|
1
|
Klesiewicz K, Orczykowska-Kotyna M, Skiba-Kurek I, Empel J, Kania K, Karczewska E. Prevalence and antimicrobial resistance of highly virulent cagA-positive Helicobacter pylori strains in Southern Poland. Eur J Clin Microbiol Infect Dis 2025; 44:405-416. [PMID: 39688753 DOI: 10.1007/s10096-024-05018-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 12/11/2024] [Indexed: 12/18/2024]
Abstract
PURPOSE Assessment of Helicobacter pylori (H. pylori) prevalence in Southern Poland, focusing on highly virulent cagA-positive strains associated with gastric cancer risk, along with analysis of antimicrobial resistance and its molecular mechanisms. METHODS A total of 130 dyspeptic patients, who underwent endoscopy, were enrolled in the study. Presence of H. pylori in gastric mucosa biopsy specimens was confirmed by rapid urease tests, histological examination, culture, and molecular assays. Antimicrobial susceptibility was tested using the E-test, while the cagA gene (virulence marker) was identified by PCR. The GenoType HelicoDR detected mutations for resistance to clarithromycin (23 S rRNA) and levofloxacin (gyrA). Resistance to rifampicin and levofloxacin was investigated by sequencing the rpoB and gyrA genes. RESULTS H. pylori prevalence in Southern Poland was 30.8%, with 60% of infections involving cagA-positive strains. Susceptibility testing revealed resistance rates of 22.9% for metronidazole, 14.3% for clarithromycin, 11.4% for levofloxacin and 25.7% for rifampicin. Among the 24 cagA-positive strains, 45.8% were resistant to at least one antibiotic. Clarithromycin resistance was caused by A2143G mutation. The gyrA gene sequence showed the N87K mutation linked to fluoroquinolone resistance. No mutations were found in the rpoB gene. CONCLUSION Infections with multidrug-resistant CagA-positive strains require recommended treatment strategies due to the high risk of progression of infection to gastric cancer.
Collapse
Affiliation(s)
- Karolina Klesiewicz
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Krakow, 30-688, Poland.
| | - Monika Orczykowska-Kotyna
- Department of Epidemiology and Clinical Microbiology, National Medicines Institute, 30/34 Chełmska Street, Warsaw, 00-725, Poland
| | - Iwona Skiba-Kurek
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Krakow, 30-688, Poland
| | - Joanna Empel
- Department of Epidemiology and Clinical Microbiology, National Medicines Institute, 30/34 Chełmska Street, Warsaw, 00-725, Poland
| | - Katarzyna Kania
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Krakow, 30-688, Poland
- Microbiological Laboratory, The St. John Paul II Specialist Hospital, Pradnicka 80 Street, Krakow, 31-202, Poland
| | - Elżbieta Karczewska
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, Krakow, 30-688, Poland
| |
Collapse
|
|
2
|
Zhang PP, Li L, Qu HY, Chen GY, Xie MZ, Chen YK. Traditional Chinese medicine in the treatment of Helicobacter pylori-related gastritis: The mechanisms of signalling pathway regulations. World J Gastroenterol 2025; 31:96582. [PMID: 39839895 PMCID: PMC11684169 DOI: 10.3748/wjg.v31.i3.96582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 09/29/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
Helicobacter pylori-associated gastritis (HPAG) is a common condition of the gastrointestinal tract. However, extensive and long-term antibiotic use has resulted in numerous adverse effects, including increased resistance, gastrointestinal dysfunction, and increased recurrence rates. When these concerns develop, traditional Chinese medicine (TCM) may have advantages. TCM is based on the concept of completeness and aims to eliminate pathogens and strengthen the body. It has the potential to prevent this condition while also boosting the rate of Helicobacter pylori eradication. This review elaborates on the mechanism of TCM treatment for HPAG based on cellular signalling pathways, which reflects the flexibility of TCM in treating diseases and the advantages of multi-level, multi-pathway, and multi-target treatments for HPAG.
Collapse
Affiliation(s)
- Pei-Pei Zhang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Liang Li
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Hao-Yu Qu
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- School of Informatics, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Guang-Yu Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Meng-Zhou Xie
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Hunan Engineering Technology Research Center for Medicinal and Functional Food, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Key Laboratory of Traditional Chinese Medicine Heart and Lung Syndrome Differentiation and Medicated Diet and Dietotherapy, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
| | - Yan-Kun Chen
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410200, Hunan Province, China
- Precision Medicine Research and Development Center, Zhuhai Institute of Advanced Technology, Chinese Academy of Sciences, Zhuhai 519000, Guangdong Province, China
| |
Collapse
|
|
3
|
Guo J, Yan S, Jiang X, Su Z, Zhang F, Xie J, Hao E, Yao C. Advances in pharmacological effects and mechanism of action of cinnamaldehyde. Front Pharmacol 2024; 15:1365949. [PMID: 38903995 PMCID: PMC11187351 DOI: 10.3389/fphar.2024.1365949] [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: 01/05/2024] [Accepted: 05/06/2024] [Indexed: 06/22/2024] Open
Abstract
Cinnamaldehyde is extracted from Cinnamomum cassia and other species, providing diverse sources for varying chemical properties and therapeutic effects. Besides natural extraction, synthetic production and biotechnological methods like microbial fermentation offer scalable and sustainable alternatives. Cinnamaldehyd demonstrates a broad pharmacological range, impacting various diseases through detailed mechanisms. This review aims to encapsulate the diverse therapeutic effects of cinnamaldehyde, its molecular interactions, and its potential in clinical applications. Drawing on recent scientific studies and databases like Web of Science, PubMed, and ScienceDirect, this review outlines cinnamaldehyde's efficacy in treating inflammatory conditions, bacterial infections, cancer, diabetes, and cardiovascular and kidney diseases. It primarily operates by inhibiting the NF-κB pathway and modulating pro-inflammatory mediators, alongside disrupting bacterial cells and inducing apoptosis in cancer cells. The compound enhances metabolic health by improving glucose uptake and insulin sensitivity and offers cardiovascular protection through its anti-inflammatory and lipid-lowering effects. Additionally, it promotes autophagy in kidney disease management. Preclinical and clinical research supports its therapeutic potential, underscoring the need for further investigation into its mechanisms and safety to develop new drugs based on cinnamaldehyde.
Collapse
Affiliation(s)
- Jiageng Guo
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Shidu Yan
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Xinya Jiang
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Zixia Su
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Fan Zhang
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Jinling Xie
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Erwei Hao
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
- Engineering Research Center of Innovative Drugs for Traditional Chinese Medicine and Zhuang and Yao Medicine, Ministry of Education, Guangxi University of Chinese Medicine, Nanning, China
| | - Chun Yao
- Engineering Research Center of Innovative Drugs for Traditional Chinese Medicine and Zhuang and Yao Medicine, Ministry of Education, Guangxi University of Chinese Medicine, Nanning, China
| |
Collapse
|
|
4
|
Domínguez-Martínez DA, Fontes-Lemus JI, García-Regalado A, Juárez-Flores Á, Fuentes-Pananá EM. IL-8 Secreted by Gastric Epithelial Cells Infected with Helicobacter pylori CagA Positive Strains Is a Chemoattractant for Epstein-Barr Virus Infected B Lymphocytes. Viruses 2023; 15:651. [PMID: 36992360 PMCID: PMC10054738 DOI: 10.3390/v15030651] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/09/2023] [Accepted: 02/14/2023] [Indexed: 03/05/2023] Open
Abstract
Helicobacter pylori and EBV are considered the main risk factors in developing gastric cancer. Both pathogens establish life-lasting infections and both are considered carcinogenic in humans. Different lines of evidence support that both pathogens cooperate to damage the gastric mucosa. Helicobacter pylori CagA positive virulent strains induce the gastric epithelial cells to secrete IL-8, which is a potent chemoattractant for neutrophils and one of the most important chemokines for the bacterium-induced chronic gastric inflammation. EBV is a lymphotropic virus that persists in memory B cells. The mechanism by which EBV reaches, infects and persists in the gastric epithelium is not presently understood. In this study, we assessed whether Helicobacter pylori infection would facilitate the chemoattraction of EBV-infected B lymphocytes. We identified IL-8 as a powerful chemoattractant for EBV-infected B lymphocytes, and CXCR2 as the main IL-8 receptor whose expression is induced by the EBV in infected B lymphocytes. The inhibition of expression and/or function of IL-8 and CXCR2 reduced the ERK1/2 and p38 MAPK signaling and the chemoattraction of EBV-infected B lymphocytes. We propose that IL-8 at least partially explains the arrival of EBV-infected B lymphocytes to the gastric mucosa, and that this illustrates a mechanism of interaction between Helicobacter pylori and EBV.
Collapse
Affiliation(s)
- Diana A. Domínguez-Martínez
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
| | - José I. Fontes-Lemus
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
| | - Alejandro García-Regalado
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
| | - Ángel Juárez-Flores
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
- Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico
| | - Ezequiel M. Fuentes-Pananá
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gómez, Mexico City 06720, Mexico
| |
Collapse
|
|
5
|
Lee J, Kim MH, Kim H. Anti-Oxidant and Anti-Inflammatory Effects of Astaxanthin on Gastrointestinal Diseases. Int J Mol Sci 2022; 23:ijms232415471. [PMID: 36555112 PMCID: PMC9779521 DOI: 10.3390/ijms232415471] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
A moderate amount of reactive oxygen species (ROS) is produced under normal conditions, where they play an important role in cell signaling and are involved in many aspects of the immune response to pathogens. On the other hand, the excessive production of ROS destructs macromolecules, cell membranes, and DNA, and activates pro-inflammatory signaling pathways, which may lead to various pathologic conditions. Gastrointestinal (GI) mucosa is constantly exposed to ROS due to the presence of bacteria and other infectious pathogens in food, as well as alcohol consumption, smoking, and the use of non-steroidal anti-inflammatory drugs (NSAID). Prolonged excessive oxidative stress and inflammation are two major risk factors for GI disorders such as ulcers and cancers. Bioactive food compounds with potent anti-oxidant and anti-inflammatory activity have been tested in experimental GI disease models to evaluate their therapeutic potential. Astaxanthin (AST) is a fat-soluble xanthophyll carotenoid that is naturally present in algae, yeast, salmon, shrimp, and krill. It has been shown that AST exhibits protective effects against GI diseases via multiple mechanisms. Residing at the surface and inside of cell membranes, AST directly neutralizes ROS and lipid peroxyl radicals, enhances the activity of anti-oxidant enzymes, and suppresses pro-inflammatory transcription factors and cytokines. In addition, AST has been shown to inhibit cancer cell growth and metastasis via modulating cell proliferation-related pathways, apoptosis, and autophagy. Considering the potential benefits of AST in GI diseases, this review paper aims to summarize recent advances in AST research, focusing on its anti-oxidant and anti-inflammatory effects against gastric and intestinal ulcers and cancers.
Collapse
Affiliation(s)
- Jaeeun Lee
- Department of Food and Nutrition, BK21 FOUR, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
| | - Min-Hyun Kim
- College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA
- Correspondence: (M.-H.K.); (H.K.); Tel.: +1-602-496-4163 (M.-H.K.); +82-2-2123-3125 (H.K.)
| | - Hyeyoung Kim
- Department of Food and Nutrition, BK21 FOUR, College of Human Ecology, Yonsei University, Seoul 03722, Republic of Korea
- Correspondence: (M.-H.K.); (H.K.); Tel.: +1-602-496-4163 (M.-H.K.); +82-2-2123-3125 (H.K.)
| |
Collapse
|
|
6
|
Sharafutdinov I, Ekici A, Vieth M, Backert S, Linz B. Early and late genome-wide gastric epithelial transcriptome response during infection with the human carcinogen Helicobacterpylori. CELL INSIGHT 2022; 1:100032. [PMID: 37193047 PMCID: PMC10120309 DOI: 10.1016/j.cellin.2022.100032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/20/2022] [Accepted: 05/21/2022] [Indexed: 05/18/2023]
Abstract
Infection of the stomach by Helicobacter pylori is a major risk factor for the development of gastric cancer. Colonization of the gastric epithelium leads to the activation of multiple disease-related signaling pathways. Serine protease HtrA represents an important secreted virulence factor that mediates cleavage of cellular junctions. However, its potential role in nuclear responses is unknown. Here, we performed a genome-wide RNA-seq analysis of polarized gastric epithelial cells infected by wild-type (wt) and ΔhtrA mutant bacteria. Fluorescence microscopy showed that H. pylori wt, but not ΔhtrA bacteria, preferably localized at cellular junctions. Our results pinpointed early (2 h) and late (6 h) transcriptional responses, with most differentially expressed genes at 6 h post infection. The transcriptomes revealed HtrA-dependent targeting of genes associated with inflammation and apoptosis (e.g. IL8, ZFP36, TNF). Accordingly, infection with the ΔhtrA mutant induced increased apoptosis rates in host cells, which was associated with reduced H. pylori CagA expression. In contrast, transcription of various carcinogenesis-associated genes (e.g. DKK1, DOCK8) was affected by H. pylori independent of HtrA. These findings suggest that H. pylori disturbs previously unknown molecular pathways in an HtrA-dependent and HtrA-independent manner, and provide valuable new insights of this significant pathogen in humans and thus potential targets for better controlling the risk of malignant transformation.
Collapse
Affiliation(s)
- Irshad Sharafutdinov
- Department of Biology, Division of Microbiology, Friedrich Alexander Universität Erlangen-Nürnberg, Staudtstr. 5, D-91058, Erlangen, Germany
| | - Arif Ekici
- Institute of Human Genetics, University Hospital, Friedrich Alexander Universität Erlangen-Nürnberg, Schwabachanlage 10, D-91054, Erlangen, Germany
| | - Michael Vieth
- Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Klinikum Bayreuth, Preuschwitzer Str 101, D-95445, Bayreuth, Germany
| | - Steffen Backert
- Department of Biology, Division of Microbiology, Friedrich Alexander Universität Erlangen-Nürnberg, Staudtstr. 5, D-91058, Erlangen, Germany
| | - Bodo Linz
- Department of Biology, Division of Microbiology, Friedrich Alexander Universität Erlangen-Nürnberg, Staudtstr. 5, D-91058, Erlangen, Germany
| |
Collapse
|
|
7
|
Kim HS, Lim JW, Kim H. Korean Red Ginseng Extract Inhibits IL-8 Expression via Nrf2 Activation in Helicobacter pylori-Infected Gastric Epithelial Cells. Nutrients 2022; 14:nu14051044. [PMID: 35268019 PMCID: PMC8912635 DOI: 10.3390/nu14051044] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 02/25/2022] [Accepted: 02/27/2022] [Indexed: 12/28/2022] Open
Abstract
Helicobacter pylori (H. pylori) causes gastric diseases by increasing reactive oxygen species (ROS) and interleukin (IL)-8 expression in gastric epithelial cells. ROS and inflammatory responses are regulated by the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of Nrf2 target genes, superoxide dismutase (SOD) and heme oxygenase-1 (HO-1). We previously demonstrated that Korean red ginseng extract (RGE) decreases H. pylori-induced increases in ROS and monocyte chemoattractant protein 1 in gastric epithelial cells. We determined whether RGE suppresses the expression of IL-8 via Nrf2 activation and the expression of SOD and HO-1 in H. pylori-infected gastric epithelial AGS cells. H. pylori-infected cells were treated with RGE with or without ML385, an Nrf2 inhibitor, or zinc protoporphyrin (ZnPP), a HO-1 inhibitor. Levels of ROS and IL-8 expression; abundance of Keap1, HO-1, and SOD; levels of total, nuclear, and phosphorylated Nrf2; indices of mitochondrial dysfunction (reduction in mitochondrial membrane potential and ATP level); and SOD activity were determined. As a result, RGE disturbed Nrf2–Keap1 interactions and increased nuclear Nrf2 levels in uninfected cells. H. pylori infection decreased the protein levels of SOD-1 and HO-1, as well as SOD activity, which was reversed by RGE treatment. RGE reduced H. pylori-induced increases in ROS and IL-8 levels as well as mitochondrial dysfunction. ML385 or ZnPP reversed the inhibitory effect of RGE on the alterations caused by H. pylori. In conclusion, RGE suppressed IL-8 expression and mitochondrial dysfunction via Nrf2 activation, induction of SOD-1 and HO-1, and reduction of ROS in H. pylori-infected cells.
Collapse
Affiliation(s)
| | | | - Hyeyoung Kim
- Correspondence: ; Tel.: +82-2-2123-3125; Fax: +82-2-364-5781
| |
Collapse
|
|
8
|
Kathi PR, Babaria R, Banerjee B. Impact of helicobacter pylori on human physiology and digestive disorders. NUTRITION AND FUNCTIONAL FOODS IN BOOSTING DIGESTION, METABOLISM AND IMMUNE HEALTH 2022:193-205. [DOI: 10.1016/b978-0-12-821232-5.00021-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
9
|
Sarsenbaeva AS. <i>Helicobacter pylori</i>-associated comorbidity. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:38-52. [DOI: 10.31146/1682-8658-ecg-193-9-38-52] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Helicobacter pylori (H. pylori) infection is known to lead to various diseases such as gastric and duodenal ulcers, chronic gastritis and malignant diseases, including MALT lymphoma and stomach cancer. To date, various factors of pathogenicity and virulence of the H. pylori bacterium have been studied. The interaction of infection with host cells leads to the induction of inflammatory responses through the release of cytokines, activation of apoptosis or proliferation, which leads to inflammation and dysfunction of the epithelial barrier. This process can facilitate the movement of H. pylori virulence factors and inflammatory mediators into the bloodstream and promote or enhance the development of a systemic inflammatory response and the possible clinical effects of H. pylori infections outside the stomach. The purpose of this review is to clarify the available data on H. pylori-associated comorbidity with diseases of the cardiovascular, nervous, endocrine systems, autoimmune diseases and some other pathologies outside the digestive system.
Collapse
Affiliation(s)
- A. S. Sarsenbaeva
- South Ural State Medical University of the Ministry of Health of the Russian Federation
| |
Collapse
|
|
10
|
Silitonga H, Siregar GA, Sembiring RJ, Nainggolan M. The Effectiveness of Sechium edule Jacq. Swartz Extract Changes in the Histopathology of Aspirin-Induced Rat Gastritis Model. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Gastritis is one of the most common diseases found in internal medicine clinics and daily life.
AIM: The purpose of this study was to determine the histopathological changes of gastric rat model of aspirin-induced gastritis.
MATERIALS AND METHODS: Group K(−) is a negative control (normal) not given any treatment, Group K(+) is a positive control induced by aspirin 200 mg/kgBW, Group 1 (P1) is a treatment group induced by aspirin 200 mg/kgBW with ethanol extract of chayote 100 mg/kgBW, po, Group 2 (P2) was the treatment group induced by aspirin 200 mg/kgBW with ethanol extract of chayote 200 mg/kgBW, po, Group 3 (P3) was the treatment group induced by aspirin 200 mg/kgBW with ethyl acetate fraction chayote 100 mg/kgBW, PO, Group 4 (P4) was the treatment group induced by aspirin 200 mg/kgBW with ethyl acetate fraction chayote 200 mg/kgBW, PO, and Group 5 (P5) was the treatment group induced by aspirin 200 mg/kgBW with omeprazole 20 mg.
RESULTS: Analysis of the results of inflammatory infiltration in gastric histopathology in Groups P1, P2, P3, and P4 showed mild inflammatory infiltration compared to Groups P(5) and K(+). The description of the acinar glands on gastric histopathology showed that the P2 group gave a better picture of the acinar gland repair than the K(+), P2, P3, P4, and P5 groups.
CONCLUSION: This study showed that ethanol extracts of squash 200 mg/KgBW own effectiveness as an anti-inflammatory on the improvement of infiltration of inflammatory and picture histopathological gastric mice compared with the ethanol extract of squash 100 mg/kg, the fraction of ethyl acetate chayote 100 mg/KgBW and 200 mg/KgBW and omeprazole 20 mg.
Collapse
|
|
11
|
Association of Helicobacter pylori Infection and Host Cytokine Gene Polymorphism with Gastric Cancer. Can J Gastroenterol Hepatol 2021; 2021:8810620. [PMID: 34136433 PMCID: PMC8177986 DOI: 10.1155/2021/8810620] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 05/18/2021] [Indexed: 12/13/2022] Open
Abstract
The global cancer burden of new cases of various types rose with millions of death in 2018. Based on the data extracted by GLOBOCAN 2018, gastric cancer (GC) is the third leading cause of mortality related to cancer across the globe. Carcinogenic or oncogenic infections associated with Helicobacter pylori (Hp) are regarded as one of the essential risk factors for GC development. It contributes to the increased production of cytokines that cause inflammation prior to their growth in the host cells. Hp infections and specific types of polymorphisms within the host cells encoding cytokines are significant contributors to the host's increased susceptibility in terms of the development of GC. Against the backdrop of such an observation is that only a small portion of the cells infected can become malignant. The diversities are a consequence of the differences in the pathogenic pathway of the Hp, susceptibility of the host, environmental conditions, and interplay between these factors. It is evident that hosts carrying cytokine genes with high inflammatory levels and polymorphism tend to exhibit an increased risk of development of GC, with special emphasis being placed on the host cytokines gene polymorphisms.
Collapse
|
|
12
|
Yoon K, Kim N. Significance of Helicobacter pylori Eradication on Atrophic Gastritis and Intestinal Metaplasia. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2020. [DOI: 10.7704/kjhugr.2020.0018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
There has been an accumulation of data regarding the chemopreventive effects of <i>Helicobacter pylori</i> (<i>H. pylori</i>) eradication. However, it remains unclear how <i>H. pylori</i> infection causes gastric cancer (GC) and how <i>H. pylori</i> eradication can prevent GC. Atrophic gastritis (AG) and intestinal metaplasia (IM) are known as precancerous lesions which mainly lead to intestinal-type GC but to some extent, can also lead to diffuse-type GC. The most important mechanism of AG/IM is <i>H. pylori</i>-induced chronic gastritis. Thus, the reversibility of AG and IM by <i>H. pylori</i> eradication therapy is very important in the prevention of GC. There have been many studies providing data supporting the improvement of AG by the eradication of <i>H. pylori</i> to some extent. In contrast, IM has been regarded as “the point of no return.” However, more recent studies have implied the improvement of IM after eradication, suggesting the importance of early eradication therapy in reversible histological status. In this review, we focused on the reversibility of AG and IM by <i>H. pylori</i> eradication and tried to investigate the predicting factors for the improvement of AG and IM including age, sex, smoking, and diet, as well as <i>H. pylori</i> infection.
Collapse
|
|
13
|
Tabata N, Sueta D, Arima Y, Okamoto K, Shono T, Hanatani S, Takashio S, Oniki K, Saruwatari J, Sakamoto K, Kaikita K, Sinning JM, Werner N, Nickenig G, Sasaki Y, Fukui T, Tsujita K. Cytotoxin-associated gene-A-seropositivity and Interleukin-1 polymorphisms influence adverse cardiovascular events. IJC HEART & VASCULATURE 2020; 27:100498. [PMID: 32181324 PMCID: PMC7062927 DOI: 10.1016/j.ijcha.2020.100498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 02/29/2020] [Accepted: 03/02/2020] [Indexed: 11/28/2022]
Abstract
Aims Although the bacterial virulent factor of cytotoxin-associated gene-A (CagA)-seropositivity and the host genetic factors of interleukin (IL)-1 polymorphisms have been suggested to influence Helicobacter pylori (HP) -related diseases, the underlying mechanisms of the association between HP infection and acute coronary syndrome (ACS) remain unknown. Methods and results Among 341 consecutive ACS patients, the clinical outcomes after ACS included composite cardiovascular events within the 2-year follow-up period. A significantly higher probability of primary outcomes was observed in HP positive patients than in HP negative patients. There were no significant differences in the rate of cardiovascular events between HP positive and HP negative patients in the absence of an IL-polymorphism, while there were significant differences in the presence of an IL-polymorphism. There were significant differences in the rate of cardiovascular events among CagA positive, CagA negative/ HP positive and CagA negative/HP negative patients. Moreover, via immunohistochemical staining, aortic CagA positive cells were confirmed in the vasa vasorum in CagA positive patients, whereas they could not be identified in CagA negative patients. Conclusions The bacterial virulence factor CagA and host genetic IL-1 polymorphisms influence the incidence of adverse cardiovascular events, possibly through infection of atherosclerotic lesions. Registration: University Hospital Medical Information Network (UMIN)-CTR (http://www.umin.ac.jp/ctr/). Identifier: UMIN000035696.
Collapse
Affiliation(s)
- Noriaki Tabata
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan.,Medizinische Klinik und Poliklinik II, Herzzentrum Bonn, Universitätsklinikum Bonn, Bonn, Germany
| | - Daisuke Sueta
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Yuichiro Arima
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Ken Okamoto
- Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Takashi Shono
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Shinsuke Hanatani
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Seiji Takashio
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Kentaro Oniki
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Junji Saruwatari
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Kenji Sakamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Koichi Kaikita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Jan-Malte Sinning
- Medizinische Klinik und Poliklinik II, Herzzentrum Bonn, Universitätsklinikum Bonn, Bonn, Germany
| | - Nikos Werner
- Medizinische Klinik und Poliklinik II, Herzzentrum Bonn, Universitätsklinikum Bonn, Bonn, Germany
| | - Georg Nickenig
- Medizinische Klinik und Poliklinik II, Herzzentrum Bonn, Universitätsklinikum Bonn, Bonn, Germany
| | - Yutaka Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Toshihiro Fukui
- Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto City, Japan
| |
Collapse
|
|
14
|
Zeng B, Chen C, Yi Q, Zhang X, Wu X, Zheng S, Li N, She F. N-terminal region of Helicobacter pylori CagA induces IL-8 production in gastric epithelial cells via the β1 integrin receptor. J Med Microbiol 2020; 69:457-464. [DOI: 10.1099/jmm.0.001088] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Introduction.
Helicobacter pylori
is associated with gastrointestinal disease, most notably gastric cancer. Cytotoxin-associated antigen A (CagA), an important virulence factor for
H. pylori
pathogenicity, induces host cells to release inflammatory factors, especially interleukin-8 (IL-8). The mechanism by which C-terminal CagA induces IL-8 production has been studied extensively, but little is known about the role of the N-terminus.
Aim. To investigate the effect of CagA303–456aa (a peptide in the N-terminal CagA) on IL-8 production by gastric epithelial cells.
Methodology. CagA303-456aa was produced by a prokaryotic expression system and purified by Strep-tag affinity chromatography. An integrin β1 (ITGB1)-deficient AGS cell line was constructed using the CRISPR/Cas9 technique, and NCTC 11637 cagA and/or cagL knockout mutants were constructed via homologous recombination. The levels of IL-8 production were determined by enzyme-linked immunosorbent assay (ELISA), and p38 and ERK1/2 phosphorylation were examined by Western blot.
Results. CagA303-456aa induced IL-8 expression by AGS cells. IL-8 induction by CagA303-456aawas specifically inhibited by ITGB1 deficiency. Notably, CagA303-456aa activated the phosphorylation of both p38 and ERK1/2, and blocking p38 and ERK1/2 activity significantly reduced IL-8 induction by CagA303-456aa. ITGB1 deficiency also inhibited the activation of p38 phosphorylation by CagA303-456aa. Finally, experiments in CagA and/or CagL knockout bacterial lines demonstrated that extracellular CagA might induce IL-8 production by AGS cells.
Conclusion. Residues 303–456 of the N-terminal region of CagA induce IL-8 production via a CagA303-456–ITGB1–p38–IL-8 pathway, and ERK1/2 is also involved in the release of IL-8. Extracellular CagA might induce IL-8 production before translocation into AGS cells.
Collapse
Affiliation(s)
- Bangwei Zeng
- Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian Province 350001, PR China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
| | - Chu Chen
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
| | - Qingfeng Yi
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
| | - Xiaoyan Zhang
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
| | - Xiangyan Wu
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
| | - Shurong Zheng
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
| | - Neng Li
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
| | - Feifei She
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
- Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, University Town, Fuzhou, Fujian Province 350122, PR China
| |
Collapse
|
|
15
|
Fang Y, Fan C, Xie H. Effect of Helicobacter pylori infection on the risk of acute coronary syndrome: A systematic review and meta-analysis. Medicine (Baltimore) 2019; 98:e18348. [PMID: 31852134 PMCID: PMC6922357 DOI: 10.1097/md.0000000000018348] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Numerous studies have illustrated the association between Helicobacter pylori (H pylori) infection and acute coronary syndrome (ACS). However, the results are contradictory. Therefore, we conducted the meta-analysis to identify the association between H pylori and ACS. METHODS We performed a systematic search through electronic databases (Excerpta Medica Database, PubMed, Cochrane Library, and Web of Science). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random effect model. We also carried out the sensitivity analysis and publication bias. RESULTS Forty-four eligible studies involving 7522 cases and 8311 controls were included. The pooled result showed that H pylori infection was associated with an increase risk of ACS (OR = 2.03, 95% CI 1.66-2.47). In addition, similar results were obtained in subgroups of study quality, area, human development index, and H pylori detection method. The OR for developing countries was significantly higher than developed countries (OR = 2.58 vs OR = 1.69). Moreover, H pylori with cytotoxin-associated antigen A was also significantly associated with an increase risk of ACS (OR = 2.39, 95% CI 1.21-4.74). CONCLUSION The meta-analysis suggested that H pylori infection was associated with an increased risk of ACS, especially in developing countries. H pylori is easily screened and can be treated with a wide range of drugs. Thus, more high-quality and well-designed studies are needed to confirm whether the treatment of H pylori is an effective way to reduce ACS risk.
Collapse
|
|
16
|
Kyung S, Lim JW, Kim H. α-Lipoic Acid Inhibits IL-8 Expression by Activating Nrf2 Signaling in Helicobacter pylori-infected Gastric Epithelial Cells. Nutrients 2019; 11:nu11102524. [PMID: 31635029 PMCID: PMC6835494 DOI: 10.3390/nu11102524] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) causes gastritis and gastric cancers. Oxidative stress is involved in the pathological mechanism of H. pylori-induced gastritis and gastric cancer induction. Therefore, reducing oxidative stress may be beneficial for preventing the development of H. pylori-associated gastric diseases. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial regulator for the expression of antioxidant enzyme heme oxygenase-1 (HO-1), which protects cells from oxidative injury. α-Lipoic acid (α-LA), a naturally occurring dithiol, shows antioxidant and anti-inflammatory effects in various cells. In the present study, we examined the mechanism by which α-LA activates the Nrf2/HO-1 pathway, suppresses the production of pro-inflammatory cytokine interleukine-8 (IL-8), and reduces reactive oxygen species (ROS) in H. pylori-infected AGS cells. α-LA increased the level of phosphorylated and nuclear-translocated Nrf2 by decreasing the amount of Nrf2 sequestered in the cytoplasm by complex formation with Kelch-like ECH1-associated protein 1 (KEAP 1). By using exogenous inhibitors targeting Nrf2 and HO-1, we showed that up-regulation of activated Nrf2 and of HO-1 results in the α-LA-induced suppression of interleukin 8 (IL-8) and ROS. Consumption of α-LA-rich foods may prevent the development of H. pylori-associated gastric diseases by decreasing ROS-mediated IL-8 expression in gastric epithelial cells.
Collapse
Affiliation(s)
- Seoyeon Kyung
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| |
Collapse
|
|
17
|
Resolution of Gastric Cancer-Promoting Inflammation: A Novel Strategy for Anti-cancer Therapy. Curr Top Microbiol Immunol 2019; 421:319-359. [PMID: 31123895 DOI: 10.1007/978-3-030-15138-6_13] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.
Collapse
|
|
18
|
Sarma A, Saikia L, Bhuyan RK, Hussain E. Molecular identification and detection of virulent factors in Helicobacter pylori from gastric biopsy samples of patients attended at Assam Medical College and Hospital, Dibrugarh, Assam, India. Indian J Med Microbiol 2018; 35:600-603. [PMID: 29405158 DOI: 10.4103/ijmm.ijmm_17_232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The present study aimed to detect the major virulence determinants of Helicobacter pylori, the gastric bacteria by polymerase chain reaction from genomic DNA of 314 gastric biopsies from dyspeptic patients in 2015-2016 through upper gastrointestinal endoscopy. In 153 cases out of 314, the high prevalence of oipA gene followed by cagA-vacA s1 m1 combined genotypes was found in mostly gastritis/duodenitis patients followed by the peptic ulcer and normal patients. Therefore, the clinical significance of the virulence markers of H. pylori associated with the severe forms of gastroduodenal diseases is still a matter of controversy since the endoscopically normal patients were found to harbour the virulent genes.
Collapse
Affiliation(s)
- Anisha Sarma
- Department of Microbiology, Assam Medical College and Hospital, Dibrugarh, Assam, India
| | - Lahari Saikia
- Department of Microbiology, Assam Medical College and Hospital, Dibrugarh, Assam, India
| | - Ratna Kanta Bhuyan
- Department of Surgery, Assam Medical College and Hospital, Dibrugarh, Assam, India
| | - Ezaz Hussain
- Department of Microbiology, Assam Medical College and Hospital, Dibrugarh, Assam, India
| |
Collapse
|
|
19
|
Park HS, Wijerathne CUB, Jeong HY, Seo CS, Ha H, Kwun HJ. Gastroprotective effects of Hwanglyeonhaedok-tang against Helicobacter pylori-induced gastric cell injury. JOURNAL OF ETHNOPHARMACOLOGY 2018; 216:239-250. [PMID: 29410309 DOI: 10.1016/j.jep.2018.01.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 01/18/2018] [Accepted: 01/19/2018] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Helicobacter pylori, which is found in the stomachs of approximately half of the world's population, has been associated with the development of chronic gastritis and gastric cancer. Hwanglyeonhaedok-tang (HHT) is a popular traditional medicine for the therapies of gastric ulcers and gastritis. AIM OF THE STUDY The emerging resistance of H. pylori to antibiotics arouses requirement on alternative nonantibiotic-based therapies. In the present study, we investigated the anti-inflammatory activity and anti-microbial activity of HHT against H. pylori in vitro and in an H. pylori-infected mouse model. MATERIALS AND METHODS H. pylori were treated with various concentrations of HHT and then incubated with human gastric carcinoma AGS cells. For the in vivo study, mice were orally infected with H. pylori three times over the course of 1 week, and then subjected to daily administration of HHT (120 or 600 mg/kg) for 4 weeks or standard triple therapy for 1 week. At the scheduled termination of the experiment, all mice were killed and their stomachs were collected for histological examination, quantitative real-time PCR, and Western blot analysis. RESULTS Our in vitro studies showed that HHT treatment inhibited the adhesion of H. pylori to AGS cells and suppressed the H. pylori-induced increases of inflammatory regulators, such as interleukin (IL)-8, cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). In the mouse model, HHT treatment significantly reduced H. pylori colonization, inflammation, and the levels of IL-1β, IL-6, C-X-C motif chemokine ligand 1 (CXCL1), tumor necrosis factor alpha (TNF-α), COX-2, and iNOS in gastric mucosa. Further investigation showed that HHT treatment reduced the H. pylori-induced phosphorylations of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and nuclear factor-kappa B (NF-κB). CONCLUSIONS Our findings collectively suggest that HHT has anti-inflammatory activity and antibacterial activity against H. pylori and could be an alternative to antibiotics for preventing H. pylori infection.
Collapse
Affiliation(s)
- Hee-Seon Park
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea..
| | - Charith U B Wijerathne
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea..
| | - Hye-Yun Jeong
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea..
| | - Chang-Seob Seo
- K-herb Research Center, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea..
| | - Hyekyung Ha
- K-herb Research Center, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea..
| | - Hyo-Jung Kwun
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea..
| |
Collapse
|
|
20
|
Park JY, Forman D, Waskito LA, Yamaoka Y, Crabtree JE. Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer. Toxins (Basel) 2018; 10:E163. [PMID: 29671784 PMCID: PMC5923329 DOI: 10.3390/toxins10040163] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/10/2018] [Accepted: 04/10/2018] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is a major health burden and is the fifth most common malignancy and the third most common cause of death from cancer worldwide. Development of gastric cancer involves several aspects, including host genetics, environmental factors, and Helicobacter pylori infection. There is increasing evidence from epidemiological studies of the association of H. pylori infection and specific virulence factors with gastric cancer. Studies in animal models indicate H. pylori is a primary factor in the development of gastric cancer. One major virulence factor in H. pylori is the cytotoxin-associated gene A (cagA), which encodes the CagA protein in the cag pathogenicity island (cag PAI). Meta-analysis of studies investigating CagA seropositivity irrespective of H. pylori status identified that CagA seropositivity increases the risk of gastric cancer (OR = 2.87, 95% CI: 1.95⁻4.22) relative to the risk of H. pylori infection alone (OR = 2.31, 95% CI: 1.58⁻3.39). Eradicating H. pylori is a strategy for reducing gastric cancer incidence. A meta-analysis of six randomised controlled trials (RCTs) suggests that searching for and eradicating H. pylori infection reduces the subsequent incidence of gastric cancer with a pooled relative risk of 0.66 (95% CI: 0.46⁻0.95). The introduction in regions of high gastric cancer incidence of population-based H. pylori screening and treatment programmes, with a scientifically valid assessment of programme processes, feasibility, effectiveness and possible adverse consequences, would impact the incidence of H. pylori-induced gastric cancer. Given the recent molecular understanding of the oncogenic role of CagA, targeting H. pylori screening and treatment programmes in populations with a high prevalence of H. pylori CagA-positive strains, particularly the more oncogenic East Asian H. pylori CagA strains, may be worth further investigation to optimise the benefits of such strategies.
Collapse
Affiliation(s)
- Jin Young Park
- International Agency for Research on Cancer, 69372 Lyon, France.
| | - David Forman
- International Agency for Research on Cancer, 69372 Lyon, France.
| | - Langgeng Agung Waskito
- Institute of Tropical Disease, Universitas Airlangga, Surabaya 60113, Indonesia.
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita 879-5503, Japan.
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita 879-5503, Japan.
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030, USA.
| | - Jean E Crabtree
- Leeds Institute Biomedical and Clinical Sciences, Wellcome Trust Brenner Building, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
| |
Collapse
|
|
21
|
Hou Y, Sun W, Zhang C, Wang T, Guo X, Wu L, Qin L, Liu T. Meta-analysis of the correlation between Helicobacter pylori infection and autoimmune thyroid diseases. Oncotarget 2017; 8:115691-115700. [PMID: 29383192 PMCID: PMC5777804 DOI: 10.18632/oncotarget.22929] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 11/14/2017] [Indexed: 01/26/2023] Open
Abstract
Objective This study presents a systematic meta-analysis of the correlation between Helicobacter pylori (H. pylori) infection and autoimmune thyroid diseases (AITD). Materials and Methods Fifteen articles including 3,046 cases were selected (1,716 observational and 1,330 control cases). These data were analyzed using Stata12.0 meta-analysis software. Results H. pylori infection was positively correlated with the occurrence of AITD (OR = 2.25, 95% CI: 1.72–2.93). Infection with H. pylori strains positive for the cytotoxin-associated gene A (CagA) were positively correlated with AITD (OR = 1.99, 95% CI: 1.07–3.70). There was no significant difference between infections detected using enzyme-linked immunosorbent assay (ELISA) and other methods (χ2 = 2.151, p = 0.143). Patients with Grave’s disease (GD) and Hashimoto’s thyroiditis (HT) were more susceptible to H. pylori infection (GD: OR = 2.78, 95% CI: 1.68–4.61; HT: OR = 2.16, 95% CI: 1.44–3.23), while the rate of H. pylori infection did not differ between GD and HT (χ2 = 3.113, p = 0.078). Conclusions H. pylori infection correlated with GD and HT, and the eradication of H. pylori infection could reduce thyroid autoantibodies.
Collapse
Affiliation(s)
- Yi Hou
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China.,Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, 100078, People's Republic of China
| | - Wen Sun
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Chengfei Zhang
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China.,Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, 100078, People's Republic of China
| | - Tieshan Wang
- Beijing Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Xuan Guo
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China.,Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, 100078, People's Republic of China
| | - Lili Wu
- Beijing Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Lingling Qin
- Department of Science and Technology, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| | - Tonghua Liu
- Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China
| |
Collapse
|
|
22
|
Helicobacter pylori γ-glutamyl transferase contributes to colonization and differential recruitment of T cells during persistence. Sci Rep 2017; 7:13636. [PMID: 29057967 PMCID: PMC5651840 DOI: 10.1038/s41598-017-14028-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 10/05/2017] [Indexed: 12/22/2022] Open
Abstract
Helicobacter pylori γ-glutamyl transferase (gGT) is a key bacterial virulence factor that is not only important for bacterial gastric colonization but also related to the development of gastric pathology. Despite accumulating evidence for pathogenic and immunologic functions of H. pylori gGT, it is still unclear how it supports gastric colonization and how its specific effects on the host’s innate and adaptive immune responses contribute to colonization and pathology. We have compared mice showing similar bacterial load after infection with gGT-proficient or gGT-deficient H. pylori to analyse the specific role of the enzyme during infection. Our data indicate that H. pylori gGT supports initial colonization. Nevertheless, bacteria lacking gGT can still colonize and persist. We observed that the presence of gGT during infection favoured a proinflammatory innate and adaptive immune response. Notably, H. pylori gGT activity was linked to increased levels of IFNγ, which were attributed to a differential recruitment of CD8+ T cells to the stomach. Our data support an essential role for H. pylori gGT in gastric colonization and further suggest that gGT favours infiltration of CD8+ cells to the gastric mucosa, which might play an important and yet overlooked role in the pathogenesis of H. pylori.
Collapse
|
|
23
|
MIFTAHUSSURUR MUHAMMAD, YAMAOKA YOSHIO, GRAHAM DAVIDY. Helicobacter pylori as an oncogenic pathogen, revisited. Expert Rev Mol Med 2017; 19:e4. [PMID: 28322182 PMCID: PMC6905048 DOI: 10.1017/erm.2017.4] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric cancer is an inflammation-associated malignancy aetiologically related to infection with the bacterium, Helicobacter pylori, which is considered a necessary but insufficient cause. Unless treated, H. pylori causes life-long acute and chronic gastric inflammation resulting in progressive gastric mucosal damage that may result in gastric cancer. The rate of progression from superficial gastritis, to an atrophic metaplastic mucosa, and ultimately to cancer relates to the virulence of the infecting H. pylori as well as host and environmental factors. H. pylori virulence is a reflection of its propensity to cause severe gastric inflammation. Both mucosal inflammation and H. pylori can cause host genomic instability, including dysregulation of DNA mismatch repair, stimulation of expression of activation-induced cytidine deaminase, abnormal DNA methylation and dysregulation of micro RNAs, which may result in an accumulation of mutations and loss of normal regulation of cell growth. The difference in cancer risk between the most and least virulent H. pylori strain is only approximately 2-fold. Overall, none of the putative virulence factors identified to date have proved to be disease-specific. The presence, severity, extent and duration of inflammation appear to be the most important factors and current evidence suggests that any host, environmental or bacterial factor that reliably enhances the inflammatory response to the H. pylori infection increases the risk of gastric cancer.
Collapse
Affiliation(s)
- MUHAMMAD MIFTAHUSSURUR
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan
- Gastroentero-Hepatology Division, Department of Internal Medicine, Faculty of Medicine – Dr Soetomo Teaching Hospital – Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia
| | - YOSHIO YAMAOKA
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan
| | - DAVID Y. GRAHAM
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
| |
Collapse
|
|
24
|
Hamashima C, Sasazuki S, Inoue M, Tsugane S. Receiver operating characteristic analysis of prediction for gastric cancer development using serum pepsinogen and Helicobacter pylori antibody tests. BMC Cancer 2017; 17:183. [PMID: 28279154 PMCID: PMC5345231 DOI: 10.1186/s12885-017-3173-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 03/04/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Chronic Helicobacter pylori infection plays a central role in the development of gastric cancer as shown by biological and epidemiological studies. The H. pylori antibody and serum pepsinogen (PG) tests have been anticipated to predict gastric cancer development. METHODS We determined the predictive sensitivity and specificity of gastric cancer development using these tests. Receiver operating characteristic analysis was performed, and areas under the curve were estimated. The predictive sensitivity and specificity of gastric cancer development were compared among single tests and combined methods using serum pepsinogen and H. pylori antibody tests. RESULTS From a large-scale population-based cohort of over 100,000 subjects followed between 1990 and 2004, 497 gastric cancer subjects and 497 matched healthy controls were chosen. The predictive sensitivity and specificity were low in all single tests and combination methods. The highest predictive sensitivity and specificity were obtained for the serum PG I/II ratio. The optimal PG I/II cut-off values were 2.5 and 3.0. At a PG I/II cut-off value of 3.0, the sensitivity was 86.9% and the specificity was 39.8%. Even if three biomarkers were combined, the sensitivity was 97.2% and the specificity was 21.1% when the cut-off values were 3.0 for PG I/II, 70 ng/mL for PG I, and 10.0 U/mL for H. pylori antibody. CONCLUSIONS The predictive accuracy of gastric cancer development was low with the serum pepsinogen and H. pylori antibody tests even if these tests were combined. To adopt these biomarkers for gastric cancer screening, a high specificity is required. When these tests are adopted for gastric cancer screening, they should be carefully interpreted with a clear understanding of their limitations.
Collapse
Affiliation(s)
- Chisato Hamashima
- Division of Cancer Screening Assessment and Management, Center for Social Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045 Japan
| | - Shizuka Sasazuki
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045 Japan
| | - Manami Inoue
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045 Japan
- Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045 Japan
| | - for the JPHC Study Group
- Division of Cancer Screening Assessment and Management, Center for Social Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045 Japan
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045 Japan
- Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| |
Collapse
|
|
25
|
Dynamic Expansion and Contraction of cagA Copy Number in Helicobacter pylori Impact Development of Gastric Disease. mBio 2017; 8:mBio.01779-16. [PMID: 28223454 PMCID: PMC5358911 DOI: 10.1128/mbio.01779-16] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Infection with Helicobacter pylori is a major risk factor for development of gastric disease, including gastric cancer. Patients infected with H. pylori strains that express CagA are at even greater risk of gastric carcinoma. Given the importance of CagA, this report describes a new molecular mechanism by which the cagA copy number dynamically expands and contracts in H. pylori. Analysis of strain PMSS1 revealed a heterogeneous population in terms of numbers of cagA copies; strains carried from zero to four copies of cagA that were arranged as direct repeats within the chromosome. Each of the multiple copies of cagA was expressed and encoded functional CagA; strains with more cagA repeats exhibited higher levels of CagA expression and increased levels of delivery and phosphorylation of CagA within host cells. This concomitantly resulted in more virulent phenotypes as measured by cell elongation and interleukin-8 (IL-8) induction. Sequence analysis of the repeat region revealed three cagA homologous areas (CHAs) within the cagA repeats. Of these, CHA-ud flanked each of the cagA copies and is likely important for the dynamic variation of cagA copy numbers. Analysis of a large panel of clinical isolates showed that 7.5% of H. pylori strains isolated in the United States harbored multiple cagA repeats, while none of the tested Korean isolates carried more than one copy of cagA. Finally, H. pylori strains carrying multiple cagA copies were differentially associated with gastric disease. Thus, the dynamic expansion and contraction of cagA copy numbers may serve as a novel mechanism by which H. pylori modulates gastric disease development. Severity of H. pylori-associated disease is directly associated with carriage of the CagA toxin. Though the sequences of the CagA protein can differ across strains, previous analyses showed that virtually all H. pylori strains carry one or no copies of cagA. This study showed that H. pylori can carry multiple tandem copies of cagA that can change dynamically. Isolates harboring more cagA copies produced more CagA, thus enhancing toxicity to host cells. Analysis of 314 H. pylori clinical strains isolated from patients in South Korea and the United States showed that 7.5% of clinical strains in the United States carried multiple cagA copies whereas none of the South Korean strains did. This study demonstrated a novel molecular mechanism by which H. pylori dynamically modulates cagA copy number, which affects CagA expression and activity and may impact downstream development of gastric disease.
Collapse
|
|
26
|
Li Z, Wu C, Li L, Wang Z, Xie H, He X, Feng J. Effect of long-term proton pump inhibitor administration on gastric mucosal atrophy: A meta-analysis. Saudi J Gastroenterol 2017; 23:222-228. [PMID: 28721975 PMCID: PMC5539675 DOI: 10.4103/sjg.sjg_573_16] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related gastrointestinal diseases. Recently, some studies have reported that PPIs can alter the gastric mucosal architecture; however, the relationship remains controversial. This meta-analysis study was designed to quantify the association between long-term PPI administration and gastric atrophy. MATERIALS AND METHODS A PubMed search was conducted to identify studies using the keywords proton pump inhibitors or PPI and gastric atrophy or atrophic gastritis; the timeframe of publication searched was up to May 2016. Heterogeneity among studies was tested with the Q test; odds ratios (OR) and 95% confidence intervals (CI) were calculated. P values were calculated by I2 tests and regarded as statistically significant when <0.05. RESULTS We identified 13 studies that included 1465 patients under long-term PPI therapy and 1603 controls, with a total gastric atrophy rate of 14.50%. There was a higher presence of gastric atrophy (15.84%; statistically significant) in PPI group compared to the control group (13.29%) (OR: 1.55, 95% CI: 1.00-2.41). CONCLUSIONS The pooled data suggest that long-term PPI use is associated with increased rates of gastric atrophy. Large-scale multicenter studies should be conducted to further investigate the relationship between acid suppressants and precancerous diseases.
Collapse
Affiliation(s)
- Zhong Li
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Cong Wu
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Ling Li
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Zhaoming Wang
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Haibin Xie
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaozhou He
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jin Feng
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, China,Address for correspondence: Dr. Jin Feng, Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China. E-mail:
| |
Collapse
|
|
27
|
Khaiboullina SF, Abdulkhakov S, Khalikova A, Safina D, Martynova EV, Davidyuk Y, Khuzin F, Faizullina R, Lombardi VC, Cherepnev GV, Rizvanov AA. Serum Cytokine Signature That Discriminates Helicobacter pylori Positive and Negative Juvenile Gastroduodenitis. Front Microbiol 2016; 7:1916. [PMID: 28018296 PMCID: PMC5156714 DOI: 10.3389/fmicb.2016.01916] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 11/15/2016] [Indexed: 12/27/2022] Open
Abstract
Gastroduodenitis caused by H. pylori, often acquired in early childhood, is found in about 50% of the adult population. Although H. pylori infections can remain asymptomatic, its virulence factors usually trigger epithelial vacuolization and degeneration, loss of microvilli, disintegration of cytoplasm, and leukocyte accumulation. It is believed that leukocyte infiltration is driven by cytokines produced locally in infected tissue. However, so far little is known about changes in serum cytokines in juvenile patients infected with H. pylori. Serum cytokine profiles were analyzed in 62 juvenile patients diagnosed with gastroduodenitis using the Bio-Plex multiplex assay. H. pylori infection was confirmed in 32 patients, while 30 patients were H. pylori-free. Cytokines CXCL5 and CXCL6, potent neutrophil chemoattractants, were upregulated in all patients diagnosed with gastroduodenitis. Serum levels of IL8, a prototype neutrophil attractant, remained unchanged in subjects with gastroduodenitis relative to controls. Therefore, our data suggest that CXCL5 and CXCL6 play a role in directing neutrophil trafficking into inflamed gastroduodenal tissue. In addition, the CCL25/GM-CSF ratio differed significantly between H. pylori-positive and -negative juveniles. Further, study is needed to evaluate the role of CCL25 and GM-CSF in the pathogenesis of the different etiologies of gastroduodenitis.
Collapse
Affiliation(s)
| | - Sayar Abdulkhakov
- Institute of Fundamental Medicine and Biology, Kazan Federal UniversityKazan, Russia; Kazan State Medical UniversityKazan, Russia
| | | | - Dilyara Safina
- Institute of Fundamental Medicine and Biology, Kazan Federal University Kazan, Russia
| | - Ekaterina V Martynova
- Institute of Fundamental Medicine and Biology, Kazan Federal University Kazan, Russia
| | - Yuriy Davidyuk
- Institute of Fundamental Medicine and Biology, Kazan Federal University Kazan, Russia
| | | | | | - Vincent C Lombardi
- Institute of Fundamental Medicine and Biology, Kazan Federal UniversityKazan, Russia; Nevada Center for Biomedical ResearchReno, NV, USA
| | - Georgi V Cherepnev
- Institute of Fundamental Medicine and Biology, Kazan Federal UniversityKazan, Russia; Department of Clinical Laboratory Diagnostics, Kazan State Medical AcademyKazan, Russia
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University Kazan, Russia
| |
Collapse
|
|
28
|
Tran CT, Garcia M, Garnier M, Burucoa C, Bodet C. Inflammatory signaling pathways induced by Helicobacter pylori in primary human gastric epithelial cells. Innate Immun 2016; 23:165-174. [DOI: 10.1177/1753425916681077] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Inflammatory signaling pathways induced by Helicobacter pylori remain unclear, having been studied mostly on cell-line models derived from gastric adenocarcinoma with potentially altered signaling pathways and nonfunctional receptors. Here, H. pylori-induced signaling pathways were investigated in primary human gastric epithelial cells. Inflammatory response was analyzed on chemokine mRNA expression and production after infection of gastric epithelial cells by H. pylori strains, B128 and B128Δ cagM, a cag type IV secretion system defective strain. Signaling pathway involvement was investigated using inhibitors of epidermal growth factor receptor (EGFR), MAPK, JAK and blocking Abs against TLR2 and TLR4. Inhibitors of EGFR, MAPK and JAK significantly reduced the chemokine mRNA expression and production induced by both H. pylori strains at 3 h and 24 h post-infection. JNK inhibitor reduced chemokine production at 24 h post-infection. Blocking Abs against TLR2 but not TLR4 showed significant reduction of chemokine secretion. Using primary culture of human gastric epithelial cells, our data suggest that H. pylori can be recognized by TLR2, leading to chemokine induction, and that EGFR, MAPK and the JAK/STAT signaling pathways play a key role in the H. pylori-induced CXCL1, CXCL5 and CXCL8 response in a cag pathogenicity island-independent manner.
Collapse
Affiliation(s)
- Cong Tri Tran
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
- Laboratoire de Bactériologie Hygiène, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Magali Garcia
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
- Laboratoire de Bactériologie Hygiène, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Martine Garnier
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
- Laboratoire de Bactériologie Hygiène, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Christophe Burucoa
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
- Laboratoire de Bactériologie Hygiène, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Charles Bodet
- Laboratoire Inflammation, Tissus Epithéliaux et Cytokines (LITEC - EA 4331), Université de Poitiers, Poitiers, France
| |
Collapse
|
|
29
|
The inhibitory effect of flavonoids on interleukin-8 release by human gastric adenocarcinoma (AGS) cells infected with cag PAI (+) Helicobacter pylori. Cent Eur J Immunol 2016; 41:229-235. [PMID: 27833438 PMCID: PMC5099377 DOI: 10.5114/ceji.2016.63119] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 03/18/2016] [Indexed: 02/07/2023] Open
Abstract
Introduction It is well known that the presence of Helicobacter pylori in the stomach induces gastritis and causes an immune response. Exposure of gastric epithelial cell lines to this germ induces the secretion of interleukin-8 (IL-8), which is a potent PMN-activating chemotactic cytokine. Interleukin-8 is usually elevated in gastric biopsy samples of patients with H. pylori-associated gastritis and significantly increases in the supernatant of in vitro cultivated biopsy samples of gastric mucosa with active H. pylori gastritis. Interleukin-8 is an activating factor for leucocytes and other pro-inflammatory factors, free radicals, and proteolytic enzymes. That is why natural compounds potentially useful in therapy are still investigated – among them flavonoids. They reveal anti-oxidative and anti-inflammatory activities and significantly inhibit the gastric mucosa damage. The aim of the study Was the estimation of the anti-inflammatory effects of flavonoids on H. pylori-induced activation of human gastric adenocarcinoma cells (AGS). After infection of AGS cells by cag PAI (+) H. pylori in vitro, secretion of IL-8, effects of flavonoids on viability of AGS cells, and effects of flavonoids on increase of H. pylori were determined. Such flavones as chrysin, quercetin, kaemferide, flavanone, galangin, and kaempferol were examined. Results This study has shown an inhibitory effect of flavonoids on the release of IL-8 through infected AGS cells (except chrysin), and no toxic effects to AGS cells were observed. Galangin revealed antibacterial effects against H. pylori. Flavonoids limit the inflammatory process through the inhibition of IL-8 release in infected AGS cells with H. pylori. The strongest inhibitor of IL-8 was galangin.
Collapse
|
|
30
|
Raei N, Latifi-Navid S, Zahri S. Helicobacter pylori cag Pathogenicity Island cagL and orf17 Genotypes Predict Risk of Peptic Ulcerations but not Gastric Cancer in Iran. Asian Pac J Cancer Prev 2016; 16:6645-50. [PMID: 26434889 DOI: 10.7314/apjcp.2015.16.15.6645] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is the third most common cancer regarding mortality in the world. The cag pathogenicity island (PAI) of Helicobacter pylori which contains genes associated with a more aggressive phenotype may involve in the pathogenesis of gastrointestinal disease. We here aimed to examine the associations of cagH, cagL, orf17, and cagG genotypes of H. pylori cag PAI with severe gastrointestinal disease. MATERIALS AND METHODS A total of 242 H. pylori strains were genotyped. Histopathological examination and classification of subjects were performed. RESULTS The frequencies of the cagH, cagL, cagG, and orf17 genotypes were 40/54 (74.1%), 53/54 (98.1%), 38/54 (70.4%), and 43/54 (79.6%), respectively, in patients with peptidic ulceration (PU),while in the control group, the frequencies were 87/147 (59.6%) for cagH, 121/146 (82.9%) for cagL, 109/146 (74.7%) for cagG, and 89/146 (61.0%) for orf17. The results of simple logistic regression analysis showed that the cagL and orf17 genotypes were significantly associated with an increased risk of PU not GC; the ORs (95% CI) were 10.950 (1.446-82.935), and 2.504 (1.193-5.253), respectively. No significant association was found between the cagH and cagG genotypes and the risk of both the PU and the GC in Iran (P>0.05). Finally, multiple logistic regression analysis showed that the cagL genotype was independently and significantly associated with the age- and sex-adjusted risk for PU; the OR (95% CI) was 9.557 (1.219-17.185). CONCLUSIONS We conclude that the orf17 and especially cagL genotypes of H. pylori cag PAI could be factors for risk prediction of PU, but not GC in Iran.
Collapse
Affiliation(s)
- Negin Raei
- Department of Biology, Faculty of Sciences, University of Mohaghegh Ardabili, Ardabil, Iran E-mail :
| | | | | |
Collapse
|
|
31
|
Zaidi SF. Helicobacter pylori associated Asian enigma: Does diet deserve distinction? World J Gastrointest Oncol 2016; 8:341-350. [PMID: 27096029 PMCID: PMC4824712 DOI: 10.4251/wjgo.v8.i4.341] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 11/23/2015] [Accepted: 01/22/2016] [Indexed: 02/05/2023] Open
Abstract
Helicobacter pylori (H. pylori) is one of the most widespread infections in humans worldwide that chronically infects up to 50% of the world’s population. The infection is involved in the pathogenesis of chronic active gastritis, peptic ulcer, mucosa-associated lymphoid tissue lymphoma and gastric cancer, therefore, it has been classified as class I definite carcinogen by the World Health Organization. Despite the established etiological role of H. pylori, its actual distribution and association with related diseases is controversial and there is a large intercountry variation especially among Asian countries. H. pylori infection is more frequent in developing countries like India, Pakistan, and Bangladesh as compared to developed Asian countries like Japan, China and South Korea. However, the frequency of gastric cancer is comparatively lower in India, Pakistan, and Bangladesh with that of Japan, China and South Korea. Such phenomenon of clinical diversity, defined as enigma, is judged by genetic variability of the infecting H. pylori strains, differences in the host genetic background in various ethnic groups, and environmental factors such as dietary habits. Most of the studies have so far focused on the bacterial factor while environmental issues, including dietary components, were not given due attention as one of the factors related with H. pylori associated gastric carcinogenesis. The dietary factor has been suggested to play an important role in H. pylori related carcinogenesis, and in this respect several studies have corroborated the intake of various dietary components as modulatory factors for gastric cancer risk. In this review, such studies, from in vitro experiments to clinical trials, are being focused in detail with respect to enigma associated with H. pylori. It may be conceivably concluded from the available evidence that dietary factor can be a game changer in the scenario of Asian enigma, particularly in high risk population infected with virulent H. pylori strains, however further affirmation studies are desperately needed to achieve conclusive outcomes.
Collapse
|
|
32
|
IL-32: A Novel Pluripotent Inflammatory Interleukin, towards Gastric Inflammation, Gastric Cancer, and Chronic Rhino Sinusitis. Mediators Inflamm 2016; 2016:8413768. [PMID: 27143819 PMCID: PMC4837279 DOI: 10.1155/2016/8413768] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Revised: 02/23/2016] [Accepted: 03/20/2016] [Indexed: 12/15/2022] Open
Abstract
A vast variety of nonstructural proteins have been studied for their key roles and involvement in a number of biological phenomenona. Interleukin-32 is a novel cytokine whose presence has been confirmed in most of the mammals except rodents. The IL-32 gene was identified on human chromosome 16 p13.3. The gene has eight exons and nine splice variants, namely, IL-32α, IL-32β, IL-32γ, IL-32δ, IL-32ε, IL-32ζ, IL-32η, IL-32θ, and IL-32s. It was found to induce the expression of various inflammatory cytokines including TNF-α, IL-6, and IL-1β as well as macrophage inflammatory protein-2 (MIP-2) and has been reported previously to be involved in the pathogenesis and progression of a number of inflammatory disorders, namely, inflammatory bowel disease (IBD), gastric inflammation and cancer, rheumatoid arthritis, and chronic obstructive pulmonary disease (COPD). In the current review, we have highlighted the involvement of IL-32 in gastric cancer, gastric inflammation, and chronic rhinosinusitis. We have also tried to explore various mechanisms suspected to induce the expression of this extraordinary cytokine as well as various mechanisms of action employed by IL-32 during the mediation and progression of the above said problems.
Collapse
|
|
33
|
|
|
34
|
Muhammad JS, Zaidi SF, Shaharyar S, Refaat A, Usmanghani K, Saiki I, Sugiyama T. Anti-inflammatory effect of cinnamaldehyde in Helicobacter pylori induced gastric inflammation. Biol Pharm Bull 2015; 38:109-15. [PMID: 25744466 DOI: 10.1248/bpb.b14-00609] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cinnamomum cassia is widely employed for gastrointestinal complaints such as dyspepsia, flatulence, diarrhea, and vomiting. Studies report cinnamaldehyde (CM) as a major active constituent of cinnamon. The aim of this study was to evaluate the anti-inflammatory mechanism of CM on Helicobacter (H.) pylori-infected gastric epithelial cells in order to validate cinnamon traditional use in gastrointestinal (GI)-related disorders. AGS/MKN-45 cells and H. pylori (193C) were employed for co-culture experiments. Anti-H. pylori cytotoxic and anti-adhesion activity of CM were determined. Enzyme linked immunosorbent assay, real time polymerase chain reaction analysis and immunoblotting were used to measure the effect on interleukin-8 (IL-8) secretion/expression. The effect on activation of nuclear factor kappa B (NF-κB) was determined by immunoblot analysis. The non-cytotoxic CM (≤125 µM) was also non-bactericidal at the given time, suggesting the effect in H. pylori/cell co-culture system was not due to alteration in H. pylori viability or the toxicity to the cells. Also, CM did not show any anti-adhesion effect against H. pylori/cell co-culture. However, pre-incubation of the cells with CM significantly inhibited the IL-8 secretion/expression from H. pylori-infected cells (p<0.01). In addition, CM suppressed H. pylori-induced NF-κB activation and prevented degradation of inhibitor (I)-κB This study provides evidence that the anti-inflammatory effect of C. cassia on H. pylori-infected gastric cells is due to blockage of the NF-κB pathway by cinnamaldehyde. This agent can be considered as a potential candidate for in vivo and clinical studies against various H. pylori related gastric pathogenic processes.
Collapse
Affiliation(s)
- Jibran Sualeh Muhammad
- Department of Gastroenterology and Hematology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama
| | | | | | | | | | | | | |
Collapse
|
|
35
|
Fox S, Ryan KA, Berger AH, Petro K, Das S, Crowe SE, Ernst PB. The role of C1q in recognition of apoptotic epithelial cells and inflammatory cytokine production by phagocytes during Helicobacter pylori infection. JOURNAL OF INFLAMMATION-LONDON 2015; 12:51. [PMID: 26357509 PMCID: PMC4563842 DOI: 10.1186/s12950-015-0098-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 08/28/2015] [Indexed: 12/11/2022]
Abstract
Background Gastric epithelial cells (GECs) undergo apoptosis during H. pylori infection and phagocytes within the mucosa engulf these cells. The recognition and clearance of apoptotic cells is a multifactorial process, enhanced by the presence of various bridging molecules and opsonins which are abundant in serum. However, it is not clear how recognition or clearance may differ in the context of H. pylori infection induced apoptosis. In addition, efferocytosis of sterile apoptotic cells is known to confer anti-inflammatory properties in the engulfing phagocyte, however it is unknown if this is maintained when phagocytes encounter H. pylori-infected cells. Thus, the ability of macrophages to bind and engulf gastric epithelial cells rendered apoptotic by H. pylori infection and the association of these interactions to the modulation of phagocyte inflammatory responses was investigated in the absence and presence of serum with a particular focus on the role of serum protein C1q. Methods Control (uninfected) or H. pylori-infected AGS cells were co-cultured with THP-1 macrophages in the presence or absence of serum or serum free conditions + C1q protein (40–80 μg/mL). Binding of AGS cells to THP-1 macrophages was assessed by microscopy and cytokine (IL-6 and TNF-α) release from LPS stimulated THP-1 macrophages was quantified by ELISA. Results We show that macrophages bound preferentially to cells undergoing apoptosis subsequent to infection with H. pylori. Binding of apoptotic AGS to THP-1 macrophages was significantly inhibited when studied in the absence of serum and reconstitution of serum-free medium with purified human C1q restored binding of macrophages to apoptotic cells. Co-culture of sterile apoptotic and H. pylori-infected AGS cells both attenuated LPS-stimulated cytokine production by THP-1 macrophages. Further, direct treatment of THP-1 macrophages with C1q attenuated LPS stimulated TNF-α production. Conclusions These studies suggest that C1q opsonizes GECs rendered apoptotic by H. pylori. No differences existed in the ability of infected or sterile apoptotic cells to attenuate macrophage cytokine production, however, there may be a direct role for C1q in modulating macrophage inflammatory cytokine production to infectious stimuli. Electronic supplementary material The online version of this article (doi:10.1186/s12950-015-0098-8) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Sarah Fox
- Department of Pathology, University of California, La Jolla, San Diego, CA USA
| | - Kieran A Ryan
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA USA ; National University Ireland, Galway, Ireland
| | - Alice H Berger
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA USA ; Broad Institute of MIT and Harvard, Boston, MA USA
| | - Katie Petro
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA USA ; Athersys, Inc, Cleveland, OH USA
| | - Soumita Das
- Department of Pathology, University of California, La Jolla, San Diego, CA USA ; Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA USA
| | - Sheila E Crowe
- Department of Pathology, University of California, La Jolla, San Diego, CA USA ; Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA USA
| | - Peter B Ernst
- Department of Pathology, University of California, La Jolla, San Diego, CA USA ; Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA USA
| |
Collapse
|
|
36
|
Sangiovanni E, Di Lorenzo C, Colombo E, Colombo F, Fumagalli M, Frigerio G, Restani P, Dell'Agli M. The effect of in vitro gastrointestinal digestion on the anti-inflammatory activity of Vitis vinifera L. leaves. Food Funct 2015; 6:2453-63. [PMID: 26102216 DOI: 10.1039/c5fo00410a] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Botanicals are widely consumed all over the world for health purposes, with increased usage in the general population, in many different types of products, including foods and plant food supplements. Several reports support for the beneficial effects of botanicals against gastrointestinal inflammation. However, no studies regarding the anti-inflammatory activity in the gastrointestinal tract of red vine leaves have been reported so far. The present work investigates the biological activity of Vitis vinifera L. water extract (VVWE) from dried leaves in two in vitro models of gastric and intestinal inflammation. The extract was characterized by a validated HPLC-DAD method, and tested on human epithelial gastric (AGS) and intestinal (Caco-2) cells with the aim to investigate the inhibitory effect on IL-8 secretion and promoter activity, before and after in vitro gastric or gastrointestinal digestion. Our results show that the water extract from red vine leaves inhibits TNFα-induced IL-8 secretion and expression in human gastric epithelial cells; the effect should be maintained, although to a lesser extent, after gastric digestion. In contrast, the effect after intestinal digestion is dramatically decreased since degradation of the active components in the gut does not allow the extract to efficiently counteract TNFα or IL-1β induced IL-8 expression and the NF-κB pathway. The main molecular target of VVWE at the gastric level includes TNFα-induced activation of NF-κB and occurs at concentrations easily reachable after PFS consumption based on red vine leaf water extract as the ingredient. Our findings suggest that PFS containing water extracts from Vitis vinifera L. leaves could be useful to inhibit/attenuate gastric inflammation inhibiting IL-8 secretion and expression through impairment of the NF-κB pathway.
Collapse
Affiliation(s)
- E Sangiovanni
- Dipartimento di Scienze Farmacologiche e Biomolecolari; Università degli Studi di Milano, Via Balzaretti, 9, 20133, Milano, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Helicobacter pylori Outer Membrane Protein 18 (Hp1125) Is Involved in Persistent Colonization by Evading Interferon- γ Signaling. BIOMED RESEARCH INTERNATIONAL 2015; 2015:571280. [PMID: 25945338 PMCID: PMC4402576 DOI: 10.1155/2015/571280] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Revised: 10/09/2014] [Accepted: 10/23/2014] [Indexed: 12/30/2022]
Abstract
Outer membrane proteins (OMPs) can induce an immune response. Omp18 (HP1125) of H. pylori is a powerful antigen that can induce significant interferon-γ (IFN-γ) levels. Previous studies have suggested that IFN-γ plays an important role in H. pylori clearance. However, H. pylori has multiple mechanisms to avoid host immune surveillance for persistent colonization. We generated an omp18 mutant (H. pylori 26695 and H. pylori SS1) strain to examine whether Omp18 interacts with IFN-γ and is involved in H. pylori colonization. qRT-PCR revealed that IFN-γ induced Omp18 expression. qRT-PCR and western blot analysis revealed reduced expressions of virulence factors CagA and NapA in H. pylori 26695 with IFN-γ treatment, but they were induced in the Δomp18 strain. In C57BL/6 mice infected with H. pylori SS1 and the Δomp18 strain, the Δomp18 strain conferred defective colonization and activated a stronger inflammatory response. Signal transducer phosphorylation and transcription 1 (STAT1) activator was downregulated by the wild-type strain but not the Δomp18 strain in IFN-γ-treated macrophages. Furthermore, Δomp18 strain survival rates were poor in macrophages compared to the wild-type strain. We concluded that H. pylori Omp18 has an important function influencing IFN-γ-mediated immune response to participate in persistent colonization.
Collapse
|
|
38
|
Chemokines and antimicrobial peptides have a cag-dependent early response to Helicobacter pylori infection in primary human gastric epithelial cells. Infect Immun 2014; 82:2881-9. [PMID: 24778119 DOI: 10.1128/iai.01517-13] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Helicobacter pylori infection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The cag pathogenicity island (cag PAI) of H. pylori allows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response to H. pylori, a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells with H. pylori B128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-α). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models with H. pylori B128ΔcagM, a cag PAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells with H. pylori, inflammatory-mediator production was largely due to cag PAI substrate-independent virulence factors. Thus, H. pylori cag PAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation during H. pylori infection.
Collapse
|
|
39
|
Ikeda A, Iso H, Sasazuki S, Inoue M, Tsugane S. The combination of Helicobacter pylori- and cytotoxin-associated gene-A seropositivity in relation to the risk of myocardial infarction in middle-aged Japanese: The Japan Public Health Center-based study. Atherosclerosis 2013; 230:67-72. [PMID: 23958254 DOI: 10.1016/j.atherosclerosis.2013.06.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Revised: 06/04/2013] [Accepted: 06/17/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND Limited evidence is available concerning the impact of the combination of Helicobacter pylori- (H. pylori) and cytotoxin-associated gene-A (CagA)-positivity on the risk of myocardial infarction (MI) and stroke, particularly in Asian populations, in which the prevalence of H. pylori infection is high. METHODS A prospective, nested case-control study was conducted to examine the association between H. pylori and CagA and risk of MI and stroke within a cohort of 29,876 men and women aged 40-69 years with no history of heart disease, stroke or cancer. Participants completed a risk factor survey and donated blood samples between 1990 and 1994. Systematic cardiovascular surveillance was performed through 2002. One control for each stroke case and two controls for each MI case were matched by sex, age, date of blood sampling, time since last meal and study location. RESULTS During the follow-up period, there were 600 strokes and 106 MIs. H. pylori-IgG positivity was not associated with the risk of MI, while CagA positivity tended to be associated with it (OR = 1.72, 95%CI: 0.91-3.26, p = 0.10). We found no association between H. pylori or CagA and risk of stroke. CONCLUSIONS H. pylori infection was not significantly associated with risk of MI and stroke among middle-aged Japanese. However, CagA positivity tended to be associated with MI.
Collapse
Affiliation(s)
- Ai Ikeda
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Chuo-ku, Tokyo, Japan
| | | | | | | | | |
Collapse
|
|
40
|
Sánchez-Zauco NA, Torres J, Pérez-Figueroa GE, Álvarez-Arellano L, Camorlinga-Ponce M, Gómez A, Giono-Cerezo S, Maldonado-Bernal C. Impact of cagPAI and T4SS on the inflammatory response of human neutrophils to Helicobacter pylori infection. PLoS One 2013; 8:e64623. [PMID: 23755130 PMCID: PMC3670914 DOI: 10.1371/journal.pone.0064623] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Accepted: 04/17/2013] [Indexed: 12/16/2022] Open
Abstract
Helicobacter pylori contains a pathogenicity island, cagPAI, with genes homologous to components of the type IV secretion system (T4SS) of Agrobacterium tumefaciens. The T4SS components assemble a structure that transfers CagA protein and peptidoglycan into host epithelial cells, causing the increased release of interleukin 8 (IL8) from the cells. The Toll-like receptors on neutrophils recognize H. pylori, initiating signaling pathways that enhance the activation of NF-κB. However, the roles of cagPAI and T4SS in the inflammatory response of neutrophils are unknown. We evaluated the participation of cagPAI and T4SS in the response of human neutrophils to H. pylori infection. Neutrophils were isolated from the blood of healthy donors and infected with H. pylori cagPAI(+), cagPAI(-), and cagPAI mutant strains virB4 (-) and virD4 (-). Whereas cagPAI(+) strain 26695 induced the greatest IL8 production, a proinflammatory response, cagPAI(-) strain 8822 induced the greatest IL10 production, an anti-inflammatory response. In contrast, the virB4 (-) and virD4 (-) mutant strains produced significantly more of the two proinflammatory cytokines IL1β and tumor necrosis factor αthan the cagPAI(+) strain 26695. We observed that H. pylori downregulated the expression of TLRs 2 and 5 but upregulated TLR9 expression in a cagPAI and T4SS-independent manner. These results show for the first time that the response of human neutrophils to H. pylori may vary from a pro-inflammatory to an anti-inflammatory response, depending on cagPAI and the integrity of T4SS.
Collapse
Affiliation(s)
- Norma Angélica Sánchez-Zauco
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, SS. Mexico City, México
- Unidad de Investigación en Enfermedades Infecciosas, Centro Médico Nacional Siglo XXI, IMSS. Mexico City, México
- Laboratorio de Bacteriología Médica, Escuela Nacional de Ciencias Biológicas-IPN, Mexico City, México
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, Centro Médico Nacional Siglo XXI, IMSS. Mexico City, México
| | - Gloria Erandi Pérez-Figueroa
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, SS. Mexico City, México
- Unidad de Investigación en Enfermedades Infecciosas, Centro Médico Nacional Siglo XXI, IMSS. Mexico City, México
| | - Lourdes Álvarez-Arellano
- Laboratorio de Neuroinmunología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, UNAM. Cuernavaca, Morelos, México
| | - Margarita Camorlinga-Ponce
- Unidad de Investigación en Enfermedades Infecciosas, Centro Médico Nacional Siglo XXI, IMSS. Mexico City, México
| | - Alejandro Gómez
- Unidad de Investigación en Enfermedades Infecciosas, Centro Médico Nacional Siglo XXI, IMSS. Mexico City, México
| | - Silvia Giono-Cerezo
- Laboratorio de Bacteriología Médica, Escuela Nacional de Ciencias Biológicas-IPN, Mexico City, México
| | - Carmen Maldonado-Bernal
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, SS. Mexico City, México
| |
Collapse
|
|
41
|
Xue H, Lu Y, Lin B, Chen J, Tang F, Huang G. The effect of XPD/ERCC2 polymorphisms on gastric cancer risk among different ethnicities: a systematic review and meta-analysis. PLoS One 2012; 7:e43431. [PMID: 23028453 PMCID: PMC3441548 DOI: 10.1371/journal.pone.0043431] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 07/20/2012] [Indexed: 12/13/2022] Open
Abstract
Background Potential xeroderma pigmentosum group D (XPD), also called excision repair cross-complimentary group two (ERCC2), Lys751Gln and Asp312Asn polymorphisms have been implicated in gastric cancer risk among different ethnicities. Methods We aimed to explore the effect of XPD Lys751Gln and Asp312Asn polymorphisms on the susceptibility to gastric cancer among different ethnicities through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. 13 studies were ultimately eligible for the meta-analysis of Lys751Gln polymorphism and 9 studies for the meta-analysis of Asp312Asn polymorphism. We adopted the most probably appropriate genetic model (recessive model) for both Lys751Gln and Asp312Asn polymorphisms. Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated. Results Statistically significant findings were apparently noted in Asians but not in Caucasians for both XPD Lys751Gln and XPD Asp312Asn polymorphisms. A statistically significant finding could be seen in noncardia-type gastric cancer for XPD Lys751Gln polymorphism. A statistically significant finding could also be seen in high quality subgroup, small-and-moderate sample size subgroup, articles published after 2007, or PCR-RFLP genotyping subgroup for XPD Asp312Asn polymorphism. Conclusions Our meta-analysis indicates that XPD Gln751Gln (CC) genotype and Asn312Asn (AA) genotype may seem to be more susceptible to gastric cancer in Asian populations but not in Caucasian populations, suggesting that the two genotypes may be important biomarkers of gastric cancer susceptibility for Asian populations, the assumption that needs to be further confirmed in well-designed studies among different ethnicities. Gln751Gln (CC) genotype may also be associated with noncardia-type gastric cancer risk, which should also be confirmed among different ethnicities in the future.
Collapse
Affiliation(s)
- Huiping Xue
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Jiaotong University, Shanghai, People's Republic of China
- * E-mail: (HX); (GH)
| | - Yan Lu
- Department of Medicine, International Peace Hospital for the Protection of Mother and Child Health, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Bing Lin
- Division of Nutrition, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, People's Republic of China
| | - Jinxian Chen
- Department of General Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
| | - Feng Tang
- Division of Pathology, Huashan Hospital, Fudan University School of Medicine, Shanghai, People's Republic of China
| | - Gang Huang
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China
- * E-mail: (HX); (GH)
| |
Collapse
|
|
42
|
Abstract
Helicobacter pylori infection is associated with gastritis and gastric cancer. An H. pylori virulence factor, the cag pathogenicity island (PAI), is related to host cell cytokine induction and gastric inflammation. Since elucidation of the mechanisms of inflammation is important for therapy, the associations between cytokines and inflammatory diseases have been investigated vigorously. Levels of interleukin-32 (IL-32), a recently described inflammatory cytokine, are increased in various inflammatory diseases, such as rheumatoid arthritis and Crohn's disease, and in malignancies, including gastric cancer. In this report, we examined IL-32 expression in human gastric disease. We also investigated the function of IL-32 in activation of the inflammatory cytokines in gastritis. IL-32 expression paralleled human gastric tissue pathology, with low IL-32 expression in H. pylori-uninfected gastric mucosa and higher expression levels in gastritis and gastric cancer tissues. H. pylori infection increased IL-32 expression in human gastric epithelial cell lines. H. pylori-induced IL-32 expression was dependent on the bacterial cagPAI genes and on activation of nuclear factor κB (NF-κB). IL-32 expression induced by H. pylori was not detected in the supernatant of AGS cells but was found in the cytosol. Expression of the H. pylori-induced cytokines CXCL1, CXCL2, and IL-8 was decreased in IL-32-knockdown AGS cell lines compared to a control AGS cell line. We also found that NF-κB activation was decreased in H. pylori-infected IL-32-knockdown cells. These results suggest that IL-32 has important functions in the regulation of cytokine expression in H. pylori-infected gastric mucosa.
Collapse
|
|
43
|
Lee KS, Kalantzis A, Jackson CB, O'Connor L, Murata-Kamiya N, Hatakeyama M, Judd LM, Giraud AS, Menheniott TR. Helicobacter pylori CagA triggers expression of the bactericidal lectin REG3γ via gastric STAT3 activation. PLoS One 2012; 7:e30786. [PMID: 22312430 PMCID: PMC3270022 DOI: 10.1371/journal.pone.0030786] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2011] [Accepted: 12/21/2011] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Most of what is known about the Helicobacter pylori (H. pylori) cytotoxin, CagA, pertains to a much-vaunted role as a determinant of gastric inflammation and cancer. Little attention has been devoted to potential roles of CagA in the majority of H. pylori infected individuals not showing oncogenic progression, particularly in relation to host tolerance. Regenerating islet-derived (REG)3γ encodes a secreted C-type lectin that exerts direct bactericidal activity against Gram-positive bacteria in the intestine. Here, we extend this paradigm of lectin-mediated innate immunity, showing that REG3γ expression is triggered by CagA in the H. pylori-infected stomach. METHODOLOGY/PRINCIPAL FINDINGS In human gastric mucosal tissues, REG3γ expression was significantly increased in CagA-positive, compared to CagA-negative H. pylori infected individuals. Using transfected CagA-inducible gastric MKN28 cells, we recapitulated REG3γ induction in vitro, also showing that tyrosine phosphorylated, not unphosphorylated CagA triggers REG3γ transcription. In concert with induced REG3γ, pro-inflammatory signalling downstream of the gp130 cytokine co-receptor via the signal transducer and activator of transcription (STAT)3 and transcription of two cognate ligands, interleukin(IL)-11 and IL-6, were significantly increased. Exogenous IL-11, but not IL-6, directly stimulated STAT3 activation and REG3γ transcription. STAT3 siRNA knockdown or IL-11 receptor blockade respectively abrogated or subdued CagA-dependent REG3γ mRNA induction, thus demonstrating a requirement for uncompromised signalling via the IL-11/STAT3 pathway. Inhibition of the gp130-related SHP2-(Ras)-ERK pathway did not affect CagA-dependent REG3γ induction, but strengthened STAT3 activation as well as augmenting transcription of mucosal innate immune regulators, IL-6, IL-8 and interferon-response factor (IRF)1. CONCLUSIONS/SIGNIFICANCE Our results support a model of CagA-directed REG3γ expression in gastric epithelial cells via activation of the IL-11/gp130/STAT3 pathway. This response might allow Gram-negative H. pylori to manipulate host immunity to favour its own survival, by reducing the fitness of co-habiting Gram-positive bacteria with which it competes for resources in the gastric mucosal niche.
Collapse
Affiliation(s)
- Kai Syin Lee
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
| | - Anastasia Kalantzis
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
| | - Cameron B. Jackson
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
| | - Louise O'Connor
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
| | - Naoko Murata-Kamiya
- Department of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Masanori Hatakeyama
- Department of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Louise M. Judd
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
- Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Australia
| | - Andrew S. Giraud
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
- Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, Australia
| | - Trevelyan R. Menheniott
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
- * E-mail:
| |
Collapse
|
|
44
|
Xue H, Liu J, Lin B, Wang Z, Sun J, Huang G. A meta-analysis of interleukin-8 -251 promoter polymorphism associated with gastric cancer risk. PLoS One 2012; 7:e28083. [PMID: 22279522 PMCID: PMC3261138 DOI: 10.1371/journal.pone.0028083] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2011] [Accepted: 10/31/2011] [Indexed: 12/16/2022] Open
Abstract
Background Potential functional allele A/T single nucleotide polymorphism (SNP) of Interleukin 8 (IL-8) promoter -251has been implicated in gastric cancer risk. Methods We aimed to explore the role of A/T SNP of IL-8 -251 in the susceptibility to gastric cancer through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. Eighteen studies were ultimately eligible for the meta-analysis of IL-8 - 251 A/T SNP. We adopted the most probably appropriate genetic model (codominant model). Potential sources of heterogeneity were sought out via stratification and sensitivity analyses, and publication biases were estimated. Results Between IL-8 -251 AA genotype with gastric cancer risk, statistically significant association could be noted with overall gastric cancer, evidently noted in Asians, witnessed in high quality subgroup, and apparently noted in intestinal-type gastric cancer. Conclusions Our meta-analysis indicates that IL-8 -251 AA genotype is associated with the overall risk of developing gastric cancer and may seem to be more susceptible to overall gastric cancer in Asian populations. IL-8 -251 AA genotype is more associated with the intestinal-type gastric cancer. IL-8 -251 AA genotype is not associated with Helicobacter Pylori infection status in our meta-analysis. Impact The analyses suggest that IL-8 -251 AA genotype may be an important biomarker of gastric cancer susceptibility for Asians, especially for Chinese Han population, the assumption that needs to be further confirmed in future well-designed studies in China.
Collapse
Affiliation(s)
- Huiping Xue
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Shanghai Jiaotong University, Shanghai, People's Republic of China
- * E-mail: (GH); (HX)
| | - Jianjun Liu
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Bing Lin
- Division of Nutrition, Zhongshan Hospital, Fudan University School of Medicine, Fundan University, Shanghai, People's Republic of China
| | - Zheng Wang
- Department of General Surgery, Renji Hospital, Shanghai, People's Republic of China
| | - Jianhua Sun
- Department of General Surgery, Renji Hospital, Shanghai, People's Republic of China
| | - Gang Huang
- Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China
- * E-mail: (GH); (HX)
| |
Collapse
|
|
45
|
Delgado-Rosado G, Dominguez-Bello MG, Massey SE. Positive selection on a bacterial oncoprotein associated with gastric cancer. Gut Pathog 2011; 3:18. [PMID: 22078307 PMCID: PMC3228766 DOI: 10.1186/1757-4749-3-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 11/11/2011] [Indexed: 01/01/2023] Open
Abstract
Background Helicobacter pylori is a vertically inherited gut commensal that is carcinogenic if it possesses the cag pathogenicity island (cag PaI); infection with H.pylori is the major risk factor for gastric cancer, the second leading cause of death from cancer worldwide (WHO). The cag PaI locus encodes the cagA gene, whose protein product is injected into stomach epithelial cells via a Type IV secretion system, also encoded by the cag PaI. Once there, the cagA protein binds to various cellular proteins, resulting in dysregulation of cell division and carcinogenesis. For this reason, cagA may be described as an oncoprotein. A clear understanding of the mechanism of action of cagA and its benefit to the bacteria is lacking.
Collapse
Affiliation(s)
- Gisela Delgado-Rosado
- Biology Department, University of Puerto Rico - Rio Piedras, PO Box 23360, San Juan, Puerto Rico, USA 00931.
| | | | | |
Collapse
|
|
46
|
Zhang L, Wang P, Wei SL, Liu CJ. [Advances in relationship between gastric disease and polymorphisms in both Helicobacter pylori virulence factors and host genetics]. YI CHUAN = HEREDITAS 2011; 33:558-566. [PMID: 21684860 DOI: 10.3724/sp.j.1005.2011.00558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Helicobacter pylori infection may cause many gastric disease, such as peptic ulcers, chronic atrophic gastritis, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. The different clinical outcomes of Helicobacter pylori infection are related to H. pylori virulence factors and host gene polymorphism. H.pylori had been confirmed to be the class I carcinogen by the World Health Organization and International Agency for Research on Cancer Consensus Group (IARC) in1994. Most severe diseases always occur in the background that certain microbial virulence markers (e.g. cagA, vacA) and susceptible host genetic polymorphisms harboured together. Herein, we reviewed the association with H. pylori-related gastric diseases in relation to diffirent H. pylori types and the host polymorphisms.
Collapse
Affiliation(s)
- Li Zhang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing 100071, China.
| | | | | | | |
Collapse
|
|
47
|
Perry S, Hussain R, Parsonnet J. The impact of mucosal infections on acquisition and progression of tuberculosis. Mucosal Immunol 2011; 4:246-51. [PMID: 21412228 PMCID: PMC5480373 DOI: 10.1038/mi.2011.11] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
More than one-third of the world's population, or over 2 billion people, are infected with Mycobacterium tuberculosis, the causative pathogen of tuberculosis in humans. Why only 10% of those infected develop active disease while the remainder harbor latent infection remains one of the greatest scientific and public health mysteries. Bacterial persistence is characterized by a dynamic state of immunological tolerance between pathogen and host. The critical role of CD4(+) T cells in defense against intracellular pathogens became evident during epidemiological studies of HIV-1 infection, which showed a clear inverse relationship between CD4(+) T-cell count in peripheral blood and increased risk of infection with M. tuberculosis, pneumocystis and Toxoplasma gondii. There is also growing evidence of a common mucosal immune system, whereby immune cells activated at one mucosal site may disseminate to remote effector sites. In this commentary, we review emerging evidence from human studies that the outcome of M. tuberculosis infection is influenced by concurrent mucosal infections, using Helicobacter pylori and geohelminths as examples. Understanding how the complexity of microbial exposures influences host immunity may have important implications for vaccine development and therapeutic interventions.
Collapse
Affiliation(s)
- S Perry
- Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA
| | - R Hussain
- Department of Molecular Biology, Aga Khan University, Karachi, Pakistan
| | - J Parsonnet
- Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA
| |
Collapse
|
|
48
|
Persson C, Jia Y, Pettersson H, Dillner J, Nyrén O, Ye W. H. pylori seropositivity before age 40 and subsequent risk of stomach cancer: a glimpse of the true relationship? PLoS One 2011; 6:e17404. [PMID: 21399687 PMCID: PMC3047545 DOI: 10.1371/journal.pone.0017404] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2010] [Accepted: 02/02/2011] [Indexed: 12/20/2022] Open
Abstract
Stomach carcinogenesis involves mucosal and luminal changes that favor spontaneous disappearance of Helicobacter pylori. Therefore, the association between the infection and cancer risk might typically be underestimated. As acquisition of the infection almost invariably occurs before adulthood, the serostatus at age 16–40 should best reflect the lifetime occurrence of the infection. We therefore conducted a case-control study nested within a historic cohort of about 400,000 individuals who donated sera before age 40 to either of two large Swedish Biobanks between 1968 and 2006, and whose records were linked to complete nationwide registers. For each stomach adenocarcinoma case occurring at least 5 years after serum donation 2 controls were selected matched on age, sex and year of donation and biobank. Serum immunoglobulin G antibodies against H. pylori cell-surface antigens (Hp-CSAs) were measured with an enzyme–linked immunosorbent assay and antibodies against CagA with an immunoblot assay. Conditional logistic regression models were used to estimate odds ratios (ORs) for stomach adenocarcinoma among H. pylori infected relative to uninfected. We confirmed 59 incident cases of stomach adenocarcinoma (41 non-cardia tumors) during follow-up. ORs for non-cardia stomach adenocarcinoma among subjects with Hp-CSA antibodies (regardless of CagA serostatus), antibodies against CagA (regardless of Hp-CSA serostatus), and antibodies to both, relative to those who were seronegative to both, were 17.1 (95% confidence interval [CI] 4.0–72.9), 10.9 (95% CI 3.2–36.9), and 48.5 (95% CI 5.8–407.4), respectively. H. pylori infection is a much stronger risk factor for non-cardia stomach adenocarcinoma than initially realized. However, further studies are needed to answer whether it is a necessary cause, as the possibility of misclassification of H. pylori status could not be ruled out in our study.
Collapse
Affiliation(s)
- Christina Persson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Yanbin Jia
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | | | - Joakim Dillner
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Olof Nyrén
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- * E-mail:
| |
Collapse
|
|
49
|
Safak B, Ciftci IH, Dilek FH, Uslan I, Cetinkaya Z, Asik G, Dilek ON. Prevalence of cagA and vacA genotypes of Helicobacter pylori isolated from Turkish patients with active or non-active chronic gastritis. ACTA ACUST UNITED AC 2010; 42:435-8. [PMID: 20136573 DOI: 10.3109/00365540903563418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Several virulence factors of Helicobacter pylori may contribute to gastric mucosal damage. In this study, the prevalence of cagA and vacA genotypes of H. pylori was examined in different patterns of chronic gastritis. Oesophagogastroendoscopy was performed in 147 dyspeptic patients. Antrum biopsies were obtained for isolation of H. pylori and for histopathological assessment. H. pylori vacAs1 and cagA genes were directly genotyped in the gastric biopsy specimens by polymerase chain reaction (PCR). A total of 102 dyspeptic patients, all H. pylori-positive by PCR, were included in the study. Of these, 59 had active chronic gastritis and 37 had non-active chronic gastritis. The prevalence of cagA and vacAs1 was higher among patients with active chronic gastritis than among those with non-active chronic gastritis (45.8% vs 21.6% (p = 0.02) and 78.0% vs 40.5% (p < 0.001), respectively). In conclusion, both cagA and vacAs1 genotypes are associated with the activity of chronic gastritis.
Collapse
Affiliation(s)
- Birol Safak
- Department of Microbiology and Clinical Microbiology, Faculty of Medicine, Kocatepe University, Afyonkarahisar, Turkey
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Peptidoglycan deacetylation in Helicobacter pylori contributes to bacterial survival by mitigating host immune responses. Infect Immun 2010; 78:4660-6. [PMID: 20805339 DOI: 10.1128/iai.00307-10] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
An oxidative stress-induced enzyme, peptidoglycan deacetylase (PgdA), in the human gastric pathogen Helicobacter pylori was previously identified and characterized. In this study, we constructed H. pylori pgdA mutants in two mouse-adapted strains, X47 and B128, to investigate the role of PgdA in vivo (to determine the mutants' abilities to colonize mice and to induce an immune response). H. pylori pgdA mutant cells showed increased sensitivity to lysozyme compared to the sensitivities of the parent strains. We demonstrated that the expression of PgdA was significantly induced (3.5-fold) when H. pylori cells were in contact with macrophages, similar to the effect observed with oxidative stress as the environmental inducer. Using a mouse infection model, we first examined the mouse colonization ability of an H. pylori pgdA mutant in X47, a strain deficient in the major pathway (cag pathogenicity island [PAI] encoded) for delivery of peptidoglycan into host cells. No animal colonization difference between the wild type and the mutant was observed 3 weeks after inoculation. However, the pgdA mutant showed a significantly attenuated ability to colonize mouse stomachs (9-fold-lower bacterial load) at 9 weeks postinoculation. With the cag PAI-positive strain B128, a significant colonization difference between the wild type and the pgdA mutant was observed at 3 weeks postinoculation (1.32 × 10(4) versus 1.85 × 10(3) CFU/gram of stomach). To monitor the immune responses elicited by H. pylori in the mouse infection model, we determined the concentrations of cytokines present in mouse sera. In the mice infected with the pgdA mutant strain, we observed a highly significant increase in the level of MIP-2. In addition, significant increases in interleukin-10 and tumor necrosis factor alpha in the pgdA mutant-infected mice compared to the levels in the wild-type H. pylori-infected mice were also observed. These results indicated that H. pylori peptidoglycan deacetylation is an important mechanism for mitigating host immune detection; this likely contributes to pathogen persistence.
Collapse
|