Helicobacter Pylori-induced Gastritis Research Articles

Impact of high-altitude hypoxia on Helicobacter pylori-induced gastritis pathological manifestations and inflammatory responses

BackgroundChronic gastritis caused by Helicobacter pylori (Hp) infection is a common gastrointestinal disorder. Despite the high prevalence of Hp infection and chronic gastritis in the Tibetan Plateau, there is a lack of studies elucidating the influence of plateau hypoxia on Hp-induced gastritis. This study aimed to investigate the impact of high-altitude hypoxia on Hp-induced gastritis, particularly focusing on pathological manifestations and inflammatory responses.MethodsThis study was conducted from July 2023 to March 2024 at the Department of Gastroenterology, Affiliated Hospital of Qinghai University. Ninety patients diagnosed with chronic gastritis were enrolled in the study and divided into four groups based on their residential altitude and Hp infection status. Data on endoscopic and pathological characteristics were collected, along with serum oxidative stress and inflammatory markers.ResultsPatients with Hp gastritis exhibit distinctive features in the gastric mucosa, including diffuse erythema, enlarged folds, and white turbid mucus during endoscopy. Notably, individuals with Hp gastritis at high altitudes show a higher prevalence of diffuse erythema and enlarged folds. Pathological analysis reveals that these patients have elevated gastric mucosal inflammation scores and increased chronic and active inflammation. Furthermore, individuals with Hp gastritis at high altitudes demonstrate elevated levels of serum TNF-α, IL-1β, IL-6, and MDA, as well as reduced serum SOD and GSH-Px activities.ConclusionsHigh-altitude hypoxia may exacerbate gastric mucosal damage by enhancing oxidative stress and inflammatory response induced by Hp infection.

Superior mesenteric artery syndrome misdiagnosed and preceded by helicobacter pylori-induced gastritis: a rare diagnosis with misleading features

Introduction and Importance: Superior mesenteric artery syndrome is a rare morbid vascular disorder that is defined as the decreasing in the aortomesenteric angle and the compression of the third part of the duodenum. This disorder mainly affects young adult females, and severe weight loss represents a leading predisposing factor. Case presentation: We report the case of a 19-year-old male who was admitted to our hospital with a three-months history of epigastric pain, nausea, and weight loss. Two months earlier, the patient was diagnosed with helicobacter pylori-induced gastritis. Nevertheless, with complaints of severe headache and epigastric pain, the patient was admitted to our hospital for further investigations. Computed tomography scan with intravenous contrast injection was performed, and interestingly, the aortomesenteric angle was 19 degrees accompanied by a compression of the third part of the duodenum, and a mild gastric dilatation. Accordingly, the diagnosis was confirmed as a superior mesenteric artery syndrome. Clinical Discussion: In our case, the non-specific clinical symptoms correlated with histopathological examinations led to the initial diagnosis of Helicobacter Pylori-induced gastritis. Surprisingly, the lack of improvements led to performing CT scan, which confirmed the diagnosis of SMA syndrome. Subsequently, HP gastritis played a significant role in misleading and delaying the diagnosis. Conclusion: We report the first case report from Syria of s superior mesenteric artery syndrome that was misdiagnosed and preceded by HP-induced gastritis, highlighting the crucial role of detailed clinical and radiological examinations in the diagnosis of challenging cases with morbid complications.

Increased infiltration of CD4+ IL-17A+ FOXP3+ T cells in Helicobacter pylori-induced gastritis.

Helicobacter pylori is one of the main predisposing factors for gastric cancer, causing chronic inflammation and proper glands atrophy in the gastric mucosa. Although H. pylori-induced inflammation is a key inducer of precancerous lesions in the gastric mucosa, it remains unclear which precise immune cell subsets are responsible for the progression of H. pylori-induced gastritis. Here, we observed an abundance of CD4+ IL-17A+ FOXP3+ T cells exhibiting a Th17-like phenotype within the microenvironment of H. pylori-induced gastritis. Mechanistically, H. pylori upregulated the expression of IL-6 in Dendritic cells and macrophages, by activating NF-κB signaling through the virulence factor CagA and thus, induced IL-17A expression in FOXP3+ T cells. Moreover, CD4+ IL-17A+ FOXP3+ T cells were positively associated with advanced precancerous lesions. Therefore, these findings offer essential insights into how FOXP3+ T cells sense inflammatory signals from the environment, such as IL-6, during H. pylori infections, thereby guiding the effector immune response and aggravating the gastritis.

Remodeling of the gastric environment in Helicobacter pylori-induced atrophic gastritis.

Helicobacter pylori colonization of the human stomach is a strong risk factor for gastric cancer. To investigate H. pylori-induced gastric molecular alterations, we used a Mongolian gerbil model of gastric carcinogenesis. Histologic evaluation revealed varying levels of atrophic gastritis (a premalignant condition characterized by parietal and chief cell loss) in H. pylori-infected animals, and transcriptional profiling revealed a loss of markers for these cell types. We then assessed the spatial distribution and relative abundance of proteins in the gastric tissues using imaging mass spectrometry and liquid chromatography with tandem mass spectrometry. We detected striking differences in the protein content of corpus and antrum tissues. Four hundred ninety-two proteins were preferentially localized to the corpus in uninfected animals. The abundance of 91 of these proteins was reduced in H. pylori-infected corpus tissues exhibiting atrophic gastritis compared with infected corpus tissues exhibiting non-atrophic gastritis or uninfected corpus tissues; these included numerous proteins with metabolic functions. Fifty proteins localized to the corpus in uninfected animals were diffusely delocalized throughout the stomach in infected tissues with atrophic gastritis; these included numerous proteins with roles in protein processing. The corresponding alterations were not detected in animals infected with a H. pylori ∆cagT mutant (lacking Cag type IV secretion system activity). These results indicate that H. pylori can cause loss of proteins normally localized to the gastric corpus as well as diffuse delocalization of corpus-specific proteins, resulting in marked changes in the normal gastric molecular partitioning into distinct corpus and antrum regions.IMPORTANCEA normal stomach is organized into distinct regions known as the corpus and antrum, which have different functions, cell types, and gland architectures. Previous studies have primarily used histologic methods to differentiate these regions and detect H. pylori-induced alterations leading to stomach cancer. In this study, we investigated H. pylori-induced gastric molecular alterations in a Mongolian gerbil model of carcinogenesis. We report the detection of numerous proteins that are preferentially localized to the gastric corpus but not the antrum in a normal stomach. We show that stomachs with H. pylori-induced atrophic gastritis (a precancerous condition characterized by the loss of specialized cell types) exhibit marked changes in the abundance and localization of proteins normally localized to the gastric corpus. These results provide new insights into H. pylori-induced gastric molecular alterations that are associated with the development of stomach cancer.

A multiserological line assay to potentially discriminate current from past Helicobacter pylori infection

ObjectivesEarly diagnosis is important in controlling Helicobacter pylori-induced gastritis and progression to gastric malignancy. Serological testing is an efficient non-invasive diagnostic method, but currently does not allow differentiation between active and past infections. To fill this diagnostic gap we investigated the diagnostic value of a panel of ten H. pylori-specific antibodies in individuals with different H. pylori infection status within a German population. MethodsWe used the recomLine Helicobacter IgG 2.0 immunoblotting assay to analyse ten H. pylori-specific antibodies in serum samples collected from 1108 volunteers. From these, 788 samples were used to build exposure and infection status models and 320 samples for model validation. H. pylori infection status was verified by histological examination. We applied logistic regression to select antibodies correlated to infection status and developed, with independent validation, discriminating models and risk scores. Receiving operating characteristic analysis was performed to assess the accuracy of the discriminating models. ResultsAntibody reactivity against cytotoxin-associated gene A (CagA), H. pylori chaperone (GroEL), and hook-associated protein 2 homologue (FliD) was independently associated with the risk of H. pylori exposure with ORs and 95% CIs of 99.24 (46.50–211.80), 46.17 (17.45–122.17), and 22.16 (8.46–55.04), respectively. A risk score comprising these three selected antibodies differentiated currently H. pylori infected or eradicated participants from negatives with an area under the curve of 0.976 (95% CI: 0.965–0.987) (Model 1). Seropositivity for vacuolating cytotoxin A (VacA), GroEL, FliD, H. pylori adhesin A (HpaA), and γ-glutamyl transpeptidase (gGT) was associated with a current infection with an area under the curve of 0.870 (95% CI: 0.837–0.903), which may help discriminate currently infected patients from eradicated ones (Model 2). DiscussionThe recomLine assay is sensitive and specific in determining H. pylori infection and eradication status and thus represents a valuable tool in the management of H. pylori infection.

Gut inflammation and tumorigenesis: every site has a different tale to tell.

Gut inflammation has been correlated with cancerogenesis by disrupting gastrointestinal homeostasis. Numerous chronic inflammatory disorders of the tubular gastrointestinal tract (e.g., gastroesophageal reflux disease, Helicobacter pylori-induced and autoimmune chronic gastritis, celiac disease, and inflammatory bowel diseases) have been variably associated with an increased neoplastic risk. Gastrointestinal inflammation-induced neoplasms include epithelial tumors (esophageal squamous cell carcinoma and adenocarcinoma, gastric adenocarcinoma and neuroendocrine tumors, small bowel adenocarcinoma and neuroendocrine tumors, and colorectal cancer) and lymphomas (such as gastric marginal zone lymphomas and enteropathy-associated T cell lymphoma). In the last decades, numerous studies have investigated the pathogenetic mechanisms and the microenvironmental/microbiome changes that trigger genetic and/or epigenetic alterations eventually leading to tumorigenesis, often through a histologically recognizable inflammation-dysplasia-carcinoma cancerogenic sequence. In the present review, an overview of the current knowledge on the links between inflammatory diseases and neoplasms of the tubular GI tract, applying a site-by-site approach, is provided.

The TLR/MyD88 signalling cascade in inflammation and gastric cancer: the immune regulatory network of Helicobacter pylori.

Helicobacter pylori-induced chronic gastritis represents a well-established risk factor for gastric cancer (GC). However, the mechanism by which chronic inflammation caused by H. pylori induces the development of GC is unclear. H. pylori can influence host cell signalling pathways to induce gastric disease development and mediate cancer promotion and progression. Toll-like receptors (TLRs), as pattern recognition receptors (PRRs), play a key role in the gastrointestinal innate immune response, and their signalling has been implicated in the pathogenesis of an increasing number of inflammation-associated cancers. The core adapter myeloid differentiation factor-88 (MyD88) is shared by most TLRs and functions primarily in H. pylori-triggered innate immune signalling. MyD88 is envisioned as a potential target for the regulation of immune responses and is involved in the regulation of tumourigenesis in a variety of cancer models. In recent years, the TLR/MyD88 signalling pathway has received increasing attention for its role in regulating innate and adaptive immune responses, inducing inflammatory activation and promoting tumour formation. In addition, TLR/MyD88 signalling can manipulate the expression of infiltrating immune cells and various cytokines in the tumour microenvironment (TME). In this review, we discuss the pathogenetic regulatory mechanisms of the TLR/MyD88 signalling cascade pathway and its downstream molecules in H. pylori infection-induced-associated GC. The focus is to elucidate the immunomolecular mechanisms of pathogen recognition and innate immune system activation of H. pylori in the TME of inflammation-associated GC. Ultimately, this study will provide insight into the mechanism of H. pylori-induced chronic inflammation-induced GC development and provide thoughts for GC prevention and treatment strategies.

Bamboo Salt and Triple Therapy Synergistically Inhibit Helicobacter pylori-Induced Gastritis In Vivo: A Preliminary Study.

Helicobacter pylori infections are a major cause of gastrointestinal disorders, including gastric ulcers, gastritis, and gastric cancer. Triple therapy, using two antibiotics and a proton pump inhibitor, is recommended for the treatment of H. pylori infections. However, antibiotic resistance in H. pylori is an emerging issue. Bamboo salt, a traditional Korean salt made by baking solar sea salt in bamboo barrels, can ameliorate the symptoms of various gastrointestinal diseases. Herein, we compared the anti-H. pylori activity of triple therapy (clarithromycin, metronidazole, and omeprazole), solar salt, and bamboo salt in vivo as a preliminary study. Four-week-old C57BL/6 male mice were inoculated for eight weeks with the H. pylori Sydney Strain 1 (SS-1) and orally administered triple therapy drugs and salts for five days. The transcript levels of the H. pylori-expressed gene CagA and inflammatory cytokines Tnfα and Il-1β significantly decreased in the bamboo salt treated mice than those in the H. pylori-infected control group. This effect was further enhanced by using triple therapy and bamboo salt together. Solar salt caused modest inhibition of H. pylori-induced inflammation. We also demonstrated the synergistic effects of bamboo salt and triple therapy against H. pylori. Thus, bamboo salt may be a potential candidate agent against the treatment of H. pylori-associated gastritis.

Preventive and therapeutic effect of Lactobacillus paracasei ZFM54 on Helicobacter pylori-induced gastritis by ameliorating inflammation and restoring gastric microbiota in mice model.

Helicobacter pylori is the most prevalent pathogen causing chronic gastritis, gastroduodenal ulcers, and gastric tumors and is asymptomatically present in 50% of the world's population. This research is focused on investigating the effect of Lactobacillus paracasei ZFM 54 (CCTCC NO:2016667) on attenuating H. pylori-induced gastritis. H. pylori ZJC03 isolated from a patient with gastritis harbored the virulence genes of vacA and cagA and was highly resistant to metronidazole (MIC > 256 μg/mL). In vitro analysis revealed that the potential anti-H. pylori characteristics of L. paracasei ZFM54 in terms of 65.57 ± 1.87% survival rate in simulated gastric juices at a pH of 2.0, 69.00 ± 2.73% auto-aggregation, 30.28 ± 2.24% co-aggregation, 70.27 ± 2.23% urease inhibition, and 57.89 ± 1.27% radical scavenging. In H. pylori infectious mice, L. paracasei ZFM54 pre- and post-treatment reduced the levels of malondialdehyde in liver tissues to 0.71 ± 0.04 nmol/mgprot (p < 0.05) and 0.70 ± 0.06 nmol/mgprot (p < 0.05), respectively. Glutathione levels were increased to 1.78 ± 0.02 μmol/gprot (p < 0.05) and 1.76 ± 0.52 μmol/gprot (p < 0.05), respectively. L. paracasei ZFM54 significantly inhibited H. pylori-mediated inflammation observed in gastric mucosal repair and downregulated the mRNA expression of pro-inflammatory cytokines IFN-γ, IL-1β, and IL-6 (p < 0.01). Importantly, L. paracasei ZFM54 increased Firmicutes and Actinobacteriota and decreased the relative abundance of bacterial taxa belonging to Campilobacterota and Proteobacteria. With the preventive and therapeutic administration of L. paracasei ZFM54, significant reductions in the average relative abundance of genera Helicobacter, Muribaculum, Staphylococcus, Lachnospiraceae_NK4A136_group, Prevotellaceae_UCG-001, Alloprevotella, and Oscillibacter were observed compared to infected mice. These findings suggest that L. paracasei ZFM 54 has the potential to protect against H. pylori infection by ameliorating inflammation and restoring the gastric microbiota.

Functional antagonism between CagA and DLC1 in gastric cancer

Helicobacter (H.) pylori-induced gastritis is a risk factor for gastric cancer (GC). Deleted-in-liver-cancer-1 (DLC1/ARHGAP7) inhibits RHOA, a downstream mediator of virulence factor cytotoxin-A (CagA) signalling and driver of consensus-molecular-subtype-2 diffuse GC. DLC1 located to enterochromaffin-like and MIST1+ stem/chief cells in the stomach. DLC1+ cells were reduced in H. pylori gastritis and GC, and in mice infected with H. pylori. DLC1 positivity inversely correlated with tumour progression in patients. GC cells retained an N-terminal truncation variant DLC1v4 in contrast to full-length DLC1v1 in non-neoplastic tissues. H. pylori and CagA downregulated DLC1v1/4 promoter activities. DLC1v1/4 inhibited cell migration and counteracted CagA-driven stress phenotypes enforcing focal adhesion. CagA and DLC1 interacted via their N- and C-terminal domains, proposing that DLC1 protects against H. pylori by neutralising CagA. H. pylori-induced DLC1 loss is an early molecular event, which makes it a potential marker or target for subtype-aware cancer prevention or therapy.

Loss of Corpus-Specific Lipids in Helicobacter pylori-Induced Atrophic Gastritis.

ABSTRACTHelicobacter pylori colonization of the stomach is a strong risk factor for the development of stomach cancer and peptic ulcer disease. In this study, we tested the hypothesis that H. pylori infection triggers alterations in gastric lipid composition. Mongolian gerbils were experimentally infected with H. pylori for 3 months. Conventional histologic staining revealed mucosal inflammation in stomachs from the H. pylori-infected animals but not in stomachs from uninfected control animals. Atrophic gastritis (a premalignant condition characterized by loss of corpus-specific parietal and chief cells), gastric mucosal hyperplasia, dysplasia, and/or gastric cancer were detected in stomachs from several infected animals. We then used imaging mass spectrometry to analyze the relative abundance and spatial distribution of gastric lipids. We detected ions corresponding to 36 distinct lipids that were differentially abundant when comparing gastric tissues from H. pylori-infected animals with tissues from uninfected animals. Liquid chromatography-tandem mass spectrometry analysis of lipid extracts from homogenized gastric tissues provided additional supportive evidence for the identification of several differentially abundant lipids. Sixteen of the differentially abundant lipids were localized mainly to the gastric corpus in stomachs from uninfected animals and were markedly reduced in abundance in stomachs from H. pylori-infected animals with severe disease (atrophic gastritis and dysplasia or gastric cancer). These findings indicate that H. pylori infection can lead to alterations in gastric lipid composition and constitute a new approach for identifying biomarkers of gastric atrophy and premalignant changes.IMPORTANCE H. pylori colonization of the stomach triggers a cascade of gastric alterations that can potentially culminate in stomach cancer. The molecular alterations that occur in gastric tissue prior to development of stomach cancer are not well understood. We demonstrate here that H. pylori-induced premalignant changes in the stomach are accompanied by extensive alterations in gastric lipid composition. These alterations are predicted to have important functional consequences relevant to H. pylori-host interactions and the pathogenesis of gastric cancer.

Zuojin Pill attenuates Helicobacter pylori-induced chronic atrophic gastritis in rats and improves gastric epithelial cells function in GES-1 cells

Ethnopharmacological relevanceZuojin pill (ZJP), a classical Chinese medicine formula, has been widely applied in Chinese clinical practice for the treatment of gastric injury such as acute gastric lesion, acute gastric mucosal injury, chronic unpredictable mild stress, gastroesophageal reflux disease, etc, thereby exerting anti-chronic atrophic gastritis (CAG) effects in traditional Chinese herbal medicine. Aim of the studyThis study was aimed to explore the therapeutic effects and molecular mechanisms of ZJP on Helicobacter pylori (H. pylori)-induced CAG based on the comprehensive approaches. Materials and methodsSprague-Dawley rats were infected with H. pylori for 8 weeks to establish CAG model. Then, rats in the ZJP groups received doses of 0.63, 1.26, and 2.52 g/kg ZJP for 4 weeks. Therapeutic effects of ZJP on serum indices and the histopathology of the gastric were analyzed in vivo. Moreover, GES-1 cells were infected with H. pylori to establish gastric epithelial cell injury model in vitro. Cell viability and gastric epithelial cell morphology were detected by a high-content screening (HCS) assay. Furthermore, the relative mRNA and protein expression of JMJD2B/COX-2/VEGF axis and HMGB1/NF-κB signaling pathway in vivo and in vitro were determined by RT-PCR and Western Blotting, respectively. ResultsThe results showed that the therapeutic effects of ZJP on CAG rats were presented in down-regulation serum biochemical indices and alleviating histological damage of gastric tissue. ZJP could dose-dependently decrease the serum IL-6, MCP-1, PGE2, TNF-α, and VEGF level and significantly improved gastric tissue inflammatory lesions. Besides, ZJP has an effect on increasing cell proliferation of GES-1 cells, ameliorating H. pylori-induced gastric epithelial cell damage. It was found that ZJP has a down-regulating effect on inflammatory reaction and could inhibit the relative mRNA and protein expression of JMJD2B/COX-2/VEGF axis and HMGB1/NF-κB signaling pathway in vivo and in vitro, including JMJD2B, COX-2, VEGF, VEGFR1, and VEGFR2, which in turn reduced the damage of gastric mucosal cells. ConclusionsThe results suggested that ZJP exerts therapeutic effects on H. pylori-induced CAG by inhibiting the JMJD2B/COX-2/VEGF axis and HMGB1/NF-κB signaling pathway. These findings deeply explained why ZJP could be used to treat CAG clinically and clarified its pharmacological effect and potential mechanism in the treatment of CAG.

Protective effect of total triterpenoids from Chaenomeles speciosa against Helicobacter pylori-induced gastritis in mice

This study investigated the protective effect of total triterpenoids from Chaenomeles speciosa against Helicobacter pylori(Hp)-induced gastritis in mice and explored its possible mechanism. The chronic atrophic gastritis(CAG) model mice were randomly divided into four groups of model, total triterpenoids from C. speciosa(50 and 100 mg·kg~(-1)) and triple therapy, with C57 BL/6 J mice without Hp infection taken as the normal group. Mice in the treatment groups were given corresponding drugs once a day for 4 weeks. Then the following indexes were detected: the contents of reactive oxygen species(ROS), monocyte chemotactic protein 1(MCP-1), keratinocyte chemokines(KC), TNF-α, IL-1β, IL-6, IL-18, IL-4 and IL-10 in blood and gastric tissue, the activities and contents of LDH, MPO, SOD, GSH-Px, CAT and MDA in gastric tissue and the activities of β-glucuronidase, β-galactosidase, cathepsins B and D in blood, gastric tissue and lysosome. Besides, the mRNA expression levels of Toll-like receptor 4(TLR4), myeloid differentiation factor 88(MyD88), Bcl-2, Bcl-xl, Bax and Bad in gastric tissue were determined by quantitative real-time PCR. Western blot was employed to detect the protein expression levels of TLR4, MyD88, p-IKKβ, p-IκBα, NOD-like receptor 3(NLRP3), apoptosis-associated speck-like protein(ASC), pro-caspase-1, caspase-1, thioredoxin-interacting protein(TXNIP), pro-IL-1β, pro-IL-18, Bcl-2, Bcl-xl, Bax, Bad, cytochrome C, apoptotic protease-activating factor-1(Apaf-1), pro-caspase-9, pro-caspase-3, cleaved-caspase-9, cleaved-caspase-3, poly(ADP-ribose) polymerase 1(PARP-1), cleaved-PARP-1 and cytosol and nucleus NF-κB p65 in gastric tissue. The results indicated that the total triterpenoids from C. speciosa significantly suppressed Hp proliferation, alleviated the damage to gastric mucosa and improved lymphocyte infiltration and gland atrophy. They were also effective in reducing the activities of β-glucuronidase, β-galactosidase, cathepsins B and D in blood and gastric tissue, elevating the activities of β-glucuronidase and cathepsin D in lysosomal organelles, decreasing the contents of ROS, MCP-1, KC, TNF-α, IL-1β, IL-6, IL-18 in blood, MDA content and MPO and LDH activities in gastric tissue and increasing the contents of IL-4 and IL-10 in blood and activities of SOD, CAT and GSH-Px in gastric tissue. Other phenomena were also observed after the treatment with total triterpenoids from C. speciosa, including the down-regulation of the mRNA and protein expression levels of TLR4, MyD88, Bax and Bad, the protein expression levels of p-IKKβ, p-IκBα, NLRP3, ASC, pro-caspase-1, caspase-1, TXNIP, pro-IL-1β, pro-IL-18, cytochrome C, Apaf-1, cleaved-caspase-9, cleaved-caspase-3, cleaved-PARP-1 and nuclear NF-κB p65, reduction of p-IKKβ/IKKβ and p-IκBα/IκBα ratios and up-regulation of the mRNA and protein expression levels of Bcl-2 and Bcl-xl, up-regulation of pro-caspase-9, pro-caspace-3, cytosol NF-κB p65 protein expression levels and Bcl-2/Bax and Bcl-xl/Bad ratios in gastric tissue. These aforementioned results suggest that the total triterpenoids from C. speciosa have significant protective effects against CAG induced by Hp, and its mechanism may be related to enhancing the function of endogenous antioxidant system, suppressing the oxidative stress and inflammatory reaction induced by Hp, correcting lysosomal dysfunction and inflammatory activation of TLR4/NF-κB/NLRP3 inflammasome signaling pathway and thus inhibiting mitochondria-mediated apoptosis.

Protective Effects of Silibinin on Helicobacter pylori-induced Gastritis: NF-κB and STAT3 as Potential Targets.

More than half of the world’s populations are considered to be infected by Helicobacter pylori. It causes a chronic inflammation of the stomach, which is implicated in the pathogenesis of gastric ulcer and cancer. Silibinin, a polyphenolic flavonoid derived from milk thistle, has been known for its hepatoprotective effects, and recent studies have revealed its chemopreventive potential. In the present study, we examined the anti-inflammatory effects of silibinin in human gastric cancer MKN-1 cells and in the stomach of C57BL/6 mice infected by H. pylori. Pretreatment with silibinin attenuated the up-regulation of COX-2 and inducible nitric oxide synthase (iNOS) in H. pylori-infected MKN-1 cells and mouse stomach. In addition, the elevated translocation and DNA binding of NF-κB and STAT3 induced by H. pylori infection were inhibited by silibinin treatment. Moreover, H. pylori infection in combination with high salt diet resulted in dysplasia and hyperplasia in mouse stomach, and these pathological manifestations were substantially mitigated by silibinin administration. Taken together, these findings suggest that silibinin exerts anti-inflammatory effects against H. pylori infection through suppression of NF-κB and STAT3 and subsequently, expression of COX-2 and iNOS.

The role of polyamines in gastric cancer.

Advancements in our understanding of polyamine molecular and cellular functions have led to increased interest in targeting polyamine metabolism for anticancer therapeutic benefits. The polyamines putrescine, spermidine, and spermine are polycationic alkylamines commonly found in all living cells and are essential for cellular growth and survival. This review summarizes the existing research on polyamine metabolism and function, specifically the role of polyamines in gastric immune cell and epithelial cell function. Polyamines have been implicated in a multitude of cancers, but in this review, we focus on the role of polyamine dysregulation in the context of Helicobacter pylori-induced gastritis and subsequent progression to gastric cancer. Due to the emerging implication of polyamines in cancer development, there is an increasing number of promising clinical trials using agents to target the polyamine metabolic pathway for potential chemoprevention and anticancer therapy.

Clinicopathological features and prognosis of developed gastric cancer based on the diagnosis of mucosal atrophy and enlarged folds of stomach by double-contrast upper gastrointestinal barium X-ray radiography.

Mucosal atrophy and enlarged folds of stomach by double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) are two major features of Helicobacter pylori-induced chronic gastritis. These were previously shown to be risk indicators of gastric cancer, but their predictability for clinicopathological characters of developed gastric cancer is unelucidated. In addition, evidence for decreasing the mortality of gastric cancer by appropriate follow-up of UGI screening is needed. The 5134 generally healthy UGI-XR examinees, who underwent follow-up UGI-XR or upper gastrointestinal endoscopy (UGI-ES) more than once, were prospectively observed for 10years. At the beginning of follow-up, 1515 (29.5%) had mucosal atrophy and 990 (19.5%) had enlarged folds. For the serum anti-H. pylori IgG, 1301 (25.3%) were positive, 177 (3.4%) were possibly positive, and 3656 (71.2%) were negative. During the 10-year observation period, gastric cancer developed in 15 subjects, among which 13 had mucosal atrophy and 10 had enlarged folds. These two features were expectedly useful indicators for gastric cancer incidence, but they showed no significant association with tumor stage or histological type of developed cancer. Only one of the 5134 subjects died of gastric cancer during 10years, which was significantly lower than the predicted number of gastric cancer death (6.78 for 10years) according to the mortality rate in Japan. Neither mucosal atrophy nor enlarged folds of stomach showed a significant association with clinicopathological features of developed gastric tumors. Appropriate follow-up of cancer screening by UGI-XR or UGI-ES can reduce the risk of gastric cancer-related death.

Berberine regulates macrophage polarization through IL-4-STAT6 signaling pathway in Helicobacter pylori-induced chronic atrophic gastritis

AimsWe will investigate the anti-inflammatory activities of berberine (BBR) in treating chronic atrophic gastritis (CAG) induced by Helicobacter pylori (H. pylori). Furthermore, the underlying molecular mechanisms of BBR also will be explored systematically. Materials and methodsRats were infected by H. pylori. Lipopolysaccharide (LPS) and H. pylori were applied to induce M1 Mφs polarization, interleukin 4 (IL-4) and BBR were used to induce M2 Mφs polarization. Supernatants of polarized Mφs were collected as conditioned media (CM) for investigating the impact of Mφs and its' secreted cytokine on gastric epithelial cells (GES-1). Cell viability, morphology, proliferation, and quantitative analysis of RAW 264.7 cells and GES-1 cells were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression were measured. Key findingsBBR inhibited M1-polarized Mφs, which was induced by H. pylori and LPS, and advocated M2-polarized Mφs. The M1-specific markers (TNF-α and IFN-γ) in supernatants were reduced significantly and M2 specific markers (TGF-β and IL-10) were increased obviously under BBR intervention. In addition, BBR significantly protected GES-1 from M1-polarized Mφs injury. The mRNA expression of M1-polarized Mφs, including TNF-α, NOS2, CCR7, and IRF-8, were suppressed by BBR administration and the mRNA expression of M2-polarized Mφs, including IL-4, STAT6, IL-10 and Chil3, were increased by BBR intervention. Meanwhile, BBR activated IL-4-STAT6 signaling pathway in vivo and in vitro when H. pylori infection and presented anti-inflammatory activities. SignificanceBBR promotes M2-polarized Mφs when H. pylori infection. The anti-inflammatory properties of BBR tightly related to M1-polarized Mφs inhibition and M2-polarized Mφs promotion. BBR activates IL-4-STAT6 signaling pathway, which is crucial exceedingly in M2 Mφs activation and anti-inflammatory response.

Inflammation-Associated Senescence Promotes Helicobacter pylori-Induced Atrophic Gastritis.

Background & AimsThe association between cellular senescence and Helicobacter pylori–induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori–induced atrophic gastritis and the underlying mechanism.MethodsC57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro.ResultsGastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori–infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression.ConclusionsOur study showed a new mechanism of H pylori–induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori–induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556.

Palmatine ameliorates Helicobacter pylori-induced chronic atrophic gastritis by inhibiting MMP-10 through ADAM17/EGFR

Palmatine (Pal), a plant-based isoquinoline alkaloid, was initially isolated from Coptidis Rhizoma (CR, Huanglian in Chinese) and considered to be a potential non-antibiotic therapeutic agent that can safely and effectively improve Helicobacter pylori (H. pylori) induced chronic atrophic gastritis (CAG). However, underlying mechanisms are unclear. In this study, we explored the protective effect of Pal on H. pylori induced CAG in vivo and in vitro. As a result, Pal alleviated the histological damage of gastric mucosa and the morphological changes of gastric epithelial cell (GES-1) caused by H. pylori. Furthermore, Pal significantly inhibited the expression of EGFR-activated ligand genes, including a disintegrin and metalloproteinase 17 (ADAM17) and heparin-binding epidermal growth factor-like growth factor (HB-EGF), and the proinflammatory factors, such as chemokine 16 (CXCL-16) and interleukin 8 (IL-8), were suppressed. In addition, Pal attenuated inflammatory infiltration of CD8+ T cells while promoted Reg3a expression to enhance host defense. Taken together, we concluded that Pal attenuated the MMP-10 dependent inflammatory response in the gastric mucosa by blocking ADAM17/EGFR signaling, which contributed to its gastrointestinal protective effect.

Current Perspectives in Atrophic Gastritis.

Atrophic gastritis is a complex syndrome with gastric atrophy as a common trait. Helicobacter pylori infection and autoimmunity are the two main contexts in which it develops. It is slightly symptomatic, affects various aspects of general health, and remains a predisposing factor for gastric cancer. This review will update current knowledge and progress on atrophic gastritis. Atrophic gastritis affects mostly adults with persistent dyspepsia, deficient anemia, autoimmunity disease, long-term proton pump inhibitor use, and a family history of gastric cancer. Gastric biopsies, expressed as Sydney system grade and OLGA/OLGIM classifications, represent the gold standard for diagnosis and cancer risk stage, respectively. Recently, electronic chromoendoscopy has allowed "targeted biopsies" of intestinal metaplasia. The associated hypochlorhydria affects the gastric microbiota composition suggesting that non-Helicobacter pylori microbiota may participate in the development of gastric cancer. Physicians should be aware of multifaceted clinical presentation of atrophic gastritis. It should be endoscopically monitored by targeted gastric biopsies. Autoimmune and Helicobacter pylori-induced atrophic gastritis are associated with different gastric microbial profiles playing different roles in gastric tumorigenesis.