CD47, a novel YAP target gene, contributes to hepatic stellate cell activation and liver fibrosis induced by high-fat diet.

Activated hepatic stellate cells (HSCs) have been widely recognized as a primary source of pathological myofibroblasts, leading to the accumulation of extracellular matrix and liver fibrosis. CD47, a transmembrane glycoprotein expressed on the surface of various cell types, has been implicated in non-alcoholic fatty liver disease. However, the precise role of CD47 in HSC activation and the underlying regulatory mechanisms governing CD47 expression remain poorly understood. In this study, we employed single-cell RNA sequencing analysis to investigate CD47 expression in HSCs from mice subjected to a high-fat diet. CD47 silencing in HSCs markedly inhibited the expression of fibrotic genes and promoted apoptosis. Mechanistically, we found that Yes-associated protein (YAP) collaborates with TEAD4 to augment the transcriptional activation of CD47 by binding to its promoter region. Notably, disruption of the interaction between YAP and TEAD4 caused a substantial decrease in CD47 expression in HSCs and reduced the development of high-fat diet-induced liver fibrosis. Our findings highlight CD47 as a critical transcriptional target of YAP in promoting HSC activation in response to a high-fat diet. Targeting the YAP/TEAD4/CD47 signaling axis may hold promise as a therapeutic strategy for liver fibrosis.

Exploration and Validation of Ferroptosis-Associated Genes in ADAR1 Deletion-Induced NAFLD through RNA-seq Analysis.

BACKGROUND: Ferroptosis, characterized by excessive iron ions and lipid peroxides accumulation, contributes to Nonalcoholic Fatty Liver Disease (NAFLD) development. The role of ADAR1, crucial for lipid metabolism and immune regulation, in ferroptosis-related NAFLD remains unexplored. METHODS: In this study, we analyzed the expression of ADAR1 in NAFLD patients using the GSE66676 database. Subsequently, We investigated the effects of ADAR1 knockdown on mitochondrial membrane potential (MMP), Fe2+ levels, oxidation products, and ferroptosis in NAFLD cells through in vitro and in vivo experiments. Additionally, RNA-seq analysis was performed following ADAR1 depletion in an NAFLD cell model. Overlapping and ferroptosis-related genes were identified using a Venn diagram, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted as well. Furthermore, a protein-protein interaction (PPI) network was constructed to identify hub genes associated with ferroptosis. RESULTS: We found the expression level of ADAR1 was downregulated in NAFLD patients and 22 ferroptosis-associated genes were differentially expressed in a NAFLD cell model upon ADAR1 knockdown. Based on PPI network, we identified NOS2, PTGS2, NOX4, ALB, IL6, and CCL5 as the central genes related to ferroptosis. ADAR1 deletion-related NAFLD was found to be involved in the ferroptosis signaling pathway. NOS2, PTGS2, ALB, and IL6 can serve as potential biomarkers. These findings offer new insights and expanded targets for NAFLD prevention and treatment. CONCLUSION: These findings provide new strategies and potential targets for preventing and treating NAFLD. NOS2, PTGS2, ALB, and IL6 may serve as biomarkers for ADAR1 deletion-related NAFLD, which could help for developing its new diagnostic and therapeutic strategies.

Enhanced LRP8 expression induced by Helicobacter pylori drives gastric cancer progression by facilitating ß-Catenin nuclear translocation.

INTRODUCTION: Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis. However, the precise involvement of LRP8, the low-density lipoprotein receptor-related protein 8, in H. pylori pathogenesis and gastric cancer (GC) remains poorly understood. OBJECTIVES: To investigate the potential role of LRP8 in H. pylori infection and gastric carcinogenesis. METHODS: Three-dimensional human-derived gastric organoids (hGO) and gastric cancer organoids (hGCO) were synthesized from the tissues obtained from human donors. In this work, multi-omics combined with in vivo and in vitro studies were conducted to investigate the potential involvement of LRP8 in H. pylori-induced GC. RESULTS: We found that H. pylori infection significantly upregulated the expression of LRP8 in human GC tissues, cells, organoids, and mouse gastric mucous. In particular, LRP8 exhibited a distinct enrichment in cancer stem cells (CSC). Functionally, silencing of LRP8 affected the formation and proliferation of tumor spheroids, while increased expression of LRP8 was associated with increased proliferation and stemness of GC cells and organoids. Mechanistically, LRP8 promotes the binding of E-cadherin to ß-catenin, thereby promoting nuclear translocation and transcriptional activity of ß-catenin. Furthermore, LRP8 interacts with the cytotoxin-associated gene A (CagA) to form the CagA/LRP8/ß-catenin complex. This complex further amplifies H. pylori-induced ß-catenin nuclear translocation, leading to increased transcription of inflammatory factors and CSC markers. Clinical analysis demonstrated that abnormal overexpression of LRP8 is correlated with a poor prognosis and resistance to 5-Fluorouracil in patients with GC. CONCLUSION: Our findings provide valuable information on the molecular intricacies of H. pylori-induced gastric carcinogenesis, offering potential therapeutic targets and prognostic markers for GC.

Insight gained via ultra-performance liquid chromatography tandem mass spectrometry-based metabolomics: Protective effect of Artemisia argyi H.Lév. & Vaniot essential oil on lipopolysaccharide-induced liver injury mice.

Artemisia argyi H.Lév. & Vaniot essential oil (AAEO) has shown pharmacological effects such as anti-inflammation, antioxidant, and anti-tumor properties. However, the protective effect of AAEO on lipopolysaccharide (LPS)-induced liver injury and its potential protective mechanism are still unclear. In this study, we used ultra-performance liquid chromatography tandem mass spectrometry metabolomics techniques to investigate the changes in liver tissue metabolites in mice exposed to LPS with or without AAEO treatment for 14 days. The biochemical results showed that compared with the control group, AAEO significantly reduced the levels of liver functional enzymes, suggesting a significant improvement in liver injury. In addition, the 18 differential metabolites identified by metabolomics were mainly involved in the reprogramming of arachidonic acid metabolism, tryptophan metabolism, and purine metabolism. AAEO could significantly inhibit the expression of COX-2, IDO1, and NF-κB; enhance the body's anti-inflammatory ability; and alleviate liver injury. In summary, our study identified the protective mechanism of AAEO on LPS-induced liver injury at the level of small molecular metabolites, providing a potential liver protective agent for the treatment of LPS-induced liver injury.

Oridonin impedes breast cancer growth by blocking cells in S phase and inhibiting the PI3K/AKT/mTOR signaling pathway.

Breast cancer is one of the most common cancers. Oridonin, a traditional Chinese medicine, is believed to inhibit tumor growth, but its particular effects on breast cancer remain unknown. In this study, we examined oridonin's effects on 4T1, MCF-7, and MDAMB-231 cellular activity using CCK8. Scratch assays were used to detect oridonin's effects on cellular migration. Oridonin's effects on the breast cancer cell cycle were studied using flow cytometry, and expression of cell cycle related proteins p53, CDK2, and p21 was detected using Western blot assays. Metabolomics assays were used to detect changes in small molecule metabolites and metabolic pathways in breast cancer cells after treatment with oridonin. Oridonin's effects on breast cancer growth were also studied using xenograft mice. Metabolomics assays were used to detect changes in metabolites and metabolic pathways in xenograft mouse plasma in a control group, model group, and drug administration group. Experimental results showed that oridonin could significantly inhibit breast cancer growth both in vivo and in vitro. Scratch experiments showed that oridonin could inhibit breast cancer cell migration. Oridonin was also able to arrest cells in S phase by affecting several cell cycle-related proteins, including p53, CDK2, and p21. Metabolomic analysis of 4T1 cells identified a total of 33 differential metabolites, including multiple amino acids (such as l-Glutamic acid, l-Asparagine, l-Histidine, l-Valine, and l-Isoleucine). KEGG pathway enrichment analysis showed significant changes in aminoacyl-tRNA biosynthesis, and in multiple amino acid metabolic pathways. Plasma metabolomic analyses of xenograft mice revealed 28 differentially-expressed metabolites between the different animal model groups, including multiple amino acids. KEGG pathway analysis showed significant alterations in multiple amino acid metabolic pathways in oridonin-treated mice. Additionally, changes in the expression of PI3K, AKT and mTOR proteins, as well as in branched amino acids, suggest that oridonin affects the PI3K/AKT/mTOR signaling pathway by inhibiting the biosynthesis of valine, leucine and isoleucine. Taken together, our results suggest that oridonin has strong anti-tumor activity in vitro and in vivo, and has potential as an adjuvant to breast cancer treatment regimens.

Hepatoprotective effect of Artemisia Argyi essential oil on bisphenol A-induced hepatotoxicity via inhibition of ferroptosis in mice.

The environmental pollutant bisphenol A (BPA), used in the manufacture of plastic packaging materials for various diets, is widely distributed in the environment and causes severe hepatotoxicity by inducing oxidative stress. Artemisia argyi essential oil (AAEO), a volatile oil component isolated from Artemisia argyi H.Lév. & Vaniot, has pharmacological effects, especially for hepatoprotective actions. However, the potential effect of AAEO in BPA induced hepatotoxicity has not been characterized. First, we analyzed the chemical composition in AAEO by gas chromatography-mass spectrometry. Herein, we investigated the effect of AAEO on hepatic metabolic changes in mice exposed to BPA. Results showed that compared with the BPA group, AAEO could reduce the level of liver function enzymes in BPA mice serum, and ameliorate hepatic lesions and fibrosis. Additionally, 20 differential metabolites screened by metabolomics were mainly involved in the reprogramming of glutathione metabolism, purine metabolism, and polyunsaturated fatty acid synthesis. Moreover, AAEO could reduce hepatic ferroptosis induced by BPA, as demonstrated by reducing xanthine oxidase activity, up-regulating the activities of glutathione peroxidase 4 (GPX4), superoxide dismutase, and catalase and the expression of SLC7A11 to promote the glutathione synthetic, while inhibiting transferrin receptor 1 (TFR1) expression to reduce the accumulation of Fe2+ in cells. Therefore, our study identified AAEO as a hepatic protectant against BPA-induced hepatotoxicity by reversing the occurrence of ferroptosis.

Perilipin 5 regulates hepatic stellate cell activation and high-fat diet-induced non-alcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases globally. Hepatic stellate cells (HSCs) are the major effector cells of liver fibrosis. HSCs contain abundant lipid droplets (LDs) in their cytoplasm during quiescence. Perilipin 5 (PLIN 5) is a LD surface-associated protein that plays a crucial role in lipid homeostasis. However, little is known about the role of PLIN 5 in HSC activation. METHODS: PLIN 5 was overexpressed in HSCs of Sprague-Dawley rats by lentivirus transfection. At the same time, PLIN 5 gene knockout mice were constructed and fed with a high-fat diet (HFD) for 20 weeks to study the role of PLIN 5 in NAFLD. The corresponding reagent kits were used to measure TG, GSH, Caspase 3 activity, ATP level, and mitochondrial DNA copy number. Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS. AMPK, mitochondrial function, cell proliferation, and apoptosis-related genes and proteins were detected by western blotting and qPCR. RESULTS: Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria, inhibition of cell proliferation, and a significant increase in cell apoptosis through AMPK activation. In addition, compared with the HFD-fed C57BL/6J mice, PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition, decreased LD abundance and size, and reduced liver fibrosis. CONCLUSION: These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.

Relationship Between CNVs and Immune Cells Infiltration in Gastric Tumor Microenvironment.

Gastric cancer (GC) is a highly fatal and common malignancy of the digestive system. Recent therapeutic advancements have significantly improved the clinical outcomes in GC, but due to the unavailability of suitable molecular targets, a large number of patients do not respond to the immune checkpoint inhibitors (ICI) therapy. To identify and validate potential therapeutic and prognostic targets of gastric cancer, we used the "inferCNV" R package for analyzing single-cell sequencing data (GSE112302) of GC and normal epithelial cells. First, by using LASSO, we screened genes that were highly correlated with copy number variations (CNVs). Therefrom, five gene signature (CPVL, DDC, GRTP1, ONECUT2, and PRSS21) was selected by cross-validating the prognosis and risk management with the GC RNA-seq data obtained from GEO and TCGA. Moreover, the correlation analyses between CNVs of these genes and immune cell infiltration in gastric cancer identified CPVL as a potential prognostic marker. Finally, CPVL showed high expression in gastric cancer samples and cell lines, then siRNA-mediated silencing of CPVL expression in gastric cancer cells showed significant proliferation arrest in MGC803 cells. Here, we conclude that CNVs are key regulators of the immune cells infiltration in gastric TME as well as cancer development, and CPVL could potentially be used as a prognostic and therapeutic marker in gastric cancer.

Role of Plin5 Deficiency in Progression of Non-Alcoholic Fatty Liver Disease Induced by a High-Fat Diet in Mice.

Characterized by steatosis, inflammation and fibrosis, non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder. As a major lipid droplet-binding protein, Plin5 has been reported to have multiple effects on metabolism, but the effect of Plin5 deficiency on NAFLD is unknown. Plin5 knockout mice and wild-type mice were used to investigate the role of Plin5 in the progression of NAFLD by feeding a high-fat diet (HFD) for 20 weeks. Plin5 deficiency improved obesity induced by the HFD and altered glucose tolerance. Histological examination revealed that Plin5 deficiency alleviated hepatic steatosis and fibrosis induced by the HFD. Plin5 deficiency was also associated with a significant change in lipid metabolism-associated molecules. Further studies of these molecules indicated that Plin5 deficiency activated the expression of AMP-activated protein kinase and inhibited the core regulator of lipogenesis, sterol regulatory element binding protein 1 and its downstream lipid synthesis-related genes. These findings suggest that Plin5 deficiency ameliorates NAFLD by regulating lipid metabolism and inhibiting lipogenesis, and may provide a new strategy for the treatment of NAFLD.

Immune infiltration profiling in gastric cancer and their clinical implications.

The abundance and type of immune cells in the tumor microenvironment (TME) significantly influence immunotherapy and tumor progression. However, the role of immune cells in the TME of gastric cancer (GC) is poorly understood. We studied the correlations, proportion, and infiltration of immune and stromal cells in GC tumors. Data analyses showed a significant association of infiltration levels of specific immune cells with the pathological characteristics and clinical outcomes of GC. Furthermore, based on the difference in infiltration levels of immune and stromal cells, GC patients were divided into two categories, those with "immunologically hot" (hot) tumors and those with "immunologically cold" (cold) tumors. The assay for transposase-accessible chromatin using sequencing and RNA sequencing analyses revealed that the hot and cold tumors had altered epigenomic and transcriptional profiles. Claudin-3 (CLDN3) was found to have high expression in the cold tumors and negatively correlated with CD8+ T cells in GC. Overexpression of CLDN3 in GC cells inhibited the expression of MHC-I and CXCL9. Finally, the differentially expressed genes between hot and cold tumors were utilized to generate a prognostic model, which predicted the overall survival of GC as well as patients with immunotherapy. Overall, we undertook a comprehensive analysis of the immune cell infiltration pattern in GC and provided an accurate model for predicting the prognosis of GC patients.

Untargeted metabolomics reveals the mechanism of quercetin enhancing the bioavailability of ticagrelor.

Ticagrelor is a first-line clinical drug for the treatment of acute coronary syndrome, but its oral bioavailability is relatively low. Flavonoids (polyphenol compounds commonly found in plant foods) seriously affect human metabolism and health. This study compared the effects of quercetin, luteolin and catechin on the pharmacokinetic parameters of ticagrelor and found that quercetin can significantly increase the Cmax and area under the curve from time zero to 36 h (AUC0-36 ) of ticagrelor, that is, quercetin can enhance the bioavailability of ticagrelor, but luteolin and catechin cannot. The difference between the ticagrelor group and the combination of quercetin and ticagrelor was analyzed through untargeted metabolomics methods and multivariate data analysis, which identified changes in the levels of seven metabolites (deoxycholic acid, taurocholic acid, glycocholic acid, glycoursodeoxycholic acid, tryptophan, phenylalanine and kynurenine). Based on the changes of these metabolites, we found that the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids were changed. A metabolomics study revealed that quercetin improves the oral bioavailability of ticagrelor and that this might rely on changing the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids. The research results at the metabolic level provide us with a strong basis and direction for further exploring the mechanism underlying quercetin's ability to enhance the bioavailability of ticagrelor, and this may be useful for finding new agents that enhance the bioavailability.

Hepatoprotective effects of oridonin against bisphenol A induced liver injury in rats via inhibiting the activity of xanthione oxidase.

Bisphenol A (BPA) is widely used to manufacture packaging materials for various daily necessities and causes harmful effects in organs, especially liver injury, by generating oxidative stress. Oridonin, an active diterpenoid isolated from Rabdosia rubescens (Hemsl.) Hara, has been reported to possess a wide range of pharmacological activities including anti-inflammatory, antioxidative and antiapoptotic effects. However, the role of oridonin in BPA--induced liver injury and its potential protective mechanism have not been well characterized. In this research, we explored the metabolic alterations in the liver tissue of rats after exposure to BPA with or without pretreatment with oridonin for 14 days by metabolomics analysis based on UPLC-MS/MS. Rats were randomly divided into groups as follows: Control, Vehicle, Oridonin (10 mg/kg), Bisphenol A (500 mg/kg), bisphenol A + Oridonin (500 + 10 mg/kg), Bisphenol A + Diammonium glycyrrhizinate (500 + 40 mg/kg). The biochemical results showed that oridonin significantly reduced the levels of AST and ALT (P < 0.05), ameliorated the abnormal histopathological changes and reduced hepatic apoptosis compared with the BPA group. Furthermore, metabolomics results revealed that purine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and phenylalanine metabolism were reprogrammed, based on 28 identified significant differential metabolites among the Vehicle, BPA and BPA + oridonin groups. In-depth studies demonstrated that pretreatment with oridonin may play a protective role by restoring BPA-induced changes in oxidative stress and the activity of oxidase (XOD) (P < 0.05). Additionally, oridonin could inhibit the activity of XOD by binding to it, therefore decreasing the reactive oxygen species (ROS) level, upregulating the content of hypoxanthine and xanthine, and reducing the level of uric acid in the liver (P < 0.05). This research presents the potential protective mechanisms of oridonin on BPA-induced liver injury at the metabolic level, which might be used to identify new protective agents that prevent BPA-induced liver injury.

cGAS regulates the DNA damage response to maintain proliferative signaling in gastric cancer cells.

The activation of some oncogenes promote cancer cell proliferation and growth, facilitate cancer progression and metastasis by induce DNA replication stress, even genome instability. Activation of the cyclic GMP-AMP synthase (cGAS) mediates classical DNA sensing, is involved in genome instability, and is linked to various tumor development or therapy. However, the function of cGAS in gastric cancer remains elusive. In this study, the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell lines. By employing cGAS high-expression gastric cancer cell lines, including AGS and MKN45, ectopic silencing of cGAS caused a significant reduction in the proliferation of the cells, tumor growth, and mass in xenograft mice. Mechanistically, database analysis predicted a possible involvement of cGAS in the DNA damage response (DDR), further data through cells revealed protein interactions of the cGAS and MRE11-RAD50-NBN (MRN) complex, which activated cell cycle checkpoints, even increased genome instability in gastric cancer cells, thereby contributing to gastric cancer progression and sensitivity to treatment with DNA damaging agents. Furthermore, the upregulation of cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic outcomes. Therefore, we concluded that cGAS is involved in gastric cancer progression by fueling genome instability, implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer.

A ceRNA network and a potential regulatory axis in gastric cancer with different degrees of immune cell infiltration.

Immune cell infiltration is an important indicator of whether tumor patients will benefit from immunotherapy. Gastric cancer is one of the most common tumors in the world, and new indicators of immunotherapy are urgently needed. The aim of this study was to construct ceRNA networks in gastric cancer with different degrees of immune cell infiltration. We analyzed the expression profiles of different gastric cancer with different degrees of immune cell infiltration retrieved from The Cancer Genome Atlas (TCGA) database and found differentially expressed lncRNAs, mRNAs, and miRNAs. A ceRNA regulatory network of gastric cancer with different degrees of immune cell infiltration was constructed using functional annotation, RNA-RNA interaction prediction, correlation analysis, survival analysis, and other comprehensive bioinformatics methods. The interaction and correlation between ceRNAs were verified using experiments on tumor tissues and cell lines. Cell line experiments showed a potential RP11-1094M14.8/miR-1269a/CXCL9 axis that was consistent with the ceRNA theory. qRT-PCR results showed that RP11-1094M14.8 knockdown significantly reduced the expression of CXCL9, and RP11-1094M14.8 overexpression had the opposite effect. The results of clinical analysis of gastric cancer samples showed that RP11-1094M14.8 and CXCL9 were highly expressed in hot tumors, and CXCL9 was positively correlated with a better prognosis for patients. The constructed novel ceRNA network and the potential regulatory axis may provide a comprehensive understanding of the potential mechanisms of development in gastric cancer with different degrees of immune cell infiltration. The RP11-1094M14.8/miR-1269a/CXCL9 axis may serve as a potential immune-therapeutic target for gastric cancer with different degrees of immune cell infiltration.

The efficacy and safety comparison of PD-1/PD-L1 antibody, chemotherapy and supportive treatment for pretreated advanced esophagogastric cancer: a network meta-analysis.

BACKGROUND: Immunotherapy is important for the treatment of esophagogastric cancer. The purpose of this study is to compare the efficacy and safety of PD-(L)1 antibody, chemotherapy, and supportive treatment in the management of pretreated advanced esophagogastric cancer. METHODS: The randomized controlled trials were identified by searching electronic databases including PubMed, Cochrane Library and Embase database. The network meta-analysis (NMA) was carried out using software R 3.3.2. Main outcomes including overall survival (OS), progression-free survival (PFS), all grades and serious treatment-related adverse events (TRAEs) were extracted and analyzed. The ranking results for all outcomes were performed to identify the best treatments. RESULTS: Seven high-quality RCTs involving 1,891 patients were taken into analysis. Compared with supportive treatment, PD-(L)1 antibody and chemotherapy both had a significantly longer OS time. Chemotherapy could obvious improve PFS than supportive treatment, but it had more all grades and serious TRAEs than PD-(L)1 antibody and supportive treatment. No significant difference was found in other comparisons. The probabilities of rank plot showed that PD-(L)1 antibody was the best in the outcome of OS. Chemotherapy ranked first in PFS and ranked last in all grades and serious TRAEs. CONCLUSIONS: According to our results, PD-(L)1 antibody had excellent survival benefits and tolerable TRAEs for pretreated advanced esophagogastric cancer. It might be a suitable potential choice, especially for patients with high PDL1 CPS or with gastroesophageal junction cancer.

The association of Helicobacter pylori CagA EPIYA motifs and vacA genotypes with homologous recombination repair markers during the gastric precancerous cascade.

BACKGROUND: Helicobacter pylori-induced DNA damage and impaired homologous recombination repair are vital molecular mechanisms for gastric cancer, which mainly count on its virulence factors cytotoxic-associated gene A (CagA) and vacuolating cytotoxin A (VacA). However, the relationship between H. pylori CagA EPIYA motifs and vacA genotypes with DNA damage and homologous recombination repair markers is still not clear. METHODS: H. pylori positive and negative gastric biopsies were taken from 165 subjects with different gastric precancerous pathologic stages, and DNA damage marker γH2AX and key homologous recombination repair proteins (CtIP and Rad51) were investigated for their association with H. pylori CagA EPIYA motifs and vacAs-, m-, i-, and d-region genotypes and histology (Sydney classification). RESULTS: Out of 165 patients, 78 were identified as H. pylori-positive. CagA EPIYA motifs were identified as AB, ABC, and ABD in 2 (3.3%), 21 (35%), and 37 (61.7%) patients, respectively, while vacA alleles were identified as: s1, s2, m1, m2, i1, i2, d1, and d2 in 50 (89.3%), 6 (10.7%), 24 (42.9%), 32 (57.1%), 45 (80.4%), 11 (19.6%), 40 (71.4%), and 16 (28.6%) patients, respectively. vacAs1m1i1d1, s1m2i1d1, and s1m2i2d2 were the most prevailing genotypes. γH2AX was highly localized in H. pylori-positive tissues with corresponding CagA EPIYA motifs and vacA genotypes, while Rad51 and CtIP signals were weak. CONCLUSION: H. pylori were positively correlated with the DNA damage marker in precancerous lesions, but were negatively correlated with the key homologous recombination repair proteins, which may be due to the specific CagA EPIYA motifs and vacA genotypes.

Transcriptome analysis reveals GPNMB as a potential therapeutic target for gastric cancer.

Gastric cancer has the fifth highest incidence of disease and is the third leading cause of cancer-associated mortality in the world. The etiology of gastric cancer is complex and needs to be fully elucidated. Thus, it is necessary to explore potential pathogenic genes and pathways that contribute to gastric cancer. Gene expression profiles of the GSE33335 and GSE54129 datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were compared and identified using R software. The DEGs were then subjected to gene set enrichment analysis and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Survival analyses based on The Cancer Genome Atlas database were used to further screen the essential DEGs. A knockdown assay was performed to determine the function of the candidate gene in gastric cancer. Finally, the association between the candidate gene and immune-related genes was investigated. We found that GPNMB serves as an essential gene, with a high expression level, and predicts a worse outcome of gastric cancer. Knockdown of GPNMB inhibited gastric cancer cell proliferation and migration. In addition, GPNMB may augment the immunosuppressive ability of gastric cancer by recruiting immunosuppressive cells and promoting immune cell exhaustion through PI3K/AKT/CCL4 signaling axis. Collectively, these data suggest that GPNMB acts as an important positive mediator of tumor progression in gastric cancer, and GPNMB could exert multimodality modulation of gastric cancer-mediated immune suppression.