Helicobacter pylori infection and the resulting inflammation of the stomach are widely recognized as the primary risk factors for the development of gastric cancer (human health). Despite numerous attempts, the correlation between various virulence factors of H. pylori and stomach cancer remains mainly unexplained. The cag pathogenicity island (cagPAI) is a widely recognized indicator of virulence in H. pylori. MicroRNAs play crucial roles in a wide range of biological and pathological processes and dysregulated expressions of miRNAs have been detected in numerous cancer types. However, research on the correlation between H. pylori infection and its cagPAI, as well as the differential expression of microRNAs in gastric cancer, is lacking.

The aim of this study was to examine the differential expression of miRNAs in 80 patients with gastric cancer, specifically in connection to the presence of H. pylori and its cag pathogenicity island (cagPAI).

Biopsies of 80 gastric cancer patients were collected and used for H. pylori DNA isolation and tissue miRNA isolation, and further analyzed for cagPAI and miRNA expression and their association.

Elevated levels of miR-21, miR-155, and miR-223 were detected in malignant tissues. The expression of miR-21 and miR-223 was considerably elevated in biopsies that tested positive for H. pylori, whereas the expression of miR-34a was reduced. H. pylori cagPAI samples that are functionally intact exhibit greater expression of miR-21 and miR-223 compared to cagPAI samples that are partially deleted, in both normal and malignant tissues.

Thus, the novelty of our study lies in its focus on the differential expression of specific miRNAs in relation to the functional integrity of the cagPAI in H. pylori-infected gastric cancer patients, offering a more detailed understanding of the interplay between H. pylori virulence factors and miRNA regulation than previous studies.

Recent advancements in nanotechnology have significantly advanced nanocarrier-mediated drug delivery systems, promoting therapeutic outcomes in mitigating chronic inflammation and cancer. Nanomaterials offer significant advantages over traditional small-molecule drugs, including a high surface-area-to-volume ratio, tunable structural features, and extended bloodstream circulation time. Chronic inflammation is a well-established mechanism for malignant initiation, progression, and metastasis, promoting the potent strategy for cancer prevention and therapy. Numerous studies revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have the therapeutic ability to manage disease progression via amolerating angiogenesis and inducing apoptosis. However, prolonged intake of NSAIDs is often limited by adverse side-effects and systemic toxicities. The encapsulation of NSAIDs in a nanocarrier have materialized as a dynamic approach to mitigate the limitations by improving pharmacokinetics and pharmacodynamics, reducing off-target effects, and enhancing the drug stability. This review encompasses recent progress in the development of NSAID-based nanotherapeutics, focusing on pivotal mechanisms underlying nanoparticle-mediated drug delivery, such as improved tumor-specific targeting and strategies to overcome drug resistance. The ability of these nano-cargoes to accommodate anti-inflammatory strategies with advanced drug delivery platforms is critically evaluated. This review also highlights the transformative potential of NSAID-encapsulated nanoparticles as a multifaceted therapeutic venue for addressing chronic inflammation and mitigating cancer progression.

Peptic ulcer disease (PUD) remains a significant yet poorly understood public health issue in Africa, despite its declining prevalence in Western countries. Studies from Africa report a highly variable burden, with the highest prevalence observed in West Africa and the lowest in Southern Africa. However, the overall burden of PUD in Africa, its patterns (duodenal ulcers, gastric ulcers, and coexisting ulcers), and its association with H. pylori infection remain unclear.

This review aims to systematically analyze the pooled prevalence and patterns of PUD in Africa through a systematic review and meta-analysis.

A systematic review and meta-analysis was conducted following the PRISMA checklist. We searched PubMed, Hinari, and Google Scholar, supplemented by Google and Yahoo search engines. Observational studies reporting the prevalence and patterns of PUD among the African population were included. Two independent reviewers extracted data and assessed study quality. Pooled prevalence estimates were calculated using a random-effects model, with heterogeneity assessed via the Cochrane Q test and I2 statistic.

A comprehensive analysis of 58 studies revealed a pooled prevalence of PUD in Africa at 15.2%. The most common ulcer pattern was DU at 10.2%, followed by GU at 5.8%, while 0.6% of cases had both types. Regional variations were observed, with West Africa having the highest prevalence (19%), followed by East Africa (15%), North Africa (12%), and Southern Africa (8%). Among individual countries, Ghana reported the highest prevalence (27%), followed by Ethiopia (19%) and Tanzania (16%). Furthermore, the pooled prevalence of PUD was 14% before 2010 and 15% in 2011 and later. Additionally, 57.1% of patients tested positive for Helicobacter pylori infection, with its prevalence reaching 76.4% among those diagnosed with PUD. Substantial heterogeneity was observed across most analyses, with I2 values exceeding 95% and p-values < 0.001.

The analysis revealed a significant burden of PUD in Africa, with DU being more common than GU. Regional disparities were observed, with the highest prevalence in West and East Africa. Over the past two decades, the burden has remained relatively stable, reflecting a concerning trend. H. pylori infection was also frequently diagnosed in individuals undergoing endoscopic examination. However, substantial heterogeneity was noted across studies, highlighting variability in reported prevalence.

Gastric cancer and ulcers are responsible for almost 1 million deaths globally each year, disproportionately affecting low- and middle-income populations. Helicobacter pylori (H. pylori) infection is a major risk factor for both gastric cancer and peptic ulcers, with infection rates surpassing 70% in developing countries and reaching 88% in Jordan. Despite strong evidence linking H. pylori infection to gastric cancer, particularly with CagA-positive strains, public awareness of H. pylori infection, its transmission routes, and associated health risks remains insufficient.

This study aimed to assess the knowledge, attitudes, and practices (KAP) related to H. pylori-induced stomach ulcers and cancer in a Jordanian population, focusing on early detection and eradication efforts. A survey was administered to 398 participants to evaluate their understanding of H. pylori and its role in gastric disease.

The findings revealed that 64.3% of respondents were aware of H. pylori, with 75.9% recognizing its association with gastric ulcers. However, awareness of the transmission routes and potential complications is limited. The frequent use of antacids for symptom relief also highlights the need for better awareness of appropriate treatments.

Public health education targeting these knowledge gaps could help reduce the incidence of H. pylori-related complications, including gastric cancer, especially in high-prevalence areas such as Jordan. Addressing these deficits and promoting preventive strategies, such as improved hygiene and regular medical check-ups, could facilitate early detection and improve health outcomes for individuals at risk of H. pylori-induced infection.

Upper gastrointestinal endoscopy (UGIE) plays a crucial role in diagnosis of gastrointestinal pathology. Therefore, this systematic review and meta-analysis aimed to assess the indications and findings UGIE, while exploring their regional distribution and temporal trend across Africa.

Systematic Reviews and Meta-Analysis of pooled prevalence for various indications and endoscopic findings were analyzed from multiple studies in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

Seventeen common indication were identified. Of these dyspepsia was the most prevalent indication 52.4%, followed by abdominal pain 17.4%, hematemesis 13.9%, and GERD symptoms 11.2%. Other indications included dysphagia 9.2%, vomiting 9.2, odynophagia 3.5%, and melena 6.2% were identified. Rare indications such as anemia 2.3%, weight loss 2.6% were also reported. Regarding endoscopic findings, thirty-one common findings were identified by UGIE. Gastritis (33.3%) was the most common findings followed by normal findings 21.8%, the third most common was PUD 15.1%, particularly duodenal ulcer (10%), gastric cancer 3.3% were also prevalent in stomach. Related to esophageal findings, GERD 9.6%, esophagitis 8.3%, esophageal varices 7.2% and esophageal cancer 6.1% were identified. Regional difference were apparent, with esophageal cancer prevalent in Eastern (10%) and Southern Africa (10%). Gastritis (45%) and GERD (18%) were more apparent and common in Northern Africa. Even though it is not significant, temporal trends showed an increase in prevalence of gastritis (26 to 36%) and esophagitis (6 to 10%) from 2000-2010 to 2011-2024.

Most UGIE indications resulted significant UGIT pathology. However, this analysis did not assess age, sex based indications and findings and their relationship among specific indications and UGIE findings. So, future analysis should focus on age and sex based difference in indications and findings, and explore their relationship among specific indication and corresponding UGIE findings.

In many solid tumours, including gastric cancer (GC), the beginning and progression of the tumour are closely correlated with the tumour microbiome. Here, we show the changes in the gastric microbiota and their influence on immune regulation and the promotion of GC progression through 16s rRNA sequencing and single cell RNA sequencing. Streptococcus lutetiensis (S. lutetiensis) was found to be enriched in the tumour tissues of GC patients. Further analysis using single-cell sequencing and flow cytometry showed that S. lutetiensis notably affects the antitumour immunity by suppressing IL17 signalling and reducing the population of CD8+IL17A+ tissue-resident memory T (TRM) cells by activating Nrf2-mediated oxidative stress response. Mouse models confirm S. lutetiensis promotes GC progression by impairing immune responses in CD8+IL17A+TRM cells, suggesting it as a potential GC prognosis indicator and immunotherapy target, highlighting the microbiome's role in cancer progression.

Assessment of Helicobacter pylori (H. pylori) prevalence in Southern Poland, focusing on highly virulent cagA-positive strains associated with gastric cancer risk, along with analysis of antimicrobial resistance and its molecular mechanisms.

A total of 130 dyspeptic patients, who underwent endoscopy, were enrolled in the study. Presence of H. pylori in gastric mucosa biopsy specimens was confirmed by rapid urease tests, histological examination, culture, and molecular assays. Antimicrobial susceptibility was tested using the E-test, while the cagA gene (virulence marker) was identified by PCR. The GenoType HelicoDR detected mutations for resistance to clarithromycin (23 S rRNA) and levofloxacin (gyrA). Resistance to rifampicin and levofloxacin was investigated by sequencing the rpoB and gyrA genes.

H. pylori prevalence in Southern Poland was 30.8%, with 60% of infections involving cagA-positive strains. Susceptibility testing revealed resistance rates of 22.9% for metronidazole, 14.3% for clarithromycin, 11.4% for levofloxacin and 25.7% for rifampicin. Among the 24 cagA-positive strains, 45.8% were resistant to at least one antibiotic. Clarithromycin resistance was caused by A2143G mutation. The gyrA gene sequence showed the N87K mutation linked to fluoroquinolone resistance. No mutations were found in the rpoB gene.

Infections with multidrug-resistant CagA-positive strains require recommended treatment strategies due to the high risk of progression of infection to gastric cancer.

Helicobacter pylori infection is the main risk factor for gastric cancer (GC). Chronic inflammation is usually induced by H. pylori infection and is accompanied by inherent immune disorders. However, the dynamic changes in the host immune response associated with the transition from normal to metaplasia, dysplasia, and GC are largely undefined.

We established the H. pylori-induced GC mice model. The gastric mucosa of H. pylori-infected mice was subjected to RNA-sequencing analysis at different stages. We analyzed systemic immune disturbances in the spleen and changes in serum inflammatory cytokines during GC development, including gastritis, premalignant lesions (pre-GC), and GC stages.

RNA-sequencing analysis of the gastric mucosa of H. pylori-infected mice highlighted the important role of immune-associated pathways (especially inflammatory pathways) during GC development. Immune cell proportion analysis revealed the stage-dependent involvement of key immune cell types, including increased Th17 cells in early gastritis and pre-GC stages and decreased central memory CD4+ and CD8+ T cells during GC transition. Serum inflammatory cytokine analysis showed that IL-6 and IL-10 levels significantly increased, whereas IL-23 levels decreased during the GC stage.

In summary, we illustrated systemic immune disturbances in the spleen and changes in serum inflammatory cytokines during GC development. Th17 cells were involved in early gastritis and premalignant processes, while central memory T cells participated in GC transition. Our findings provide valuable insights into identifying key inflection points and associated biomarkers for the early detection, diagnosis, and treatment of GC.

Infection with H. pylori (Helicobacter pylori) is the most prevalent human infection worldwide and is strongly associated with many gastrointestinal disorders, including gastric cancer. Endoscopy is mainly used to diagnose H. pylori infection in gastric biopsies. However, this approach is invasive, time-consuming and expensive. On the other hand, serology-based methods can be considered as a non-invasive approach to detecting H. pylori infection. The LFA (lateral flow assay) serves as a rapid point-of-care diagnostic tool. This paper-based platform facilitates the detection and quantification of analytes within human fluids such as blood, serum and urine. Due to ease of production, rapid results, and low costs, LFAs have a wide application in clinical laboratories and hospitals. In this comprehensive review, we examined LFA-based approaches for detection of H. pylori infection from human fluids and compare them with other high-sensitivity methods like ELISA (Enzyme-linked immunosorbent assay). Furthermore, we reviewed methods to elevate LFA sensitivity during H. pylori infection including, CRISPR/Cas system and isothermal amplification approaches. The development and optimization of novel labeling agents such as nanozyme to enhance the performance of LFA devices in detecting H. pylori were reviewed. These innovations aim to improve signal amplification and stability, thereby increasing the diagnostic accuracy of LFA devices. A combination of advances in LFA technology and molecular insight could significantly improve diagnostic accuracy, resulting in a significant improvement in clinical and remote diagnostic accuracy.

The development of second primary cancers (SPCs) following a diagnosis of stomach cancer presents a significant clinical challenge, with varying risks depending on the anatomic subsite of the primary tumor, patient demographics, and treatment modalities. This study aims to assess the risk of SPCs in stomach cancer survivors, focusing on differences across anatomic subsites, sex, age, and treatment periods.

The authors conducted a retrospective cohort study using data from stomach cancer patients, analyzing the incidence of SPCs based on the anatomic location of the primary tumor, with stratifications by sex, age, latency period, and year of diagnosis. Standardized incidence ratios (SIRs) were calculated to compare the observed SPC rates with those expected in the general population.

Elevated stomach SPC risk was observed across most anatomic subsites, particularly in the body (SIR 8.84) and fundus (SIR 7.34). Females exhibited higher SIRs compared to males, especially in the fundus (SIR 13.33 for females vs. 4.55 for males). Younger patients (<50 years) had significantly higher SPC risks, particularly for cancers originating in the fundus (SIR 49.56). Notably, patients diagnosed after 2010 showed the highest SIRs, indicating a potential impact of advances in diagnostic and therapeutic modalities. Nonstomach SPCs, including colorectal, lung, and thyroid cancers, were significantly elevated, with distinct patterns based on the primary tumor site.

The study highlights the critical role of primary tumor location, sex, age, and treatment era in determining SPC risk in stomach cancer survivors. These findings underscore the need for tailored surveillance strategies to manage long-term cancer risks in this population.

Helicobacter pylori infection is still the main risk factor for the development of gastric cancer (GC). We explore the scientific evidence for the role of the gastric microbiome beyond Helicobacter pylori (H. pylori) in gastric carcinogenesis. The composition of the gastric microbiome in healthy individuals, in presence and absence of H. pylori infection, in proton pump inhibitor (PPI)-users, obese individuals, and GC patients was investigated. Possible mechanisms for microbial involvement, limitations of available research and options for future studies are provided. A common finding amongst studies was increased levels of Streptococcus, Prevotella, Neisseria, and Actinomyces in healthy individuals or those with H. pylori-negative gastritis. In PPI-users the risk for GC increases with the treatment duration, and the gastric microbiome shifts, with the most consistent increase in the genus Streptococcus. Similarly, in obese individuals, Streptococcus was the most abundant genus, with an increased risk for cardia GC. The genera Streptococcus, Lactobacillus and Prevotella were found to be more prominent in GC patients in multiple studies. Potential mechanisms of non-H. pylori microbiota contributing to GC are linked to lipopolysaccharide production, contribution to inflammatory pathways, and the formation of N-nitroso compounds and reactive oxygen species. In conclusion, the knowledge of the gastric microbiome in GC is mainly descriptive and based on sequencing of gastric mucosal samples. For a better mechanistic understanding of microbes in GC development, longitudinal cohorts including precancerous lesions, different regions in the stomach, and subtypes of GC, and gastric organoid models for diffuse and intestinal type GC should be employed.

Gastric cancer remains a significant global health challenge, causing a substantial number of cancer-related deaths, particularly in China. While the exact causes of gastric cancer are still being investigated, Helicobacter pylori (H. pylori) infection has been identified as the primary risk factor, which triggers chronic inflammation and a multistage progression of gastric lesions that may lead to carcinogenesis over a long latency time. Since the 1990s, numerous efforts have focused on assessing the effectiveness of H. pylori eradication in preventing new cases of gastric cancer among both the general population and patients who have undergone early-stage cancer treatment. This body of work, including several community-based interventions and meta-analyses, has shown a reduction in both the incidence of and mortality from gastric cancer following H. pylori treatment, alongside a decreased risk of metachronous gastric cancer. In this review, we seek to consolidate current knowledge on the effects of H. pylori treatment on gastric cancer prevention, its systemic consequences, cost-effectiveness, and the influence of antibiotic resistance and host characteristics on treatment outcomes. We further discuss the potential for precision primary prevention of H. pylori treatment and comment on the efficient implementation of test-and-treat policies and allocation of health resources towards minimizing the burden of gastric cancer globally.

The microbiota plays a significant role in the tumor microenvironment, and its impact on tumor development and treatment outcome cannot be overlooked. Thus, it is essential to comprehend the interactions between the microbiota and the tumor microenvironment.

With the advent of next-generation sequencing, microbiota research has advanced significantly in recent years. The interaction between the intratumoral microbiota and the tumor microenvironment is an emerging area of research that holds great promise for understanding and treating solid tumor progression. This crosstalk between the intratumoral microbiota and the tumor microenvironment is a complex process that involves a multitude of factors, including the immune system, cellular signaling pathways, and metabolic processes. The origin of the intratumoral microbiota differs between various solid tumor, and the quantity and diversity of intratumoral microbiota also fluctuate significantly within each solid tumor.

The aim of this review is to provide a detailed summary of the intratumoral microbiota in various types of solid tumors. This will include an analysis of their origins, differences, and how they impact the progression of solid tumors. Furthermore, we will emphasize the significant potential that the intratumoral microbiota holds for the diagnosis and treatment of solid tumors.

Tumor microenvironment (TME) immune cells and gastric mucosal microbiome constitute two vital elements of tumor tissue. Increasing evidence has elucidated their clinicopathological significance in predicting outcomes and therapeutic efficacy. However, comprehensive characterization of immune cell-associated microbiome signatures in the TME is still in the early stages of development. Here, we characterized the gastric mucosa microbiome and its associations with immune-activated related transcripts (IATs) in 170 GC tumor tissues and matched non-tumor tissues using 16s rRNA gene sequencing and quantitative reverse transcription-PCR. Microbial diversity and richness were significantly higher in GC tumor tissues than in non-tumor tissues. Differences in microbial composition between the groups were evident, with Firmicutes, Proteobacteria, Bacteroidota, Campilobacterota, Actinobacteria, Fusobacteriota, Verrucomicrobiota, Acidobacteriota, and Cyanobacteria being the dominant phyla in the gastric mucosal microbiota. Microbial interaction network analysis revealed distinctive centralities of oral bacteria (such as Fusobacterium, Porphyromonas, Prevotella, etc.) in both tumor and normal mucosae networks, suggesting their significant influence on GC microbial ecology. Furthermore, we analyzed the expression of IATs (CXCL9, CXCL10, GZMA, GZMB, PRF1, CD8A, IFNG, TBX2, and TNF) and characterized IAT-relevant gastric microbiome signatures in GC patients. Our results showed that the expression of CXCL9, CXCL10, GZMA, GZMB, PRF1 and IFNG was significantly higher in tumor tissues than in adjacent normal tissues in GC patients. Notably, high expression of IATs in tumor tissues was associated with improved survival in GC patients and could serve as a powerful predictor for disease-free survival. Additionally, analysis of IAT levels and mucosal microbiota diversity revealed a correlation between higher IAT expression and increased microbiota richness and evenness in the IATs high group, suggesting potential interactions between mucosal microbiota and tumor immunopathology. Spearman correlation analysis showed positive associations between IAT expression and specific mucosal bacterial species. Notably, Akkermansia muciniphila demonstrated potential involvement in modulating GZMB expression in the GC mucosal microenvironment. These findings underscore the importance of mucosal microbiota alterations in GC and suggest potential therapeutic targets focusing on modulating the tumor microbiota for improved clinical outcomes. The detailed characterization of these elements has profound implications for both treatment and survival prediction in GC. We observed that microbial diversity and richness were significantly higher in GC tumor tissues compared to non-tumor tissues. These differences highlight the unique microbial landscape of GC tumors and suggest that the microbiome could influence tumor development and progression. Importantly, our study demonstrated that high expression levels of IATs in GC tumor tissues were associated with improved patient survival. This suggests that IATs not only reflect immune activation but also serve as valuable biomarkers for predicting disease-free survival. The potential of IATs as predictive markers underscores their utility in guiding therapeutic strategies and personalizing treatment approaches. Moreover, the correlation between higher IAT expression and increased microbiota richness and evenness suggests that a diverse and balanced microbiome may enhance immune responses and contribute to better clinical outcomes. These findings highlight the critical need to consider mucosal microbiota alterations in GC management. Targeting the tumor microbiota could emerge as a promising therapeutic strategy, potentially leading to more effective treatments and improved patient outcomes. Understanding and modulating the microbiome's role in GC opens new avenues for innovative therapeutic interventions and personalized medicine.

Cancer research has extensively explored various factors contributing to cancer development, including chemicals, drugs, smoking, and obesity. However, the role of bacterial infections in cancer induction remains underexplored. In particular, the mechanisms underlying H. pylori-induced B-cell lymphoma, a potential consequence of bacterial infection, have received little attention. In recent years, there has been speculation about contagious agents causing persistent inflammation and encouraging B-lymphocyte transition along with lymphomagenesis. MALT lymphoma associated with chronic H. pylori infection, apart from two other central associated lymphomas - Burkitt's Lymphoma and DLBCL, is well studied. Owing to the increasing colonization of H. pylori in the host gut and its possible action in the development of B-cell lymphoma, this review aims to summarize the existing reports on different B-cell lymphomas' probable association with H. pylori infections; also emphasizing the function of the organism in lymphomagenesis; including its interaction with the host, pathogen and host-specific factors, and tumor microenvironment.

Rates of antimicrobial-resistant Helicobacter pylori infection are rising globally, but little is known about contemporary resistance patterns, virulence factors, and phylogenetic patterns of isolates within Australia. We aimed to characterize antimicrobial resistance and genetic mutations associated with adverse clinical outcomes.

Whole genome sequencing, culturing, and antibiotic sensitivity data for refractory H. pylori isolates at Australian centers were collected between 2013 and 2022. Phylogenetic origins, antibiotic resistance mutations, and virulence factors were examined with phenotypic resistance profiles.

One hundred thirty-five isolates underwent culture, with 109 of these undergoing whole genome sequencing. Forty-three isolates were isolated from patients in South Australia and 66 from Western Australia. Isolates originated primarily from hpEurope (59.6%), hpEastAsia (25.7%), and hpNEAfrica (6.4%). Antimicrobial resistance to clarithromycin was seen in 85% of isolates, metronidazole in 52%, levofloxacin in 18%, rifampicin in 14%, and amoxicillin in 9%. Most isolates (59%) were multi-drug resistant. Resistance concordance between genetically determined resistance and phenotypic resistance was 92% for clarithromycin and 94% for levofloxacin. Analysis of virulence factors demonstrated cag pathogenicity island (cagPAI) in 67% of isolates and cagA in 61%, correlating with isolate genetic origin. The most virulent s1m1 vacuolating cytotoxin A genotype was present in 26% of isolates.

Refractory H. pylori isolates in Australia emanate from multiple global origins. Strong concordance between genetic and phenotypic antibiotic resistance profiles raises the possibility of utilizing genetic profiling in clinical practice. The dynamic landscape of H. pylori in Australia warrants the establishment of a national database to monitor H. pylori resistance and evolving virulence.

The gastric microbial community plays a fundamental role in gastric cancer (GC), and the two main anatomical subtypes of GC, non-cardia and cardia GC, are associated with different risk factors (Helicobacter pylori for non-cardia GC). To decipher the different microbial spatial communities of GC, we performed a multicenter retrospective analysis to characterize the gastric microbiota in 223 GC patients, including H. pylori-positive or -negative patients, with tumors and paired adjacent normal tissues, using third-generation sequencing. In the independent validation cohort, both dental plaque and GC tumoral tissue samples were collected and sequenced. The prevalence of H. pylori and oral-associated bacteria was verified using fluorescence in situ hybridization (FISH) assays in GC tumoral tissues and matched nontumoral tissues. We found that the vertical distribution of the gastric microbiota, at the upper, middle, and lower third sites of GC, was likely an important factor causing microbial diversity in GC tumor tissues. The oral-associated microbiota cluster, which included Veillonella parvula, Streptococcus oralis, and Prevotella intermedia, was more abundant in the upper third of the GC. However, H. pylori was more abundant in the lower third of the GC and exhibited a significantly high degree of microbial correlation. The oral-associated microbiota module was co-exclusive with H. pylori in the lower third site of the GC tumoral tissue. Importantly, H. pylori-negative GC patients with oral-associated gastric microbiota showed worse overall survival, while the increase in microbial abundance in H. pylori-positive GC patients showed no difference in overall survival. The prevalence of V. parvula in both the dental plaque and GC tissue samples was concordant in the independent validation phase. We showed that the oral-associated species V. parvula and S. oralis were correlated with overall survival. Our study highlights the roles of the oral-associated microbiota in the upper third of the GC. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for H. pylori-negative GCs.

Our study highlights the roles of the oral-associated microbiota in the upper third of gastric cancer (GC).We showed that the oral-associated species Veillonella parvula and Streptococcus oralis were correlated with overall survival. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for Helicobacter pylori-negative GCs.

: Nutritional factors associated with gastric cancer (GC) are not completely understood. We aimed to determine the effect of nutrient intake on the incidence of GC.

: This was a post hoc analysis of a prospective trial that evaluated modalities for GC screening in participants aged 30 to 74 years living in high-risk areas for GC in Japan between June 2011 and March 2013. The patients were followed up for GC incidence for 6 years. All participants completed a self-administered food frequency questionnaire (FFQ) upon enrollment before GC screening. Daily nutrient intake was calculated from the FFQ and dichotomized at each cutoff value using receiver operating characteristic analysis. Risk factors associated with GC incidence were investigated in terms of nutrient intake and participant characteristics using Cox proportional hazards regression analysis.

: Overall, 1,147 participants were included in this analysis. The median age was 62 years, and 50.7% of the participants were men. The median follow-up period was 2,184 days. GC was detected in 25 participants during the follow-up. Multivariate Cox proportional hazards regression analysis revealed that the intake of sodium (adjusted hazards ratio [aHR], 3.905; 95% confidence interval [CI], 1.520 to 10.035; p=0.005) and vitamin D (aHR, 2.747; 95% CI, 1.111 to 6.788, p=0.029) were positively associated with GC incidence, whereas the intake of soluble dietary fiber (aHR, 0.104; 95% CI, 0.012 to 0.905; p=0.040) was inversely associated with GC incidence.

: Daily high intake of sodium and vitamin D and low soluble dietary fiber intake are associated with GC incidence.

Helicobacter pylori represents the major pathogen in the pathophysiology of diverse gastrointestinal conditions. This study sought to determine the endoscopic aspect of the gastric mucosa in relation to H. pylori infection in Cameroon.

This study was conducted in three reference health facilities in Cameroon from October 2020 to October 2022. The study enrolled 494 consecutive volunteer dyspeptic patients attending to the gastroenterology department of the selected health facilities. A description of the aspect of gastric mucosa of all participants was performed during endoscopy examination, and biopsies were collected for H. pylori detection using rapid urease tests.

Gastritis, ulcerated lesions, duodenitis, esophagitis, normal mucosa aspect, bulbitis, and gastric neoplastic lesions were found in 40.1, 22.3, 10.9, 10.3, 9.7, 6.3, and 0.40% of biopsy samples, respectively. Erythematous/exudative (45.9%) and enterogastric reflux (12.2%) were the main gastritis types recorded. H. pylori was present in 58.1, 46.3, 87.1, 66.7, and 61.8% in gastritis, duodenitis, bulbitis, esophagitis, and ulcerated lesions, respectively. A positive relationship was noticed between the presence of H. pylori and gastritis (1.037 [0.720-1.493]; P = 0.845), bulbitis (4.237 [1.602-11.235]; P = 0.004), esophagitis (1.515 [0.822-2.793]; P = 0.183), ulcerated lesions (1.233 [0.798-1.904]; P = 0.345), erythematous/exudative gastritis (1.354 [0.768-2.389]; P = 0.295), and enterogastric reflux gastritis (1.159 [0.492-2.733]; P = 0.736).

Gastritis and erythematous/exudative gastritis are the most frequent gastrointestinal pathophysiology conditions in dyspeptic patient in our milieu. H. pylori infection is responsible for 94.8% of the gastrointestinal pathophysiology conditions with bulbitis as the condition is significantly associated with this bacterium infection.

Bovine milk and meat factors (BMMFs) are plasmid-like DNA molecules isolated from bovine milk and serum, as well as the peritumor of colorectal cancer (CRC) patients. BMMFs have been proposed as zoonotic infectious agents and drivers of indirect carcinogenesis of CRC, inducing chronic tissue inflammation, radical formation and increased levels of DNA damage. Data on expression of BMMFs in large clinical cohorts to test an association with co-markers and clinical parameters were not previously available and were therefore assessed in this study. Tissue sections with paired tumor-adjacent mucosa and tumor tissues of CRC patients [individual cohorts and tissue microarrays (TMAs) (n = 246)], low-/high-grade dysplasia (LGD/HGD) and mucosa of healthy donors were used for immunohistochemical quantification of the expression of BMMF replication protein (Rep) and CD68/CD163 (macrophages) by co-immunofluorescence microscopy and immunohistochemical scoring (TMA). Rep was expressed in the tumor-adjacent mucosa of 99% of CRC patients (TMA), was histologically associated with CD68+/CD163+ macrophages and was increased in CRC patients when compared to healthy controls. Tumor tissues showed only low stromal Rep expression. Rep was expressed in LGD and less in HGD but was strongly expressed in LGD/HGD-adjacent tissues. Albeit not reaching statistical significance, incidence curves for CRC-specific death were increased for higher Rep expression (TMA), with high tumor-adjacent Rep expression being linked to the highest incidence of death. BMMF Rep expression might represent a marker and early risk factor for CRC. The correlation between Rep and CD68 expression supports a previous hypothesis that BMMF-specific inflammatory regulations, including macrophages, are involved in the pathogenesis of CRC.

Colorectal cancer (CRC) is a substantial source of global morbidity and mortality in dire need of improved prevention and treatment strategies. As our understanding of CRC grows, it is becoming increasingly evident that the gut microbiota, consisting of trillions of microorganisms in direct interface with the colon, plays a substantial role in CRC development and progression. Understanding the roles that individual microorganisms and complex microbial communities play in CRC pathogenesis, along with their attendant mechanisms, will help yield novel preventive and therapeutic interventions for CRC. In this Review, we discuss recent evidence concerning global perturbations of the gut microbiota in CRC, associations of specific microorganisms with CRC, the underlying mechanisms by which microorganisms potentially drive CRC development and the roles of complex microbial communities in CRC pathogenesis. While our understanding of the relationship between the microbiota and CRC has improved in recent years, our findings highlight substantial gaps in current research that need to be filled before this knowledge can be used to the benefit of patients.

Intratumoral microbiota has become research hotspots, and emerges as a non-negligent new component of tumor microenvironments (TME), due to its powerful influence on tumor initiation, metastasis, immunosurveillance and prognosis despite in low-biomass. The accumulations of microbes, and their related components and metabolites within tumor tissues, endow TME with additional pluralistic features which are distinct from the conventional one. Therefore, it's definitely necessary to comprehensively delineate the sophisticated landscapes of tumor microbe microenvironment, as well as their functions and related underlying mechanisms. Herein, in this review, we focused on the fields of tumor microbe microenvironment, including the heterogeneity of intratumor microbiota in different types of tumors, the controversial roles of intratumoral microbiota, the basic features of tumor microbe microenvironment (i.e., pathogen-associated molecular patterns (PAMPs), typical microbial metabolites, autophagy, inflammation, multi-faceted immunomodulation and chemoresistance), as well as the multidisciplinary approach-based intervention of tumor microbiome for cancer therapy by applying wild-type or engineered live microbes, microbiota metabolites, antibiotics, synthetic biology and rationally designed biomaterials. We hope our work will provide valuable insight to deeply understand the interplay of cancer-immune-microbial, and facilitate the development of microbes-based tumor-specific treatments.

Ferroptosis holds great potential as a therapeutic approach for gastric cancer (GC), a prevalent and deadly malignant tumor associated with high rates of incidence and mortality. Myricetin, well-known for its multifaceted biomedical attributes, particularly its anticancer properties, has yet to be thoroughly investigated regarding its involvement in ferroptosis. The aim of this research was to elucidate the impact of myricetin on ferroptosis in GC progression. The present study observed that myricetin could trigger ferroptosis in GC cells by enhancing malondialdehyde production and Fe2+ accumulation while suppressing glutathione levels. Mechanistically, myricetin directly interacted with NADPH oxidase 4 (NOX4), influencing its stability by inhibiting its ubiquitin degradation. Moreover, myricetin regulated the inhibition of ferroptosis induced by Helicobacter pylori cytotoxin-associated gene A (CagA) through the NOX4/NRF2/GPX4 pathway. In vivo experiments demonstrated that myricetin treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice. It was accompanied by increased NOX4 expression in tumor tissue and suppression of the NRF2/GPX4 antioxidant pathway. Therefore, this research underscores myricetin as a novel inducer of ferroptosis in GC cells through its interaction with NOX4. It is a promising candidate for GC treatment.

Helicobacter pylori is a bacterium that exhibits strict host restriction to humans and non-human primates, and the bacterium is widely acknowledged as a significant etiological factor in the development of chronic gastritis, peptic ulcers, and gastric cancers. The pathogenic potential of this organism lies in its adeptness at colonizing the gastric mucosa, which is facilitated by a diverse repertoire of virulence factors, including adhesins that promote the attachment of the bacteria to the gastric epithelium. Among these adhesins, HpaA stands out due to its conserved nature and pivotal role in establishing H. pylori colonization. Moreover, this lipoprotein holds promise as an antigen for the development of effective H. pylori vaccines, thus attracting considerable attention for in-depth investigations into its molecular function and identification of binding determinants. Here, we present the elucidation of the crystallographic structure of HpaA at 2.9 Å resolution. The folding adopts an elongated protein shape, which is distinctive to the Helicobacteraceae family, and features an apical domain extension that plays a critical role in the cell-adhesion activity on gastric epithelial cells. Our study also demonstrates the ability of HpaA to induce TNF-α expression in macrophages, highlighting a novel role as an immunoregulatory effector promoting the pro-inflammatory response in vitro. These findings not only contribute to a deeper comprehension of the multifaceted role of HpaA in H. pylori pathogenesis but also establish a fundamental basis for the design and development of structure-based derivatives, aimed at enhancing the efficacy of H. pylori vaccines.

Helicobacter pylori is a bacterium that can cause chronic gastritis, peptic ulcers, and gastric cancers. The bacterium adheres to the lining of the stomach using proteins called adhesins. One of these proteins, HpaA, is particularly important for H. pylori colonization and is considered a promising vaccine candidate against H. pylori infections. In this work, we determined the atomic structure of HpaA, identifying a characteristic protein fold to the Helicobacter family and delineating specific amino acids that are crucial to support the attachment to the gastric cells. Additionally, we discovered that HpaA can trigger the production of TNF-α, a proinflammatory molecule, in macrophages. These findings provide valuable insights into how H. pylori causes disease and suggest that HpaA has a dual role in both attachment and immune activation. This knowledge could contribute to the development of improved vaccine strategies for preventing H. pylori infections.

Female genital tract (FGT) microbiota has been associated with the development of gynaecological cancers. Thus, the possibility of whether manipulation of the FGT microbiota can help in the prevention of disease should be investigated. Various prebiotics, probiotics, and other non-clinician prescribed agents have been reported to have therapeutic effects in cervical disease. Numerous studies have reported an association between human papillomavirus infection and subsequent cervical dysplasia and a decrease in the abundance of Lactobacillus species. A continuum of microbiota composition is observed from the vagina to the upper parts of the FGT, but no evidence suggests that manipulation of the vaginal microbiota can help to modify the composition of other FGT compartments. Although prebiotics and probiotics have been reported to be beneficial, the studies are small and of varying design, and high-quality evidence to support their use is lacking. Currently, no studies have examined these therapeutics in other gynaecological malignancies. Thus, recommendation of probiotics, prebiotics, or other over-the-counter supplements for the prevention of gynaecological cancers warrants larger, well designed studies.

Helicobacter pylori (H. pylori) is a pathogen which colonizes the stomach, causing ulcers, chronic gastritis and other related diseases. Protein post-translational modifications (PTMs) in bacteria mainly include glycosylation, ubiquitination, nitrosylation, methylation, phosphorylation and acetylation, all of which have divergent functions in the physiology and pathology of the bacterium. Lysine 2-hydroxyisobutyrylation (Khib) is a newly discovered type of PTM in recent years in some kinds of organisms, and this PTM is involved in the regulation of a variety of metabolic process, such as bacterial glucose metabolism, lipid metabolism and protein synthesis. This study performed the first qualitative lysine 2-hydroxyisobutyrylome in H. pylori, and a total of 4419 Khib sites in 812 proteins were identified. The results show that Khib sites are mainly located in the key functional regions or active domains of proteins involved in nickel-trafficking, energy production, virulence factors, anti-oxidation, metal resistance, and ribosome biosynthesis in H. pylori. The study presented here provides new hints in the metabolism and pathology of H. pylori and the proteins with Khib modification may be potentially promising targets for the further development of antibiotics, especially considering the high occurrence of treatment failure of H. pylori failure due to development of antibiotics-resistance.

Helicobacter pylori, a dominant member of the gastric microbiota was associated with various gastrointestinal diseases and presents a significant challenge due to increasing antibiotic resistance. This study identifies H. pylori's phospholipase A (PldA) as a critical factor in modulating host macrophage responses, facilitating H. pylori 's evasion of the immune system and persistence. PldA alters membrane lipids through reversible acylation and deacylation, affecting their structure and function. We found that PldA incorporates lysophosphatidylethanolamine into macrophage membranes, disrupting their bilayer structure and impairing TNFR1-mediated p38-MK2 signaling. This disruption results in reduced macrophage autophagy and elevated RIP1-dependent apoptosis, thereby enhancing H. pylori survival, a mechanism also observed in multidrug-resistant strains. Pharmacological inhibition of PldA significantly decreases H. pylori viability and increases macrophage survival. In vivo studies corroborate PldA's essential role in H. pylori persistence and immune cell recruitment. Our findings position PldA as a pivotal element in H. pylori pathogenesis through TNFR1-mediated membrane modulation, offering a promising therapeutic target to counteract bacterial resistance.

The discovery of Helicobacter pylori (Hp) infection of gastric mucosa leading to active chronic gastritis, gastroduodenal ulcers, and MALT lymphoma laid the groundwork for understanding of the general relationship between chronic infection, inflammation, and cancer. Nevertheless, this sequence of events is still far from full understanding with new players and mediators being constantly identified. Originally, the Hp virulence factors affecting mainly gastric epithelium were proposed to contribute considerably to gastric inflammation, ulceration, and cancer. Furthermore, it has been shown that Hp possesses the ability to penetrate the mucus layer and directly interact with stroma components including fibroblasts and myofibroblasts. These cells, which are the source of biophysical and biochemical signals providing the proper balance between cell proliferation and differentiation within gastric epithelial stem cell compartment, when exposed to Hp, can convert into cancer-associated fibroblast (CAF) phenotype. The crosstalk between fibroblasts and myofibroblasts with gastric epithelial cells including stem/progenitor cell niche involves several pathways mediated by non-coding RNAs, Wnt, BMP, TGF-β, and Notch signaling ligands. The current review concentrates on the consequences of Hp-induced increase in gastric fibroblast and myofibroblast number, and their activation towards CAFs with the emphasis to the altered communication between mesenchymal and epithelial cell compartment, which may lead to inflammation, epithelial stem cell overproliferation, disturbed differentiation, and gradual gastric cancer development. Thus, Hp-activated fibroblasts may constitute the target for anti-cancer treatment and, importantly, for the pharmacotherapies diminishing their activation particularly at the early stages of Hp infection.

Helicobacter pylori (H. pylori) infection is a major risk factor for gastric diseases, including gastritis and gastric cancer. Heat shock protein 60 (HSP60) is a chaperone protein involved in various cellular processes and has been implicated in the immune response to bacterial infections. Extracellular vesicles (EVs) containing various protein components play important roles in cell communication. In the present study, a systematic proteomic analysis of EVs obtained from H. pylori infected cells was performed and the EV-derived HSP60 function was studied.

EVs were evaluated by nanoparticle tracking analysis, transmission electron microscopy and western blotting. The recognized protein components were quantified by label-free proteomics and subjected to bioinformatics assays. The expression of HSP60 in EVs, host cells and gastric cancers infected by H. pylori was determined by western blotting and immunohistochemical, respectively. In addition, the apoptotic regulation mechanisms of HSP60 in H. pylori infection were analyzed by western blotting and flow cytometry.

A total of 120 important differential proteins were identified in the EVs from H. pylori-infected cells and subjected to Gene Ontology analysis. Among them, CD63, HSP-70 and TSG101 were verified via western blotting. Moreover, HSP60 expression was significantly increased in the EVs from H. pylori-infected GES-1 cells. H. pylori infection promoted an abnormal increase in HSP60 expression in GES-1 cells, AGS cells, gastric mucosa and gastric cancer. In addition, knockdown of HSP60 suppressed the apoptosis of infected cells and the expression of Bcl2, and promoted the upregulation of Bax.

This study provides a comprehensive proteomic profile of EVs from H. pylori-infected cells, shedding light on the potential role of HSP60 in H. pylori infection. The findings underscore the significance of EV-derived HSP60 in the pathophysiology of H. pylori-associated diseases.

Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its lethal outcome. The complex molecular events that promote metastasis are a combination of both, the acquired pro-metastatic properties of cancer cells and a metastasis-permissive or -supportive tumor micro-environment (TME). Yet, dissemination is a challenging process for cancer cells that requires a series of events to enable cancer cell survival and growth. Metastatic cancer cells have to initially detach themselves from primary tumors, overcome the challenges of their intravasal journey and colonize distant sites that are suited for their metastases. The implicated obstacles including anoikis and immune surveillance, can be overcome by intricate intra- and extracellular signaling pathways, which we will summarize and discuss in this review. Further, emerging modulators of metastasis, like the immune-microenvironment, microbiome, sublethal cell death engagement, or the nervous system will be integrated into the existing working model of metastasis.

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are intracellular proteins with a central role in innate and adaptive immunity. As a member of pattern recognition receptors (PRRs), NLRs sense specific pathogen-associated molecular patterns, trigger numerous signaling pathways and lead to the secretion of various cytokines. In recent years, cumulative studies have revealed the significant impacts of NLRs in gastrointestinal (GI) inflammatory diseases and cancers. Deciphering the role and molecular mechanism of the NLR signaling pathways may provide new opportunities for the development of therapeutic strategies related to GI inflammatory diseases and GI cancers. This review presents the structures and signaling pathways of NLRs, summarizes the recent advances regarding NLR signaling in GI inflammatory diseases and GI cancers and describes comprehensive therapeutic strategies based on this signaling pathway.

Gastric cancer, a multifactorial disease, is considered one of the most common malignancies worldwide. In addition to genetic and environmental risk factors, infectious agents, such as Epstein-Barr virus (EBV) and Helicobacter pylori (H.pylori) contribute to the onset and development of gastric cancer. H. pylori is a type I carcinogen that colonizes the gastric epithelium of approximately 50% of the world's population, thus increasing the risk of gastric cancer development. On the other hand, epithelial mesenchymal transition (EMT) is a fundamental process crucial to embryogenic growth, wound healing, organ fibrosis and cancer progression. Several studies associate gastric pathogen infection of the epithelium with EMT initiation, provoking cancer metastasis in the gastric mucosa through various molecular signaling pathways. Additionally, EMT is implicated in the progression and development of H. pylori-associated gastric cancer. In this review, we recapitulate recent findings elucidating the association between H. pylori infection in EMT promotion leading to gastric cancer progression and metastasis.

Bacteria have been found in tumors for over 100 years, but the irreproducibility of experiments on bacteria, the limitations of science and technology, and the contamination of the host environment have severely hampered most research into the role of bacteria in carcinogenesis and cancer treatment. With the development of molecular tools and techniques (e.g., macrogenomics, metabolomics, lipidomics, and macrotranscriptomics), the complex relationships between hosts and different microorganisms are gradually being deciphered. In the past, attention has been focused on the impact of the gut microbiota, the site where the body's microbes gather most, on tumors. However, little is known about the role of microbes from other sites, particularly the intratumor microbiota, in cancer. In recent years, an increasing number of studies have identified the presence of symbiotic microbiota within a large number of tumors, bringing the intratumor microbiota into the limelight. In this review, we aim to provide a better understanding of the role of the intratumor microbiota in cancer, to provide direction for future experimental and translational research, and to offer new approaches to the treatment of cancer and the improvement of patient prognosis.

Gastric cancer is characterised by high inter- and intratumour heterogeneity. The majority of patients are older than 65 years and the global burden of this disease is increasing due to the aging of the population. The disease is usually diagnosed at advanced stages, which is a consequence of nonspecific symptoms. Few improvements have been made at the level of noninvasive molecular diagnosis of sporadic gastric cancer, and therefore the mortality rate remains high. A new field of mutational signatures has emerged in the past decade with advances in the genome sequencing technology. These distinct mutational patterns in the genome, caused by exogenous and endogenous mutational processes, can be associated with tumour aetiology and disease progression, and could provide novel perception on the treatment possibilities. This review assesses the mutational signatures found in gastric cancer and summarises their potential for use in clinical setting as diagnostic or prognostic biomarkers. Associated treatment options and biomarkers already implemented in clinical use are discussed, together with those that are still being explored or are in clinical studies.

Helicobacter pylori infection often occurs in early childhood, and can last a lifetime if not treated with medication. H. pylori infection can also cause a variety of stomach diseases, which can only be treated with a combination of antibiotics. Combinations of antibiotics can cure H. pylori infection, but it is easy to relapse and develop drug resistance. Therefore, a vaccine is a promising strategy for prevention and therapy for the infection of H. pylori. After decades of research and development, there has been no appearance of any H. pylori vaccine reaching the market, unfortunately. This review summarizes the aspects of candidate antigens, immunoadjuvants, and delivery systems in the long journey of H. pylori vaccine research, and also introduces some clinical trials that have displayed encouraging or depressing results. Possible reasons for the inability of an H. pylori vaccine to be available over the counter are cautiously discussed and some propositions for the future of H. pylori vaccines are outlined.

Cancer is characterized by mutagenic events that lead to disrupted cell signaling and cellular functions. It is one of the leading causes of death worldwide. Literature suggests that pathogens, mainly Helicobacter pylori and Epstein-Barr virus (EBV), have been associated with the etiology of human cancer. Notably, their co-infection may lead to gastric cancer. Pathogen-mediated DNA damage could be the first and crucial step in the carcinogenesis process that modulates numerous cellular signaling pathways. Altogether, it dysregulates the metabolic pathways linked with cell growth, apoptosis, and DNA repair. Modulation in these pathways leads to abnormal growth and proliferation. Several signaling pathways such RTK, RAS/MAPK, PI3K/Akt, NFκB, JAK/STAT, HIF1α, and Wnt/β-catenin are known to be altered in cancer. Therefore, this review focuses on the oncogenic roles of H. pylori, EBV, and its associated signaling cascades in various cancers. Scrutinizing these signaling pathways is crucial and may provide new insights and targets for preventing and treating H. pylori and EBV-associated cancers.

The reversible post-translational modifications of protein ubiquitination and deubiquitination play a crucial regulatory role in cellular homeostasis. Deubiquitinases (DUBs) are responsible for the removal of ubiquitin from the protein substrates. The dysregulation of the DUBs may give rise to the occurrence and development of tumors. In this study, we investigated the gastric cancer (GC) data from the TCGA and GEO databases and found that ubiquitin-specific protease USP13 was significantly up-regulated in GC samples. The higher expression of USP13 was associated with the worse prognosis and shorter overall survival (OS) of GC patients. Enforced expression of USP13 in GC cells promoted the cell cycle progression and cell proliferation in an enzymatically dependent manner. Conversely, suppression of USP13 led to GC cell cycle arrest in G1 phase and the inhibition of cell proliferation. Nude mouse experiments indicated that depletion of USP13 in GC cells dramatically suppressed tumor growth in vivo. Mechanistically, USP13 physically bound to the N-terminal domain of cyclin D1 and removed its K48- but not K63-linked polyubiquitination chain, thereby stabilizing and increasing cyclin D1. Furthermore, re-expression of cyclin D1 partially reversed the cell cycle arrest and cell proliferation inhibition induced by USP13 depletion in GC cells. Additionally, USP13 protein abundance was positively correlated with the protein level of cyclin D1 in human GC tissues. Taken together, our data demonstrate that USP13 deubiquitinates and stabilizes cyclin D1, thereby promoting cell cycle progression and cell proliferation in GC. These findings suggest that USP13 might be a promising therapeutic target for the treatment of GC.

The cag pathogenicity island (cagPAI) is the main virulence factor of gastric carcinoma induced by Helicobacter pylori (H. pylori). The lytic transglycosylase Cag4 is an important component that assists in the translocation of the bacterial oncoprotein CagA and maintains the peptidoglycan cycle. The allosteric regulation of Cag4 has been preliminarily demonstrated to inhibit H. pylori infection. Unfortunately, a rapid screening technology for allosteric regulators of Cag4 has not been established. In this study, a novel Cag4-double nanoporous gold (NPG) biosensor based on enzyme-inorganic co-catalysis was constructed using the heterologously expressed H. pylori 26695 Cag4 as the biological recognition element for screening Cag4 allosteric regulators. The results showed that chitosan or carboxymethyl chitosan was a mixed Cag4 inhibitor combining non-competition with uncompetition. The inhibition constants were K_i' _Chitosan = 0.88909 mg/mL and K_i' _{Carboxymethyl chitosan} = 1.13480 mg/mL, respectively. Surprisingly, D-(+)-cellobiose showed the activation effect of Cag4 on E. coli MG1655 cell wall lysis by decreasing the K_a value by 29.7% and increasing the V_max value by 71.3%. In addition, molecular docking revealed the importance of the polarity of the C₂ substituent group with glucose as the main structure in the Cag4 allosteric regulator. This study provides a fast and useful platform for screening potential new drugs based on the Cag4 allosteric regulator.

Chronic gastric infection with Helicobacter pylori can lead to progressive tissue changes that culminate in cancer, but how H. pylori adapts to the changing tissue environment during disease development is not fully understood. In a transgenic mouse gastric metaplasia model, we found that strains from unrelated individuals differed in their ability to infect the stomach, to colonize metaplastic glands, and to alter the expression of the metaplasia-associated protein TFF3. H. pylori isolates from different stages of disease from a single individual had differential ability to colonize healthy and metaplastic gastric glands. Exposure to the metaplastic environment selected for high gastric colonization by one of these strains. Complete genome sequencing revealed a unique alteration in the frequency of a variant allele of the putative adhesin sabB, arising from a recombination event with the related sialic acid binding adhesin (SabA) gene. Mutation of sabB in multiple H. pylori strain backgrounds strongly reduced adherence to both normal and metaplastic gastric tissue, and highly attenuated stomach colonization in mice. Thus, the changing gastric environment during disease development promotes bacterial adhesin gene variation associated with enhanced gastric colonization. IMPORTANCE Chronic infection with Helicobacter pylori is the primary risk factor for developing stomach cancer. As disease progresses H. pylori must adapt to a changing host tissue environment that includes induction of new cell fates in the cells that line the stomach. We tested representative H. pylori isolates collected from the same patient during early and later stages of disease in a mouse model where we can rapidly induce disease-associated tissue changes. Only the later-stage H. pylori strains could robustly colonize the diseased stomach environment. We also found that the ability to colonize the diseased stomach was associated with genetic variation in a putative cell surface adhesin gene called sabB. Additional experiments revealed that SabB promotes binding to stomach tissue and is critical for stomach colonization by the late-stage strains. Thus, H. pylori diversifies its genome during disease progression and these genomic changes highlight critical factors for bacterial persistence.