. Meta-analyses were performed to estimate the association between gastric cancer incidence and different types of index-based dietary patterns. The OR and hazard ratios (HR) of gastric cancer incidence were calculated by regression models in case­control studies and prospective cohort studies, respectively. The studies were pooled in the random effects model to calculate the summarised risk estimate of the highest quantile interval of dietary indices, taking the lowest as the referent. The dietary indices included different versions of Mediterranean diet score (MDS) and dietary inflammatory index (DII), healthy eating index, Chinese Food Pagoda score and food index score. The meta-analysis was carried out for studies on MDS and DII. The combined OR of gastric cancer for the highest MDS v. the referent was 0·42 (95 % CI 0·2, 0·86), and the combined HR was 0·89 (95 % CI 0·68, 1·17). The combined OR for DII was 2·11 (95 % CI 1·41, 3·15). Higher Mediterranean dietary pattern consumption might reduce gastric cancer risk, while higher inflammatory diet pattern consumption might increase gastric cancer risk.

Efficacy and safety of acupuncture therapy for chronic atrophic gastritis: A meta-analysis and trial sequential analysis protocol.

BACKGROUND: The proportion of application of acupuncture for chronic atrophic gastritis (CAG) is increasing over time. We will conduct this study to explore the efficacy and safety of acupuncture as a treatment method for CAG. METHODS: We will go through domestic and foreign databases until July 2019 to identify related randomized controlled trials that explored the effectiveness of acupuncture for CAG. RevMan (V.5.3) and test sequential analysis (V.0.9) will be used for mata-analysis and trial sequential analysis. RESULTS: This study will update previous evidence summaries of acupuncture and determine the efficacy and safety of acupuncture for CAG based on clinical effectiveness rate, clearance of Helicobacter pylori (H pylori) infection, and quality of life and symptom scores. CONCLUSION: This study will determine the evidence for judging whether acupuncture provides benefits in the treatment of CAG, and will support the application of acupuncture in the recovery of patients with CAG. REGISTRATION NUMBER: CRD42019127916.

Hierarchical and Complex System Entropy Clustering Analysis Based Validation for Traditional Chinese Medicine Syndrome Patterns of Chronic Atrophic Gastritis.

Objectives: Chronic atrophic gastritis (CAG) is the precancerous stage of gastric carcinoma. Traditional Chinese Medicine (TCM) has been widely used in treating CAG. This study aimed to reveal core pathogenesis of CAG by validating the TCM syndrome patterns and provide evidence for optimization of treatment strategies. Design: This is a cross-sectional study conducted in 4 hospitals in China. Hierarchical clustering analysis (HCA) and complex system entropy clustering analysis (CSECA) were performed, respectively, to achieve syndrome pattern validation. Results: Based on HCA, 15 common factors were assigned to 6 syndrome patterns: liver depression and spleen deficiency and blood stasis in the stomach collateral, internal harassment of phlegm-heat and blood stasis in the stomach collateral, phlegm-turbidity internal obstruction, spleen yang deficiency, internal harassment of phlegm-heat and spleen deficiency, and spleen qi deficiency. By CSECA, 22 common factors were assigned to 7 syndrome patterns: qi deficiency, qi stagnation, blood stasis, phlegm turbidity, heat, yang deficiency, and yin deficiency. Conclusions: Combination of qi deficiency, qi stagnation, blood stasis, phlegm turbidity, heat, yang deficiency, and yin deficiency may play a crucial role in CAG pathogenesis. In accord with this, treatment strategies by TCM herbal prescriptions should be targeted to regulating qi, activating blood, resolving turbidity, clearing heat, removing toxin, nourishing yin, and warming yang. Further explorations are needed to verify and expand the current conclusions.

Validating traditional Chinese syndrome features in varied stages of chronic gastritis malignant transformation: study protocol for a cross-sectional study.

INTRODUCTION: The transition from chronic non-atrophic gastritis (CNAG) to chronic atrophic gastritis (CAG) and gastric carcinoma (GC) is regarded as a representative disease model of gastric mucosa malignant transformation led by uncontrolled inflammation. Traditional Chinese medicine (TCM) syndrome-targeted therapies have been applied in treating chronic gastritis (CG) malignant transformation in China with satisfying efficacy. This study aims to validate TCM syndrome features in each stage of CG malignant transformation. The findings may shed light on the TCM hypothesis of CG malignant transformation, and thus optimise syndrome-targeted treatment strategies of CNAG, CAG and GC, respectively. METHODS AND ANALYSIS: The present study is a cross-sectional study conducted in China. A total of 2000 eligible patients, including 500 CNAG cases, 1000 CAG cases and 500 GC cases, will be recruited from four TCM hospitals. Primary outcome measures include the prevalence of TCM syndrome patterns in varied stages of CG malignant transformation. Secondary outcome measures include prevalence and severity of all the presenting signs and symptoms collected by using TCM four diagnostic methods. Descriptive analysis, comparative analysis and correlation analysis of all the measurement data will be performed by biostatisticians. Unsupervised data mining analyses, including exploratory factor analysis, association rule analysis, hierarchical clustering analysis, complex system entropy clustering analysis, and so on, will also be performed by data scientists respectively for in-depth analyses of TCM syndrome-related indicators. ETHICS AND DISSEMINATION: The protocol has been approved by the Ethical Review Board of Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine (No ECPJ-BDY-2014-02). All the study outcomes will be disseminated through national conference reports and in the meantime published on peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03314038; Pre-results.

MST4 kinase phosphorylates ACAP4 protein to orchestrate apical membrane remodeling during gastric acid secretion.

Digestion in the stomach depends on acidification of the lumen. Histamine-elicited acid secretion is triggered by activation of the PKA cascade, which ultimately results in the insertion of gastric H,K-ATPases into the apical plasma membranes of parietal cells. Our recent study revealed the functional role of PKA-MST4-ezrin signaling axis in histamine-elicited acid secretion. However, it remains uncharacterized how the PKA-MST4-ezrin signaling axis operates the insertion of H,K-ATPases into the apical plasma membranes of gastric parietal cells. Here we show that MST4 phosphorylates ACAP4, an ARF6 GTPase-activating protein, at Thr545 Histamine stimulation activates MST4 and promotes MST4 interaction with ACAP4. ACAP4 physically interacts with MST4 and is a cognate substrate of MST4 during parietal cell activation. The phosphorylation site of ACAP4 by MST4 was mapped to Thr545 by mass spectrometric analyses. Importantly, phosphorylation of Thr545 is essential for acid secretion in parietal cells because either suppression of ACAP4 or overexpression of non-phosphorylatable ACAP4 prevents the apical membrane reorganization and proton pump translocation elicited by histamine stimulation. In addition, persistent overexpression of MST4 phosphorylation-deficient ACAP4 results in inhibition of gastric acid secretion and blockage of tubulovesicle fusion to the apical membranes. Significantly, phosphorylation of Thr545 enables ACAP4 to interact with ezrin. Given the location of Thr545 between the GTPase-activating protein domain and the first ankyrin repeat, we reason that MST4 phosphorylation elicits a conformational change that enables ezrin-ACAP4 interaction. Taken together, these results define a novel molecular mechanism linking the PKA-MST4-ACAP4 signaling cascade to polarized acid secretion in gastric parietal cells.

Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation.

Faithful segregation of chromosomes in mammalian cells requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying cyclin-dependent kinase 1 (CDK1) activation, which triggers mitotic entry, have been extensively studied, the regulatory mechanisms that couple CDK1-cyclin B activity to chromosome stability are not well understood. Here, we identified a signaling axis in which Aurora B activity is modulated by CDK1-cyclin B via the acetyltransferase TIP60 in human cell division. CDK1-cyclin B phosphorylates Ser90 of TIP60, which elicits TIP60-dependent acetylation of Aurora B and promotes accurate chromosome segregation in mitosis. Mechanistically, TIP60 acetylation of Aurora B at Lys215 protects Aurora B's activation loop from dephosphorylation by the phosphatase PP2A to ensure a robust, error-free metaphase-anaphase transition. These findings delineate a conserved signaling cascade that integrates protein phosphorylation and acetylation with cell cycle progression for maintenance of genomic stability.

Mitotic Protein CSPP1 Interacts with CENP-H Protein to Coordinate Accurate Chromosome Oscillation in Mitosis.

Mitotic chromosome segregation is orchestrated by the dynamic interaction of spindle microtubules with the kinetochores. During chromosome alignment, kinetochore-bound microtubules undergo dynamic cycles between growth and shrinkage, leading to an oscillatory movement of chromosomes along the spindle axis. Although kinetochore protein CENP-H serves as a molecular control of kinetochore-microtubule dynamics, the mechanistic link between CENP-H and kinetochore microtubules (kMT) has remained less characterized. Here, we show that CSPP1 is a kinetochore protein essential for accurate chromosome movements in mitosis. CSPP1 binds to CENP-H in vitro and in vivo. Suppression of CSPP1 perturbs proper mitotic progression and compromises the satisfaction of spindle assembly checkpoint. In addition, chromosome oscillation is greatly attenuated in CSPP1-depleted cells, similar to what was observed in the CENP-H-depleted cells. Importantly, CSPP1 depletion enhances velocity of kinetochore movement, and overexpression of CSPP1 decreases the speed, suggesting that CSPP1 promotes kMT stability during cell division. Specific perturbation of CENP-H/CSPP1 interaction using a membrane-permeable competing peptide resulted in a transient mitotic arrest and chromosome segregation defect. Based on these findings, we propose that CSPP1 cooperates with CENP-H on kinetochores to serve as a novel regulator of kMT dynamics for accurate chromosome segregation.

Signaling Scaffold Protein IQGAP1 Interacts with Microtubule Plus-end Tracking Protein SKAP and Links Dynamic Microtubule Plus-end to Steer Cell Migration.

Cell migration is orchestrated by dynamic interaction of microtubules with the plasma membrane cortex. However, the regulatory mechanisms underlying the cortical actin cytoskeleton and microtubule dynamics are less characterized. Our earlier study showed that small GTPase-activating proteins, IQGAPs, regulate polarized secretion in epithelial cells (1). Here, we show that IQGAP1 links dynamic microtubules to steer cell migration via interacting with the plus-end tracking protein, SKAP. Biochemical characterizations revealed that IQGAP1 and SKAP form a cognate complex and that their binding interfaces map to the WWIQ motif and the C-terminal of SKAP, respectively. The WWIQ peptide disrupts the biochemical interaction between IQGAP1 and SKAP in vitro, and perturbation of the IQGAP1-SKAP interaction in vivo using a membrane-permeable TAT-WWIQ peptide results in inhibition of directional cell migration elicited by EGF. Mechanistically, the N-terminal of SKAP binds to EB1, and its C terminus binds to IQGAP1 in migrating cells. Thus, we reason that a novel IQGAP1 complex orchestrates directional cell migration via coupling dynamic microtubule plus-ends to the cell cortex.