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1
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Stein RA, Gomaa FE, Raparla P, Riber L. Now and then in eukaryotic DNA methylation. Physiol Genomics 2024; 56:741-763. [PMID: 39250426 DOI: 10.1152/physiolgenomics.00091.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024] Open
Abstract
Since the mid-1970s, increasingly innovative methods to detect DNA methylation provided detailed information about its distribution, functions, and dynamics. As a result, new concepts were formulated and older ones were revised, transforming our understanding of the associated biology and catalyzing unprecedented advances in biomedical research, drug development, anthropology, and evolutionary biology. In this review, we discuss a few of the most notable advances, which are intimately intertwined with the study of DNA methylation, with a particular emphasis on the past three decades. Examples of these strides include elucidating the intricacies of 5-methylcytosine (5-mC) oxidation, which are at the core of the reversibility of this epigenetic modification; the three-dimensional structural characterization of eukaryotic DNA methyltransferases, which offered insights into the mechanisms that explain several disease-associated mutations; a more in-depth understanding of DNA methylation in development and disease; the possibility to learn about the biology of extinct species; the development of epigenetic clocks and their use to interrogate aging and disease; and the emergence of epigenetic biomarkers and therapies.
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Affiliation(s)
- Richard A Stein
- Department of Chemical and Biomolecular Engineering, NYU Tandon School of Engineering, Brooklyn, New York, United States
| | - Faris E Gomaa
- Department of Chemical and Biomolecular Engineering, NYU Tandon School of Engineering, Brooklyn, New York, United States
| | - Pranaya Raparla
- Department of Chemical and Biomolecular Engineering, NYU Tandon School of Engineering, Brooklyn, New York, United States
| | - Leise Riber
- Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark
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2
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Liu Z, Li H, Huang X, Liu Q. Animal Models of Helicobacter pylori Infection and Vaccines: Current Status and Future Prospects. Helicobacter 2024; 29:e13119. [PMID: 39108210 DOI: 10.1111/hel.13119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/10/2024] [Accepted: 07/23/2024] [Indexed: 01/02/2025]
Abstract
Helicobacter pylori infection causes chronic gastritis, ulcers, and gastric cancer, making it a threat to human health. Despite the use of antibiotic therapy, the global prevalence of H. pylori infection remains high, necessitating early eradication measures. Immunotherapy, especially vaccine development, is a promising solution in this direction, albeit the selection of an appropriate animal model is critical in efficient vaccine production. Accordingly, we conducted a literature, search and summarized the commonly used H. pylori strains, H. pylori infection-related animal models, and models for evaluating H. pylori vaccines. Based on factors such as the ability to replicate human diseases, strain compatibility, vaccine types, and eliciting of immune responses, we systematically compared the advantages and disadvantages of different animal models, to obtain the informed recommendations. In addition, we have proposed novel perspectives on H. pylori-related animal models to advance research and vaccine evaluation for the prevention and treatment of diseases such as gastric cancer.
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Affiliation(s)
- Zhili Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- HuanKui Academy, Nanchang University, Nanchang, China
| | - He Li
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xiaotian Huang
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Qiong Liu
- Department of Medical Microbiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
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3
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Zhou S, Li C, Liu L, Yuan Q, Miao J, Wang H, Ding C, Guan W. Gastric microbiota: an emerging player in gastric cancer. Front Microbiol 2023; 14:1130001. [PMID: 37180252 PMCID: PMC10172576 DOI: 10.3389/fmicb.2023.1130001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/04/2023] [Indexed: 05/16/2023] Open
Abstract
Gastric cancer (GC) is a common cancer worldwide with a high mortality rate. Many microbial factors influence GC, of which the most widely accepted one is Helicobacter pylori (H. pylori) infection. H. pylori causes inflammation, immune reactions and activation of multiple signaling pathways, leading to acid deficiency, epithelial atrophy, dysplasia and ultimately GC. It has been proved that complex microbial populations exist in the human stomach. H. pylori can affect the abundance and diversity of other bacteria. The interactions among gastric microbiota are collectively implicated in the onset of GC. Certain intervention strategies may regulate gastric homeostasis and mitigate gastric disorders. Probiotics, dietary fiber, and microbiota transplantation can potentially restore healthy microbiota. In this review, we elucidate the specific role of the gastric microbiota in GC and hope these data can facilitate the development of effective prevention and therapeutic approaches for GC.
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Affiliation(s)
- Shizhen Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Chenxi Li
- Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lixiang Liu
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qinggang Yuan
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, Jiangsu, China
| | - Ji Miao
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Hao Wang
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Chao Ding
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wenxian Guan
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
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4
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Amalia R, Panenggak NSR, Doohan D, Rezkitha YAA, Waskito LA, Syam AF, Lubis M, Yamaoka Y, Miftahussurur M. A comprehensive evaluation of an animal model for Helicobacter pylori-associated stomach cancer: Fact and controversy. Helicobacter 2023; 28:e12943. [PMID: 36627714 DOI: 10.1111/hel.12943] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 01/12/2023]
Abstract
Even though Helicobacter pylori infection was the most causative factor of gastric cancer, numerous in vivo studies failed to induce gastric cancer using H. pylori infection only. The utilization of established animal studies in cancer research is crucial as they aim to investigate the coincidental association between suspected oncogenes and pathogenesis as well as generate models for the development and testing of potential treatments. The methods to establish gastric cancer using infected animal models remain limited, diverse in methods, and showed different results. This study investigates the differences in animal models, which highlight different pathological results in gaster by literature research. Electronic databases searched were performed in PubMed, Science Direct, and Cochrane, without a period filter. A total of 135 articles were used in this study after a full-text assessment was conducted. The most frequent animal models used for gastric cancer were Mice, while Mongolian gerbils and Transgenic mice were the most susceptible model for gastric cancer associated with H. pylori infection. Additionally, transgenic mice showed that the susceptibility to gastric cancer progression was due to genetic and epigenetic factors. These studies showed that in Mongolian gerbil models, H. pylori could function as a single agent to trigger stomach cancer. However, most gastric cancer susceptibilities were not solely relying on H. pylori infection, and numerous factors are involved in cancer progression. Further study using Mongolian gerbils and Transgenic mice is crucial to conduct and establish the best models for gastric cancer associated H. pylori.
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Affiliation(s)
- Rizki Amalia
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Nur Syahadati Retno Panenggak
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Dalla Doohan
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Anatomy, Histology and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Yudith Annisa Ayu Rezkitha
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Internal Medicine, Faculty of Medicine, Universitas Muhammadiyah Surabaya, Surabaya, Indonesia
| | - Langgeng Agung Waskito
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ari Fahrial Syam
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Masrul Lubis
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan.,Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Texas, Houston, USA
| | - Muhammad Miftahussurur
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, Indonesia
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5
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Wroblewski LE, Peek RM. Clinical Pathogenesis, Molecular Mechanisms of Gastric Cancer Development. Curr Top Microbiol Immunol 2023; 444:25-52. [PMID: 38231214 PMCID: PMC10924282 DOI: 10.1007/978-3-031-47331-9_2] [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] [Indexed: 01/18/2024]
Abstract
The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA. Additional risk factors for gastric cancer include dietary factors such as diets that are high in salt or low in iron, H. pylori-induced perturbations of the gastric microbiome, host genetic polymorphisms, and infection with Epstein-Barr virus. This chapter discusses in detail host factors and how H. pylori virulence factors augment the risk of developing gastric cancer in human patients as well as how the Mongolian gerbil model has been used to define mechanisms of H. pylori-induced inflammation and cancer.
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Affiliation(s)
- Lydia E Wroblewski
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Richard M Peek
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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6
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Ansari S, Yamaoka Y. Animal Models and Helicobacter pylori Infection. J Clin Med 2022; 11:jcm11113141. [PMID: 35683528 PMCID: PMC9181647 DOI: 10.3390/jcm11113141] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/25/2022] [Accepted: 05/25/2022] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori colonize the gastric mucosa of at least half of the world’s population. Persistent infection is associated with the development of gastritis, peptic ulcer disease, and an increased risk of gastric cancer and gastric-mucosa-associated lymphoid tissue (MALT) lymphoma. In vivo studies using several animal models have provided crucial evidence for understanding the pathophysiology of H. pylori-associated complications. Numerous animal models, such as Mongolian gerbils, transgenic mouse models, guinea pigs, and other animals, including non-human primates, are being widely used due to their persistent association in causing gastric complications. However, finding suitable animal models for in vivo experimentation to understand the pathophysiology of gastric cancer and MALT lymphoma is a complicated task. In this review, we summarized the most appropriate and latest information in the scientific literature to understand the role and importance of H. pylori infection animal models.
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Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA
- Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia
- Correspondence: ; Tel.: +81-97-586-5740
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Mamgain G, Patra P, Naithani M, Nath UK. The Role of Microbiota in the Development of Cancer Tumour Cells and Lymphoma of B and T Cells. Cureus 2021; 13:e19047. [PMID: 34853760 PMCID: PMC8608681 DOI: 10.7759/cureus.19047] [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] [Accepted: 10/25/2021] [Indexed: 11/26/2022] Open
Abstract
Human body harbours enormous numbers of microbial organisms, including bacteria, viruses, and fungi which have a momentous role in well-being and illness in humans. Immune system shelters us from pathogenic bacteria, microorganisms found in human tissues have many benefits related to the functional movement of the host by regulating important procedures such as immunity, signalling, and breakdown. Lymphocytes assume a significant part in the reaction to bacterial colonization, primarily by prompting a safe reaction to obstruction or initiation. Most immunologically occupant cells have a place with the mucosal invulnerable framework and are continually motioned by dendritic cells or other Antigen introducing cells that gather intestinal samples. Thus, Microbiome is a key contributor to developing lymphoma and specific alterations to microbiome composition could attenuate the risk. There is an indication that microbial morphology can affect and control humanoids. The difference in the composition of these microorganisms is associated with tumour development. With the increased knowledge of the connection among the human microbiome and carcinogenesis, the use of these findings to prevent, predict or diagnose of lymphomas has attracted a great attention. In this article, we explored current knowledge of various microbial ecosystems, their connection with carcinogens and the potential for useful microorganisms to control and prevent B and T cell lymphoma.
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Affiliation(s)
- Garima Mamgain
- Medical Oncology and Haematology, All India Institute of Medical Sciences, Rishikesh, IND
| | - Priyanka Patra
- Biochemistry, All India Institute of Medical Sciences, Rishikesh, IND
| | - Manisha Naithani
- Biochemistry & Advanced Center of Continuous Professional Development, All India Institute of Medical Sciences, Rishikesh, IND
| | - Uttam Kumar Nath
- Medical Oncology and Haematology, All India Institute of Medical Sciences, Rishikesh, IND
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Abstract
Summary
The human microbiota has a tremendous effect on our health. In the last decades, our knowledge about interactions between bacteria and humans have grown greatly. Not only is it necessary for humans to synthesize vitamins, to have tight intestinal barriers or protect from pathogens, it also has an impact on our immune system and thus plays an important role in autoimmune diseases and prevention of excessive inflammatory response. The idea of probiotics is to restore the balance in humans digestive microbiota. There is a growing number of scientific papers that proves a positive impact of using probiotics in various diseases. However, there are still questions that need to be answered before probiotics play a bigger role in the treatment. This paper presents the information about the use of probiotics in most common diseases of gastrointestinal tract.
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9
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Jones DW, Zavros Y. In vivo and in vitro models of gastric cancer. RESEARCH AND CLINICAL APPLICATIONS OF TARGETING GASTRIC NEOPLASMS 2021:157-184. [DOI: 10.1016/b978-0-323-85563-1.00003-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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10
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Hatakeyama M. The role of Helicobacter pylori CagA oncoprotein in neoplastic transformation of gastric epithelial cells. RESEARCH AND CLINICAL APPLICATIONS OF TARGETING GASTRIC NEOPLASMS 2021:119-144. [DOI: 10.1016/b978-0-323-85563-1.00005-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Helicobacter pylori Oncogenicity: Mechanism, Prevention, and Risk Factors. ScientificWorldJournal 2020; 2020:3018326. [PMID: 32765194 PMCID: PMC7374235 DOI: 10.1155/2020/3018326] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/04/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is the most common cause of gastric ulcer; however, its association with gastric cancer has been proved through a variety of studies. Importantly, H. pylori infection affects around half of the world's population leading to a variety of gastric problems and is mostly present in asymptomatic form. Although about 20% of people infected with H. pylori develop preneoplastic gastric lesions in later stages of their life, around 2% of infected individuals develop gastric cancer. Nevertheless, the outcome of H. pylori infection is determined by complex interaction between the host genetics, its environment, and virulence factors of infecting strain. There are several biomarkers/traits of H. pylori that have been linked with the onset of cancer. Among these, presence of certain major virulence factors including cytotoxin-associated gene A (CagA), vacuolating cytotoxin (VacA), and outer inflammatory protein A (OipA) plays a significant role in triggering gastric cancer. These factors of H. pylori make it a potent carcinogen. Therefore, eradication of H. pylori infection has shown positive effects on decreasing the risk of gastric cancer, but this has become a challenge due to the development of antibiotic resistance in H. pylori against the antibiotics of choice. Thus, the unmet need is to develop new and effective treatments for H. pylori infection, considering the antimicrobial resistance in different regions of the world. This review discusses the properties of H. pylori associated with increased risk of gastric cancer, antibiotic resistance pattern, and the possible role of eradication of H. pylori in preventing gastric cancer.
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Yi R, Wang FB, Tan F, Long X, Pan Y, Zhao X. Intervention effects of lotus leaf flavonoids on gastric mucosal lesions in mice infected with Helicobacter pylori. RSC Adv 2020; 10:23510-23521. [PMID: 35517367 PMCID: PMC9055112 DOI: 10.1039/d0ra03311a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 06/15/2020] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori (H. pylori) is one of the main factors that cause gastric lesions. The lotus leaf is an edible plant used in traditional Eastern medicine. This study evaluates the intervention effects of lotus leaf flavonoids (LLF) on gastric mucosal lesions in mice infected with H. pylori and explores their mechanism of action. High-performance liquid chromatography analysis reveals that LLF contain kaempferitrin (kaempferol-3,7-dirhamnoside), hypericin, astragalin (kaempferol-3-glucoside), phlorizin, and quercetin. LLF can reduce the number of gastric mucosal lesions and tissue lesions in mice with H. pylori-induced gastric lesions. LLF can increase the levels of somatostatin and vasoactive intestinal peptide in the serum of mice with gastric lesions and decrease the levels of substance P and endothelin-1 to inhibit gastric lesions. LLF can also reduce the levels of interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α, and interferon-gamma cytokines in the serum of mice with gastric lesions. Using a quantitative polymerase chain reaction assay it can be seen that LLF can downregulate mRNA expressions of TNF-α, IL-1β, myeloperoxidase, keratin (KRT) 16, KRT6b, and transglutaminase 3 epidermal in the gastric tissues of mice with gastric lesions. Western blot analysis indicates that LLF can downregulate the protein expressions of caspase-1, Nod-like receptor protein 3, IL-1β, TNF-α, and Toll-like receptor 4 in the gastric tissues of mice with gastric lesions. LLF have beneficial effects on gastric lesions induced by H. pylori. Meanwhile LLF is more active in competition with ranitidine. LLF represent an active substance that can inhibit H. pylori-induced gastric lesions. The flavones of LLF may enhance the inhibition of gastric mucosal lesions by promoting the interaction between the compounds.
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Affiliation(s)
- Ruokun Yi
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 P. R. China +86-23-6265-3650
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education Chongqing 400067 P. R. China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education Chongqing 400067 P. R. China
| | - Feng-Bo Wang
- Department of Rehabilitation, First Affiliated Hospital of Chengdu Medical College Chengdu 610500 P. R. China
| | - Fang Tan
- Department of Public Health, Our Lady of Fatima University Valenzuela 838 Philippines
| | - Xingyao Long
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 P. R. China +86-23-6265-3650
| | - Yanni Pan
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 P. R. China +86-23-6265-3650
| | - Xin Zhao
- Chongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education Chongqing 400067 P. R. China +86-23-6265-3650
- Chongqing Engineering Research Center of Functional Food, Chongqing University of Education Chongqing 400067 P. R. China
- Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education Chongqing 400067 P. R. China
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Cheng S, Fu Y, Zhang Y, Xian W, Wang H, Grothe B, Liu X, Xu X, Klug A, McCullagh EA. Enhancement of de novo sequencing, assembly and annotation of the Mongolian gerbil genome with transcriptome sequencing and assembly from several different tissues. BMC Genomics 2019; 20:903. [PMID: 31775624 PMCID: PMC6882081 DOI: 10.1186/s12864-019-6276-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 11/12/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The Mongolian gerbil (Meriones unguiculatus) has historically been used as a model organism for the auditory and visual systems, stroke/ischemia, epilepsy and aging related research since 1935 when laboratory gerbils were separated from their wild counterparts. In this study we report genome sequencing, assembly, and annotation further supported by transcriptome sequencing and assembly from 27 different tissues samples. RESULTS The genome was sequenced using Illumina HiSeq 2000 and after assembly resulted in a final genome size of 2.54 Gbp with contig and scaffold N50 values of 31.4 Kbp and 500.0 Kbp, respectively. Based on the k-mer estimated genome size of 2.48 Gbp, the assembly appears to be complete. The genome annotation was supported by transcriptome data that identified 31,769 (> 2000 bp) predicted protein-coding genes across 27 tissue samples. A BUSCO search of 3023 mammalian groups resulted in 86% of curated single copy orthologs present among predicted genes, indicating a high level of completeness of the genome. CONCLUSIONS We report the first de novo assembly of the Mongolian gerbil genome enhanced by assembly of transcriptome data from several tissues. Sequencing of this genome and transcriptome increases the utility of the gerbil as a model organism, opening the availability of now widely used genetic tools.
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Affiliation(s)
- Shifeng Cheng
- BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083 China
- State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen, 51803 China
| | - Yuan Fu
- BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083 China
- China National GeneBank, BGI-Shenzhen, Shenzhen, 518083 China
| | - Yaolei Zhang
- BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083 China
- China National GeneBank, BGI-Shenzhen, Shenzhen, 518083 China
| | - Wenfei Xian
- BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083 China
- State Key Laboratory of Agricultural Genomics, BGI-Shenzhen, Shenzhen, 51803 China
| | - Hongli Wang
- BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083 China
- China National GeneBank, BGI-Shenzhen, Shenzhen, 518083 China
| | - Benedikt Grothe
- Division of Neurobiology, Ludwig-Maximilians-Universitaet Munich, 82152 Planegg, Martinsried Germany
| | - Xin Liu
- BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083 China
- China National GeneBank, BGI-Shenzhen, Shenzhen, 518083 China
| | - Xun Xu
- BGI-Shenzhen, Beishan Industrial Zone, Yantian District, Shenzhen, 518083 China
- China National GeneBank, BGI-Shenzhen, Shenzhen, 518083 China
| | - Achim Klug
- Department of Physiology and Biophysics, School of Medicine, University of Colorado Denver, Aurora, CO 80045 USA
| | - Elizabeth A. McCullagh
- Department of Physiology and Biophysics, School of Medicine, University of Colorado Denver, Aurora, CO 80045 USA
- Present Address: Department of Integrative Biology, Oklahoma State University, Stillwater, OK 74074 USA
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14
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Peng C, Li NS, Hu Y, Lu NH. Impact factors that modulate gastric cancer risk in Helicobacter pylori-infected rodent models. Helicobacter 2019; 24:e12580. [PMID: 30950162 DOI: 10.1111/hel.12580] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 02/08/2019] [Accepted: 02/26/2019] [Indexed: 12/24/2022]
Abstract
Gastric cancer causes a large social and economic burden to humans. Helicobacter pylori (H pylori) infection is a major risk factor for distal gastric cancer. Detailed elucidation of H pylori pathogenesis is significant for the prevention and treatment of gastric cancer. Animal models of H pylori-induced gastric cancer have provided an invaluable resource to help elucidate the mechanisms of H pylori-induced carcinogenesis as well as the interaction between host and the bacterium. Rodent models are commonly used to study H pylori infection because H pylori-induced pathological processes in the stomachs of rodents are similar to those in the stomachs of humans. The risk of gastric cancer in H pylori-infected animal models is greatly dependent on host factors, bacterial determinants, environmental factors, and microbiota. However, the related mechanisms and the effects of the interactions among these impact factors on gastric carcinogenesis remain unclear. In this review, we summarize the impact factors mediating gastric cancer risk when establishing H pylori-infected animal models. Clarifying these factors and their potential interactions will provide insights to construct animal models of gastric cancer and investigate the in-depth mechanisms of H pylori pathogenesis, which might contribute to the management of H pylori-associated gastric diseases.
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Affiliation(s)
- Chao Peng
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Nian-Shuang Li
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Nong-Hua Lu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Guo L, Hong D, Wang S, Zhang F, Tang F, Wu T, Chu Y, Liu H, He M, Yang H, Yin R, Liu K. Therapeutic Protection Against H. pylori Infection in Mongolian Gerbils by Oral Immunization With a Tetravalent Epitope-Based Vaccine With Polysaccharide Adjuvant. Front Immunol 2019; 10:1185. [PMID: 31191547 PMCID: PMC6546824 DOI: 10.3389/fimmu.2019.01185] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 05/09/2019] [Indexed: 12/28/2022] Open
Abstract
Urease is an effective target for design of a therapeutic epitope vaccine against Helicobacter pylori (H. pylori). In our previous studies, an epitope vaccine CTB-UE containing Th and B epitopes from H. pylori urease was constructed, and the CTB-UE vaccine could provide therapeutic effect on H. pylori infection in mice. However, a multivalent vaccine, combining different antigens participating in different aspects of H. pylori colonization and pathogenesis, may be more effective as a therapeutic vaccine than a univalent vaccine targetting urease. Therefore, a multivalent epitope vaccine FVpE, containing Th1-type immune adjuvant NAP, three selected functional fragments from CagA and VacA, and an urease multi-epitope peptide (UE) from CTB-UE, was constructed in this study and expected to obtain better sterilizing immunity than the univalent epitope vaccine CTB-UE. The therapeutic effect of multivalent epitope vaccine FVpE with polysaccharide adjuvant (PA) was evaluated in H. pylori-infected Mongolian gerbil model. The results showed that both FvpE and CTB-UE vaccine could induce similar levels of specific antibodies against H. pylori urease, and had similar inhibition effect on H. pylori urease activity. However, only FVpE could induce high levels of specific antibodies to CagA, VacA, and NAP. In addition, oral therapeutic immunization with FVpE plus PA significantly reduced the number of H. pylori colonies in the stomach of Mongolian gerbils compared with oral immunization with CTB-UE plus PA, or FVpE only, and the FVpE vaccine with PA even exhibited sterilizing immunity. The protection of FVpE was related to the mixed CD4+ T cell responses and epitope-specific antibodies against various H. pylori antigens. These results indicate that a multivalent epitope vaccine targetting various H. pylori antigens could be a promising candidate against H. pylori infection.
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Affiliation(s)
- Le Guo
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, China.,Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China.,Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Dantong Hong
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Shue Wang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Fan Zhang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Feng Tang
- Research Center for High Altitude Medicine, Qinghai University, Xining, China
| | - Tao Wu
- Clinical Laboratory, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China
| | - Yuankui Chu
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Hongpeng Liu
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Meng He
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Hua Yang
- Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
| | - Runting Yin
- Center for Cell Therapy, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Kunmei Liu
- Ningxia Key Laboratory of Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, China.,Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, China
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16
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Chakravarty K, Gaur S. Role of Probiotics in Prophylaxis of Helicobacter pylori Infection. Curr Pharm Biotechnol 2019; 20:137-145. [PMID: 30827235 DOI: 10.2174/1389201020666190227203107] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/30/2019] [Accepted: 02/15/2019] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori, a pathogenic bacterium, has been known to be the root cause of numerous gastrointestinal disorders. In patients showing symptoms of its infection, antibiotic therapy is a likely treatment. However, the high cost of antibiotic therapy, associated antibiotic resistance along with other adverse effects has led to the use of probiotics for Helicobacter pylori treatment. In recent times, probiotics have played an essential role as complementary prophylaxis for gastrointestinal diseases, thus minimizing antibiotics’ usage and their side effects. Probiotics are live microbial agents that exude beneficial effects on their hosts when administered in the proper dosage. The growth of the organism has been reported to be inhibited to a great extent by probiotics and research employing animal models has shown a significant reduction in H. pylori-associated gastric inflammation. In human clinical trials, it has been observed that treatment with probiotics alleviated gastritis symptoms caused by H. pylori and reduced colonization of the organism. As expected, complete eradication of H. pylori infection has not yet been reported by the administration of probiotics alone. Complement treatments using probiotics have shown to benefit infected individuals by decreasing the harmful effects of H. pylori eradication treatment using antibiotics. Long-term administration of probiotics might have favourable outcomes in H. pylori infection especially by decreasing the risk of development of diseases caused by increased levels of gastric inflammation. One such chronic condition is gastric ulcer which occurs due to considerable damage to the mucosal barrier by H. pylori colonization. This review provides a brief description of the promising role of probiotics as a complementary treatment to control H. pylori infection and consequently the management of various gastrointestinal disorders among populations with a special focus on gastric ulcer.
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Affiliation(s)
- Kashyapi Chakravarty
- Department of Biotechnology, Jaypee Institute of Information Technology, Sector - 62, Noida, U.P, India
| | - Smriti Gaur
- Department of Biotechnology, Jaypee Institute of Information Technology, Sector - 62, Noida, U.P, India
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17
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Li J, Perez Perez GI. Is There a Role for the Non- Helicobacter pylori Bacteria in the Risk of Developing Gastric Cancer? Int J Mol Sci 2018; 19:E1353. [PMID: 29751550 PMCID: PMC5983810 DOI: 10.3390/ijms19051353] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 04/26/2018] [Accepted: 04/27/2018] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori is the most abundant bacterium in the gastric epithelium, and its presence has been associated with the risk of developing gastric cancer. As of 15 years ago, no other bacteria were associated with gastric epithelial colonization; but thanks to new methodologies, many other non-H. pylori bacteria have been identified. It is possible that non-H. pylori may have a significant role in the development of gastric cancer. Here, we discuss the specific role of H. pylori as a potential trigger for events that may be conducive to gastric cancer, and consider whether or not the rest of the gastric microbiota represent an additional risk in the development of this disease.
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Affiliation(s)
- Jackie Li
- Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
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18
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Noto JM, Romero-Gallo J, Piazuelo MB, Peek RM. The Mongolian Gerbil: A Robust Model of Helicobacter pylori-Induced Gastric Inflammation and Cancer. Methods Mol Biol 2017; 1422:263-80. [PMID: 27246040 DOI: 10.1007/978-1-4939-3603-8_24] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The Mongolian gerbil is an efficient, robust, and cost-effective rodent model that recapitulates many features of H. pylori-induced gastric inflammation and carcinogenesis in humans, allowing for targeted investigation of the bacterial determinants and environmental factors and, to a lesser degree, host constituents that govern H. pylori-mediated disease. This chapter discusses means through which the Mongolian gerbil model has been used to define mechanisms of H. pylori-inflammation and cancer as well as the current materials and methods for utilizing this model of microbially induced disease.
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Affiliation(s)
- Jennifer M Noto
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue MRB IV 1030C, Nashville, TN, 37232-0252, USA
| | - Judith Romero-Gallo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue MRB IV 1030C, Nashville, TN, 37232-0252, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue MRB IV 1030C, Nashville, TN, 37232-0252, USA
| | - Richard M Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue MRB IV 1030C, Nashville, TN, 37232-0252, USA.
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19
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Prevention of Gastric Cancer: Eradication of Helicobacter Pylori and Beyond. Int J Mol Sci 2017; 18:ijms18081699. [PMID: 28771198 PMCID: PMC5578089 DOI: 10.3390/ijms18081699] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 07/31/2017] [Accepted: 07/31/2017] [Indexed: 12/15/2022] Open
Abstract
Although its prevalence is declining, gastric cancer remains a significant public health issue. The bacterium Helicobacter pylori is known to colonize the human stomach and induce chronic atrophic gastritis, intestinal metaplasia, and gastric cancer. Results using a Mongolian gerbil model revealed that H. pylori infection increased the incidence of carcinogen-induced adenocarcinoma, whereas curative treatment of H. pylori significantly lowered cancer incidence. Furthermore, some epidemiological studies have shown that eradication of H. pylori reduces the development of metachronous cancer in humans. However, other reports have warned that human cases of atrophic metaplastic gastritis are already at risk for gastric cancer development, even after eradication of these bacteria. In this article, we discuss the effectiveness of H. pylori eradication and the morphological changes that occur in gastric dysplasia/cancer lesions. We further assess the control of gastric cancer using various chemopreventive agents.
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20
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HATAKEYAMA M. Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2017; 93:196-219. [PMID: 28413197 PMCID: PMC5489429 DOI: 10.2183/pjab.93.013] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor of gastric cancer. The cagA gene-encoded CagA protein is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Delivered CagA then acts as a non-physiological scaffold/hub protein by interacting with multiple host signaling molecules, most notably the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1/MARK, in both tyrosine phosphorylation-dependent and -independent manners. CagA-mediated manipulation of intracellular signaling promotes neoplastic transformation of gastric epithelial cells. Transgenic expression of CagA in experimental animals has confirmed the oncogenic potential of the bacterial protein. Structural polymorphism of CagA influences its scaffold function, which may underlie the geographic difference in the incidence of gastric cancer. Since CagA is no longer required for the maintenance of established gastric cancer cells, studying the role of CagA during neoplastic transformation will provide an excellent opportunity to understand molecular processes underlying "Hit-and-Run" carcinogenesis.
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Affiliation(s)
- Masanori HATAKEYAMA
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Correspondence should be addressed: M. Hatakeyama, Division of Microbiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan (e-mail: )
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21
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Ribeiro ARS, do Nascimento Valença JD, da Silva Santos J, Boeing T, da Silva LM, de Andrade SF, Albuquerque-Júnior RLC, Thomazzi SM. The effects of baicalein on gastric mucosal ulcerations in mice: Protective pathways and anti-secretory mechanisms. Chem Biol Interact 2016; 260:33-41. [PMID: 27780710 DOI: 10.1016/j.cbi.2016.10.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 10/10/2016] [Accepted: 10/21/2016] [Indexed: 01/15/2023]
Abstract
Many flavonoids have been shown to present good results for the treatment of gastric ulcers. Baicalein, a bioactive flavonoid derived from the Scutellaria baicalensis Georgi root, possesses several biological effects, such as anti-inflammatory and antioxidant. This study was conducted to assess the gastroprotective properties of baicalein. Anti-ulcerogenic assay was performed using the protocol of ulcer induced by ethanol/HCl in mice; then, the role of presynaptic α2-receptors, sulfhydryl (SH) compounds, nitric oxide (NO), prostaglandin (PG) and ATP-sensitive K+ (KATP) channels in gastroprotection of baicalein was investigated. The levels of reduced glutathione (GSH) and the myeloperoxidase (MPO) activity were measured in the gastric mucosa. Parameters of gastric secretion (volume, [H+] and pH) were determined with or without the presence of the secretagogue agent histamine, as well as mucus in gastric contents, by the pylorus ligation model. In vitro H+,K+-ATPase activity was also determined. Baicalein (10, 30 and 100 mg/kg) exhibited a dose related gastroprotective effect (P < 0.001) against acidified ethanol-induced lesions. The intraperitoneal treatment of mice with a α2-adrenoreceptor antagonist (yohimbine; 2 mg/kg), a SH compounds blocker (N-ethylmaleimide, NEM; 10 mg/kg), a non-selective inhibitor of NO synthase (Nw-nitro-L-arginine methyl ester hydrochloride, L-NAME; 10 mg/kg), a non-selective inhibitor of cyclo-oxygenase (indomethacin; 10 mg/kg) or a KATP channel blocker (glibenclamide; 10 mg/kg) was able to reverse (P < 0.001) the gastroprotective response caused by baicalein (30 mg/kg). Baicalein (30 mg/kg; P < 0.05) was able to increase GSH levels and decreasing MPO activity. The intraduodenal treatment with baicalein (30 and 100 mg/kg) significantly increased (P < 0.05) the gastric mucus secretion. Additionally, the treatment with baicalein reduced (30 and 100 mg/kg; P < 0.05) the secretion volume and total acid secretion, and also increased (10, 30 and 100 mg/kg; P < 0.001) the pH value, after pylorus ligature. Baicalein (30 mg/kg) was also effective in inhibiting the effects of histamine on gastric secretion (volume, [H+] and pH; P < 0.001). Baicalein at 10 and 30 μg/mL showed anti-H+,K+-ATPase activity. In conclusion, the present results provide convincing evidence that baicalein could be used as a cytoprotective (preventive effect) and anti-ulcerogenic (anti-secretory effect) agent in the gastric ulcers.
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Affiliation(s)
- Ana Roseli S Ribeiro
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil
| | - José Diego do Nascimento Valença
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil
| | - Jeferson da Silva Santos
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, CEP 88302-202 Itajaí, Santa Catarina, Brazil
| | - Luisa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, CEP 88302-202 Itajaí, Santa Catarina, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, CEP 88302-202 Itajaí, Santa Catarina, Brazil
| | - Ricardo L C Albuquerque-Júnior
- Instituto de Tecnologia e Pesquisa-ITP, Universidade Tiradentes, Av. Murilo Dantas, 300, CEP 49032-490 Aracaju, Sergipe, Brazil
| | - Sara Maria Thomazzi
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil.
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22
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KHODER GHALIA, AL-MENHALI ASMAA, AL-YASSIR FARAH, KARAM SHERIFM. Potential role of probiotics in the management of gastric ulcer. Exp Ther Med 2016; 12:3-17. [PMID: 27347010 PMCID: PMC4906699 DOI: 10.3892/etm.2016.3293] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Accepted: 03/03/2016] [Indexed: 02/07/2023] Open
Abstract
Gastric ulcer is one of the most common chronic gastrointestinal diseases characterized by a significant defect in the mucosal barrier. Helicobacter pylori (H. pylori) infection and the frequent long-term use of non-steroidal anti-inflammatory drugs are major factors involved in gastric ulcer development. Acid inhibitors and antibiotics are commonly used to treat gastric ulcer. However, in the last few decades, the accumulating evidence for resistance to antibiotics and the side effects of antibiotics and acid inhibitors have drawn attention to the possible use of probiotics in the prevention and treatment of gastric ulcer. Probiotics are live microorganisms that when administered in adequate amounts confer health benefits on the host. Currently, the available experimental and clinical studies indicate that probiotics are promising for future applications in the management of gastric ulcers. This review aims to provide an overview of the general health benefits of probiotics on various systemic and gastrointestinal disorders with a special focus on gastric ulcer and the involved cellular and molecular mechanisms: i) Protection of gastric mucosal barrier; ii) upregulation of prostaglandins, mucus, growth factors and anti-inflammatory cytokines; iii) increased cell proliferation to apoptosis ratio; and iv) induction of angiogenesis. Finally, some of the available data on the possible use of probiotics in H. pylori eradication are discussed.
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Affiliation(s)
- GHALIA KHODER
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - ASMA A. AL-MENHALI
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain 17666, United Arab Emirates
| | - FARAH AL-YASSIR
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates
| | - SHERIF M. KARAM
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates
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23
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Woods SE, Ek C, Shen Z, Feng Y, Ge Z, Muthupalani S, Whary MT, Fox JG. Male Syrian Hamsters Experimentally Infected with Helicobacter spp. of the H. bilis Cluster Develop MALT-Associated Gastrointestinal Lymphomas. Helicobacter 2016; 21:201-17. [PMID: 26348390 PMCID: PMC4783298 DOI: 10.1111/hel.12265] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Aged hamsters naturally infected with novel Helicobacter spp. classified in the H. bilis cluster develop hepatobiliary lesions and typhlocolitis. METHODS To determine whether enterohepatic H. spp. contribute to disease, Helicobacter-free hamsters were experimentally infected with H. spp. after suppression of intestinal bacteria by tetracycline treatment of dams and pups. After antibiotic withdrawal, weanlings were gavaged with four H. bilis-like Helicobacter spp. isolated from hamsters or H. bilis ATCC 43879 isolated from human feces and compared to controls (n = 7 per group). RESULTS Helicobacter bilis 43879-dosed hamsters were necropsied at 33 weeks postinfection (WPI) due to the lack of detectable infection by fecal PCR; at necropsy, 5 of 7 were weakly PCR positive but lacked intestinal lesions. The remaining hamsters were maintained for ~95 WPI; chronic H. spp. infection in hamsters (6/7) was confirmed by PCR, bacterial culture, fluorescent in situ hybridization, and ELISA. Hamsters had mild-to-moderate typhlitis, and three of the male H. spp.-infected hamsters developed small intestinal lymphoma, in contrast to one control. Of the three lymphomas in H. spp.-infected hamsters, one was a focal ileal mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, while the other two were multicentric small intestinal large B-cell lymphomas involving both the MALT and extra-MALT mucosal sites with lymphoepithelial lesions. The lymphoma in the control hamster was a diffuse small intestinal lymphoma with a mixed population of T and B cells. CONCLUSIONS Results suggest persistent H. spp. infection may augment risk for gastrointestinal MALT origin lymphomas. This model is consistent with H. pylori/heilmannii-associated MALT lymphoma in humans and could be further utilized to investigate the mechanisms of intestinal lymphoma development.
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Affiliation(s)
- Stephanie E Woods
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Courtney Ek
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Zeli Shen
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - Mark T Whary
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
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The Protective Effects of 18β-Glycyrrhetinic Acid on Helicobacter pylori-Infected Gastric Mucosa in Mongolian Gerbils. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4943793. [PMID: 27006947 PMCID: PMC4783533 DOI: 10.1155/2016/4943793] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 01/14/2016] [Accepted: 01/21/2016] [Indexed: 12/13/2022]
Abstract
18β-Glycyrrhetinic acid (GRA), a major component of Glycyrrhiza glabra, is widely used therapeutically in clinic. In this study, the effect of GRA on Helicobacter pylori- (H. pylori-) infected gastritis was investigated in Mongolian gerbils in vivo. The gerbils were randomly divided into groups: uninfected; H. pylori-infected; H. pylori + antibiotics (clarithromycin, amoxicillin, and esomeprazole); and H. pylori + GRA. The gastric intraluminal pH value, histopathological changes, and the expression levels of inflammation-related cytokines (IL-1β, TNF-α, COX-2, and iNOS) were investigated. The results showed that, in the H. pylori + GRA group, the intraluminal gastric pH value was lower (2.14 ± 0.08 versus 3.17 ± 0.23, P < 0.05), erosion and hyperplasia were alleviated, the infiltration of neutrophils and mononuclear cells was attenuated (P < 0.05), and the expression levels of TNF-α, IL-1β, COX-2, and iNOS were decreased (P < 0.05) compared with the H. pylori-infected group. There was no significant difference in results between the H. pylori + GRA group and the H. pylori + antibiotics group. This study indicated that GRA significantly attenuated H. pylori-infected gastritis in gerbils and has the potential to be developed as a new therapeutic drug.
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25
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Solnick JV, Eaton KA, Peek RM. Animal Models of Helicobacter pylori Infection. HELICOBACTER PYLORI RESEARCH 2016:273-297. [DOI: 10.1007/978-4-431-55936-8_11] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Abstract
The intestinal microbiota and gut immune system must communicate to maintain a balance between tolerance and activation. Our immune system protects us from pathogenic microbes at the same time that our bodies are host to trillions of microbes, symbionts, mutualists, and some that are essential to human health. Since there is such a close interaction between the immune system and the intestinal microbiota, it is not surprising that some lymphomas such as mucosal-associated lymphoid tissue lymphoma have been shown to be caused by the presence of certain bacteria. Animal models have played an important role in elucidating the causation and establishing the mechanism of bacteria-induced mucosal-associated lymphoid tissue lymphoma. In this review, we discuss different ways that animal models have been applied to investigate links between the gut microbiota and lymphoma and have helped to reveal the mechanisms of microbiota-induced lymphoma. Although there is a paucity of published studies demonstrating the interplay between the microbiota and lymphoma development, we believe that the connection is real and that it can be exploited in the future to enhance our understanding of causation and to improve the prognosis and treatment of lymphoma.
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Yamamoto ML, Schiestl RH. Lymphoma caused by intestinal microbiota. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2014; 11:9038-49. [PMID: 25257357 PMCID: PMC4199005 DOI: 10.3390/ijerph110909038] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 08/14/2014] [Accepted: 08/15/2014] [Indexed: 12/17/2022]
Abstract
The intestinal microbiota and gut immune system must constantly communicate to maintain a balance between tolerance and activation: on the one hand, our immune system should protect us from pathogenic microbes and on the other hand, most of the millions of microbes in and on our body are innocuous symbionts and some can even be beneficial. Since there is such a close interaction between the immune system and the intestinal microbiota, it is not surprising that some lymphomas such as mucosal-associated lymphoid tissue (MALT) lymphoma have been shown to be caused by the presence of certain bacteria. Animal models played an important role in establishing causation and mechanism of bacteria-induced MALT lymphoma. In this review we discuss different ways that animal models have been applied to establish a link between the gut microbiota and lymphoma and how animal models have helped to elucidate mechanisms of microbiota-induced lymphoma. While there are not a plethora of studies demonstrating a connection between microbiota and lymphoma development, we believe that animal models are a system which can be exploited in the future to enhance our understanding of causation and improve prognosis and treatment of lymphoma.
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Affiliation(s)
- Mitsuko L Yamamoto
- Department of Pathology, Environmental Health and Radiation Oncology, University of California, Los Angeles, Schools of Medicine and Public Health, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
| | - Robert H Schiestl
- Department of Pathology, Environmental Health and Radiation Oncology, University of California, Los Angeles, Schools of Medicine and Public Health, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
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28
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Heimesaat MM, Fischer A, Plickert R, Wiedemann T, Loddenkemper C, Göbel UB, Bereswill S, Rieder G. Helicobacter pylori induced gastric immunopathology is associated with distinct microbiota changes in the large intestines of long-term infected Mongolian gerbils. PLoS One 2014; 9:e100362. [PMID: 24941045 PMCID: PMC4062524 DOI: 10.1371/journal.pone.0100362] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 05/27/2014] [Indexed: 12/16/2022] Open
Abstract
Background Gastrointestinal (GI) inflammation in mice and men are frequently accompanied by distinct changes of the GI microbiota composition at sites of inflammation. Helicobacter (H.) pylori infection results in gastric immunopathology accompanied by colonization of stomachs with bacterial species, which are usually restricted to the lower intestine. Potential microbiota shifts distal to the inflammatory process following long-term H. pylori infection, however, have not been studied so far. Methodology/Principal Findings For the first time, we investigated microbiota changes along the entire GI tract of Mongolian gerbils after 14 months of infection with H. pylori B8 wildtype (WT) or its isogenic ΔcagY mutant (MUT) strain which is defective in the type IV secretion system and thus unable to modulate specific host pathways. Comprehensive cultural analyses revealed that severe gastric diseases such as atrophic pangastritis and precancerous transformations were accompanied by elevated luminal loads of E. coli and enterococci in the caecum and together with Bacteroides/Prevotella spp. in the colon of H. pylori WT, but not MUT infected gerbils as compared to naïve animals. Strikingly, molecular analyses revealed that Akkermansia, an uncultivable species involved in mucus degradation, was exclusively abundant in large intestines of H. pylori WT, but not MUT infected nor naïve gerbils. Conclusion/Significance Taken together, long-term infection of Mongolian gerbils with a H. pylori WT strain displaying an intact type IV secretion system leads to distinct shifts of the microbiota composition in the distal uninflamed, but not proximal inflamed GI tract. Hence, H. pylori induced immunopathogenesis of the stomach, including hypochlorhydria and hypergastrinemia, might trigger large intestinal microbiota changes whereas the exact underlying mechanisms need to be further unraveled.
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Affiliation(s)
- Markus M. Heimesaat
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany
- * E-mail:
| | - André Fischer
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany
| | - Rita Plickert
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany
| | - Tobias Wiedemann
- German Research Center for Environmental Health, Helmholtz Zentrum München, Munich, Germany
| | - Christoph Loddenkemper
- Department of Pathology/Research Center ImmunoSciences (RCIS), Charité - University Medicine Berlin, Berlin, Germany
| | - Ulf B. Göbel
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany
| | - Stefan Bereswill
- Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany
| | - Gabriele Rieder
- Division of Molecular Biology, Department of Microbiology, University of Salzburg, Salzburg, Austria
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Werawatganon D. Simple animal model of Helicobacter pylori infection. World J Gastroenterol 2014; 20:6420-6424. [PMID: 24914363 PMCID: PMC4047327 DOI: 10.3748/wjg.v20.i21.6420] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 01/17/2014] [Accepted: 03/19/2014] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) has become accepted as a human pathogen for the development of gastritis and gastroduodenal ulcer. To develop a simple rat model of chronic H. pylori infection, male Sprague-Dawley rats were pretreated with streptomycin suspended in tap water (5 mg/mL) for 3 d. The rats were inoculated by gavage at 1 mL/rat with H. pylori suspension (5 × 108-5 × 1010 CFU/mL) twice daily at an interval of 4 h for three consecutive days. Two weeks after inoculation, rats were sacrificed and the stomachs were removed. Antral biopsies were performed for urease test and the stomachs were taken for histopathology. Successful H. pylori inoculation was defined as a positive urease test and histopathology. We reported a 69.8%-83.0% success rate for H. pylori infection using the urease test, and hematoxylin and eosin staining confirmed the results. Histopathological analysis detected bacteria along the mucous lining of the surface epithelium and crypt lumen and demonstrated mild to moderate gastric inflammation in successfully inoculated rats. We developed a simple rat model of chronic H. pylori infection for research into gastric microcirculatory changes and therapy with plant products.
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Leaf Extract ofWasabia japonicaRelieved Oxidative Stress Induced byHelicobacter pyloriInfection and Stress Loading in Mongolian Gerbils. Biosci Biotechnol Biochem 2014; 74:1194-9. [DOI: 10.1271/bbb.90919] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Yamada T, Wei M, Toyoda T, Yamano S, Wanibuchi H. Inhibitory effect of Raphanobrassica on Helicobacter pylori-induced gastritis in Mongolian gerbils. Food Chem Toxicol 2014; 70:107-13. [PMID: 24835035 DOI: 10.1016/j.fct.2014.04.037] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Revised: 03/28/2014] [Accepted: 04/24/2014] [Indexed: 01/28/2023]
Abstract
Helicobacter pylori (H. pylori) infection is well known to be associated with chronic gastritis and also development of gastric cancer. Raphanobrassica (RB) is an intergeneric hybrid of the genera Raphanus (radish) and Brassica (cabbages) containing appreciable amounts of glucoraphanin (GR) and glucoraphenin (GRe), which are actively hydrolyzed by the enzyme myrosinase to sulforaphane and sulforaphene, respectively. Both of these metabolites exert antimicrobial and anti-inflammatory activity. The purpose of the present study was to investigate the effect of two freeze-dried products of RB (RB1 and RB2) on H. pylori-induced gastritis in Mongolian gerbils. Six-week-old male Mongolian gerbils were inoculated orally with H. pylori (ATCC 43504), and 2weeks later were fed diets containing no additives or diets supplemented with 2% RB1 (containing both GR and GRe) or 2% RB2 (containing GR only) for 10weeks. In the RB1, but not the RB2 group, mononuclear cell infiltration, mRNA expression of IL-6, and cell proliferation in the gastric mucosa were significantly suppressed. These results indicate that RB1 containing both GR and GRe exerted significant inhibitory effects on H. pylori-induced gastritis in Mongolian gerbils apparently mediated via suppression of IL-6 expression and chronic inflammation.
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Affiliation(s)
- Takanori Yamada
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Min Wei
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Takeshi Toyoda
- Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan
| | - Shoutaro Yamano
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Hideki Wanibuchi
- Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
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Thiraworawong T, Spinler JK, Werawatganon D, Klaikeaw N, Venable SF, Versalovic J, Tumwasorn S. Anti-inflammatory properties of gastric-derived Lactobacillus plantarum XB7 in the context of Helicobacter pylori infection. Helicobacter 2014; 19:144-55. [PMID: 24387083 DOI: 10.1111/hel.12105] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Helicobacter pylori colonization of the gastric epithelium induces interleukin-8 (IL-8) production and inflammation leading to host cell damage. We searched for gastric-derived Lactobacillus with the ability to suppress H. pylori-induced inflammation. MATERIALS AND METHODS Conditioned media from gastric-derived Lactobacillus spp. were tested for the ability to suppress H. pylori-induced IL-8 production in AGS gastric epithelial cells. IL-8 protein and mRNA levels were measured by ELISA and qPCR, respectively. The changes on host cell signaling pathway were analyzed by Western blotting and the anti-inflammatory effect was tested in a Sprague-Dawley rat model. RESULTS Conditioned media from L. salivarius B101, L. rhamnosus B103, and L. plantarum XB7 suppressed IL-8 production and IL-8 mRNA expression in H. pylori-induced AGS cells without inhibiting H. pylori growth. Conditioned media from LS-B101, LR-B103, and LP-XB7 suppressed the activation of NF-κB in AGS cells, while strain LP-XB7 also suppressed c-Jun activation. The anti-inflammatory effect of LP-XB7 was further assessed in vivo using a H. pylori-infected Sprague-Dawley rat model. Strain LP-XB7 contributed to a delay in the detection and colonization of H. pylori in rat stomachs, attenuated gastric inflammation, and ameliorated gastric histopathology. Additionally, the administration of LP-XB7 correlated with the suppression of TNF-α and CINC-1 in sera, and suppression of CINC-1 in the gastric mucosa of H. pylori-infected rats. CONCLUSIONS These results suggest that L. plantarum XB7 produces secreted factors capable of modulating inflammation during H. pylori infection, and this probiotic Lactobacillus strain shows promise as an adjunctive therapy for treating H. pylori-associated disease.
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Affiliation(s)
- Thien Thiraworawong
- Interdisciplinary Program of Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand
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Abstract
Since its discovery in 1982, the global importance of Helicobacter pylori-induced disease, particularly in developing countries, remains high. The use of rodent models, particularly mice, and the unanticipated usefulness of the gerbil to study H. pylori pathogenesis have been used extensively to study the interactions of the host, the pathogen, and the environmental conditions influencing the outcome of persistent H. pylori infection. Dietary factors in humans are increasingly recognized as being important factors in modulating progression and severity of H. pylori-induced gastric cancer. Studies using rodent models to verify and help explain mechanisms whereby various dietary ingredients impact disease outcome should continue to be extremely productive.
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Affiliation(s)
- James G. Fox
- Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Timothy C. Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York
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Sørdal Ø, Waldum H, Nordrum IS, Boyce M, Bergh K, Munkvold B, Qvigstad G. The gastrin receptor antagonist netazepide (YF476) prevents oxyntic mucosal inflammation induced by Helicobacter pylori infection in Mongolian gerbils. Helicobacter 2013; 18:397-405. [PMID: 23865485 DOI: 10.1111/hel.12066] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Long-term Helicobacter pylori infection causes gastritis leading to hypergastrinemia and predisposes to gastric cancer. Our aim was to assess the role of gastrin in oxyntic mucosal inflammation in H. pylori-infected Mongolian gerbils by means of the gastrin receptor antagonist netazepide (YF476). DESIGN We studied 60 gerbils for 18 months and left five animals uninfected (control group), inoculated 55 with H. pylori, and treated 28 of the infected animals with netazepide (Hp+YF476 group). Twenty-seven infected animals were given no treatment (Hp group). We measured plasma gastrin and intraluminal pH. H. pylori detection and histologic evaluations of the stomach were carried out. RESULTS All 55 inoculated animals were H. pylori positive at termination. Eighteen animals in the Hp group had gastritis. There was a threefold increase in mucosal thickness in the Hp group compared to the Hp+YF476 group, and a threefold increase in oxyntic neuroendocrine cells in the Hp group compared to the Hp+YF476 group (p < .05). All animals in the Hp+YF476 group had macro- and microscopically normal findings in the stomach. Plasma gastrin was higher in the Hp group than in the control group (172 ± 16 pmol/L vs 124 ± 5 pmol/L, p < .05) and highest in the Hp+YF476 group (530 ± 36 pmol/L). Intraluminal pH was higher in the Hp group than in the Hp+YF476 group (2.51 vs 2.30, p < .05). CONCLUSION The gastrin antagonist netazepide prevents H. pylori-induced gastritis in Mongolian gerbils. Thus, gastrin has a key role in the inflammatory reaction of the gastric mucosa to H. pylori infection in this species.
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Affiliation(s)
- Øystein Sørdal
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
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Yim S, Gwon SY, Hwang S, Kim NH, Jung BD, Rhee KJ. Enterotoxigenic Bacteroides fragilis causes lethal colitis in Mongolian gerbils. Anaerobe 2013; 21:64-6. [DOI: 10.1016/j.anaerobe.2013.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Revised: 03/14/2013] [Accepted: 03/17/2013] [Indexed: 12/29/2022]
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Murakami M, Fukuzawa M, Yamamoto M, Hamaya K, Tamura Y, Sugiyama A, Takahashi R, Murakami T, Amagase K, Takeuchi K. Effects of Helicobacter pylori infection on gastric parietal cells and E-cadherin in Mongolian gerbils. J Pharmacol Sci 2013; 121:305-11. [PMID: 23545479 DOI: 10.1254/jphs.12191fp] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
Atrophic gastritis caused by infection with Helicobacter pylori is characterized by parietal cell loss, which is a main risk factor for gastric cancer. Parietal cells play a crucial role in the regulation of cell lineage maturation and proliferation in the gastric units. Among the classical cadherins, E-cadherin plays an important role not only in epithelial cell-cell connections, but also in the maintenance of epithelial polarity and gastric glandular architecture and regulation of cell proliferation. The aim of this study is to elucidate how parietal cells and E-cadherin are altered in gastritis with Helicobacter pylori infection. We studied the effects of Helicobacter pylori on gastric mucosal E-cadherin 2 weeks after inoculation and investigated the relationship between parietal cell loss and the amount of E-cadherin on parietal cells in Mongolian gerbils. The number of parietal cells and amount of staining of E-cadherin below the isthmus were investigated by immunohistochemistry. It was shown that a reduction in intercellular E-cadherin preceded the disappearance of parietal cells. The gastric glands where parietal cells were lost were replaced by mucus secreting cells without E-cadherin. These results suggest that Helicobacter pylori damaged E-cadherin on parietal cells and caused massive parietal cell loss, leading to the deregulation of gastric morphology.
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Affiliation(s)
- Motonobu Murakami
- Department of Pharmacotherapy, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Japan.
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Wang F, Luo LD, Pan JH, Huang LH, Lv HW, Guo Q, Xu CX, Shen SR. Comparative genomic study of gastric epithelial cells co-cultured with Helicobacter pylori. World J Gastroenterol 2012; 18:7212-24. [PMID: 23326126 PMCID: PMC3544023 DOI: 10.3748/wjg.v18.i48.7212] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2012] [Revised: 11/19/2012] [Accepted: 11/24/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify genes potentially involved in Helicobacter pylori (H. pylori)-induced gastric carcinogenesis.
METHODS: GES-1 cells were co-cultured with H. pylori strains isolated from patients with gastric carcinoma (GC, n = 10) or chronic gastritis (CG, n = 10) for in vitro proliferation and apoptosis assays to identify the most and least virulent strains. These two strains were cagA-genotyped and used for further in vivo carcinogenic virulence assays by infecting Mongolian gerbils for 52 wk, respectively; a broth free of H. pylori was lavaged as control. Genomic profiles of GES-1 cells co-cultured with the most and least virulent strains were determined by microarray analysis. The most differentially expressed genes were further verified using quantitative real-time polymerase chain reaction in GES-1 cells infected with the most and least virulent strains, and by immunohistochemistry in H. pylori positive CG, precancerous diseases, and GC biopsy specimens in an independent experiment.
RESULTS: GC-derived H. pylori strains induced a potent proliferative effect in GES-1 cells in co-culture, whereas CG-derived strains did not. The most (from a GC patient) and least (from a CG patient) virulent strains were cagA-positive and negative, respectively. At week 52, CG, atrophy, metaplasia, dysplasia, and GC were observed in 90.0%, 80.0%, 80.0%, 90%, and 60.0%, respectively, of the animals lavaged with the most virulent strain. However, only mild CG was observed in 90% of the animals lavaged with the least virulent strain. On microarray analysis, 800 differentially expressed genes (49 up- and 751 down-regulated), involving those associated with cell cycle regulation, cell apoptosis, cytoskeleton, immune response, and substance and energy metabolisms, were identified in cells co-cultured with the most virulent strain as compared with those co-cultured with the least virulent strain. The six most differentially expressed genes (with a betweenness centrality of 0.1-0.2) were identified among the significant differential gene profile network, including JUN, KRAS, BRCA1, SMAD2, TRAF1, and HDAC6. Quantitative real-time polymerase chain reaction analyses verified that HDAC6 and TRFA1 mRNA expressions were significantly more up-regulated in GES-1 cells co-cultured with the most virulent strain than in those co-cultured with the least virulent strain. Immunohistochemistry of gastric mucosal specimens from H. pylori-positive patients with CG, intestinal metaplasia (IM), dysplasia, and GC showed that moderately positive and strongly positive HDAC6 expression was detected in 21.7% of CG patients, 30.0% of IM patients, 54.5% of dysplasia patients, and 77.8% of GC patients (P < 0.001). The up-regulation of TRAF1 expressions was detected in 34.8%, 53.3%, 72.7%, and 88.9% specimens of CG, IM, dysplasia, and GC, respectively (P < 0.001).
CONCLUSION: The overexpression of HDAC6 and TRAF1 in GES-1 cells co-cultured with the GC-derived strain and in H. pylori-positive dysplasia and GC suggests that HDAC6 and TRAF1 may be involved in H. pylori-induced gastric carcinogenesis.
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Affiliation(s)
- Fen Wang
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
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Comparative analysis of gastric bacterial microbiota in Mongolian gerbils after long-term infection with Helicobacter pylori. Microb Pathog 2012; 53:12-8. [PMID: 22783557 DOI: 10.1016/j.micpath.2012.03.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Quantitative (qt) real time PCR using 16SrDNA primers is useful for determination of the bacterial composition of the gastric microbiota in Mongolian gerbils. The aim of this study was to determine the change in the gastric microbiota after long-term infection with Helicobacter pylori. One year after inoculation with H. pylori, five gerbils were determined as H. pylori-positive and 6 gerbils H. pylori-negative by culture and real time qt PCR methods. The gastric microbiota of each group of gerbils was also compared with that of 6 gerbils uninfected with H. pylori. DNA from the Atopobium cluster, Bifidobacterium spp., Clostridium coccoides group, Clostridium leptum subgroup, Enterococcus spp. and Lactobacillus spp. were detected in the gastric mucus of both infected and uninfected gerbils. In contrast, Eubacterium cylindroides group and Prevotella spp. were detected only in H. pylori-negative gerbils. The numbers of C. leptum subgroup, C. coccoides group and Bifidobacterium spp. in gastric mucus of H. pylori-negative Mongolian gerbils were significantly lower than those in non-infected gerbils. The results obtained suggest that the composition of gastric indigenous microbiota in Mongolian gerbils may be disturbed by long-term infection with H. pylori, and that these changes may in fact inhibit H. pylori infection.
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Sekiguchi H, Takabayashi F, Irie K, Murakami A. Auraptene attenuates gastritis via reduction of Helicobacter pylori colonization and pro-inflammatory mediator production in C57BL/6 mice. J Med Food 2012; 15:658-63. [PMID: 22471969 DOI: 10.1089/jmf.2011.1844] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori is a major human pathogen that plays central roles in chronic gastritis and gastric cancer. Recently, we reported that auraptene suppressed H. pylori adhesion via expression of CD74, which has been identified as a new receptor for H. pylori urease. In this study, we attempted to clarify the effects of oral feeding of auraptene on H. pylori infection and resultant inflammatory responses in C57BL/6 mice and found that it remarkably attenuated H. pylori colonization and gastritis. Biochemical analyses revealed that auraptene inhibited H. pylori-induced expression and/or production of CD74, macrophage migration inhibitory factor, interleukin-1β, and tumor necrosis factor-α in gastric mucosa, together with serum macrophage inhibitory protein-2. It is notable that treatment with this coumarin during the pretreatment period was more effective than that during posttreatment. Our results suggest that auraptene is a promising phytochemical for reducing the risk of H. pylori-induced gastritis and carcinogenesis.
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Affiliation(s)
- Hirotaka Sekiguchi
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
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Rogers AB. Gastric Helicobacter spp. in animal models: pathogenesis and modulation by extragastric coinfections. Methods Mol Biol 2012; 921:175-188. [PMID: 23015504 DOI: 10.1007/978-1-62703-005-2_21] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Animal models are used to study complex host, microbial, and environmental influences associated with gastric Helicobacter infection. Evidence that gastric helicobacters are pathogenic in animals first came from ferrets. Felids, nonhuman primates, and many other species also harbor stomach helicobacters. Today, mice are preferred by most researchers for scientific investigation because of cost-efficiencies, rapid reproduction, choice of laboratory reagents, and availability of genetically engineered models. Infection with Helicobacter felis or H. pylori Sydney strain-1 in appropriate mouse strains produces disease with remarkable similarities to H. pylori in humans. Due to recent advances in genetic engineering, in vivo imaging, and system-wide genomics and proteomics, these models will become even more widespread in the future. Recently, it has been shown that extragastric infections can dramatically affect the severity of disease induced by gastric Helicobacter spp. through heterologous immunity. These models provide proof-of-principle for the "African enigma" wherein gastric cancer is underrepresented in low-lying tropical countries with concurrently high H. pylori and internal parasite prevalence. Helicobacter gastritis and carcinogenesis in mouse models may be augmented or ameliorated by other infectious agents depending on the character of the invoked immune response. Knowledge gained from the Human Microbiome Project and other investigations is certain to shed new light on the influence of extragastric bacterial, viral, fungal, and parasitic coinfections on H. pylori-associated peptic ulcer disease and gastric adenocarcinoma.
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Affiliation(s)
- Arlin B Rogers
- Lineberger Comprehensive Cancer Center and Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
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Taylor NS, Fox JG. Animal models of Helicobacter-induced disease: methods to successfully infect the mouse. Methods Mol Biol 2012; 921:131-42. [PMID: 23015501 PMCID: PMC3545442 DOI: 10.1007/978-1-62703-005-2_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Animal models of microbial diseases in humans are an essential component for determining fulfillment of Koch's postulates and determining how the organism causes disease, host response(s), disease prevention, and treatment. In the case of Helicobacter pylori, establishing an animal model to fulfill Koch's postulates initially proved so challenging that out of frustration a human volunteer undertook an experiment to become infected with H. pylori and to monitor disease progression in order to determine if it did cause gastritis. For the discovery of the organism and his fulfillment of Koch's postulates he and a colleague were awarded the Nobel Prize in Medicine. After H. pylori was established as a gastric pathogen, it took several years before a model was developed in mice, opening the study of the organism and its pathogenicity to the general scientific community. However, while the model is widely utilized, there are a number of difficulties that can arise and need to be overcome. The purpose of this chapter is to raise awareness regarding the problems, and to offer reliable protocols for successfully establishing the H. pylori mouse model.
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Affiliation(s)
- Nancy S Taylor
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
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Cinghu S, Goh YM, Oh BC, Lee YS, Lee OJ, Devaraj H, Bae SC. Phosphorylation of the gastric tumor suppressor RUNX3 following H. pylori infection results in its localization to the cytoplasm. J Cell Physiol 2011; 227:1071-80. [DOI: 10.1002/jcp.22820] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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AMAGASE K, NAKAMURA E, KATO S, TAKEUCHI K. Prophylactic Effect of Glutamate on Gastrointestinal Damage. YAKUGAKU ZASSHI 2011; 131:1711-9. [DOI: 10.1248/yakushi.131.1711] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Kikuko AMAGASE
- Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University
| | - Eiji NAKAMURA
- Frontier Research Labs., Institute for Innovation, AJINOMOTO CO., INC
| | - Shinichi KATO
- Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University
| | - Koji TAKEUCHI
- Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University
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Sugimoto M, Ohno T, Graham DY, Yamaoka Y. Helicobacter pylori outer membrane proteins on gastric mucosal interleukin 6 and 11 expression in Mongolian gerbils. J Gastroenterol Hepatol 2011; 26:1677-84. [PMID: 21679252 PMCID: PMC3407248 DOI: 10.1111/j.1440-1746.2011.06817.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND AND AIM The levels of interleukin (IL)-6 and IL-11 in the gastric mucosa are related to mucosal inflammation; however, the chronological changes in cytokine expression during different phases of Helicobacter pylori infection and the effects of H. pylori virulence factors, particularly those of outer membrane proteins, remain obscure. The aim of this study was to clarify the chronological changes in cytokine levels in relation to several H. pylori outer membrane proteins. METHODS We studied Mongolian gerbils inoculated with wild-type H. pylori 7.13 for up to 48 weeks and then examined animals infected with oipA, babA, or alpAB isogenic mutants for 12 weeks. Mucosal IL-6 and IL-11 mRNA levels were measured using real-time reverse transcription-polymerase chain reactions. RESULTS High levels of gastric mucosal IL-6 and IL-11 mRNA in gerbils infected with wild-type H. pylori were observed during the chronic phase of infection, reaching maximums at 12 and 6 months, respectively. Infection with oipA and babA mutants resulted in significantly reduced cytokine levels and inflammatory cell infiltrations compared to gerbils infected with wild-type strains, and this persisted throughout the observation period. The alpAB mutants did not infect gerbils. Mucosal IL-6 and IL-11 levels were significantly associated with the grade of inflammatory cell infiltration. CONCLUSIONS OipA and BabA result in more severe H. pylori infection and increased IL-6 and IL-11 levels, which in turn may increase the risk of developing H. pylori-induced gastrointestinal diseases.
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Affiliation(s)
- Mitsushige Sugimoto
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas USA
| | - Tomoyuki Ohno
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas USA
| | - David Y Graham
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas USA
| | - Yoshio Yamaoka
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas USA
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
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45
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Sugimoto M, Ohno T, Yamaoka Y. Expression of angiotensin II type 1 and type 2 receptor mRNAs in the gastric mucosa of Helicobacter pylori-infected Mongolian gerbils. J Gastroenterol 2011; 46:1177-86. [PMID: 21750885 PMCID: PMC3404294 DOI: 10.1007/s00535-011-0433-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Accepted: 06/12/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND The renin-angiotensin system (RAS) plays an important role in normal homeostasis, carcinogenesis-related angiogenesis, and cell proliferation. Helicobacter pylori infection causes infiltration of inflammatory cells into the gastric mucosa and is considered the major cause of gastric cancer. Whether RAS plays a role in H. pylori infection-related gastric diseases remains unclear. We investigated the changes in gastric mucosal angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R) mRNA levels throughout the time course of H. pylori infection in Mongolian gerbils. METHODS Mongolian gerbils were infected with wild-type H. pylori (for 12 months) or with its isogenic oipA mutant (for 3 months). Gastric mucosal AT1R and AT2R mRNA levels were assessed using real-time reverse transcription-polymerase chain reaction. RESULTS The gastric mucosal AT1R mRNA level was significantly associated with the severity of inflammatory cell infiltration into the gastric mucosa that reached maximal levels at 12 months after infection in both the antrum and body. Inflammatory cell infiltration scores and AT1R and AT2R mRNA levels were significantly lower in oipA mutant than wild-type infections. Mucosal AT1R and AT2R mRNA expressions in wild-type H. pylori-infected gerbils with gastric ulcers were significantly higher than in those without ulcers (P < 0.01). CONCLUSIONS Gastric mucosal ATR expression gradually increases during the course of H. pylori infection. Up-regulation of the RAS in association with progressive gastric inflammation suggests a potential role of the RAS in gastric carcinogenesis. OipA appears to play a role in AT1R and AT2R expression and the resulting inflammation.
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Affiliation(s)
- Mitsushige Sugimoto
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Tomoyuki Ohno
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Yoshio Yamaoka
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA. Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan
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46
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Goldenring JR, Nam KT, Mills JC. The origin of pre-neoplastic metaplasia in the stomach: chief cells emerge from the Mist. Exp Cell Res 2011; 317:2759-64. [PMID: 21907708 DOI: 10.1016/j.yexcr.2011.08.017] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2011] [Revised: 08/23/2011] [Accepted: 08/24/2011] [Indexed: 12/11/2022]
Abstract
The digestive-enzyme secreting, gastric epithelial chief (zymogenic) cell is remarkable and underappreciated. Here, we discuss how all available evidence suggests that mature chief cells in the adult, mammalian stomach are postmitotic, slowly turning over cells that arise via a relatively long-lived progenitor, the mucous neck cell, The differentiation of chief cells from neck cells does not involve cell division, and the neck cell has its own distinct pattern of gene expression and putative physiological function. Thus, the ontogeny of the normal chief cell lineage exemplifies transdifferentiation. Furthermore, under pathophysiogical loss of acid-secreting parietal cell, the chief cell lineage can itself trasndifferentiate into a mucous cell metaplasia designated Spasmolytic Polypeptide Expressing Metaplasia (SPEM). Especially in the presence of inflammation, this metaplastic lineage can regain proliferative capacity and, in humans may also further differentiate into intestinal metaplasia. The results indicate that gastric fundic lineages display remarkable plasticity in both physiological ontogeny and pathophysiological pre-neoplastic metaplasia.
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Affiliation(s)
- James R Goldenring
- Nashville Department of Veterans Affairs Medical Center, Nashville, TN, USA.
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47
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Kim J, Kim SW, Jang S, Merrell DS, Cha JH. Complementation system for Helicobacter pylori. J Microbiol 2011; 49:481-6. [PMID: 21717336 DOI: 10.1007/s12275-011-1196-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Accepted: 04/19/2011] [Indexed: 12/12/2022]
Abstract
Previously Langford et al. (2006) developed the pIR203C04 complementation system for Helicobacter pylori, which can be used to complement and restore phenotypic effects in H. pylori mutant, and furthermore they used the complementation system in vivo experiments to animals without altering the ability of strain SSI to colonize mice. In their previous study, the pIR203C04 was able to transform 26695, SSI, J99, and 43504 H. pylori strains by an electroporation method. However, in the present study using a natural transformation the pIR203C04 transformed only 26695 H. pylori but not SSI, J99, 7.13, and G27 H. pylori strains. Since the useful complementation system has a limitation of narrow selection among H. pylori strains, we redesigned the complementation system for the improvement. The same intergenic chromosomal site between hp0203 and hp0204 was utilized for the new complementation system because the insertion at the intergenic site didn't show any polar effects and disruption of other H. pylori genes. The genome sequence analysis showed that the intergenic regions among H. pylori strains may have too low homology to each others to do a homologous recombination. Thus, in addition to the short intergenic region, the fragments of the new complementation system included 3' conserved parts of hp0203 and hp0204 coding regions. Between the fragments there are a chloramphenicol acetyltransferase cassette and multicloning sites, resulting in pKJMSH. DNA fragment of the interest can be cloned into the multicloning sites of pKJMSH and the fragment can be integrated at the intergenic region of H. pylori chromosome by the homologous recombination. Indeed, by the natural transformation, pKJMSH was able to transform all five H. pylori strains of 26695, SSI, J99, 7.13, and G27, which are common for the investigation of molecular pathogenesis. Thus, the new pKJMSH complementation system is applicable to most H. pylori wild-type stains.
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Affiliation(s)
- Jinmoon Kim
- Department of Oral Biology, Oral Science Research Center, BK21 Project, Research Center for Orofacial Hard Tissue Regeneration, Yonsei University College of Dentistry, Seoul, 120-752, Republic of Korea
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48
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Ishijima N, Suzuki M, Ashida H, Ichikawa Y, Kanegae Y, Saito I, Borén T, Haas R, Sasakawa C, Mimuro H. BabA-mediated adherence is a potentiator of the Helicobacter pylori type IV secretion system activity. J Biol Chem 2011; 286:25256-64. [PMID: 21596743 DOI: 10.1074/jbc.m111.233601] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Chronic infection of Helicobacter pylori in the stomach mucosa with translocation of the bacterial cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV secretion system (TFSS) into host epithelial cells are major risk factors for gastritis, gastric ulcers, and cancer. The blood group antigen-binding adhesin BabA mediates the adherence of H. pylori to ABO/Lewis b (Le(b)) blood group antigens in the gastric pit region of the human stomach mucosa. Here, we show both in vitro and in vivo that BabA-mediated binding of H. pylori to Le(b) on the epithelial surface augments TFSS-dependent H. pylori pathogenicity by triggering the production of proinflammatory cytokines and precancer-related factors. We successfully generated Le(b)-positive cell lineages by transfecting Le(b)-negative cells with several glycosyltransferase genes. Using these established cell lines, we found increased mRNA levels of proinflammatory cytokines (CCL5 and IL-8) as well as precancer-related factors (CDX2 and MUC2) after the infection of Le(b)-positive cells with WT H. pylori but not with babA or TFSS deletion mutants. This increased mRNA expression was abrogated when Le(b)-negative cells were infected with WT H. pylori. Thus, H. pylori can exploit BabA-Le(b) binding to trigger TFSS-dependent host cell signaling to induce the transcription of genes that enhance inflammation, development of intestinal metaplasia, and associated precancerous transformations.
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Affiliation(s)
- Nozomi Ishijima
- Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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49
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Shinozaki K, Kamada T, Sugiu K, Kusunoki H, Manabe N, Shiotani A, Hata J, Teramoto F, Haruma K. High-protein diet suppresses corpus atrophic gastritis in Helicobacter pylori infected Mongolian gerbils. Nutr Cancer 2011; 62:1067-73. [PMID: 21058194 DOI: 10.1080/01635581.2010.492086] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
To investigate the effect of a high-protein diet on corpus atrophic gastritis in Helicobacter pylori-infected Mongolian gerbils, H. pylori was administered orally to 5-wk-old Mongolian gerbils; and the animals were then fed a control diet (Group C); a high-fat diet (Group F: 40% fat); a high-protein diet (Group P: 32% protein); or a high-fat, high-protein diet (Group FP: 40% fat, 32% protein) for 50 wk beginning at 7 wk of age. In uninfected animals, the mucosal thickness of the corpus was significantly greater in Group P and Group FP than in Group C (P < 0.05). In infected animals, the serum gastrin level was significantly decreased in Group FP and marginally significantly decreased in Group P (P = 0.057) in comparison to Group C. The mucosal thickness of the corpus was significantly greater in Group P and Group FP than in Group C (P < 0.05). Mean inflammation and atrophy scores in the corpus were significantly lower in the high-protein groups (Groups P and FP) than in the control groups (Groups C and F; both inflammation and atrophy: P < 0.05). In conclusion, long-term administration of a high-protein diet suppresses corpus atrophic gastritis in H. pylori-infected Mongolian gerbils.
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50
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Ohno T, Vallström A, Rugge M, Ota H, Graham DY, Arnqvist A, Yamaoka Y. Effects of blood group antigen-binding adhesin expression during Helicobacter pylori infection of Mongolian gerbils. J Infect Dis 2011; 203:726-35. [PMID: 21227917 DOI: 10.1093/infdis/jiq090] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori outer membrane proteins, such as the blood group antigen-binding adhesin (BabA), are associated with severe pathological outcomes. However, the in vivo role of BabA during long-term infection is not clear. In this study, Mongolian gerbils were infected with H. pylori and necropsied continuously during 18 months. Bacterial clones were recovered and analyzed for BabA expression, Leb-binding activity, and adhesion to gastric mucosa. BabA expression was completely absent by 6 months post-infection. Loss of BabA expression was attributable to nucleotide changes within the babA gene that resulted in a truncated BabA. In response to the infection, changes in the epithelial glycosylation pattern were observed that were similar to responses observed in humans and monkeys. Furthermore, infections with BabA-expressing and BabA-nonexpressing H. pylori showed no differences in colonization, but infection with the BabA-expressing strain exhibited histological changes and increased inflammatory cell infiltration. This suggests that BabA expression contributes to severe mucosal injury.
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Affiliation(s)
- Tomoyuki Ohno
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas 77030, USA
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