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Yang Q, Huang G, Zhuang M, Yangqian S, Wei Y, Kong F, Zhong L, Hu S. Helicobacter pylori and arsenic co-exposure Intensify gastric barrier damage and serum metabolic disorder. Microb Pathog 2025; 205:107667. [PMID: 40345345 DOI: 10.1016/j.micpath.2025.107667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 04/20/2025] [Accepted: 05/02/2025] [Indexed: 05/11/2025]
Abstract
Environmental arsenic exposure and Helicobacter pylori (H. pylori) infection are widespread public health concerns, yet their combined effects on gastric pathophysiology remain poorly understood. This study investigated the impact of H. pylori infection and arsenic co-exposure on gastric barrier integrity, oxidative stress, and serum metabolic profiles using a murine model. Mice were divided into control, single-exposure (arsenic), and multiple exposure group (H. pylori infection and arsenic exposure). Gastric barrier function was assessed via immunofluorescence staining of ZO-1 and occludin proteins. Untargeted metabolomics, including PCA, PLS-DA, and KEGG pathway enrichment analyses, were employed to characterize serum metabolic alterations. Gene expression levels of IL-18, Nrf2, Keap1, Cat, Sod1, and Hmox1 in gastric tissues were quantified by qRT-PCR, with Spearman correlation analysis to evaluate metabolite-gene expression relationships. Fluorescence intensity of ZO-1 and occludin was significantly reduced in H. pylori-infected mice, with further deterioration under arsenic co-exposure. Metabolomic profiling revealed distinct serum metabolic perturbations across groups, with the multiple exposure group exhibiting more pronounced fluctuations in metabolite levels (e.g., lipids, amino acids, and peptides) and greater pathway diversity compared to single exposure groups. qRT-PCR analysis demonstrated synergistic upregulation of oxidative stress (Nrf2, Hmox1) and inflammatory (IL-18) markers in the multiple exposure group. Spearman correlation analysis identified significant associations between specific metabolites (e.g., acylcarnitines, bile acids) and antioxidant gene expression, suggesting bidirectional interactions between systemic metabolism and gastric oxidative responses. This study establishes a murine model of H. pylori infection and arsenic co-exposure, revealing synergistic disruption of gastric barrier function, oxidative homeostasis, and metabolic regulation. These findings provide critical insights into the pathophysiological interplay between microbial infection and environmental toxicants, highlighting potential therapeutic targets for mitigating combined exposure risks.
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Affiliation(s)
- Qiling Yang
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, 350122, China
| | - Guanze Huang
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, 350122, China
| | - Miaohui Zhuang
- Xiamen International Travel Healthcare Center (Xiamen Customs Port Outpatient Department), Xiamen, Fujian, 361001, China
| | - Siru Yangqian
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, 350122, China
| | - Yuhuan Wei
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, 350122, China
| | - Fenying Kong
- School of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng, 224051, China
| | - Linmin Zhong
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, 350122, China
| | - Shanwen Hu
- Department of Health Inspection and Quarantine, School of Public Health, Fujian Medical University, Fuzhou, 350122, China.
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Nov P, Zheng C, Wang D, Sou S, Touch S, Kouy S, Ni P, Kou Q, Li Y, Prasai A, Fu W, Du K, Li J. Causal association between metabolites and upper gastrointestinal tumors: A Mendelian randomization study. Mol Med Rep 2024; 30:212. [PMID: 39370813 PMCID: PMC11450430 DOI: 10.3892/mmr.2024.13336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 09/03/2024] [Indexed: 10/08/2024] Open
Abstract
Upper gastrointestinal (UGI) tumors, notably gastric cancer (GC) and esophageal cancer (EC), are significant global health concerns due to their high morbidity and mortality rates. However, only a limited number of metabolites have been identified as biomarkers for these cancers. To explore the association between metabolites and UGI tumors, the present study conducted a comprehensive two‑sample Mendelian randomization (MR) analysis using publicly available genetic data. In the present study, the causal relationships were examined between 1,400 metabolites and UGI cancer using methods such as inverse variance weighting and weighted medians, along with sensitivity analyses for heterogeneity and pleiotropy. Functional experiments were conducted to validate the MR results. The analysis identified 57 metabolites associated with EC and 58 with GC. Key metabolites included fructosyllysine [EC: Odds ratio (OR)=1.450, 95% confidence interval (CI)=1.087‑1.934, P=0.011; GC: OR=1.728, 95% CI=1.202‑2.483, P=0.003], 2'‑deoxyuridine to cytidine ratio (EC: OR=1.464, 95% CI=1.111‑1.929, P=0.007; GC: OR=1.464, 95% CI=1.094‑1.957, P=0.010) and carnitine to protonylcarnitine (C3) ratio (EC: OR=0.655, 95% CI=0.499‑0.861, P=0.002; GC: OR=0.664, 95% CI=0.486‑0.906, P=0.010). Notably, fructosyllysine levels and the 2'‑deoxyuridine to cytidine ratio were identified as risk factors for both EC and GC, while the C3 ratio served as a protective factor. Functional experiments demonstrated that fructosyllysine and the 2'‑deoxyuridine to cytidine ratio promoted the proliferation of EC and GC cells, whereas carnitine inhibited their proliferation. In conclusion, the present findings provide insights into the causal factors and biomarkers associated with UGI tumors, which may be instrumental in guiding targeted dietary and pharmacological interventions, thereby contributing to the prevention and treatment of UGI cancer.
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Affiliation(s)
- Pengkhun Nov
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Chongyang Zheng
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Duanyu Wang
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Syphanna Sou
- Department of Radiation Oncology and Oncology, Khmer-Soviet Friendship Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Socheat Touch
- Department of Radiation Oncology and Oncology, Khmer-Soviet Friendship Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Samnang Kouy
- Department of Radiation Oncology and Oncology, Khmer-Soviet Friendship Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Peizan Ni
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Qianzi Kou
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Ying Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Arzoo Prasai
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Wen Fu
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Kunpeng Du
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Jiqiang Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
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Lee BE, Park SJ, Kim GH, Joo DC, Lee MW. Anti-inflammatory effects of eupatilin on Helicobacter pylori CagA-induced gastric inflammation. PLoS One 2024; 19:e0313251. [PMID: 39499687 PMCID: PMC11537371 DOI: 10.1371/journal.pone.0313251] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/21/2024] [Indexed: 11/07/2024] Open
Abstract
BACKGROUND Eupatilin, a flavone isolated from Artemisia species, exerts anti-inflammatory, anti-oxidative, and anti-neoplastic activities. However, the effects of eupatilin on H. pylori-associated gastritis remain unclear. Thus, this study aimed to investigate the anti-inflammatory effects of eupatilin on gastric epithelial cells infected with cytotoxin-associated gene A (CagA)-positive Helicobacter pylori. MATERIALS AND METHODS AGS human gastric carcinoma cells were infected with a CagA-positive H. pylori strain and then treated with 10, 50, or 100 ng of eupatilin. After 24 h, the expression levels of CagA, phosphoinositide 3-kinase 1 (PI3K), nuclear factor (NF)-κB, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α in the cell lysates were measured using western blotting, and the mRNA levels of IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 were measured using real-time polymerase chain reaction. RESULTS CagA translocation into AGS cells resulted in an elongated cell morphology, which was significantly suppressed by eupatilin treatment in a dose-dependent manner. Immunofluorescence staining for anti-CagA showed that eupatilin treatment dose-dependently inhibited CagA expression in the H. pylori-infected AGS cells. H. pylori infection increased the levels of pro-inflammatory cytokines including IL-1β, TNF-α, IL-6, IL-8, and MCP-1, and eupatilin treatment significantly reduced the levels of these cytokines in a dose-dependent manner. Additionally, eupatilin treatment dose-dependently suppressed the expression of PI3K and NF-κB. CONCLUSIONS Eupatilin treatment demonstrated anti-inflammatory effects on CagA-positive H. pylori-infected gastric epithelial cells by inhibiting CagA translocation, thereby suppressing the NF-κB signaling pathway. These results suggest that eupatilin plays a protective role against CagA-positive H. pylori-induced gastritis.
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Affiliation(s)
- Bong Eun Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Su Jin Park
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Gwang Ha Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Dong Chan Joo
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Moon Won Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
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Li Y, Sun W, Yuan S, Liu X, Zhang Z, Gu R, Li P, Gu X. The role of cuproptosis in gastric cancer. Front Immunol 2024; 15:1435651. [PMID: 39539553 PMCID: PMC11558255 DOI: 10.3389/fimmu.2024.1435651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/19/2024] [Indexed: 11/16/2024] Open
Abstract
As a biologically essential transition metal, copper is widely involved in various enzymatic reactions and crucial biological processes in the body. It plays an increasingly important role in maintaining normal cellular metabolism and supporting the growth and development of the human body. As a trace element, copper maintains the dynamic balance of its concentration in body fluids through active homeostatic mechanisms. Both excess and deficiency of copper ions can impair cell function, ultimately leading to cell damage and death. Cuproptosis is a novel form of cell death where copper ions cause cell death by directly binding to the lipoylated components of the citric acid cycle (CAC) in mitochondrial respiration and interfering with the levels of iron-sulfur cluster (Fe-S cluster) proteins, ultimately causing protein toxic stress. Its primary characteristics are Cu2+ concentration dependence and high expression in mitochondrial respiratory cells. Recent research has revealed that, compared to other forms of programmed cell death such as apoptosis, necrosis, and autophagy, cuproptosis has unique morphological and biochemical features. Cuproptosis is associated with the occurrence and development of various diseases, including cancer, neurodegenerative diseases, and cardiovascular diseases. This article focuses on a review of the relevance of cuproptosis in gastric cancer (GC).
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Affiliation(s)
- Yixian Li
- Nanjing University of Chinese Medicine, the First Clinical Medical College, Nanjing, Jiangsu, China
| | - Wenhao Sun
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine Jiangsu Province, Nanjing, Jiangsu, China
| | - Shaolin Yuan
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine Jiangsu Province, Nanjing, Jiangsu, China
| | - Xinxin Liu
- Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine Jiangsu Province, Nanjing, Jiangsu, China
| | - Ziqi Zhang
- Department of Endocrinology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Renjun Gu
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Pengfei Li
- Department of Clinical Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xin Gu
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Jia C, Yi D, Ma M, Xu Q, Ou Y, Kong F, Jia Y. Genetically predicted 486 blood metabolites in relation to risk of esophageal cancer: a Mendelian randomization study. Front Mol Biosci 2024; 11:1391419. [PMID: 39417005 PMCID: PMC11479936 DOI: 10.3389/fmolb.2024.1391419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 09/16/2024] [Indexed: 10/19/2024] Open
Abstract
Background and Objective Enhancing therapy choices for varying stages of esophageal cancer and improving patient survival depend on timely and precise diagnosis. Blood metabolites may play a role in either causing or preventing esophageal cancer, but further research is needed to determine whether blood metabolites constitute a genetic risk factor for the disease. In order to tackle these problems, we evaluated the causal association between esophageal cancer and 486 blood metabolites that functioned as genetic proxies using a two-sample Mendelian randomization (MR) study. Methods We utilized two-sample MR analyses to evaluate the causal links between blood metabolites and esophageal cancer. For the exposure, we used a genome-wide association study (GWAS) of 486 metabolites, and a GWAS study on esophageal cancer from Sakaue et al. was used for preliminary analyses. Causal analyses employed randomized inverse variance weighted (IVW) as the main method, supplemented by MR-Egger and weighted median (WM) analyses. Sensitivity analyses included the MR-Egger intercept test, Cochran Q test, MR-PRESSO, and leave-one-out analysis. Additionally, independent esophageal cancer GWAS data were utilized for replication and meta-analysis. FDR correction was applied to discern features with causal relationships. For conclusive metabolite identification, we conducted Steiger tests, linkage disequilibrium score regression, and colocalization analyses. Moreover, we utilized the program MetaboAnalyst 5.0 to analyze metabolic pathways. Results This study found an important association between esophageal cancer and three metabolites: 1-linoleoylglycerophosphoethanolamine* [odds ratio (OR) = 3.21, 95% confidence interval (CI): 1.42-7.26, p < 0.01], pyroglutamine* (OR = 1.92, 95% CI: 1.17-3.17, p < 0.01), and laurate (12:0) (OR = 3.06, 95% CI: 1.38-6.78, p < 0.01). Conclusion This study establishes a causal link between three defined blood metabolites and esophageal cancer, offering fresh insights into its pathogenesis.
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Affiliation(s)
- Caiyan Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Dan Yi
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Mingze Ma
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Qian Xu
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yan Ou
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Fanming Kong
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yingjie Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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6
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Nov P, Wang D, Zheng C, Sou S, Touch S, Kouy S, Vicheth V, Li L, Zhang Y, Liu X, Wang C, Ni P, Kou Q, Li Y, Prasai A, Fu W, Li W, Du K, Li J. Phosphate-to-alanine ratio and bilirubin-to-androsterone glucuronide ratio are the hub metabolites in upper gastrointestinal cancers: a Mendelian randomisation (MR) study. Ecancermedicalscience 2024; 18:1731. [PMID: 39421169 PMCID: PMC11484670 DOI: 10.3332/ecancer.2024.1731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Indexed: 10/19/2024] Open
Abstract
Objective Upper gastrointestinal (UGI) cancers, particularly esophageal cancer (EC) and gastric cancer (GC) represent a significant health burden with complex etiologies. Metabolic alterations are known to play a crucial role in cancer development and progression. Identifying key metabolic biomarkers may offer insights into the pathophysiology of UGI cancers and potential therapeutic targets. This study aimed to investigate the causal associations between 1,400 types of metabolites, specifically phosphate-to-alanine and bilirubin-to-androsterone glucuronide, and the risk of developing UGI cancers using Mendelian randomisation (MR) analysis. Method We conducted a two-sample MR study utilising genetic instruments identified from large-scale genome-wide association studies (GWASs) for metabolic traits. The outcomes were derived from GWAS datasets of UGI cancer patients, including EC and GC. Several MR methods were employed to ensure the robustness of the findings, including inverse variance weighted (IVW), MR-Egger and weighted median approaches. Results Our analysis found a total of 44 metabolites associated with EC and 15 metabolites associated with GC. The MR analyses revealed a significant causal relationship between the phosphate-to-alanine ratio (EC: OR = 1.002,95% CI = 1.00034-1.0037, p = 0.0037; GC: OR = 1.24,95% CI = 1.046-1.476, p = 0.01) and increased risk of UGI cancers. In contrast, the bilirubin-to-androsterone glucuronide ratio (EC: OR = 0.998,95% CI = 0.997-0.999, p = 0.03; GC: OR = 0.80,95% CI = 0.656-0.991, p = 0.04) was inversely associated with the risk, suggesting a potential protective effect. Conclusion Our findings suggest that the phosphate-to-alanine ratio and bilirubin-to-androsterone glucuronide ratio are key hub metabolites in the etiology of UGI cancers. These metabolic ratios could serve as potential biomarkers for early detection or targets for therapeutic intervention. Further research is warranted to elucidate the underlying biological mechanisms and to validate the clinical utility of these associations.
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Affiliation(s)
- Pengkhun Nov
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
- These authors contributed equally to this work
| | - Duanyu Wang
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
- These authors contributed equally to this work
| | - Chongyang Zheng
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Syphanna Sou
- Department of Radiation Oncology and Oncology, Khmer-Soviet Friendship Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Socheat Touch
- Department of Radiation Oncology and Oncology, Khmer-Soviet Friendship Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Samnang Kouy
- Department of Radiation Oncology and Oncology, Khmer-Soviet Friendship Hospital of University of Health Sciences, Phnom Penh 120110, Cambodia
| | - Virak Vicheth
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Lilin Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Yangfeng Zhang
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Xiang Liu
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Changqian Wang
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Peizan Ni
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Qianzi Kou
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Ying Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Arzoo Prasai
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Wen Fu
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Wandan Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
| | - Kunpeng Du
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
- https://orcid.org/0000-0002-0684-7291
| | - Jiqiang Li
- Department of Radiation Oncology, Oncology Center, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province 510282, China
- https://orcid.org/0000-0002-585-5911
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Wang L, Gong WH. Predictive model using four ferroptosis-related genes accurately predicts gastric cancer prognosis. World J Gastrointest Oncol 2024; 16:2018-2037. [PMID: 38764813 PMCID: PMC11099433 DOI: 10.4251/wjgo.v16.i5.2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/31/2024] [Accepted: 03/08/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a common malignancy of the digestive system. According to global 2018 cancer data, GC has the fifth-highest incidence and the third-highest fatality rate among malignant tumors. More than 60% of GC are linked to infection with Helicobacter pylori (H. pylori), a gram-negative, active, microaerophilic, and helical bacterium. This parasite induces GC by producing toxic factors, such as cytotoxin-related gene A, vacuolar cytotoxin A, and outer membrane proteins. Ferroptosis, or iron-dependent programmed cell death, has been linked to GC, although there has been little research on the link between H. pylori infection-related GC and ferroptosis. AIM To identify coregulated differentially expressed genes among ferroptosis-related genes (FRGs) in GC patients and develop a ferroptosis-related prognostic model with discrimination ability. METHODS Gene expression profiles of GC patients and those with H. pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. The FRGs were acquired from the FerrDb database. A ferroptosis-related gene prognostic index (FRGPI) was created using least absolute shrinkage and selection operator-Cox regression. The predictive ability of the FRGPI was validated in the GEO cohort. Finally, we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues. RESULTS Four hub genes were identified (NOX4, MTCH1, GABARAPL2, and SLC2A3) and shown to accurately predict GC and H. pylori-associated GC. The FRGPI based on the hub genes could independently predict GC patient survival; GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group. The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression. Moreover, the gene expression levels of common immune checkpoint proteins dramatically increased in the high-risk subgroup of the FRGPI cohort. The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane. The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner. CONCLUSION In this study, we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.
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Affiliation(s)
- Li Wang
- Department of Emergency, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Wei-Hua Gong
- Department of Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
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Wang J, Li X, Qiang X, Yin X, Guo L. Analyzing the expression and clinical significance of CENPE in gastric cancer. BMC Med Genomics 2024; 17:119. [PMID: 38702677 PMCID: PMC11067209 DOI: 10.1186/s12920-024-01887-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 04/22/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Gastric cancer (GC) is a prevalent type of malignant gastrointestinal tumor. Many studies have shown that CENPE acts as an oncogene in some cancers. However, its expression level and clinical value in GC are not clear. METHODS Obtaining clinical data information on gastric adenocarcinoma from TCGA and GEO databases. The gene expression profiling interaction analysis (GEPIA) was used to evaluate the relationship between prognosis and CENPE expression in gastric cancer patients. Utilizing the UALCAN platform, the correlation between CENPE expression and clinical parameters was examined. Functions and signaling pathways of CENPE were analyzed using the Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The association between immunological infiltrating cells and CENPE expression was examined using TIMER2.0. Validation was performed by real-time quantitative PCR (qPT-PCR) and immunohistochemical analysis. RESULTS According to the analysis of the GEPIA database, the expression of CENPE is increased in gastric cancer tissues compared to normal tissues. It was also found to have an important relationship with the prognosis of the patient (p<0.05). The prognosis was worse and overall survival was lower in individuals with increased expression of CENPE. In line with the findings of the GEPIA, real-time fluorescence quantitative PCR (qPT-PCR) confirmed that CENPE was overexpressed in gastric cancer cells. Furthermore, It was discovered that H. pylori infection status and tumor grade were related to CENPE expression. Enrichment analysis revealed that CENPE expression was linked to multiple biological functions and tumor-associated pathways. CENPE expression also correlated with immune-infiltrating cells in the gastric cancer microenvironment and was positively connected to NK cells and mast cells. According to immunohistochemical examination, paracancerous tissues had minimal expression of CENPE, but gastric cancer showed significant expression of the protein. CONCLUSIONS According to our findings, CENPE is substantially expressed in GC and may perhaps contribute to its growth. CENPE might be a target for gastric cancer therapy and a predictor of a bad prognosis.
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Affiliation(s)
- Jing Wang
- Department of Gastroenterology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China
| | - Xiaofei Li
- Department of Gastroenterology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China
| | - Xihui Qiang
- Department of Gastroenterology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China
| | - Xueqing Yin
- Department of Gastroenterology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China
| | - Lianyi Guo
- Department of Gastroenterology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China.
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An WT, Hao YX, Li HX, Wu XK. Urinary metabolic profiles during Helicobacter pylori eradication in chronic gastritis. World J Clin Cases 2024; 12:951-965. [PMID: 38414611 PMCID: PMC10895622 DOI: 10.12998/wjcc.v12.i5.951] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/14/2023] [Accepted: 01/22/2024] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) infection is a major risk factor for chronic gastritis, affecting approximately half of the global population. H. pylori eradication is a popular treatment method for H. pylori-positive chronic gastritis, but its mechanism remains unclear. Urinary metabolomics has been used to elucidate the mechanisms of gastric disease treatment. However, no clinical study has been conducted on urinary metabolomics of chronic gastritis. AIM To elucidate the urinary metabolic profiles during H. pylori eradication in patients with chronic gastritis. METHODS We applied LC-MS-based metabolomics and network pharmacology to investigate the relationships between urinary metabolites and H. pylori-positive chronic gastritis via a clinical follow-up study. RESULTS Our study revealed the different urinary metabolic profiles of H. pylori-positive chronic gastritis before and after H. pylori eradication. The metabolites regulated by H. pylori eradication therapy include cis-aconitic acid, isocitric acid, citric acid, L-tyrosine, L-phenylalanine, L-tryptophan, and hippuric acid, which were involved in four metabolic pathways: (1) Phenylalanine metabolism; (2) phenylalanine, tyrosine, and tryptophan biosynthesis; (3) citrate cycle; and (4) glyoxylate and dicarboxylate metabolism. Integrated metabolomics and network pharmacology revealed that MPO, COMT, TPO, TH, EPX, CMA1, DDC, TPH1, and LPO were the key proteins involved in the biological progress of H. pylori eradication in chronic gastritis. CONCLUSION Our research provides a new perspective for exploring the significance of urinary metabolites in evaluating the treatment and prognosis of H. pylori-positive chronic gastritis patients.
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Affiliation(s)
- Wen-Ting An
- Department of Pharmacy, Shanxi Provincial People’s Hospital, Taiyuan 030012, Shanxi Province, China
| | - Yu-Xia Hao
- Department of Gastroenterology, Shanxi Provincial People's Hospital, Taiyuan 030012, Shanxi Province, China
| | - Hong-Xia Li
- Department of Oncology, Shanxi Provincial People’s Hospital, Taiyuan 030012, Shanxi Province, China
| | - Xing-Kang Wu
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, Shanxi Province, China
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10
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Wang L, Zhang Z. Diabetes Mellitus and Gastric Cancer: Correlation and Potential Mechanisms. J Diabetes Res 2023; 2023:4388437. [PMID: 38020199 PMCID: PMC10653978 DOI: 10.1155/2023/4388437] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 10/22/2023] [Accepted: 10/27/2023] [Indexed: 12/01/2023] Open
Abstract
This review summarizes the correlation between diabetes mellitus (DM) and gastric cancer (GC) from the perspectives of epidemiology, drug use, and potential mechanisms. The association between DM and GC is inconclusive, and the positive direction of the association reported in most published meta-analyses suggests that DM may be an independent risk factor for GC. Many clinical investigations have shown that people with DM and GC who undergo gastrectomy may have better glycemic control. The potential link between DM and GC may involve the interaction of multiple common risk factors, such as obesity, hyperglycemia and hyperinsulinemia, H. pylori infection, and the use of metformin. Although in vitro and in vivo data support that H. pylori infection status and metformin can influence GC risk in DM patients, there are conflicting results. Patient survival outcomes are influenced by multiple factors, so further research is needed to identify the patients who may benefit.
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Affiliation(s)
- Li Wang
- Department of Emergency, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310052, China
- Zhejiang Provincial Critical Research Center for Emergency Medicine Clinic, Hangzhou 310052, China
- Key Laboratory of Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Hangzhou 310052, China
| | - Zhe Zhang
- Department of Emergency Medicine, The First People's Hospital of Linping District, 311100, Hangzhou, Zhejiang, China
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11
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Wang L, Wang H. The putative role of ferroptosis in gastric cancer: a review. Eur J Cancer Prev 2023; 32:575-583. [PMID: 37318883 PMCID: PMC10538621 DOI: 10.1097/cej.0000000000000817] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/30/2023] [Indexed: 06/17/2023]
Abstract
Ferroptosis is a unique cell death modality triggered by iron-dependent lipid peroxidation, with cysteine metabolism and glutathione-dependent antioxidant defence responses as the primary triggering mechanisms. Ferroptosis is an independent tumour suppression mechanism and has been implicated in various disorders. In tumourigenesis, ferroptosis plays a dual role in promoting and inhibiting tumours. P53, NFE2L2, BAP1, HIF, and other tumour suppressor genes regulate ferroptosis, releasing damage-associated molecular patterns or lipid metabolites to influence cellular immune responses. Ferroptosis is also involved in tumour suppression and metabolism. The combination of amino acid, lipid, and iron metabolism is involved in the initiation and execution of ferroptosis, and metabolic regulatory mechanisms also play roles in malignancies. Most investigations into ferroptosis in gastric cancer are concentrated on predictive models, not the underlying processes. This review investigates the underlying mechanisms of ferroptosis, tumour suppressor genes, and the tumour microenvironment.
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Affiliation(s)
- Li Wang
- Department of Emergency Medicine, Second Affiliated Hospital of School of Medicine and
| | - Haibin Wang
- Department of Radiology, Hangzhou First People’s Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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12
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Nabavi-Rad A, Yadegar A, Sadeghi A, Aghdaei HA, Zali MR, Klionsky DJ, Yamaoka Y. The interaction between autophagy, Helicobacter pylori, and gut microbiota in gastric carcinogenesis. Trends Microbiol 2023; 31:1024-1043. [PMID: 37120362 PMCID: PMC10523907 DOI: 10.1016/j.tim.2023.04.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 05/01/2023]
Abstract
Chronic infection with Helicobacter pylori is the primary risk factor for the development of gastric cancer. Hindering our ability to comprehend the precise role of autophagy during H. pylori infection is the complexity of context-dependent autophagy signaling pathways. Recent and ongoing progress in understanding H. pylori virulence allows new frontiers of research for the crosstalk between autophagy and H. pylori. Novel approaches toward discovering autophagy signaling networks have further revealed their critical influence on the structure of gut microbiota and the metabolome. Here we intend to present a holistic view of the perplexing role of autophagy in H. pylori pathogenesis and carcinogenesis. We also discuss the intermediate role of autophagy in H. pylori-mediated modification of gut inflammatory responses and microbiota structure.
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Affiliation(s)
- Ali Nabavi-Rad
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Amir Sadeghi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Daniel J Klionsky
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Oita, Japan; Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX, USA; Research Center for Global and Local Infectious Diseases, Oita University, Oita, Japan.
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13
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Liang X, Du W, Huang L, Xiang L, Pan W, Yang F, Zheng F, Xie Y, Geng L, Gong S, Xu W. Helicobacter pylori promotes gastric intestinal metaplasia through activation of IRF3-mediated kynurenine pathway. Cell Commun Signal 2023; 21:141. [PMID: 37328804 PMCID: PMC10273570 DOI: 10.1186/s12964-023-01162-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 05/07/2023] [Indexed: 06/18/2023] Open
Abstract
BACKGROUND Metabolic reprogramming is a critical event for cell fate and function, making it an attractive target for clinical therapy. The function of metabolic reprogramming in Helicobacter pylori (H. pylori)-infected gastric intestinal metaplasia remained to be identified. METHODS Xanthurenic acid (XA) was measured in gastric cancer cells treated with H. pylori or H. pylori virulence factor, respectively, and qPCR and WB were performed to detect CDX2 and key metabolic enzymes expression. A subcellular fractionation approach, luciferase and ChIP combined with immunofluorescence were applied to reveal the mechanism underlying H. pylori mediated kynurenine pathway in intestinal metaplasia in vivo and in vitro. RESULTS Herein, we, for the first time, demonstrated that H. pylori contributed to gastric intestinal metaplasia characterized by enhanced Caudal-related homeobox transcription factor-2 (CDX2) and mucin2 (MUC2) expression, which was attributed to activation of kynurenine pathway. H. pylori promoted kynurenine aminotransferase II (KAT2)-mediated kynurenine pathway of tryptophan metabolism, leading to XA production, which further induced CDX2 expression in gastric epithelial cells. Mechanically, H. pylori activated cyclic guanylate adenylate synthase (cGAS)-interferon regulatory factor 3 (IRF3) pathway in gastric epithelial cells, leading to enhance IRF3 nuclear translocation and the binding of IRF3 to KAT2 promoter. Inhibition of KAT2 could significantly reverse the effect of H. pylori on CDX2 expression. Also, the rescue phenomenon was observed in gastric epithelial cells treated with H. pylori after IRF3 inhibition in vitro and in vivo. Most importantly, phospho-IRF3 was confirmed to be a clinical positive relationship with CDX2. CONCLUSION These finding suggested H. pylori contributed to gastric intestinal metaplasia through KAT2-mediated kynurenine pathway of tryptophan metabolism via cGAS-IRF3 signaling, targeting the kynurenine pathway could be a promising strategy to prevent gastric intestinal metaplasia caused by H. pylori infection. Video Abstract.
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Affiliation(s)
- Xinhua Liang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China
| | - Wenjun Du
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China
| | - Ling Huang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China
| | - Li Xiang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China
- Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, 510623, China
| | - Wenxu Pan
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China
| | - Fangying Yang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China
| | - Fengfeng Zheng
- Department of Infectious Diseases, The Affiliated Hospital of Putian University, Putian, 351100, China
| | - Yongwu Xie
- Department of Hematology, Zhuhai Center for Maternal and Child Health Care, Zhuhai, China
| | - Lanlan Geng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China.
- Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China.
- Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, 510623, China.
| | - Wanfu Xu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China.
- Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, 510623, China.
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14
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Zang H, Wang J, Wang H, Guo J, Li Y, Zhao Y, Song J, Liu F, Liu X, Zhao Y. Metabolic alterations in patients with Helicobacter pylori-related gastritis: The H. pylori-gut microbiota-metabolism axis in progression of the chronic inflammation in the gastric mucosa. Helicobacter 2023:e12984. [PMID: 37186092 DOI: 10.1111/hel.12984] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 02/15/2023] [Accepted: 03/13/2023] [Indexed: 05/17/2023]
Abstract
PURPOSE To characterize the serum metabolism in patients with Helicobacter pylori-positive and H. pylori-negative gastritis. METHODS Clinical data and serum gastric function parameters, PGI (pepsinogen I), PGII, PGR (PGI/II), and G-17 (gastrin-17) of 117 patients with chronic gastritis were collected, including 57 H. pylori positive and 60 H. pylori negative subjects. Twenty cases in each group were randomly selected to collect intestinal mucosa specimens and serum samples. The gut microbiota profiles were generated by 16S rRNA gene sequencing, and the serum metabolites were analyzed by a targeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) technology. RESULTS Altered expression of 20 metabolites, including isovaleric acid, was detected in patients with HPAG. Some taxa of Bacteroides, Fusobacterium, and Prevotella in the gut microbiota showed significant correlations with differentially expressed metabolites between H. pylori positive and H. pylori negative individuals. As a result, an H. pylori-gut microbiota-metabolism (HGM) axis was proposed. CONCLUSION Helicobacter pylori infection may influence the progression of mucosal diseases and the emergence of other complications in the host by altering the gut microbiota, and thus affecting the host serum metabolism.
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Affiliation(s)
- Hongmin Zang
- Hebei University of Chinese Medicine, Shijiazhuang, China
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Jin Wang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Huijie Wang
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Jiaxuan Guo
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yuchan Li
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Yinuo Zhao
- School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Jinzhong Song
- Hebei University of Chinese Medicine, Shijiazhuang, China
- The Traditional Chinese Medicine Hospital of Shijiazhuang, Shijiazhuang, China
| | - Fengshuang Liu
- Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Academy of Traditional Chinese Medicine, Shijiazhuang, China
| | - Xuzhao Liu
- North China University of Science and Technology, Tangshan, China
| | - Yubin Zhao
- Hebei University of Chinese Medicine, Shijiazhuang, China
- North China University of Science and Technology, Tangshan, China
- Shijiazhuang People's Hospital, Shijiazhuang, China
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15
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Wang Z, Shao SL, Xu XH, Zhao X, Wang MY, Chen A, Cong HY. Helicobacter pylori and gastric microbiota homeostasis: progress and prospects. Future Microbiol 2023; 18:137-157. [PMID: 36688318 DOI: 10.2217/fmb-2022-0102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Helicobacter pylori, a Gram-negative microaerobic bacteria belonging to the phylum Proteobacteria, can colonize in the stomach and duodenum, and cause a series of gastrointestinal diseases such as gastritis, gastric ulcer and even gastric cancer. At present, the high diversity of the microorganisms in the stomach has been confirmed with culture-independent methods; some researchers have also studied the stomach microbiota composition at different stages of H. pylori carcinogenesis. Here, we mainly review the possible role of H. pylori-mediated microbiota changes in the occurrence and development of gastric cancer to provide new ideas for preventing H. pylori infection and regulating microecological imbalance.
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Affiliation(s)
- Zan Wang
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, 261053, People's Republic of China
| | - Shu-Li Shao
- Department of Central Lab, Weihai Municipal Hospital. Weihai, Shandong, 264200, People's Republic of China
| | - Xiao-Han Xu
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, 261053, People's Republic of China
| | - Xue Zhao
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, 261053, People's Republic of China
| | - Ming-Yi Wang
- Department of Central Lab, Weihai Municipal Hospital. Weihai, Shandong, 264200, People's Republic of China
| | - Ai Chen
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, 261053, People's Republic of China.,Department of Central Lab, Weihai Municipal Hospital. Weihai, Shandong, 264200, People's Republic of China
| | - Hai-Yan Cong
- School of Medical Laboratory, Weifang Medical University, Weifang, Shandong, 261053, People's Republic of China.,Department of Central Lab, Weihai Municipal Hospital. Weihai, Shandong, 264200, People's Republic of China
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16
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Liang B, Yuan Y, Peng XJ, Liu XL, Hu XK, Xing DM. Current and future perspectives for Helicobacter pylori treatment and management: From antibiotics to probiotics. Front Cell Infect Microbiol 2022; 12:1042070. [PMID: 36506013 PMCID: PMC9732553 DOI: 10.3389/fcimb.2022.1042070] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/02/2022] [Indexed: 11/27/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a Gram-negative anaerobic bacterium that colonizes the human stomach and is the leading cause of gastric diseases such as chronic gastritis and peptic ulcers, as well as the most definite and controllable risk factor for the development of gastric cancer. Currently, the regimen for H. pylori eradication has changed from triple to quadruple, the course of treatment has been extended, and the type and dose of antibiotics have been adjusted, with limited improvement in efficacy but gradually increasing side effects and repeated treatment failures in an increasing number of patients. In recent years, probiotics have become one of the most important tools for supporting intestinal health and immunity. Numerous in vitro studies, animal studies, and clinical observations have demonstrated that probiotics have the advantage of reducing side effects and increasing eradication rates in adjuvant anti-H. pylori therapy and are a valuable supplement to conventional therapy. However, many different types of probiotics are used as adjuncts against H. pylori, in various combinations, with different doses and timing, and the quality of clinical studies varies, making it difficult to standardize the results. In this paper, we focus on the risk, status, prevention, control, and treatment of H. pylori infection and review international consensus guidelines. We also summarize the available scientific evidence on using Limosilactobacillus reuteri (L. reuteri) as a critical probiotic for H. pylori treatment and discuss its clinical research and application from an evidence-based perspective.
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Affiliation(s)
- Bing Liang
- Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yang Yuan
- Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiao-Jin Peng
- Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xin-Lin Liu
- Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiao-Kun Hu
- Intervention Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dong-Ming Xing
- Qingdao Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, China,School of Life Sciences, Tsinghua University, Beijing, China,*Correspondence: Dong-Ming Xing,
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17
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Zhang J, Xiao X, Guo Q, Wei Z, Hua W. Identification of Four Metabolic Subtypes of Glioma Based on Glycolysis-Cholesterol Synthesis Genes. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:9448144. [PMID: 35242216 PMCID: PMC8886743 DOI: 10.1155/2022/9448144] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/06/2022] [Accepted: 01/17/2022] [Indexed: 12/21/2022]
Abstract
Based on alterations in gene expression associated with the production of glycolysis and cholesterol, this research classified glioma into prognostic metabolic subgroups. In this study, data from the CGGA325 and The Cancer Genome Atlas (TCGA) datasets were utilized to extract single nucleotide variants (SNVs), RNA-seq expression data, copy number variation data, short insertions and deletions (InDel) mutation data, and clinical follow-up information from glioma patients. Glioma metabolic subtypes were classified using the ConsensusClusterPlus algorithm. This study determined four metabolic subgroups (glycolytic, cholesterogenic, quiescent, and mixed). Cholesterogenic patients had a higher survival chance. Genome-wide investigation revealed that inappropriate amplification of MYC and TERT was associated with improper cholesterol anabolic metabolism. In glioma metabolic subtypes, the mRNA levels of mitochondrial pyruvate carriers 1 and 2 (MPC1/2) presented deletion and amplification, respectively. Differentially upregulated genes in the glycolysis group were related to pathways, including IL-17, HIF-1, and TNF signaling pathways and carbon metabolism. Downregulated genes in the glycolysis group were enriched in terpenoid backbone biosynthesis, nitrogen metabolism, butanoate metabolism, and fatty acid metabolism pathway. Cox analysis of univariate and multivariate survival showed that risks of glycolysis subtypes were significantly higher than other subtypes. Those results were validated in the CGGA325 dataset. The current findings greatly contribute to a comprehensive understanding of glioma and personalized treatment.
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Affiliation(s)
- Jinsen Zhang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
- Neurosurgical Institute of Fudan University, Shanghai 200040, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China
| | - Xing Xiao
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
- Neurosurgical Institute of Fudan University, Shanghai 200040, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China
| | - Qinglong Guo
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
- Neurosurgical Institute of Fudan University, Shanghai 200040, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China
| | - Zixuan Wei
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Wei Hua
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
- Neurosurgical Institute of Fudan University, Shanghai 200040, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China
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Khatun S, Appidi T, Rengan AK. The role played by bacterial infections in the onset and metastasis of cancer. CURRENT RESEARCH IN MICROBIAL SCIENCES 2021; 2:100078. [PMID: 34841367 PMCID: PMC8610348 DOI: 10.1016/j.crmicr.2021.100078] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 10/04/2021] [Accepted: 10/24/2021] [Indexed: 02/09/2023] Open
Abstract
Understanding various responses of cells towards change in their external environment, presence of other species and is important in identifying and correlating the mechanisms leading to malignant transformations and cancer development. Although uncovering and comprehending the association between bacteria and cancer is highly challenging, it promises excellent perspectives and approaches for successful cancer therapy. This review introduces various bacterial species, their virulence factors, and their role in cell transformations leading to cancer (particularly gastric, oral, colon, and breast cancer). Bacterial dysbiosis permutates host cells, causes inflammation, and results in tumorigenesis. This review explored bacterial-mediated host cell transformation causing chronic inflammation, immune receptor hyperactivation/absconding immune recognition, and genomic instability. Bacterial infections downregulate E-cadherin, leading to loosening of epithelial tight junction polarity and triggers metastasis. In addition to understanding the role of bacterial infections in cancer development, we have also reviewed the application of bacteria for cancer therapy. The emergence of bacteriotherapy combined with conventional therapies led to new and effective ways of overcoming challenges associated with available treatments. This review discusses the application of bacterial minicells, microswimmers, and outer cell membrane vesicles (OMV) for drug delivery applications.
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Affiliation(s)
- Sajmina Khatun
- Department of Biomedical Engineering, IIT Hyderabad, Kandi, Sangareddy 502284, Telangana, India
| | - Tejaswini Appidi
- Department of Biomedical Engineering, IIT Hyderabad, Kandi, Sangareddy 502284, Telangana, India
| | - Aravind Kumar Rengan
- Department of Biomedical Engineering, IIT Hyderabad, Kandi, Sangareddy 502284, Telangana, India
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19
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Kao CY, Kuo PY, Liao HW. Untargeted Microbial Exometabolomics and Metabolomics Analysis of Helicobacter pylori J99 and jhp0106 Mutant. Metabolites 2021; 11:metabo11120808. [PMID: 34940566 PMCID: PMC8707867 DOI: 10.3390/metabo11120808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/26/2021] [Accepted: 11/26/2021] [Indexed: 11/16/2022] Open
Abstract
Untargeted metabolomic profiling provides the opportunity to comprehensively explore metabolites of interest. Herein, we investigated the metabolic pathways associated with Jhp0106, a glycosyltransferase enzyme in Helicobacter pylori. Through untargeted exometabolomic and metabolomic profiling, we identified 9 and 10 features with significant differences in the culture media and pellets of the wild-type (WT) J99 and jhp0106 mutant (Δjhp0106). After tentative identification, several phosphatidylethanolamines (PEs) were identified in the culture medium, the levels of which were significantly higher in WT J99 than in Δjhp0106. Moreover, the reduced lysophosphatidic acid absorption from the culture medium and the reduced intrinsic diacylglycerol levels observed in Δjhp0106 indicate the possibility of reduced PE synthesis in Δjhp0106. The results suggest an association of the PE synthesis pathway with flagellar formation in H. pylori. Further investigations should be conducted to confirm this finding and the roles of the PE synthesis pathway in flagellar formation. This study successfully demonstrates the feasibility of the proposed extraction procedure and untargeted exometabolomic and metabolomic profiling strategies for microbial metabolomics. They may also extend our understanding of metabolic pathways associated with flagellar formation in H. pylori.
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Affiliation(s)
- Cheng-Yen Kao
- Institute of Microbiology and Immunology, School of Life Science, National Yang Ming Chiao Tung University, Taipei 122, Taiwan; (C.-Y.K.); (P.-Y.K.)
| | - Pei-Yun Kuo
- Institute of Microbiology and Immunology, School of Life Science, National Yang Ming Chiao Tung University, Taipei 122, Taiwan; (C.-Y.K.); (P.-Y.K.)
| | - Hsiao-Wei Liao
- Department of Pharmacy, National Yang Ming Chiao Tung University, Taipei 122, Taiwan
- Correspondence: ; Tel.: +886-2826-7927
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20
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Lee Y, Lee SM, Choi J, Kang S, So S, Kim D, Ahn JY, Jung HY, Jeong JY, Kang E. Mitochondrial DNA Haplogroup Related to the Prevalence of Helicobacter pylori. Cells 2021; 10:cells10092482. [PMID: 34572132 PMCID: PMC8469812 DOI: 10.3390/cells10092482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 11/16/2022] Open
Abstract
Mitochondria are essential organelles that are not only responsible for energy production but are also involved in cell metabolism, calcium homeostasis, and apoptosis. Targeting mitochondria is a key strategy for bacteria to subvert host cells' physiology and promote infection. Helicobacter (H.) pylori targets mitochondria directly. However, mitochondrial genome (mtDNA) polymorphism (haplogroup) is not yet considered an important factor for H. pylori infection. Here, we clarified the association of mitochondrial haplogroups with H. pylori prevalence and the ability to perform damage. Seven mtDNA haplogroups were identified among 28 H. pylori-positive subjects. Haplogroup B was present at a higher frequency and haplotype D at a lower one in the H. pylori population than in that of the H. pylori-negative one. The fibroblasts carrying high-frequency haplogroup displayed a higher apoptotic rate and diminished mitochondrial respiration following H. pylori infection. mtDNA mutations were accumulated more in the H. pylori-positive population than in that of the H. pylori-negative one in old age. Among the mutations, 57% were located in RNA genes or nonsynonymous protein-coding regions in the H. pylori-positive population, while 35% were in the H. pylori-negative one. We concluded that gastric disease caused by Helicobacter virulence could be associated with haplogroups and mtDNA mutations.
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Affiliation(s)
- Yeonmi Lee
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
| | - Sun-Mi Lee
- Asan Medical Center, Asan Institute for Life Sciences, Seoul 05505, Korea;
| | - Jiwan Choi
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
| | - Seoon Kang
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
| | - Seongjun So
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Deokhoon Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Ji-Yong Ahn
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Hwoon-Yong Jung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Correspondence: (H.-Y.J.); (J.-Y.J.); (E.K.); Tel.: +82-2-3010-3197 (H.-Y.J.); +82-2-3010-4105 (J.-Y.J.); +82-31-881-7846 (E.K.)
| | - Jin-Yong Jeong
- Asan Medical Center, Asan Institute for Life Sciences, Seoul 05505, Korea;
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Correspondence: (H.-Y.J.); (J.-Y.J.); (E.K.); Tel.: +82-2-3010-3197 (H.-Y.J.); +82-2-3010-4105 (J.-Y.J.); +82-31-881-7846 (E.K.)
| | - Eunju Kang
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
- Correspondence: (H.-Y.J.); (J.-Y.J.); (E.K.); Tel.: +82-2-3010-3197 (H.-Y.J.); +82-2-3010-4105 (J.-Y.J.); +82-31-881-7846 (E.K.)
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21
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Huang S, Guo Y, Li Z, Zhang Y, Zhou T, You W, Pan K, Li W. A systematic review of metabolomic profiling of gastric cancer and esophageal cancer. Cancer Biol Med 2021; 17:181-198. [PMID: 32296585 PMCID: PMC7142846 DOI: 10.20892/j.issn.2095-3941.2019.0348] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 12/03/2019] [Indexed: 12/13/2022] Open
Abstract
Objective: Upper gastrointestinal (UGI) cancers, predominantly gastric cancer (GC) and esophageal cancer (EC), are malignant tumor types with high morbidity and mortality rates. Accumulating studies have focused on metabolomic profiling of UGI cancers in recent years. In this systematic review, we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with GC and EC. Methods: A systematic search of three databases (Embase, PubMed, and Web of Science) for molecular epidemiologic studies on the metabolomic profiles of GC and EC was conducted. The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included articles. Results: A total of 52 original studies were included for review. A number of metabolites were differentially distributed between GC and EC cases and non-cases, including those involved in glycolysis, anaerobic respiration, tricarboxylic acid cycle, and protein and lipid metabolism. Lactic acid, glucose, citrate, and fumaric acid were among the most frequently reported metabolites of cellular respiration while glutamine, glutamate, and valine were among the most commonly reported amino acids. The lipid metabolites identified previously included saturated and unsaturated free fatty acids, aldehydes, and ketones. However, the key findings across studies to date have been inconsistent, potentially due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group. Conclusions: Studies on metabolomics have thus far provided insights into etiological factors and biomarkers for UGI cancers, supporting the potential of applying metabolomic profiling in cancer prevention and management efforts.
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Affiliation(s)
- Sha Huang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yang Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhexuan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yang Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Tong Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Weicheng You
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Kaifeng Pan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Wenqing Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China.,Joint International Research Center of Translational and Clinical Research, Beijing 100142, China
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22
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Zhu Z, Qin J, Dong C, Yang J, Yang M, Tian J, Zhong X. Identification of four gastric cancer subtypes based on genetic analysis of cholesterogenic and glycolytic pathways. Bioengineered 2021; 12:4780-4793. [PMID: 34346836 PMCID: PMC8806458 DOI: 10.1080/21655979.2021.1956247] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Warburg phenomenon refers to the development of unique metabolic patterns during the growth of tumor cells. This study stratified gastric cancer into prognostic metabolic subgroups according to changes in gene expressions related to glycolysis and cholesterol synthesis. The RNA-seq expression data, single nucleotide variants (SNV), short insertions and deletions (InDel) mutation data, copy number variation (CNV) data and clinical follow-up information data of gastric cancer tissues were downloaded from The Cancer Genome Atlas (TCGA) database. ConsensusClusterPlus was used to stratify the metabolic subtypes of gastric cancer. Four metabolic subtypes (Cholesterogenic, Glycolytic, Mixed and Quiescent) of gastric cancer were identified, and patients with cholesterogenic tumors had the longest disease-specific survival (DSS). Genome-wide analysis showed that aberrant amplification of TP53 and MYC in gastric cancer was associated with abnormal cholesterol anabolic metabolism. The mRNA levels of mitochondrial pyruvate carriers 1 and 2 (MPC1/2) differed among the four subtypes. Tumors in the glycolytic group showed a higher PDCD1. A genomic signature based on tumor metabolism of different cancer types was established. This study showed that genes related to glucose and lipid metabolism play an important role in gastric cancer and facilitate a personalized treatment of gastric cancer.
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Affiliation(s)
- Zhou Zhu
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Jian Qin
- Department of Radiation Oncology of Clinical Cancer Center, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Chencheng Dong
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Jin Yang
- Strategic Operations Department, YuceBio Technology Co., Ltd, Guangzhou, China
| | - Maughan Yang
- Strategy DevelopmentDepartment, Meta Health Sector of Yuanzhi Technology Group, Beijing, China
| | - Jana Tian
- Strategy DevelopmentDepartment, Meta Health Sector of Yuanzhi Technology Group, Beijing, China
| | - Xiaogang Zhong
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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23
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Zhou Y, Chen S, Yang F, Zhang Y, Xiong L, Zhao J, Huang L, Chen P, Ren L, Li H, Liang D, Wu P, Chen H, Chen J, Gong S, Xu W, Geng L. Rabeprazole suppresses cell proliferation in gastric epithelial cells by targeting STAT3-mediated glycolysis. Biochem Pharmacol 2021; 188:114525. [PMID: 33744226 DOI: 10.1016/j.bcp.2021.114525] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/07/2021] [Accepted: 03/11/2021] [Indexed: 02/07/2023]
Abstract
The dysregulation of glycolysis leads to serials of disease. Rabeprazole is a representative of proton pump inhibitors and widely used in anti-ulcer treatment. However, the function of Rabeprazole on glycolysis in gastric epithelial cells remained to be identified. In this study, 30（Helicobacter pylori）H. pylori-negative cases and 26H. pylori-positive cases treated with Rabeprazole were recruited. The qPCR and Western blotting results showed that Rabeprazole suppressed cell proliferation by inhibition of HK2-mediated glycolysis in BGC823 cells, leading to decrease glucose uptake and lactate production in a dose-dependent way. Furthermore, the phosphorylation of signal transducer and activator of transcription 3 (STAT3) was drastically reduced in response to Rabeprazole stimulation, leading to attenuate STAT3 nuclear translocation. Luciferase and Chromatin immunoprecipitation (ChIP) analysis showed that Rabeprazole treatment led to a significant inhibition of the binding of STAT3 to the promoter of the HK2 gene, repressing transcriptional activation of HK2. Moreover, the ectopic expression of STAT3 in BGC823 cells resulted in recovery of HK2 transactivation and cell proliferation in Rabeprazole-treated cells. Most importantly, HK2 expression was significantly increased in H. pylori-infected gastric mucosa. These findings suggested that Rabeprazole inhibited cell proliferation by targeting STAT3/HK2 signaling-mediated glucose metabolism in gastric epithelial cells. Therefore, targeting HK2 is an alternative strategy in improving the treatment of patients with H. pylori infection.
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Affiliation(s)
- Yanhe Zhou
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Sidong Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Fangying Yang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Yuhua Zhang
- Department of Pediatrics, Putian medical district, The 900th Hospital of Joint Logistic Support Force, PLA, Putian 351164, China
| | - Liya Xiong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Junhong Zhao
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Ling Huang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Peiyu Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Lu Ren
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Huiwen Li
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Defeng Liang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Peiqun Wu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Huan Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Jiayu Chen
- Department of Neonatal Intensive Care Unit, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Sitang Gong
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
| | - Wanfu Xu
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
| | - Lanlan Geng
- Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China; Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
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24
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Abstract
INTRODUCTION Various types of cancers threaten human life. The role of bacteria in causing cancer is controversial, but it has been determined that the Helicobacter pylori infection is one of the identified risk factors for gastric cancer. Helicobacter pylori infection is highly prevalent, and about half of the world,s population is infected with it. OBJECTIVE The aim of this study was the role of Helicobacter pylori in the development of gastric cancer. METHOD We obtained information from previously published articles. RESULTS AND CONCLUSION The bacterium has various virulence factors, including cytotoxin- associated gene A, vacuolating cytotoxin A, and the different outer membrane proteins that cause cancer by different mechanisms. These virulence factors activate cell signaling pathways such as PI3-kinase/Akt, JAK/STAT and Ras, Raf, and ERK signaling that control cell proliferation. Uncontrolled proliferation can lead to cancer.
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Affiliation(s)
- Majid Alipour
- Department of Cell and Molecular Biology, Islamic Azad University, Babol Branch, Babol, Iran.
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25
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The Dark Side of the Force: When the Immune System Is the Fuel of Tumor Onset. Int J Mol Sci 2021; 22:ijms22031224. [PMID: 33513730 PMCID: PMC7865698 DOI: 10.3390/ijms22031224] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 12/26/2022] Open
Abstract
Nowadays, it is well accepted that inflammation is a critical player in cancer, being, in most cases, the main character of the process. Different types of tumor arise from sites of infection or chronic inflammation. This non-resolving inflammation is responsible for tumor development at different levels: it promotes tumor initiation, as well as tumor progression, stimulating both tumor growth and metastasis. Environmental factors, lifestyle and infections are the three main triggers of chronic immune activation that promote or increase the risk of many different cancers. In this review, we focus our attention on tumor onset; in particular, we summarize the knowledge about the cause and the mechanisms behind the inflammation-driven cancer development.
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26
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Cuomo P, Papaianni M, Sansone C, Iannelli A, Iannelli D, Medaglia C, Paris D, Motta A, Capparelli R. An In Vitro Model to Investigate the Role of Helicobacter pylori in Type 2 Diabetes, Obesity, Alzheimer's Disease and Cardiometabolic Disease. Int J Mol Sci 2020; 21:ijms21218369. [PMID: 33171588 PMCID: PMC7664682 DOI: 10.3390/ijms21218369] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/30/2020] [Accepted: 11/04/2020] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (Hp) is a Gram-negative bacterium colonizing the human stomach. Nuclear Magnetic Resonance (NMR) analysis of intracellular human gastric carcinoma cells (MKN-28) incubated with the Hp cell filtrate (Hpcf) displays high levels of amino acids, including the branched chain amino acids (BCAA) isoleucine, leucine, and valine. Polymerase chain reaction (PCR) Array Technology shows upregulation of mammalian Target Of Rapamycin Complex 1 (mTORC1), inflammation, and mitochondrial dysfunction. The review of literature indicates that these traits are common to type 2 diabetes, obesity, Alzheimer’s diseases, and cardiometabolic disease. Here, we demonstrate how Hp may modulate these traits. Hp induces high levels of amino acids, which, in turn, activate mTORC1, which is the complex regulating the metabolism of the host. A high level of BCAA and upregulation of mTORC1 are, thus, directly regulated by Hp. Furthermore, Hp modulates inflammation, which is functional to the persistence of chronic infection and the asymptomatic state of the host. Finally, in order to induce autophagy and sustain bacterial colonization of gastric mucosa, the Hp toxin VacA localizes within mitochondria, causing fragmentation of these organelles, depletion of ATP, and oxidative stress. In conclusion, our in vitro disease model replicates the main traits common to the above four diseases and shows how Hp may potentially manipulate them.
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Affiliation(s)
- Paola Cuomo
- Department of Agriculture Sciences, University of Naples “Federico II”, via Università, 100-Portici, 80055 Naples, Italy; (P.C.); (M.P.)
| | - Marina Papaianni
- Department of Agriculture Sciences, University of Naples “Federico II”, via Università, 100-Portici, 80055 Naples, Italy; (P.C.); (M.P.)
| | - Clementina Sansone
- Department of Marine Biotechnology, Stazione Zoologica Anton Dohrn, 80121 Naples, Italy;
| | - Antonio Iannelli
- Department of Digestive Surgery, Université Côte d’Azur, Campus Valrose, Batiment L, Avenue de Valrose, 28-CEDEX 2, 06108 Nice, France;
- Inserm, U1065, Team 8 “Hepatic Complications of Obesity and Alcohol”, Route Saint Antoine de Ginestière 151, BP 2 3194, CEDEX 3, 06204 Nice, France
| | - Domenico Iannelli
- Department of Agriculture Sciences, University of Naples “Federico II”, via Università, 100-Portici, 80055 Naples, Italy; (P.C.); (M.P.)
- Correspondence: (D.I.); (R.C.)
| | - Chiara Medaglia
- Department of Microbiology and Molecular Medicine, University of Geneva Medical School, rue du Général-Dufour, 1211 Genève, Switzerland;
| | - Debora Paris
- Institute of Biomolecular Chemistry, National Research Council, via Campi Flegrei, 34-Pozzuoli, 80078 Naples, Italy; (D.P.); (A.M.)
| | - Andrea Motta
- Institute of Biomolecular Chemistry, National Research Council, via Campi Flegrei, 34-Pozzuoli, 80078 Naples, Italy; (D.P.); (A.M.)
| | - Rosanna Capparelli
- Department of Agriculture Sciences, University of Naples “Federico II”, via Università, 100-Portici, 80055 Naples, Italy; (P.C.); (M.P.)
- Correspondence: (D.I.); (R.C.)
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27
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Yang S, Lv Y, Wu C, Liu B, Shu Z, Lin Y. Pickled Vegetables Intake Impacts the Metabolites for Gastric Cancer. Cancer Manag Res 2020; 12:8263-8273. [PMID: 32982422 PMCID: PMC7490060 DOI: 10.2147/cmar.s271277] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 08/20/2020] [Indexed: 01/19/2023] Open
Abstract
Purpose An increased risk of gastric cancer (GC) for pickled vegetables intake has been suggested, but a complete understanding of its pathogenic origin is still lacking, especially from a metabolic viewpoint. We investigated the plasma metabolites and metabolic pathway alteration of GC related to pickled vegetables intake. Methods We analyzed plasma samples collected from 365 gastric cancer patients and 347 healthy individuals, and divided them into three subgroups according to the intake of pickled vegetables. Plasma samples were detected by untargeted metabolomics. Results Nine metabolites were significantly altered in GC patients among pickled vegetables intake groups (FDR P-value<0.05). All of them were associated with the risk of gastric cancer adjusted for gender, age, smoking status, Helicobacter pylori infection. Pathway analysis showed significant alteration in the folate biosynthesis pathway. Conclusion In short, we provide new insights from a metabolic perspective on the relationship between pickled vegetables intake and the occurrence of gastric cancer.
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Affiliation(s)
- Shuangfeng Yang
- School of Public Health, Fujian Medical University, Fuzhou, People's Republic of China.,Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, People's Republic of China
| | - Yanping Lv
- School of Public Health, Fujian Medical University, Fuzhou, People's Republic of China.,Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, People's Republic of China
| | - Chuancheng Wu
- School of Public Health, Fujian Medical University, Fuzhou, People's Republic of China.,Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, People's Republic of China
| | - Baoying Liu
- School of Public Health, Fujian Medical University, Fuzhou, People's Republic of China.,Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, People's Republic of China
| | - Zhixiong Shu
- School of Public Health, Fujian Medical University, Fuzhou, People's Republic of China.,Fujian Provincial Key Laboratory of Environment Factors and Cancer, Fuzhou, People's Republic of China
| | - Yulan Lin
- School of Public Health, Fujian Medical University, Fuzhou, People's Republic of China
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28
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Matsuoka K, Nishiumi S, Yoshida M, Kodama Y. Effects of Helicobacter pylori on the glutathione-related pathway in gastric epithelial cells. Biochem Biophys Res Commun 2020; 526:1118-1124. [PMID: 32312521 DOI: 10.1016/j.bbrc.2020.04.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 04/08/2020] [Indexed: 01/25/2023]
Abstract
Virulence factors of Helicobacter pylori (H. pylori) are diverse, so various biological responses happen in a host infected with H. pylori. The aim of this study is to conduct the metabolomics-based evaluation on H. pylori infection. AGS human gastric carcinoma cells were infected with H. pylori strain 26695, and then the altered metabolite pathways in the infected AGS cells were analyzed by metabolomics. Metabolites related to the glutathione (GSH) cycle were downregulated by H. pylori infection. Next, we evaluated the effects of H. pylori on the GSH-related pathway in AGS cells infected with H. pylori isolated from patients with atrophic gastritis (AG), duodenal ulcer (DU) and gastric cancer (GC). We found that the declined degree of GSH levels and oxidative stress were greater in AGS cells infected with GC strains than DU and AG-derived strains. There were no significant differences in almost mRNA expressions of GSH-related factors among different clinical strains, but the protein expression of glutathione synthetase was lower in AGS cells infected with GC-derived strains than DU and AG-derived strains. Our data demonstrates that GC-derived H. pylori-induced oxidative stress in a host is stronger and GC-derived strains may have suppressive influences on the host's GSH-related defense systems.
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Affiliation(s)
- Koki Matsuoka
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shin Nishiumi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Omics Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
| | - Masaru Yoshida
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Metabolomics Research, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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29
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Fu L, Xie C. A lucid review of Helicobacter pylori-induced DNA damage in gastric cancer. Helicobacter 2019; 24:e12631. [PMID: 31295756 DOI: 10.1111/hel.12631] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/03/2019] [Accepted: 06/03/2019] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori (H pylori) is the main risk factor for gastric cancer (GC). In recent years, many studies have addressed the effects of H pylori itself and of H pylori-induced chronic inflammation on DNA damage. Unrepaired or inappropriately repaired DNA damage is one possible carcinogenic mechanism. We may conclude that H pylori-induced DNA damage is one of the carcinogenic mechanisms of GC. In this review, we summarize the interactions between H pylori and DNA damage and the effects of H pylori-induced DNA damage on GC. Then, focusing on oxidative stress, we introduce the application of antioxidants in GC. At the end of this review, we discuss the outlook for further research on H pylori-induced DNA damage.
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Affiliation(s)
- Li Fu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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30
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Abstract
In this review, we shall focus on the last year progression understanding the pathogenesis of Helicobacter pylori infection in the light of recent data related to adaptation of H pylori to the harsh acidic environment in the stomach, colonization of gastric mucosa via interaction with mucin 5 (MUC5AC) and other host cell receptors, the ability to form biofilm, interference with the host metabolic pathways, and induction of neuroimmune cross-talk as well as downregulation of gastric barrier homeostasis and its consequences for the disease development. The role of the membrane vesicles of these bacteria has been emphasized as an important source of virulence factors. Furthermore, we shall describe molecular and functional studies on new aspects of VacA and CagA virulence, including the role of urease in the upregulation of VacA toxicity, an epithelial-mesenchymal transition mediated by CagA, and the role of interaction of HopQ adhesin with carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in CagA translocation into the host cells by the type IV secretion system (T4SS). The role of molecular mimicry between a common sequence (ATVLA) of H pylori heat shock protein (Hsp) B and human Hsp60 in the induction of potentially autoreactive antibodies is discussed. All these new data illustrate further progress in understanding H pylori pathogenicity and facilitate the search for new therapeutic targets as well as development of immunoprophylaxis methods based on new chimeric UreB and HpA proteins.
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Affiliation(s)
- Magdalena Chmiela
- Laboratory of GastroimmunologyDepartment of Immunology and Infectious BiologyInstitute of Microbiology, Biotechnology and ImmunologyFaculty of Biology and Environmental ProtectionUniversity of ŁódźŁódźPoland
| | - Juozas Kupcinskas
- Institute for Digestive ResearchAcademy of MedicineLithuanian University of Health SciencesKaunasLithuania
- Department of GastroenterologyAcademy of MedicineLithuanian University of Health ScienceKaunasLithuania
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