Gastric Epithelial Cell Proliferation Research Articles

Exploring the therapeutic mechanisms of Coptidis Rhizoma in gastric precancerous lesions: a network pharmacology approach

BackgroundGastric precancerous lesions are a critical stage in the development of gastric cancer or gastric adenocarcinoma, and their outcome plays an important role in the malignant progression of gastric cancer. Coptidis Rhizoma has a good effect on Gastric precancerous lesions. However, the specific mechanisms of its action remain incompletely elucidated.MethodsNetwork pharmacology and molecular docking techniques were used to explore the active ingredients and molecular mechanism of Coptidis Rhizoma in treating gastric precancerous lesions. The active compounds of Coptidis Rhizoma and their potential gastric precancerous lesions related targets were obtained from TCMSP, GeneCards, and OMIM databases. An interaction network based on protein–protein interactions (PPIs) was constructed to visualize the interactions between hub genes. Analysis of GO enrichment and KEGG pathway were conducted using the DAVID database. An investigation of interactions between active compounds and potential targets was carried out by molecular docking. Finally, animal experiments were conducted to verify the effect and mechanism of Coptidis Rhizoma in treating precancerous lesions of gastric cancer.ResultsA total of 11 active compounds and 95 anti-gastric precancerous lesions targets of Coptidis Rhizoma were screened for analysis. GO enrichment analysis showed that the mechanism of Coptidis Rhizoma acting on gastric precancerous lesions involves gene expression regulation and apoptosis regulation. KEGG pathway enrichment analysis showed that Coptidis Rhizoma against gastric precancerous lesions involving the AKT /HIF-1α/VEGF signalling pathway. Molecular docking simulations indicated potential interactions between these compounds and core targets involved in anti-gastric precancerous lesions activity. In addition, it was confirmed in vivo that Berberine and Coptidis Rhizoma may reverse atrophy and potential intestinal metaplasia by inhibiting the expression of p-AKT, HIFA, and VEGF.ConclusionBioactive compounds in Coptidis Rhizoma have the potential to prevent atrophy and intestinal metaplasia. These compounds function by regulating the proteins implicated in AKT /HIF-1α/VEGF signalling pathways that are crucial in gastric epithelial cell differentiation, proliferation and maturation.

Overexpression of HSP27 accelerates stress-induced gastric ulcer healing via the CXCL12/CXCR4 axis.

Chronic stress often triggers gastrointestinal complications, including gastric injury and ulcers. Understanding the role of heat shock protein 27 (HSP27) in stress-induced gastric ulcers could unveil novel therapeutic targets. Here, we established a stress-induced gastric ulcer rat model using water immersion restraint stress and administered adenovirus-packaged HSP27 overexpression vector. Gastric ulcer severity was scored, and mucosal changes were assessed. Gastric epithelial and endothelial cells were treated with lipopolysaccharide and transfected with HSP27 overexpression vectors to evaluate cell viability, migration and angiogenesis. Expression levels of HSP27, C-X-C motif chemokine ligand 12 (CXCL12) and C-X-C motif chemokine receptor 4 (CXCR4) were measured in tissues and cells. HSP27 expression was initially low during stress-induced gastric ulceration but increased during ulcer healing. HSP27 overexpression accelerated ulcer healing in rats, promoting gastric epithelial cell proliferation and migration and gastric endothelial cell angiogenesis through the CXCL12/CXCR4 axis. Inhibitor IT1t reversed the effects of HSP27 overexpression on cell proliferation, migration and angiogenesis. In summary, HSP27 overexpression facilitated ulcer healing, which was partially mediated by the CXCL12/CXCR4 axis.

Mitochondrial carrier homolog 2 increases malignant phenotype of human gastric epithelial cells and promotes proliferation, invasion, and migration of gastric cancer cells.

The precise role of mitochondrial carrier homolog 2 (MTCH2) in promoting malignancy in gastric mucosal cells and its involvement in gastric cancer cell metastasis have not been fully elucidated. To determine the role of MTCH2 in gastric cancer. We collected 65 samples of poorly differentiated gastric cancer tissue and adjacent tissues, constructed MTCH2-overexpressing and MTCH2-knockdown cell models, and evaluated the proliferation, migration, and invasion of human gastric epithelial cells (GES-1) and human gastric cancer cells (AGS) cells. The mitochondrial membrane potential (MMP), mitochondrial permeability transformation pore (mPTP) and ATP fluorescence probe were used to detect mitochondrial function. Mitochondrial function and ATP synthase protein levels were detected via Western blotting. The expression of MTCH2 and ATP2A2 in gastric cancer tissues was significantly greater than that in adjacent tissues. Overexpression of MTCH2 promoted colony formation, invasion, migration, MMP expression and ATP production in GES-1 and AGS cells while upregulating ATP2A2 expression and inhibiting cell apoptosis; knockdown of MTCH2 had the opposite effect, promoting overactivation of the mPTP and promoting apoptosis. MTCH2 can increase the malignant phenotype of GES-1 cells and promote the proliferation, invasion, and migration of gastric cancer cells by regulating mitochondrial function, providing a basis for targeted therapy for gastric cancer cells.

A162 DEFINING INNATE IMMUNE CELL MECHANISMS UPON HELICOBACTER PYLORI MEDIATED TUMORIGENESIS

Abstract Aims Hypothesis: H. pylori interacts with eosinophils to inhibit degranulation, alter eosinophil gene expression and promote gastric tumorigenesis Aim 1: Elucidate the mechanisms underlying the interactions between eosinophils and H. pylori. Aim 2: Determine the role of eosinophils during H. pylori mediated gastric tumorigenesis. Methods Histological and immunofluorescent staining. Hemotoxilin and eosin staining is important to analyze gastric gland structure and parietal cell loss. Immunofluorescent staining is used to detect and localize specific antigens present in cells and cell membranes. Gastric organoids: Gastric organoids are an important tool for modelling dissease. Gastric organoids generated from adult stem cells from gastric glands depend on growth factors that mimic tissue regeneration. Bone marrow derived eosinophils: Bone marrow progenitor cells isolated from murine femur and tibia are easily converted into maturer eosinophils with the addition of cytokine interleukin-5. Results Addition of mouse derived eosinophils to gastric organoids significantly increases number of organoids. To understand the relationship between eosinophils and gastric epithelial cell (GEC) growth, I designed a co-culture experiment that involved incubating mature eosinophils with gastric glands in an extracellular matrix. These findings revealed a significant increase in the number of gastric organoids per well when eosinophils were present compared to the gastric organoids without eosinophils. This observation supports the hypothesis that eosinophils may play a crucial role in promoting gastric tumorigenesis. Exposure of mouse derived eosinophils to H. pylori significantly increases gastric organoid proliferation. To explore the impact of stimulating eosinophils prior to incubation with GECs I incubated the eosinophils with H. pylori. As expected, there was a significant increase in the number of organoids per well with the addition of uninfected eosinophils. Interestingly, when H. pylori incubated eosinophils were added to the gastric glands, there was a significant increase in the number of gastric organoids per well compared to uninfected eosinophils. Conclusions My preliminary findings have indicated that eosinophils can promote gastric epithelial stem cell proliferation. These results led me to ask how treatment of eosinophils with H. pylori subsequently impacts gastric organoid growth and gastric stem cell proliferation. Interestingly, I found H. pylori treated eosinophils increase growth and gastric stem cell proliferation. These results support my hypothesis as increased proliferation is considered a hallmark of tumorigenesis. There little known about resident and inflammatory GI eosinophils and the role of eosinophils during tumorigenesis in unknown. A better understanding of the role eosinophils play can uncover novel mechanisms to be targeted for therapeutic intervention. Funding Agencies CIHR

Seven-Month Vitamin D Deficiency Inhibits Gastric Epithelial Cell Proliferation, Stimulates Acid Secretion, and Differentially Alters Cell Lineages in the Gastric Glands.

Vitamin D (VD) deficiency can result from insufficiency of either light exposure or VD intake. We investigated the biological effects of VD deficiency for 7 months on the mouse gastric glands. Varying degrees of VD deficiency were induced in C57BL/6 mice by keeping them on standard diet with constant-dark conditions (SDD) or VD deficient diet with constant-dark conditions (VDD). Samples of serum, glandular stomach, and gastric contents were collected for LCMS/MS, RT-PCR, immunohistochemistry, and acid content measurements. Both SDD and VDD mice had a significant decline in 25OHVD metabolite, gastric epithelial cell proliferation, and mucin 6 gene expression. These effects were enhanced with the severity of VD deficiency from SDD to VDD. Besides and compared to the control group, SDD mice only displayed a significant increase in the number of zymogenic cells (p ≤ 0.0001) and high expression of the adiponectin (p ≤ 0.05), gastrin (p ≤ 0.0001), mucin 5AC (*** p ≤ 0.001) and the Cyclin-dependent kinase inhibitor 1A (**** p ≤ 0.0001). These phenotypes were unique to SDD gastric samples and not seen in the VDD or control groups. This study suggests that the body reacts differently to diverse VD deficiency sources, light or diet.

Novel and efficient method for culturing patient-derived gastric cancer stem cells.

Experimental techniques for patient-derived cancer stem-cell organoids/spheroids can be powerful diagnostic tools for personalized chemotherapy. However, establishing their cultures from gastric cancer remains challenging due to low culture efficiency and cumbersome methods. To propagate gastric cancer cells as highly proliferative stem-cell spheroids in vitro, we initially used a similar method to that for colorectal cancer stem cells, which, unfortunately, resulted in a low success rate (25%, 18 of 71 cases). We scrutinized the protocol and found that the unsuccessful cases were largely caused by the paucity of cancer stem cells in the sampled tissues as well as insufficient culture media. To overcome these obstacles, we extensively revised our sample collection protocol and culture conditions. We then investigated the following second cohort and, consequently, achieved a significantly higher success rate (88%, 29 of 33 cases). One of the key improvements included new sampling procedures for tumor tissues from wider and deeper areas of gastric cancer specimens, which allowed securing cancer stem cells more reproducibly. Additionally, we embedded tumor epithelial pieces separately in both Matrigel and collagen type-I as their preference to the extracellular matrix was different depending on the tumors. We also added a low concentration of Wnt ligands to the culture, which helped the growth of occasional Wnt-responsive gastric cancer stem-cell spheroids without allowing proliferation of the normal gastric epithelial stem cells. This newly improved spheroid culture method may facilitate further studies, including personalized drug-sensitivity tests prior to drug therapy.

The cytosolic DNA sensor AIM2 promotes Helicobacter-induced gastric pathology via the inflammasome.

Helicobacter pylori (H. pylori) infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system, leading to a cascade of precancerous lesions culminating in gastric cancer. However, key regulators of innate immunity that promote H. pylori-induced gastric pathology remain ill-defined. The innate immune cytosolic DNA sensor absent in melanoma 2 (AIM2) contributes to the pathogenesis of numerous autoimmune and chronic inflammatory diseases, as well as cancers including gastric cancer. We therefore investigated whether AIM2 contributed to the pathogenesis of Helicobacter-induced gastric disease. Here, we reveal that AIM2 messenger RNA and protein expression levels are elevated in H. pylori-positive versus H. pylori-negative human gastric biopsies. Similarly, chronic Helicobacter felis infection in wild-type mice augmented Aim2 gene expression levels compared with uninfected controls. Notably, gastric inflammation and hyperplasia were less severe in H. felis-infected Aim2-/- versus wild-type mice, evidenced by reductions in gastric immune cell infiltrates, mucosal thickness and proinflammatory cytokine and chemokine release. In addition, H. felis-driven proliferation and apoptosis in both gastric epithelial and immune cells were largely attenuated in Aim2-/- stomachs. These observations in Aim2-/- mouse stomachs correlated with decreased levels of inflammasome activity (caspase-1 cleavage) and the mature inflammasome effector cytokine, interleukin-1β. Taken together, this work uncovers a pathogenic role for the AIM2 inflammasome in Helicobacter-induced gastric disease, and furthers our understanding of the host immune response to a common pathogen and the complex and varying roles of AIM2 at different stages of cancerous and precancerous gastric disease.

A review of signal pathway induced by virulent protein CagA of Helicobacter pylori.

Gastric cancer (GC), a common and high-mortality disease, still occupies an important position in current cancer research, and Helicobacter pylori (H. pylori) infection as its important risk factor has been a hot and challenging research area. Among the numerous pathogenic factors of H. pylori, the virulence protein CagA has been widely studied as the only bacterial-derived oncoprotein. It was found that CagA entering into gastric epithelial cells (GECs) can induce the dysregulation of multiple cellular pathways such as MAPK signaling pathway, PI3K/Akt signaling pathway, NF-κB signaling pathway, Wnt/β-catenin signaling pathway, JAK-STAT signaling pathway, Hippo signaling pathway through phosphorylation and non-phosphorylation. These disordered pathways cause pathological changes in morphology, adhesion, polarity, proliferation, movement, and other processes of GECs, which eventually promotes the occurrence of GC. With the deepening of H. pylori-related research, the research on CagA-induced abnormal signaling pathway has been updated and deepened to some extent, so the key signaling pathways activated by CagA are used as the main stem to sort out the pathogenesis of CagA in this paper, aiming to provide new strategies for the H. pylori infection and treatment of GC in the future.

FTO-mediated m6A modification promotes malignant transformation of gastric mucosal epithelial cells in chronic Cag A+ Helicobacter pylori infection.

Cag A+ Helicobacter pylori chronic infection cause malignant transformation of the human gastric mucosa. N6-methyladenosine (m6A) modifications are the most common and abundant mRNA modifications and one of the pathways affecting tumorigenicity and tumor progression. However, the role of m6A modification in the process of chronic H. pylori infection leading to malignant transformation of gastric mucosa is unclear. In this study, we used Cag A- and Cag A+H. pylori chronic infection to establish cellular models in GES-1 cells and analyzed the cellular morphology, proliferation, apoptosis, invasiveness and tumorigenicity of gastric mucosal epithelial cells. The m6A expression levels of GES-1 cells after chronic infection with Cag A- and Cag A+H. pylori were examined, and modifying effect of FTO (the fat mass and obesity-associated protein) on CD44 was verified by MeRIP-qPCR. Finally, the FTO expression changes and m6A expression levels were further validated in clinical gastric cancer tissues. Chronic Cag A+H. pylori-infected GES-1 cells exhibit altered cell morphology, apoptosis inhibition, abnormal proliferation, enhanced migration, colony formation, and increased stem cell-like properties. Meanwhile, FTO and CD44 expression was enhanced, and FTO may induce malignant transformation of gastric mucosa by regulating CD44 mRNA m6A methylation modifications. We verified the effect of chronic stimulation of Cag A+H. pylori on malignant transformation of gastric mucosal epithelium. revealing the possibility of FTO in promoting malignant transformation of gastric mucosa by modifying CD44 mRNA methylation, suggesting that FTO expression is a potential molecule for malignant transformation of gastric mucosal epithelial cells.

Long-Term Supplementation of Canthaxanthin Does Not Inhibit Gastric Epithelial Cell Proliferation in Helicobacter mustelae-Infected Ferrets

The effect of canthaxanthin (CX), a non-provitamin A carotenoid, on gastric epithelial proliferation was studied in ferrets colonized with Helicobacter mustelae, which causes a chronic gastritis and an increased gastric epithelial cell proliferation. Seven spayed female ferrets were dosed by gavage with CX beadlets (50 mg/kg body wt, 5 d/wk) over 2 y, whereas seven control animals were given placebo beadlets. At the end of the 2-y-period, ferrets were killed, and gastric tissues were obtained from the antrum and body regions. A cell-proliferating biomarker, proliferating cell nuclear antigen (PCNA), was assayed by immunohistochemistry. The PCNA positivity was measured by a computer-based image analysis system. Serum concentrations of carotenoids, retinoids and tocopherols were analyzed by HPLC. Serum antioxidant status was measured by the oxygen radical absorbance capacity (ORAC) assay. The PCNA positivity in both antrum and body regions was not significantly different between CX-fed ferrets and controls. Serum CX concentrations were significantly higher in CX-fed ferrets vs. controls (P<0.001), whereas levels of other carotenoids, retinoids and tocopherols were not significantly different. The ORAC values were not significantly different between groups. This study does not suggest inhibitory effects of CX on gastric epithelial cell proliferation in H. mustelae infected ferrets.

KLF4 Mutation Shapes Pathologic Characteristics of Foveolar-Type Gastric Adenoma in Helicobacter pylori–Naive Patients

Along with a recent remarkable decrease in Helicobacter pylori-infected individuals, reports of gastricneoplasms such as sporadic foveolar-type gastric adenoma (FGA) in H. pylori-naive patients have been increasing. This tumor, with its raspberry-like appearance, is common in H. pylori-naive gastric mucosa. The current study investigated the genomic features of sporadic FGA. Fresh-frozen sporadic FGA tissue samples from H. pylori-naive patients were subjected to whole genome analysis using a next-generation sequencer. Proliferation ability and apoptotic profiles of human gastric epithelial cells, along with plasmid transfection of candidate variants, were examined. A mean of 6.65×108 total reads were obtained for each sample. Common genetic abnormalities in well-known proliferation driver genes of conventional gastric dysplasia/cancer were not found. However, a common single-nucleotide variation (SNV) was noted within the DNA-binding domain of the tumor suppressor gene KLF4. This novel SNV was located in the zinc finger 2region. Additional experiments showed that it significantly suppressed proliferation of gastric epithelial cells compared with wild-type KLF4 plasmid-transfected cells, although suppression was reduced in early apoptotic phase-related genes. A novel SNV in the KLF4 zinc finger 2 region was commonly found in sporadic FGA tissue samples, which may explain the slow-growing properties of this neoplasm.

Helicobacter pylori-mediated gastric pathogenesis is attenuated by treatment of 2-deoxyglucose and metformin.

Helicobacter pylori infection causes chronic inflammation in the stomach, which is linked to the development of gastric cancer. The anti-inflammatory and anticancer effects of a glycolysis inhibitor 2-deoxyglucose (2DG) and an antidiabetic medication metformin (Met) have gotten attention. Using a Mongolian gerbil animal model, we investigated H. pylori-mediated gastric pathogenesis and how this pathogenesis is influenced by 2DG and Met. Five-week-old male gerbils were infected with H. pylori strain 7.13. After 2 weeks of infection, gerbils were fed 2DG-containing food (0.03% w/w), Met-containing water (0.5% w/v), or both (Combi) for 2 (short-term) or 10 weeks (long-term). Gastric pathogenesis and host response to H. pylori infection were examined by macroscopic and histopathologic analysis of gerbils' stomach. As a result, indicators of gastric pathogenesis by H. pylori infection including infiltration of polymorphonuclear neutrophils and lymphocytes, intestinal metaplasia, atrophy, and proliferation of gastric epithelial cells were attenuated by short-term administration of 2DG, Met, or Combi. When the infection was sustained for long-term, gastric pathogenesis in drug-treated gerbils was equivalent to that in untreated gerbils, with the exception that the infiltration of neutrophil was reduced by 2DG. Colonization of H. pylori in stomach was unaffected by both short- and long-term treatments. Our findings demonstrate that the progression of gastric pathogenesis induced by H. pylori infection can be attenuated by the short-term individual or combinational treatment of 2DG and Met, implying that 2DG or Met could be considered as a treatment option for gastric diseases in the early stages of infection.

Preventative Effect of Astaxanthin Against Helicobacter pylori-Induced Proliferation of Gastric Epithelial Cells via the Suppression of Wnt/β-Catenin Signaling Pathway.

ObjectivesHelicobacter pylori (H. pylori) infection has been regarded as a major risk factor for gastric cancer. Various In vivo and in vitro studies have reported that H. pylori infection induces hyper-proliferation, a hallmark of carcinogenesis, in gastric epithelial cells by activating Wnt/β-catenin signaling pathway. Wnt/β-catenin signaling is associated with cell proliferation, which is believed to be linked to various types of human cancer when β-catenin is over-accumulated in the cytoplasm and translocated into the nucleus. Astaxanthin is a reddish carotenoid pigment that has powerful anti-oxidant, anti-inflammatory, and anti-microbial properties. We aim to investigate whether astaxanthin inhibits H. pylori-induced hyper-proliferation in gastric epithelial cells by suppressing Wnt/β-catenin signaling pathway. MethodsThe AGS cell line (a human gastric adenocarcinoma cell-line), H. pylori (NCTC 11,637 strain), and Astaxanthin were used. Cell viability was assessed by WST assay and Colony forming assay. Levels of proteins involved in Wnt/β-catenin signaling pathway were measured by Western blot assay. Real-time PCR assay was used to measure mRNA expression of oncogenes such as c-myc and cyclin E. ResultsH. pylori stimulation increased levels of proteins involved in Wnt/β-catenin signaling pathway. mRNA expression of oncogenes such as c-myc and cyclin E were also elevated by H. pylori stimulation. Astaxanthin suppressed cell growth in H. pylori–stimulated AGS cells. Levels of Wnt/β-catenin signaling pathway proteins were decreased by astaxanthin treatment in H. pylori-stimulated AGS cells. ConclusionsThis study suggested that AST may inhibit H. pylori-induced hyper-proliferation by suppressing Wnt/β-catenin signaling pathway. Funding SourcesBK21 FOUR.

Bile Acid-Microbiome Interaction Promotes Gastric Carcinogenesis.

Bile reflux gastritis (BRG) is associated with the development of gastric cancer (GC), but the specific mechanism remains elusive. Here, a comprehensive study is conducted to explore the roles of refluxed bile acids (BAs) and microbiome in gastric carcinogenesis. The results show that conjugated BAs, interleukin 6 (IL‐6), lipopolysaccharide (LPS), and the relative abundance of LPS‐producing bacteria are increased significantly in the gastric juice of both BRG and GC patients. A secondary BA, taurodeoxycholic acid (TDCA), is significantly and positively correlated with the LPS‐producing bacteria in the gastric juice of these patients. TDCA promotes the proliferation of normal gastric epithelial cells (GES‐1) through activation of the IL‐6/JAK1/STAT3 pathway. These results are further verified in two mouse models, one by gavage of TDCA, LPS, and LPS‐producing bacteria (Prevotella melaninogenica), respectively, and the other by bile reflux (BR) surgery, mimicking clinical bile refluxing. Moreover, the bile reflux induced gastric precancerous lesions observed in the post BR surgery mice can be prevented by treatment with cryptotanshinone, a plant‐derived STAT3 inhibitor. These results reveal an important underlying mechanism by which bile reflux promotes gastric carcinogenesis and provide an alternative strategy for the prevention of GC associated with BRG.

Gastrin-17 Levels in Pre-malignancy Gastritis Lesions

Background: Gastritis is an inflammatory process on the lining of the stomach that could be caused by various factors. Untreated inflammatory processes could lead to ulcers. Gastrin hormone is released by gastrin-secreting enteroendocrine cells (G cells) in the stomach, which influence the secretion of gastric acid and helps the proliferation of gastric epithelial cells. Its abnormal secretion in H. pylori infection, with food-stimulated excessive release of gastrin, is the most prominent abnormality. One concern is the relationship of excess gastrin secretion to the incidence of gastric cancer. This study aimed to show the difference in gastrin levels on patients with gastritis, both with and without pre-malignant lesions. Methods: This research was a cross-sectional study with 40 samples that had met the inclusion and exclusion criteria. Endoscopy was performed to assess the gastric mucosa and tissue biopsy was performed afterward. The data was analysed in univariate and bivariate ways. Results: From this study, 20 people were positive for pre-malignant lesions (50%). Mann–Whitney test analysis was used to analyse the data and showed there was a significant difference between gastrin levels on patients with gastritis with and without pre-malignant lesions, with a p value of 0.01. Conclusion: There is a significant difference between gastrin levels in patients with gastritis with and without pre-malignant lesions, which could be the basis for early detection of patients with gastric cancer.

Показатели клеточного обновления эпителиоцитов желудка у коренных и пришлых жителей Республики Тыва с атрофическим гастритом

Study Objective: to study the indicators of apoptosis and proliferation in gastric epitheliocytes in indigenous and alien inhabitants of the Republic of Tyva with atrophic and non-atrophic gastritis. Study Design: cross-sectional comparative study in rural areas of the Republic of Tyva. Material and methods. Clinical examination and endoscopic examination with biopsy sampling from the mucosa of the antrum and gastric body were carried out in 61 Tuvinian and 65 alien inhabitants in the village of Saryg-Sep of the Republic of Tyva, of which 91 people had nonatrophic, and 35 — atrophic gastritis. Helicobacter pylori was determined by two methods: morphological and urease. Morphological diagnosis of gastritis was performed in accordance with the modified Sydney classification (1994). The markers of proliferation (Ki67 and PCNA) and apoptosis (bcl-2 and p53) in gastric epithelial cells were assessed by immunohistochemical method. Study Results. H. pylori was found in 85.2% (52 of 61) of the examined natives and 81.5% (of 53 of 65) of the visitors (odds ratio — 1.29; 95% confidence interval: 0.51–3.26, p = 0.75). In both populations, in patients with atrophy in the antrum and gastric body, the apoptosis index p53 was significantly higher than in patients without atrophy. Proliferation indicators Ki67 and PCNA in gastric epithelial cells significantly decreased in patients with atrophic gastritis compared to those in patients without atrophy among Caucasoids, but not among Tuvinians. Conclusion. The obtained results indicate deeper disturbances in the cellular renewal of gastric epitheliocytes in alien inhabitants with atrophic gastritis than in indigenous people with this disease. We suggest that indicators characterizing the proliferation of epitheliocytes in patients with atrophic gastritis may be markers of the risk of developing gastric cancer. Keywords: apoptosis, proliferation, atrophic gastritis.

Inhibitory Effect of Astaxanthin on Gene Expression Changes in Helicobacter pylori-Infected Human Gastric Epithelial Cells.

Helicobacter pylori (H. pylori) infection promotes gastric carcinogenesis by increasing oxidative stress, inflammation, and dysregulation of cell survival and proliferation of gastric epithelial cells. Astaxanthin (ASTX), a bioactive carotenoid, exhibits antioxidant and anticancer effects by modulating aberrant signaling pathways that lead to dysregulation of cell death and proliferation. To elucidate the molecular mechanism of H. pylori-induced gastric carcinogenesis and to examine the inhibitory effect of ASTX on H. pylori-induced gastric epithelial cell gene expression changes, we performed comparative RNA-sequencing (RNA-Seq) analysis for H. pylori-infected gastric epithelial cells treated with or without ASTX. RNA-Seq results reveal that differentially expressed genes (DEGs) in H. pylori-infected cells were mainly associated with the Wnt/β-catenin signaling pathway, which is related to cell proliferation. ASTX significantly reversed H. pylori-induced transcriptional alterations of the key mediators involved in β-catenin signaling, notably, porcupine (gene symbol, PORCN), spermine oxidase (SMOX), bone morphogenetic protein (BMP) and activin membrane-bound inhibitor (BAMBI), SMAD family member 4 (SMAD4), transforming growth factor-β1 (TGFB1), Fos-like 1 (FOSLI), and c-myc (MYC). We suggest that ASTX may be a potential therapeutic agent that can suppress H. pylori-induced proliferation-associated gene expression changes, in part, by counter-regulating the Wnt/β-catenin signaling pathway.

The protective effect of NF-κB signaling pathway inhibitor PDTC on mice with chronic atrophic gastritis

Objective To understand the protective effect of NF-κB signaling pathway inhibitor pyrrolidinedithiocarbamate (PDTC) on mice with chronic atrophic gastritis (CAG). Methods Helicobacter pylori (H. pylori) infection combined with high-salt diet was used to construct the CAG mouse model, and 100 or 200 mg/kg/day PDTC was intragastrically treated for 8 weeks. Then, hematoxylin and eosin (HE) and Alcian blue-periodic acid-Schiff (AB-PAS) staining were used to observe the pathology of gastric mucosa, while immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immuno sorbent assay (ELISA) and western blotting were determined to detect the expression of related molecules. Results The nuclear content of NF-κB p65 in the gastric mucosa of the CAG mice was increased accompanying by the structural disorder of the gastric mucosal epithelium, inflammatory cell infiltration, intestinal metaplasia, and increased MUC2 expression, but the symptoms were alleviated after PDTC treatment. In addition, the expressions of TNF-α, IL-1β, IL-6 and COX2 in the gastric mucosa and serum of CAG mice were higher than those control mice, which were reduced in CAG mice treated with either 100 or 200 mg/kg PDTC. Furthermore, 100 mg/kg and 200 mg/kg PDTC treatments reduced the serum PGE2 in CAG mice with the decreased PCNA and Ki-67 expression in gastric mucosa. The therapeutic effect of 200 mg/kg PDTC was significantly better than that of 100 mg/kg PDTC. Conclusion PDTC inhibited inflammation and the excessive proliferation of gastric mucosal epithelial cells, thereby exerting a potential therapeutic effect on CAG.

Modulation of Stem Cell Progeny by Probiotics during Regeneration of Gastric Mucosal Erosions.

Simple SummaryThe wall of the stomach is easily damaged by different factors leading to serious diseases such as ulcers and cancer. In this study, the effects of a mixture of different types of beneficial bacteria (De Simone Formulation) were investigated in a mouse model of stomach wall damages induced by single or multiple doses of acetylsalicylic acid. Control mice received water. The stomachs of all mice were processed for microscopic examination and labeling of dividing stem cells and stomach cell lineages secreting mucus, acid, pepsin, and hormones. The results reveal beneficial effects for the multiple bacterial strain of De Simone Formulation given before or after the induction of stomach erosions. The regeneration of the stomach wall was associated with an increase in stem cell proliferation and enhanced production of protective factors such as mucus, and restoration of the aggressive factors produced by acid and pepsin secreting cell lineages. Therefore, the protective and therapeutic effects of the multi-strain healthy bacteria against stomach erosions involve modulation of not only dividing stem cells but also the multiple secretory cell lineages of the stomach.Patients with gastric mucosal erosions are predisposed to chronic gastritis, ulcer or even cancer. The repair of mucosal erosions involves several events including proliferation of gastric epithelial stem cells. The aim of this study was to investigate the effects of the probiotic mixture of De Simone Formulation on gastric epithelial stem cell lineages in mouse models of gastric mucosal erosions. Gastric erosions were induced by a single oral gavage of 80% ethanol containing 15 mg/mL acetylsalicylic acid (5 mL/kg) following a daily dose of probiotic mixture (5 mg/day/mouse) for 10 days. In another protocol, erosions were induced by a daily gavage of acetylsalicylic acid (400 mg/kg/day/mouse) for 5 days before or after daily administration of probiotic mixture for 5 days. Control mice received water gavage for 10 days. All mice were injected with bromodeoxyuridine two hours before sacrifice to label S-phase cells. The stomachs of all mice were processed for histological examination, lectin binding, and immunohistochemical analysis. The results reveal that mice that received probiotics before or after the induction of erosion showed a decrease in erosion index with an increase in gastric epithelial stem/progenitor cell proliferation and enhanced production of mucus, trefoil factors, and ghrelin by mucous and enteroendocrine cell lineages. These mice also showed restoration of the amount of H+,K+-ATPase and pepsinogen involved in the production of the harsh acidic environment by parietal and chief cell lineages. In conclusion, this study demonstrates the beneficial effects of probiotics against gastric mucosal erosion and highlights the involvement and modulation of proliferative stem cells and their multiple glandular epithelial cell lineages.

Rabeprazole suppresses cell proliferation in gastric epithelial cells by targeting STAT3-mediated glycolysis

The dysregulation of glycolysis leads to serials of disease. Rabeprazole is a representative of proton pump inhibitors and widely used in anti-ulcer treatment. However, the function of Rabeprazole on glycolysis in gastric epithelial cells remained to be identified. In this study, 30（Helicobacter pylori）H. pylori-negative cases and 26H. pylori-positive cases treated with Rabeprazole were recruited. The qPCR and Western blotting results showed that Rabeprazole suppressed cell proliferation by inhibition of HK2-mediated glycolysis in BGC823 cells, leading to decrease glucose uptake and lactate production in a dose-dependent way. Furthermore, the phosphorylation of signal transducer and activator of transcription 3 (STAT3) was drastically reduced in response to Rabeprazole stimulation, leading to attenuate STAT3 nuclear translocation. Luciferase and Chromatin immunoprecipitation (ChIP) analysis showed that Rabeprazole treatment led to a significant inhibition of the binding of STAT3 to the promoter of the HK2 gene, repressing transcriptional activation of HK2. Moreover, the ectopic expression of STAT3 in BGC823 cells resulted in recovery of HK2 transactivation and cell proliferation in Rabeprazole-treated cells. Most importantly, HK2 expression was significantly increased in H. pylori-infected gastric mucosa. These findings suggested that Rabeprazole inhibited cell proliferation by targeting STAT3/HK2 signaling-mediated glucose metabolism in gastric epithelial cells. Therefore, targeting HK2 is an alternative strategy in improving the treatment of patients with H. pylori infection.