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Kong W, Liu W, Wang M, Hui W, Feng Y, Lu J, Miranbieke B, Liu H, Gao F. OUP accepted manuscript. Pathog Dis 2022; 80:6534255. [PMID: 35191475 DOI: 10.1093/femspd/ftac005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/24/2022] [Accepted: 02/20/2022] [Indexed: 11/14/2022] Open
Affiliation(s)
- Wenjie Kong
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
| | - Weidong Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
| | - Man Wang
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
| | - Wenjia Hui
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
| | - Yan Feng
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
| | - Jiajie Lu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
| | - Buya Miranbieke
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
| | - Huan Liu
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
| | - Feng Gao
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
- Xinjiang Digestive System Disease Clinical Medicine Research Center, Urumqi 830001, China
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Crowley E, Hussey S. Helicobacter pylori in Childhood. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2021:275-292.e12. [DOI: 10.1016/b978-0-323-67293-1.00027-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Dey TK, Karmakar BC, Sarkar A, Paul S, Mukhopadhyay AK. A Mouse Model of Helicobacter pylori Infection. Methods Mol Biol 2021; 2283:131-151. [PMID: 33765316 DOI: 10.1007/978-1-0716-1302-3_14] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Infection with Helicobacter pylori (H. pylori) is of great distress because of its vital role in the pathogenesis of chronic gastritis, peptic ulcers, and in the multi-step carcinogenic process of gastric cancer. The increasing antibiotic resistance pattern of H. pylori worldwide has prompted the World Health Organization to put this organism in the priority pathogens list. To study the disease biology, evaluation of drugs, treatment outcome and to come up with probable vaccination strategies, competent animal models that reproduce the signature of human infection are essential. Initial reports about animal colonization with H. pylori have shown significant heterogeneity, to such an extent that Barry Marshall, Nobel laureate for the discovery of H. pylori , infected himself with the bacterium to show its involvement in acute gastric illness. A paradigm-shift discovery of the H. pylori mouse-adapted strain SS1 has opened the avenues of research regarding the organism and its pathogenicity. Although the mouse model of H. pylori infection is being utilized all over the world, there are certain issues that need awareness and specific information to achieve successful, consistent colonization with symptoms resembling human. This chapter details an established and reliable protocol for the development of a competent mouse model for H. pylori infection leading to various gastro-intestinal diseases.
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Affiliation(s)
- Tanmoy Kumar Dey
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Bipul Chandra Karmakar
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Avijit Sarkar
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Sangita Paul
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India
| | - Asish Kumar Mukhopadhyay
- Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases, Kolkata, India.
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De R, Sarkar A, Ghosh P, Ganguly M, Karmakar BC, Saha DR, Halder A, Chowdhury A, Mukhopadhyay AK. Antimicrobial activity of ellagic acid against Helicobacter pylori isolates from India and during infections in mice. J Antimicrob Chemother 2019; 73:1595-1603. [PMID: 29566160 DOI: 10.1093/jac/dky079] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 02/13/2018] [Indexed: 12/11/2022] Open
Abstract
Objectives Because of the rise in antimicrobial resistance, an inexpensive, diet-based treatment against Helicobacter pylori infection would be of great interest. The present study was performed to assess the in vitro effects of ellagic acid against clinical H. pylori strains that were resistant to antibiotics used for therapy and also to observe the morphological structure following treatment with ellagic acid. The effectiveness of ellagic acid in eradicating H. pylori infection in a murine (C57BL/6) infection model, one of the standard inbred mouse lines often used for experimental infection, was also assessed. Methods A total of 55 strains were screened. The agar dilution method was used to determine the susceptibility of isolates to test compounds. Transmission electron microscopy was used to observe the morphology following treatment with ellagic acid. The antibacterial activity of ellagic acid in an H. pylori SS1-infected mouse model and its effect on gastric mucosal injury were determined by histology and PCR. Results Ellagic acid inhibited the growth of all 55 of the H. pylori strains tested. The MIC of ellagic acid ranged from 5 to 30 mg/L, showing its bactericidal properties in vitro. Ellagic acid also demonstrated anti-H. pylori efficacy in eradication of this organism in an in vivo model, as well as restitution and repair of H. pylori-induced gastric mucosal damage. Conclusions The present study paves the way for the preventive and therapeutic use of ellagic acid against H. pylori infection and, thus, ellagic acid can be considered a promising antibacterial agent against H. pylori-associated gastroduodenal diseases in humans.
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Affiliation(s)
- Ronita De
- Division of Bacteriology, National Institute of Cholera and Enteric Diseases, P 33 CIT Road Scheme XM, Beliaghata, Kolkata, 700010, India
| | - Avijit Sarkar
- Division of Bacteriology, National Institute of Cholera and Enteric Diseases, P 33 CIT Road Scheme XM, Beliaghata, Kolkata, 700010, India
| | - Prachetash Ghosh
- Division of Bacteriology, National Institute of Cholera and Enteric Diseases, P 33 CIT Road Scheme XM, Beliaghata, Kolkata, 700010, India
| | - Mou Ganguly
- Division of Bacteriology, National Institute of Cholera and Enteric Diseases, P 33 CIT Road Scheme XM, Beliaghata, Kolkata, 700010, India
| | - Bipul Chandra Karmakar
- Division of Bacteriology, National Institute of Cholera and Enteric Diseases, P 33 CIT Road Scheme XM, Beliaghata, Kolkata, 700010, India
| | - Dhira Rani Saha
- Division of Bacteriology, National Institute of Cholera and Enteric Diseases, P 33 CIT Road Scheme XM, Beliaghata, Kolkata, 700010, India
| | - Aniket Halder
- School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Abhijit Chowdhury
- School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Asish K Mukhopadhyay
- Division of Bacteriology, National Institute of Cholera and Enteric Diseases, P 33 CIT Road Scheme XM, Beliaghata, Kolkata, 700010, India
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Park HS, Wijerathne CUB, Jeong HY, Seo CS, Ha H, Kwun HJ. Gastroprotective effects of Hwanglyeonhaedok-tang against Helicobacter pylori-induced gastric cell injury. JOURNAL OF ETHNOPHARMACOLOGY 2018; 216:239-250. [PMID: 29410309 DOI: 10.1016/j.jep.2018.01.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 01/18/2018] [Accepted: 01/19/2018] [Indexed: 06/07/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Helicobacter pylori, which is found in the stomachs of approximately half of the world's population, has been associated with the development of chronic gastritis and gastric cancer. Hwanglyeonhaedok-tang (HHT) is a popular traditional medicine for the therapies of gastric ulcers and gastritis. AIM OF THE STUDY The emerging resistance of H. pylori to antibiotics arouses requirement on alternative nonantibiotic-based therapies. In the present study, we investigated the anti-inflammatory activity and anti-microbial activity of HHT against H. pylori in vitro and in an H. pylori-infected mouse model. MATERIALS AND METHODS H. pylori were treated with various concentrations of HHT and then incubated with human gastric carcinoma AGS cells. For the in vivo study, mice were orally infected with H. pylori three times over the course of 1 week, and then subjected to daily administration of HHT (120 or 600 mg/kg) for 4 weeks or standard triple therapy for 1 week. At the scheduled termination of the experiment, all mice were killed and their stomachs were collected for histological examination, quantitative real-time PCR, and Western blot analysis. RESULTS Our in vitro studies showed that HHT treatment inhibited the adhesion of H. pylori to AGS cells and suppressed the H. pylori-induced increases of inflammatory regulators, such as interleukin (IL)-8, cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). In the mouse model, HHT treatment significantly reduced H. pylori colonization, inflammation, and the levels of IL-1β, IL-6, C-X-C motif chemokine ligand 1 (CXCL1), tumor necrosis factor alpha (TNF-α), COX-2, and iNOS in gastric mucosa. Further investigation showed that HHT treatment reduced the H. pylori-induced phosphorylations of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and nuclear factor-kappa B (NF-κB). CONCLUSIONS Our findings collectively suggest that HHT has anti-inflammatory activity and antibacterial activity against H. pylori and could be an alternative to antibiotics for preventing H. pylori infection.
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Affiliation(s)
- Hee-Seon Park
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea..
| | - Charith U B Wijerathne
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea..
| | - Hye-Yun Jeong
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea..
| | - Chang-Seob Seo
- K-herb Research Center, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea..
| | - Hyekyung Ha
- K-herb Research Center, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea..
| | - Hyo-Jung Kwun
- Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea..
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AMARAL TY, PADILHA IG, PRESÍDIO GA, SILVEIRA EAASD, DUARTE AWF, BARBOSA APF, BEZERRA AFDS, LÓPEZ AMQ. Antimicrobial and anti-inflammatory activities of Apis mellifera honey on the Helicobacter pylori infection of Wistar rats gastric mucosa. FOOD SCIENCE AND TECHNOLOGY 2017. [DOI: 10.1590/1678-457x.31016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
| | - Igor Gomes PADILHA
- Universidade Federal de Alagoas, Brazil; Universidade Federal de Alagoas, Brazil
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Thi Huyen Trang T, Thanh Binh T, Yamaoka Y. Relationship between vacA Types and Development of Gastroduodenal Diseases. Toxins (Basel) 2016; 8:toxins8060182. [PMID: 27294955 PMCID: PMC4926148 DOI: 10.3390/toxins8060182] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/29/2016] [Accepted: 05/31/2016] [Indexed: 02/07/2023] Open
Abstract
The Helicobacter pylori vacuolating cytotoxin (VacA) is a secreted pore-forming toxin and a major virulence factor in the pathogenesis of H. pylori infection. While VacA is present in almost all strains, only some forms are toxigenic and pathogenic. While vacA and its genotypes are considered as markers of H. pylori-related diseases or disorders, the pathophysiological mechanisms of VacA and its genotypes remain controversial. This review outlines key findings of publications regarding vacA with emphasis on the relationship between vacA genotypes and the development of human disease.
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Affiliation(s)
- Tran Thi Huyen Trang
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu-City, Oita 879-5593, Japan.
- Department of Molecular Biology, 108 Hospital, Hanoi, Vietnam.
| | - Tran Thanh Binh
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu-City, Oita 879-5593, Japan.
- Department of Endoscopy, Cho Ray Hospital, Ho Chi Minh, Vietnam.
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-Machi, Yufu-City, Oita 879-5593, Japan.
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030, USA.
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Caulfield AJ, Walker ME, Gielda LM, Lathem WW. The Pla protease of Yersinia pestis degrades fas ligand to manipulate host cell death and inflammation. Cell Host Microbe 2015; 15:424-34. [PMID: 24721571 DOI: 10.1016/j.chom.2014.03.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 01/16/2014] [Accepted: 02/28/2014] [Indexed: 01/27/2023]
Abstract
Pneumonic plague is a deadly respiratory disease caused by Yersinia pestis. The bacterial protease Pla contributes to disease progression and manipulation of host immunity, but the mechanisms by which this occurs are largely unknown. Here we show that Pla degrades the apoptotic signaling molecule Fas ligand (FasL) to prevent host cell apoptosis and inflammation. Wild-type Y. pestis, but not a Pla mutant (Δpla), degrades FasL, which results in decreased downstream caspase-3/7 activation and reduced apoptosis. Similarly, lungs of mice challenged with wild-type Y. pestis show reduced levels of FasL and activated caspase-3/7 compared to Δpla infection. Consistent with a role for FasL in regulating immune responses, Δpla infection results in aberrant proinflammatory cytokine levels. The loss of FasL or inhibition of caspase activity alters host inflammatory responses and enables enhanced Y. pestis outgrowth in the lungs. Thus, by degrading FasL, Y. pestis manipulates host cell death pathways to facilitate infection.
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Affiliation(s)
- Adam J Caulfield
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Margaret E Walker
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Lindsay M Gielda
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Wyndham W Lathem
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Santos AM, Lopes T, Oleastro M, Gato IV, Floch P, Benejat L, Chaves P, Pereira T, Seixas E, Machado J, Guerreiro AS. Curcumin inhibits gastric inflammation induced by Helicobacter pylori infection in a mouse model. Nutrients 2015; 7:306-20. [PMID: 25569625 PMCID: PMC4303841 DOI: 10.3390/nu7010306] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/09/2014] [Indexed: 12/17/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection triggers a sequence of gastric alterations starting with an inflammation of the gastric mucosa that, in some cases, evolves to gastric cancer. Efficient vaccination has not been achieved, thus it is essential to find alternative therapies, particularly in the nutritional field. The current study evaluated whether curcumin could attenuate inflammation of the gastric mucosa due to H. pylori infection. Twenty-eight C57BL/6 mice, were inoculated with the H. pylori SS1 strain; ten non-infected mice were used as controls. H. pylori infection in live mice was followed-up using a modified 13C-Urea Breath Test (13C-UBT) and quantitative real-time polymerase chain reaction (PCR). Histologically confirmed, gastritis was observed in 42% of infected non-treated mice at both 6 and 18 weeks post-infection. These mice showed an up-regulation of the expression of inflammatory cytokines and chemokines, as well as of toll-like receptors (TLRs) and MyD88, at both time points. Treatment with curcumin decreased the expression of all these mediators. No inflammation was observed by histology in this group. Curcumin treatment exerted a significant anti-inflammatory effect in H. pylori-infected mucosa, pointing to the promising role of a nutritional approach in the prevention of H. pylori induced deleterious inflammation while the eradication or prevention of colonization by effective vaccine is not available.
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Affiliation(s)
- António M Santos
- Serviço de Medicina 4-Hospital de Santa Marta/Centro Hospitalar de Lisboa Central, Rua de Santa Marta, 50, 1169-024 Lisboa, Portugal.
| | - Teresa Lopes
- CEDOC-Nova Medical School-Faculdade de Ciências Médicas Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal.
| | - Mónica Oleastro
- Departamento de Doenças Infecciosas, Instituto Nacional de Saúde Dr. Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal.
| | - Inês Vale Gato
- Departamento de Doenças Infecciosas, Instituto Nacional de Saúde Dr. Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal.
| | - Pauline Floch
- Bacteriology Laboratory, Bordeaux University, 146 rue Léo Saignat F-33000 Bordeaux, France.
| | - Lucie Benejat
- Bacteriology Laboratory, Bordeaux University, 146 rue Léo Saignat F-33000 Bordeaux, France.
| | - Paula Chaves
- Serviço de Anatomia Patológica-Instituto Português de Oncologia Dr. Francisco Gentil, R. Prof. Lima Basto, 1099-023 Lisboa, Portugal.
| | - Teresa Pereira
- Serviço de Anatomia Patológica-Instituto Português de Oncologia Dr. Francisco Gentil, R. Prof. Lima Basto, 1099-023 Lisboa, Portugal.
| | - Elsa Seixas
- CEDOC-Nova Medical School-Faculdade de Ciências Médicas Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal.
| | - Jorge Machado
- Departamento de Doenças Infecciosas, Instituto Nacional de Saúde Dr. Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal.
| | - António S Guerreiro
- Serviço de Medicina 4-Hospital de Santa Marta/Centro Hospitalar de Lisboa Central, Rua de Santa Marta, 50, 1169-024 Lisboa, Portugal.
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Caulfield AJ, Lathem WW. Disruption of fas-fas ligand signaling, apoptosis, and innate immunity by bacterial pathogens. PLoS Pathog 2014; 10:e1004252. [PMID: 25101900 PMCID: PMC4125287 DOI: 10.1371/journal.ppat.1004252] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Adam J. Caulfield
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Wyndham W. Lathem
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
- * E-mail:
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Hayakawa Y, Fox JG, Gonda T, Worthley DL, Muthupalani S, Wang TC. Mouse models of gastric cancer. Cancers (Basel) 2013; 5:92-130. [PMID: 24216700 PMCID: PMC3730302 DOI: 10.3390/cancers5010092] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/08/2013] [Accepted: 01/15/2013] [Indexed: 12/12/2022] Open
Abstract
Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field.
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Affiliation(s)
- Yoku Hayakawa
- Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA.
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Kim IJ, Blanke SR. Remodeling the host environment: modulation of the gastric epithelium by the Helicobacter pylori vacuolating toxin (VacA). Front Cell Infect Microbiol 2012; 2:37. [PMID: 22919629 PMCID: PMC3417592 DOI: 10.3389/fcimb.2012.00037] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 03/05/2012] [Indexed: 12/13/2022] Open
Abstract
Virulence mechanisms underlying Helicobacter pylori persistence and disease remain poorly understood, in part, because the factors underlying disease risk are multifactorial and complex. Among the bacterial factors that contribute to the cumulative pathophysiology associated with H. pylori infections, the vacuolating cytotoxin (VacA) is one of the most important. Analogous to a number of H. pylori genes, the vacA gene exhibits allelic mosaicism, and human epidemiological studies have revealed that several families of toxin alleles are predictive of more severe disease. Animal model studies suggest that VacA may contribute to pathogenesis in several ways. VacA functions as an intracellular-acting protein exotoxin. However, VacA does not fit the current prototype of AB intracellular-acting bacterial toxins, which elaborate modulatory effects through the action of an enzymatic domain translocated inside host cells. Rather, VacA may represent an alternative prototype for AB intracellular acting toxins that modulate cellular homeostasis by forming ion-conducting intracellular membrane channels. Although VacA seems to form channels in several different membranes, one of the most important target sites is the mitochondrial inner membrane. VacA apparently take advantage of an unusual intracellular trafficking pathway to mitochondria, where the toxin is imported and depolarizes the inner membrane to disrupt mitochondrial dynamics and cellular energy homeostasis as a mechanism for engaging the apoptotic machinery within host cells. VacA remodeling of the gastric environment appears to be fine-tuned through the action of the Type IV effector protein CagA which, in part, limits the cytotoxic effects of VacA in cells colonized by H. pylori.
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Affiliation(s)
- Ik-Jung Kim
- Department of Microbiology, Institute for Genomic Biology, University of Illinois, Urbana IL, USA
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Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death. Proc Natl Acad Sci U S A 2011; 108:16032-7. [PMID: 21903925 DOI: 10.1073/pnas.1105175108] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
A number of pathogenic bacteria target mitochondria to modulate the host's apoptotic machinery. Studies here revealed that infection with the human gastric pathogen Helicobacter pylori disrupts the morphological dynamics of mitochondria as a mechanism to induce host cell death. The vacuolating cytotoxin A (VacA) is both essential and sufficient for inducing mitochondrial network fragmentation through the mitochondrial recruitment and activation of dynamin-related protein 1 (Drp1), which is a critical regulator of mitochondrial fission within cells. Inhibition of Drp1-induced mitochondrial fission within VacA-intoxicated cells inhibited the activation of the proapoptotic Bcl-2-associated X (Bax) protein, permeabilization of the mitochondrial outer membrane, and cell death. Our data reveal a heretofore unrecognized strategy by which a pathogenic microbe engages the host's apoptotic machinery.
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Malekshahi ZV, Gargari SLM, Rasooli I, Ebrahimizadeh W. Treatment of Helicobacter pylori infection in mice with oral administration of egg yolk-driven anti-UreC immunoglobulin. Microb Pathog 2011; 51:366-72. [PMID: 21803146 DOI: 10.1016/j.micpath.2011.06.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2011] [Revised: 05/30/2011] [Accepted: 06/02/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND Helicobacter pylori, the causative agent of gastritis and gastric ulcer, plays a crucial role in development of gastric carcinomas. Antibiotic therapy fails in almost 20% of cases due to development of antibiotic resistance. Development of antibodies against specific H. pylori targets could have significant therapeutic effect. In the present research attempts have been made to study the effect of IgY purified from egg yolk of hens immunized with recombinant UreC in treatment of mice infected with H. pylori. MATERIALS AND METHODS Purified IgY-HpUc was used in two forms: powdered and PBS dissolved. 10(9) bacteria in BHI were orally administered to C57BL6/j mice three times on alternate day intervals. Eight weeks after the last inoculation, the serum was assayed for infection rate by ELISA. The severity of gastritis was analyzed histopathologically. Infected mice were randomly divided into three groups. Groups one and two were treated with dietary IgY-HpUc and IgY-HpUc dissolved in PBS respectively for 28 days. The untreated group served as control. RESULTS Serology and histopathology confirmed the establishment of the infection. Indirect ELISA results in the treated animals showed considerable reduction of H. pylori specific antibodies in their sera. Pathological examination of gastric mucosa of infected mice treated with IgY-HpUc showed considerable reduction of inflammation in the stomach tissues. The bacterial presence on mucosal layer of the stomach was considerably reduced. CONCLUSIONS UreC-induced IgY is specifically successful in inhibition of H. pylori infection and could be an alternative to antibiotic treatment.
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Affiliation(s)
- Ziba V Malekshahi
- Department of Biology, Faculty of Science, Shahed University, Tehran, Iran
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15
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Hussey S, Jones NL. Helicobacter pylori in Childhood. PEDIATRIC GASTROINTESTINAL AND LIVER DISEASE 2011:293-308.e10. [DOI: 10.1016/b978-1-4377-0774-8.10028-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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Lamkanfi M, Dixit VM. Manipulation of host cell death pathways during microbial infections. Cell Host Microbe 2010; 8:44-54. [PMID: 20638641 DOI: 10.1016/j.chom.2010.06.007] [Citation(s) in RCA: 326] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2010] [Revised: 06/01/2010] [Accepted: 06/21/2010] [Indexed: 01/24/2023]
Abstract
Viral and microbial infections often elicit programmed cell death as part of the host defense system or as a component of the survival strategy of the pathogen. It is thus not surprising that pathogens have evolved an array of toxins and virulence factors to modulate host cell death pathways. Apoptosis, necrosis, and pyroptosis constitute the three major cell death modes for elimination of infected cells. Herein, we discuss the signaling pathways underlying the principal host cell death mechanisms and provide an overview of the strategies employed by viral and microbial pathogens to manipulate these cell death processes.
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Affiliation(s)
- Mohamed Lamkanfi
- Department of Biochemistry, Ghent University, B-9000 Ghent, Belgium.
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17
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Shen-Tu G, Schauer DB, Jones NL, Sherman PM. Detergent-resistant microdomains mediate activation of host cell signaling in response to attaching-effacing bacteria. J Transl Med 2010; 90:266-81. [PMID: 19997063 DOI: 10.1038/labinvest.2009.131] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes outbreaks of bloody diarrhea and the hemolytic-uremic syndrome. EHEC intimately adheres to epithelial cells, effaces microvilli and induces attaching-effacing (AE) lesions. Detergent-resistant microdomains (lipid rafts) serve as membrane platforms for the recruitment of signaling complexes to mediate host responses to infection. The aim of this study was to define the role of lipid rafts in activating signal transduction pathways in response to AE bacterial pathogens. Epithelial cell monolayers were infected with EHEC (MOI 100:1, 3 h, 37 degrees C) and lipid rafts isolated by buoyant density ultracentrifugation. Phosphoinositide 3-kinase (PI3K) localization to lipid rafts was confirmed using PI3K and anti-caveolin-1 antibodies. Mice with cholesterol storage disease Niemann-Pick, type C were used as in vivo models to confirm the role of lipid rafts in mediating signaling response to AE organisms. In contrast to uninfected cells, PI3K was recruited to lipid rafts in response to EHEC infection. Metabolically active bacteria and cells with intact cholesterol-rich microdomains were necessary for the recruitment of second messengers to lipid rafts. Recruitment of PI3K to lipid rafts was independent of the intimin (eaeA) gene, type III secretion system, and production of Shiga-like toxins. Colonization of NPC(-/-) colonic mucosa by Citrobacter rodentium and AE lesion formation were both delayed, compared with wild-type mice infected with the murine-specific AE bacterial pathogen. C. rodentium-infected NPC(-/-) mice had reduced colonic epithelial hyperplasia (64+/-8.251 vs 112+/-2.958 microm; P<0.05) and decreased secretion of IFN-gamma (17.6+/-17.6 vs 71+/-26.3 pg/ml, P<0.001). Lipid rafts mediate host cell signal transduction responses to AE bacterial infections both in vitro and in vivo. These findings advance the current understanding of microbial-eukaryotic cell interactions in response to enteric pathogens that hijack signaling responses mediated through lipid rafts.
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Affiliation(s)
- Grace Shen-Tu
- Research Institute, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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18
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Bergman MP, Vandenbroucke-Grauls CMJE, Appelmelk BJ, D'Elios MM, Amedei A, Azzurri A, Benagiano M, Del Prete G. The Story So Far:Helicobacter Pyloriand Gastric Autoimmunity. Int Rev Immunol 2009; 24:63-91. [PMID: 15763990 DOI: 10.1080/08830180590884648] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The gastric mucosal pathogen Helicobacter pylori induces autoantibodies directed against the gastric proton pump H+,K+-ATPase in 20-30% of infected patients. The presence of these autoantibodies is associated with severity of gastritis, increased atrophy, and apoptosis in the corpus mucosa, and patients with these autoantibodies infected with H. pylori display histopathological and clinical features that are similar to those of autoimmune gastritis (AIG). This review will focus on the T helper cell responses, cytokines, and adhesion molecules involved in corpus mucosal atrophy in chronic H. pylori gastritis and in AIG, and the role of H. pylori in the onset of AIG.
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Affiliation(s)
- Mathijs P Bergman
- Department of Medical Microbiology and Infection Control, VU Medical Center, Amsterdam, The Netherlands.
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19
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Yeretssian G, Labbé K, Saleh M. Molecular regulation of inflammation and cell death. Cytokine 2008; 43:380-90. [PMID: 18703350 DOI: 10.1016/j.cyto.2008.07.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2008] [Accepted: 06/19/2008] [Indexed: 01/01/2023]
Abstract
Cell death and innate immunity are ancient evolutionary conserved processes that utilize a dazzling number of related molecular effectors and parallel signal transduction mechanisms. The investigation of the molecular mechanisms linking the sensing of a danger signal (pathogens or tissue damage) to the induction of an inflammatory response has witnessed a renaissance in the last few years. This was initiated by the identification of pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and more recently cytosolic Nod-like receptors (NLRs), that brought innate immunity to center stage and opened the field to the study of signal transduction pathways, adaptors and central effectors linked to PRRs. This led to the characterization of the inflammasome, a macromolecular complex, scaffolded by NLRs, that recruits and activates inflammatory caspases, which are essential effectors in inflammation and cell death responses. In this review, we describe the molecular pathways of cell death and innate immunity with a focus on recent advancements in both fields and an emphasis on the striking analogies between NLR innate immunity and mitochondrial apoptosis pathways.
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Affiliation(s)
- Garabet Yeretssian
- Department of Medicine, Division of Critical Care, and Centre for the Study of Host Resistance, McGill University, Montreal, Que., Canada
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20
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21
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Atherton JC. The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2007; 1:63-96. [PMID: 18039108 DOI: 10.1146/annurev.pathol.1.110304.100125] [Citation(s) in RCA: 408] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Helicobacter pylori is the main cause of peptic ulceration, distal gastric adenocarcinoma, and gastric lymphoma. Only 15% of those colonized develop disease, and pathogenesis depends upon strain virulence, host genetic susceptibility, and environmental cofactors. Virulence factors include the cag pathogenicity island, which induces proinflammatory, pro-proliferative epithelial cell signaling; the cytotoxin VacA, which causes epithelial damage; and an adhesin, BabA. Host genetic polymorphisms that lead to high-level pro-inflammatory cytokine release in response to infection increase cancer risk. Pathogenesis is dependent upon inflammation, a Th-1 acquired immune response and hormonal changes including hypergastrinaemia. Antral-predominant inflammation leads to increased acid production from the uninflamed corpus and predisposes to duodenal ulceration; corpus-predominant gastritis leads to hypochlorhydria and predisposes to gastric ulceration and adenocarcinoma. Falling prevalence of H. pylori in developed countries has led to a falling incidence of associated diseases. However, whether there are disadvantages of an H. pylori-free stomach, for example increased risk of esosphageal adenocarcinoma, remains unclear.
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Affiliation(s)
- John C Atherton
- Wolfson Digestive Diseases Centre and Institute of Infections, Immunity, and Inflammation, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
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22
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Ganten TM, Aravena E, Sykora J, Koschny R, Mohr J, Rudi J, Stremmel W, Walczak H. Helicobacter pylori-induced apoptosis in T cells is mediated by the mitochondrial pathway independent of death receptors. Eur J Clin Invest 2007; 37:117-25. [PMID: 17217377 DOI: 10.1111/j.1365-2362.2007.01761.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Chronic infection with Helicobacter pylori is related to the pathogenesis of the noncardia carcinoma of the stomach. In this study we investigated the mechanisms of H. pylori-induced apoptosis in T lymphocytes, which could explain a mechanism of immune evasion facilitating chronic inflammation of the mucosa and gastric carcinogenesis. MATERIALS AND METHODS The supernatant of H. pylori culture was used to study the mechanism of apoptosis induction in human leukaemia T cell lines Jurkat and CEM and in primary T cells. The cytotoxin associated gene A (CagA) and vacuolating cytotoxin A (Vac A) positive bacterial strain H. pylori 60190 (CagA(+), VacA(+)) and as a control the less toxic H. pylori strain Tx30a (CagA(-), VacA(-)) were used to produce the supernatant. Cell death was determined by DNA fragmentation and protein expression by Western blot. RESULTS H. pylori 60190-induced apoptosis was neither blocked by inhibition of the death ligands TRAIL (TNF-related apoptosis-inducing ligand), CD95L/FasL and TNF-alpha (tumour necrosis factor-a) in wild type Jurkat cells nor in FADD(def) (Fas-associated death domain protein) and caspase-8(def) subclones of the Jurkat cell line. Yet, the pancaspase inhibitor zVAD-fmk could inhibit up to 90% of H. pylori-induced apoptosis. Stable transfection of Jurkat wild type cells with Bcl-x(L and) Bcl-2 resulted in marked reduction of H. pylori-induced apoptosis, showing that the mitochondrial pathway is the key regulator. This is supported by the finding that surviving primary human lymphocytes upregulate Bcl-2 when exposed to H. pylori supernatant. CONCLUSIONS H. pylori-induced apoptosis of T cells is mediated by the mitochondrial pathway and could create a local environment that facilitates life-long infection by immune evasion.
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Algood HMS, Cover TL. Helicobacter pylori persistence: an overview of interactions between H. pylori and host immune defenses. Clin Microbiol Rev 2006; 19:597-613. [PMID: 17041136 PMCID: PMC1592695 DOI: 10.1128/cmr.00006-06] [Citation(s) in RCA: 183] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori is a gram-negative bacterium that persistently colonizes more than half of the global human population. In order to successfully colonize the human stomach, H. pylori must initially overcome multiple innate host defenses. Remarkably, H. pylori can persistently colonize the stomach for decades or an entire lifetime despite development of an acquired immune response. This review focuses on the immune response to H. pylori and the mechanisms by which H. pylori resists immune clearance. Three main sections of the review are devoted to (i) analysis of the immune response to H. pylori in humans, (ii) analysis of interactions of H. pylori with host immune defenses in animal models, and (iii) interactions of H. pylori with immune cells in vitro. The topics addressed in this review are important for understanding how H. pylori resists immune clearance and also are relevant for understanding the pathogenesis of diseases caused by H. pylori (peptic ulcer disease, gastric adenocarcinoma, and gastric lymphoma).
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Affiliation(s)
- Holly M Scott Algood
- Division of Infectious Diseases, A2200 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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24
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Kountouras J, Gavalas E, Zavos C, Stergiopoulos C, Chatzopoulos D, Kapetanakis N, Gisakis D. Alzheimer's disease and Helicobacter pylori infection: Defective immune regulation and apoptosis as proposed common links. Med Hypotheses 2006; 68:378-88. [PMID: 16979298 DOI: 10.1016/j.mehy.2006.06.052] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2006] [Accepted: 06/21/2006] [Indexed: 11/20/2022]
Abstract
Although degenerative diseases of the central nervous system, including Alzheimer's disease (AD), have an increasingly high impact on aged population their association with Helicobacter pylori (H. pylori) infection has not as yet been thoroughly researched. Current H. pylori infection appears to induce irregular humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of nerves, thereby contributing and possibly perpetuating the apoptotic neural tissue damage observed in neurodegenerative diseases including AD. An association between AD and H. pylori infection has been recently addressed by two studies. A higher seropositivity for anti-H. pylori immunoglobulin G antibodies in 30 patients with AD than in 30 age-matched controls was reported in one study; this serological test, however, has limitations because it does not discriminate between current and old infections. In the other study, by introducing the histological method (the actual gold standard) for diagnosis of H. pylori infection, we reported a higher prevalence of H. pylori infection in 50 AD patients than in 30 anemic controls. This pathogen may influence the pathophysiology of AD by promoting platelet and platelet-leukocyte aggregation; releasing various pro-inflammatory and vasoactive substances; developing cross-mimicry with host antigens; producing reactive oxygen metabolites and circulating lipid peroxides; influencing the apoptotic process; and increasing, through induction of atrophic gastritis, homocysteine, which contributes to vascular disorders implicated in endothelial damage and neurodegeneration.
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Affiliation(s)
- Jannis Kountouras
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece.
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Bland DA, Suarez G, Beswick EJ, Sierra JC, Reyes VE. H pylori receptor MHC class II contributes to the dynamic gastric epithelial apoptotic response. World J Gastroenterol 2006; 12:5306-10. [PMID: 16981259 PMCID: PMC4088196 DOI: 10.3748/wjg.v12.i33.5306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of MHC class II in the modulation of gastric epithelial cell apoptosis induced by H pylori infection.
METHODS: After stimulating a human gastric epithelial cell line with bacteria or agonist antibodies specific for MHC class II and CD95, the quantitation of apoptotic and anti-apoptotic events, including caspase activation, BCL-2 activation, and FADD recruitment, was performed with a fluorometric assay, a cytometric bead array, and confocal microscopy, respectively.
RESULTS: Pretreatment of N87 cells with the anti-MHC class II IgM antibody RFD1 resulted in a reduction in global caspase activation at 24 h of H pylori infection. When caspase 3 activation was specifically measured, crosslinking of MHC class II resulted in a marked reduced caspase activation, while simple ligation of MHC class II did not. Crosslinking of MHC class II also resulted in an increased activation of the anti-apoptosis molecule BCL-2 compared to simple ligation. Confocal microscope analysis demonstrated that the pretreatment of gastric epithelial cells with a crosslinking anti-MHC class II IgM blocked the recruitment of FADD to the cell surface.
CONCLUSION: The results presented here demonstrate that the ability of MHC class II to modulate gastric epithelial apoptosis is at least partially dependent on its crosslinking. Furthermore, while previous research has demonstrated that MHC class II signaling can be pro-apoptotic during extended ligation, we have shown that the crosslinking of this molecule has anti-apoptotic effects during the earlier time points of H pylori infection. This effect is possibly mediated by the ability of MHC class II to modulate the activation of the pro-apoptotic receptor Fas by blocking the recruitment of the accessory molecule FADD, and this delay in apoptosis induction could allow for prolonged cytokine secretion by H pylori-infected gastric epithelial cells.
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Affiliation(s)
- David A Bland
- Children's Hospital, Room 2.300, University of Texas Medical Branch, 301 University Blvd. Galveston, TX 77555, USA
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Bland DA, Suarez G, Beswick EJ, Sierra JC, Reyes VE. H pylori receptor MHC class II contributes to the dynamic gastric epithelial apoptotic response. World J Gastroenterol 2006; 12:4689-93. [PMID: 16937440 PMCID: PMC4087834 DOI: 10.3748/wjg.v12.i29.4689] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of MHC class II in the modulation of gastric epithelial cell apoptosis induced by H pylori infection.
METHODS: After stimulating a human gastric epithelial cell line with bacteria or agonist antibodies specific for MHC class II and CD95, the quantitation of apoptotic and anti-apoptotic events, including caspase activation, BCL-2 activation, and FADD recruitment, was performed with a fluorometric assay, a cytometric bead array, and confocal microscopy, respectively.
RESULTS: Pretreatment of N87 cells with the anti-MHC class II IgM antibody RFD1 resulted in a reduction in global caspase activation at 24 h of H pylori infection. When caspase 3 activation was specifically measured, crosslinking of MHC class II resulted in markedly reduced caspase activation, while simple ligation of MHC class II did not. Crosslinking of MHC class II also resulted in an increased activation of the anti-apoptosis molecule BCL-2 compared to simple ligation. Confocal microscope analysis demonstrated that the pretreatment of gastric epithelial cells with a crosslinking anti-MHC class II IgM blocked the recruitment of FADD to the cell surface.
CONCLUSION: The ability of MHC class II to modulate gastric epithelial apoptosis is at least partially dependent on its crosslinking. The crosslinking of this molecule has anti-apoptotic effects during the earlier time points of H pylori infection. This effect is possibly mediated by the ability of MHC class II to modulate the activation of the pro-apoptotic receptor Fas by blocking the recruitment of the accessory molecule FADD, and this delay in apoptosis induction could allow for prolonged cytokine secretion by H pylori-infected gastric epithelial cells.
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Affiliation(s)
- David A Bland
- Department of Pediatrics, GI Immunology Core, Texas Gulf Coast Digestive Diseases Center, Technical Director, Child Health Research Center, The University of Texas Medical Branch at Galveston, Galveston, TX 77555-0366, USA
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Avitzur Y, Galindo-Mata E, Jones NL. Oral vaccination against Helicobacter pylori infection is not effective in mice with Fas ligand deficiency. Dig Dis Sci 2005; 50:2300-6. [PMID: 16416178 DOI: 10.1007/s10620-005-3051-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2005] [Accepted: 03/08/2005] [Indexed: 01/05/2023]
Abstract
The aim of this study was to delineate the role of the Fas pathway in vaccination against Helicobacter pylori. C57BL/6 and Fas ligand-deficient (gld) mice were divided into 3 groups: control, H. pylori infected, and orally vaccinated (H. pylori whole cell sonicate and cholera toxin adjuvant). Oral vaccination prevented H. pylori colonization in 78% of C57BL/6 mice compared to only 18% of gld mice. Vaccination did not alter the degree of apoptosis in either strain of mice. Vaccination led to significant increase in interleukin (IL)-5 and IL-10 in C57BL/6 but not gld mice. H. pylori infection increased interferon (IFN)-gamma levels in C57BL/6 but not in gld mice while vaccination had no effect on IFN-gamma levels in either strain. Oral vaccination is not effective in Fas ligand-deficient mice likely owing to lack of effective cytokine responses. This indicates that the Fas pathway plays a critical role in promoting an appropriate effector response following H. pylori vaccination.
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Affiliation(s)
- Yaron Avitzur
- Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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Abstract
Eukaryotic cell viability is largely regulated at the level of mitochondria, with cell death executed by endogenous proteins that act to increase the permeability of the inner and/or outer membranes of these organelles. The gastric pathogen, Helicobacter pylori, can mimic this mechanism by producing the pro-apoptotic toxin, VacA, which was recently demonstrated to (i) localize to mitochondria within epithelial cells, (ii) rapidly transport into mitochondria in vitro, and (iii) induce changes consistent with permeabilization of mitochondrial membranes by a mechanism dependent on cellular entry and toxin membrane channel activity. The targeting of mitochondrial membranes is emerging as a strategy used by pathogenic microbes to control cell viability while circumventing upstream pathways and checkpoints of cell death.
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Affiliation(s)
- Steven R Blanke
- Department of Microbiology and Molecular Genetics, University of Illinois, 302 Burrill Hall, Urbana-Champaign, IL 61801, USA.
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Stoicov C, Saffari R, Cai X, Hasyagar C, Houghton J. Molecular biology of gastric cancer: Helicobacter infection and gastric adenocarcinoma: bacterial and host factors responsible for altered growth signaling. Gene 2005; 341:1-17. [PMID: 15474284 DOI: 10.1016/j.gene.2004.07.023] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2004] [Revised: 07/06/2004] [Accepted: 07/26/2004] [Indexed: 02/07/2023]
Abstract
Gastric cancer remains the second most common cause of cancer-related mortality worldwide. The single most common cause of gastric cancer is chronic infection with the gram-negative microaerophilic spiral bacterium: Helicobacter pylori. Recent advances in this field have identified host factors which predispose to gastric cancer formation via modulation of the host immune response. In addition, recent work has explored bacterial virulence factors which may directly cause tissue damage, and lead to gastric carcinogenesis, as well as factors responsible for enhanced immune response. Environmental factors, long associated with a predilection for gastric cancer, are recognized as modifiers of key growth signalling pathways within the gastric mucosa and as such lead to growth alterations. This review focuses on exploring new advances in our understanding of bacterial factors, host genetic polymorphisms and the interaction between the bacterium and host at the level of the immune response and the regulation of proliferative and apoptotic signal transduction cascades. Modulation of the pivotal balance between cell growth and cell death leads to the formation of gastric adenocarcinoma.
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Affiliation(s)
- Calin Stoicov
- Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building Room, 2nd floor, Room 209, Worcester, MA 01605, USA
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Johnson-Henry KC, Mitchell DJ, Avitzur Y, Galindo-Mata E, Jones NL, Sherman PM. Probiotics reduce bacterial colonization and gastric inflammation in H. pylori-infected mice. Dig Dis Sci 2004. [PMID: 15387328 DOI: 10.1023/b: ddas.0000037794.02040.c2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Probiotics are characterized by their ability to interact with commensal microflora in the gastrointestinal tract to produce beneficial health effects. In vitro studies suggest that Lactobacillus species have the potential to suppress the growth of Helicobacter pylori. The goal of this study was to determine if pretreatment of mice with a commercial mixture of live probiotics (L. rhamnosus, strain R0011, and L. acidophilus, strain R0052) would suppress colonization of H. pylori, strain SS1. Thirty C57BL/6 female mice were divided into four groups: Group A was fed sterile water, group B received probiotics in sterile drinking water, group C was challenged orogastrically with H. pylori, and group D was pretreated with probiotics in drinking water prior to and following challenge with H. pylori. Rectal swabs, stomach homogenates, and luminal contents from ileum and colon were plated onto colistin nalidixic acid plates. Serial dilutions of stomach homogenates were plated onto H. pylori-sensitive agar plates and incubated under microaerophilic conditions. Tissue samples from the stomach were analyzed histologically to determine the degree of H. pylori colonization, mucosal inflammation, and epithelial cell apoptosis. Probiotics in drinking water did not affect the overall well-being of mice. Lactobacillus species were excreted in stools over the entire duration of treatment. Pretreatment with probiotics reduced the number of mice with H. pylori growth from stomach homgenates (100 to 50%; P = 0.02). The percentage of mice with moderate-severe H. pylori-induced inflammation in the gastric antrum was reduced with probiotic pretreatment (71 to 29%; P = 0.14). However, pretreatment with probiotics did not prevent H. pylori-induced apoptosis in the gastric mucosa. This preparation of probiotics provided a safe and novel approach for reducing H. pylori colonization and bacterial-induced inflammation of mice.
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Affiliation(s)
- Kathene Candace Johnson-Henry
- University of Toronto, Research Institute, Hospital for Sick Children, Department of Gastroenterology and Nutrition, Infection, Immunity, Injury and Repair, Toronto, Ontario, Canada.
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Johnson-Henry KC, Mitchell DJ, Avitzur Y, Galindo-Mata E, Jones NL, Sherman PM. Probiotics reduce bacterial colonization and gastric inflammation in H. pylori-infected mice. Dig Dis Sci 2004; 49:1095-102. [PMID: 15387328 DOI: 10.1023/b:ddas.0000037794.02040.c2] [Citation(s) in RCA: 104] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Probiotics are characterized by their ability to interact with commensal microflora in the gastrointestinal tract to produce beneficial health effects. In vitro studies suggest that Lactobacillus species have the potential to suppress the growth of Helicobacter pylori. The goal of this study was to determine if pretreatment of mice with a commercial mixture of live probiotics (L. rhamnosus, strain R0011, and L. acidophilus, strain R0052) would suppress colonization of H. pylori, strain SS1. Thirty C57BL/6 female mice were divided into four groups: Group A was fed sterile water, group B received probiotics in sterile drinking water, group C was challenged orogastrically with H. pylori, and group D was pretreated with probiotics in drinking water prior to and following challenge with H. pylori. Rectal swabs, stomach homogenates, and luminal contents from ileum and colon were plated onto colistin nalidixic acid plates. Serial dilutions of stomach homogenates were plated onto H. pylori-sensitive agar plates and incubated under microaerophilic conditions. Tissue samples from the stomach were analyzed histologically to determine the degree of H. pylori colonization, mucosal inflammation, and epithelial cell apoptosis. Probiotics in drinking water did not affect the overall well-being of mice. Lactobacillus species were excreted in stools over the entire duration of treatment. Pretreatment with probiotics reduced the number of mice with H. pylori growth from stomach homgenates (100 to 50%; P = 0.02). The percentage of mice with moderate-severe H. pylori-induced inflammation in the gastric antrum was reduced with probiotic pretreatment (71 to 29%; P = 0.14). However, pretreatment with probiotics did not prevent H. pylori-induced apoptosis in the gastric mucosa. This preparation of probiotics provided a safe and novel approach for reducing H. pylori colonization and bacterial-induced inflammation of mice.
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Affiliation(s)
- Kathene Candace Johnson-Henry
- University of Toronto, Research Institute, Hospital for Sick Children, Department of Gastroenterology and Nutrition, Infection, Immunity, Injury and Repair, Toronto, Ontario, Canada.
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Menaker RJ, Ceponis PJM, Jones NL. Helicobacter pylori induces apoptosis of macrophages in association with alterations in the mitochondrial pathway. Infect Immun 2004; 72:2889-98. [PMID: 15102801 PMCID: PMC387848 DOI: 10.1128/iai.72.5.2889-2898.2004] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Helicobacter pylori is a gastric bacterial pathogen that evades host immune responses in vivo and is associated with the development of gastritis, peptic ulcer disease, and gastric cancers. Induction of macrophage apoptosis is a method employed by multiple pathogens to escape host immune responses. Therefore, we hypothesized that H. pylori induces apoptosis of infected macrophages. RAW 264.7 cells were infected with H. pylori strain 60190, and apoptosis was assessed. Transmission electron microscopy and fluorescence microscopy showed that infected macrophages displayed morphological features characteristic of apoptosis. Quantification by acridine orange-ethidium bromide fluorescent-dye staining showed that apoptosis was dose and time dependent, and apoptosis was further confirmed by increased binding of annexin V-fluorescein isothiocyanate (FITC) to externalized phosphatidylserine of infected but not of control macrophages. Macrophages infected with isogenic mutants of H. pylori strain 60190 deficient in either cagA or vacA induced significantly less apoptosis than the parental strain, as assessed by increased binding of annexin V-FITC. Western blot analysis of whole-cell protein lysates revealed that infection with strain 60190 induced a time-dependent increase in cleavage of procaspase 8 and disappearance of full-length Bid compared with uninfected cells. Furthermore, pharmacological inhibition of caspase 8 caused a decrease in levels of apoptosis. Finally, infection caused a time-dependent increase in mitochondrial-membrane permeability and release of cytochrome c into the cytosol. These results suggest that H. pylori induces apoptosis of macrophages in association with alterations in the mitochondrial pathway. Elimination of this key immunomodulatory cell may represent a mechanism employed by the bacterium to evade host immune responses.
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Affiliation(s)
- Rena J Menaker
- Hospital for Sick Children, Department of Physiology, University of Toronto, Toronto, Canada
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Abstract
Gastric cancer is the second most common cause of cancer-related mortality world-wide. In most cases, it develops via the pre-malignant stages of atrophic gastritis, intestinal metaplasia and dysplasia, following Helicobacter pylori infection of susceptible individuals. A number of rodent models have recently provided valuable insights into the host, bacterial and environmental factors involved in gastric carcinogenesis. Wild-type rodents do not develop gastric adenocarcinoma, but early studies showed that the disease could be induced in several rodent species by chemical carcinogens. More recently, it has been demonstrated that gastric adenocarcinoma can be induced in Mongolian gerbils by H. pylori infection and in C57BL/6 mice by long-term H. felis infection. These models have allowed the importance of Helicobacter virulence genes, host factors, such as gender, strain and immune response, and environmental factors, such as dietary salt, to be explored. A number of transgenic mice with alterations in various pathways, including the immune response, gastrin biosynthesis, parietal cell development, growth factors and tumour suppressors, have also provided models of various stages of gastric carcinogenesis. One model that has proved to be particularly valuable is the hypergastrinaemic INS-GAS mouse, in which gastric carcinoma develops spontaneously in old animals, but the process is greatly accelerated by Helicobacter infection.
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Affiliation(s)
- D M Pritchard
- Department of Medicine, University of Liverpool, Liverpool, UK.
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Willhite DC, Blanke SR. Helicobacter pylori vacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity. Cell Microbiol 2004; 6:143-54. [PMID: 14706100 DOI: 10.1046/j.1462-5822.2003.00347.x] [Citation(s) in RCA: 119] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The Helicobacter pylori vacuolating cytotoxin (VacA) intoxicates mammalian cells resulting in reduction of mitochondrial transmembrane potential (Delta Psi m reduction) and cytochrome c release, two events consistent with the modulation of mitochondrial membrane permeability. We now demonstrate that the entry of VacA into cells and the capacity of VacA to form anion-selective channels are both essential for Delta Psi m reduction and cytochrome c release. Subsequent to cell entry, a substantial fraction of VacA localizes to the mitochondria. Neither Delta Psi m reduction nor cytochrome c release within VacA-intoxicated cells requires cellular caspase activity. Moreover, VacA cellular activity is not sensitive to cyclosporin A, suggesting that VacA does not induce the mitochondrial permeability transition as a mechanism for Delta Psi m reduction and cytochrome c release. Time-course and dose-response studies indicate that Delta Psi m reduction occurs substantially before and at lower concentrations of VacA than cytochrome c release. Collectively, these results support a model that VacA enters mammalian cells, localizes to the mitochondria, and modulates mitochondrial membrane permeability by a mechanism dependent on toxin channel activity ultimately resulting in cytochrome c release. This model represents a novel mechanism for regulation of a mitochondrial-dependent apoptosis pathway by a bacterial toxin.
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Affiliation(s)
- David C Willhite
- Department of Biology and Biochemistry, University of Houston, 369 Science and Research Building II, Houston, TX 77204-5001, USA
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Menaker RJ, Jones NL. Fascination with bacteria-triggered cell death: the significance of Fas-mediated apoptosis during bacterial infection in vivo. Microbes Infect 2004; 5:1149-58. [PMID: 14554257 DOI: 10.1016/j.micinf.2003.08.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Increasing evidence indicates that bacterial pathogens have developed mechanisms to modulate the apoptotic signaling cascade of host cells and thereby cause disease. The Fas death receptor pathway is one of the most extensively investigated apoptotic signaling pathways. In this review we discuss the role of Fas signaling during the interplay between bacterial pathogens and the host in vivo.
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Affiliation(s)
- Rena J Menaker
- Research Institute, Rm. 8409, Hospital for Sick Children, 555 University Avenue, Toronto, Ont., Canada M5G 1X8
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Willhite DC, Cover TL, Blanke SR. Cellular vacuolation and mitochondrial cytochrome c release are independent outcomes of Helicobacter pylori vacuolating cytotoxin activity that are each dependent on membrane channel formation. J Biol Chem 2003; 278:48204-9. [PMID: 13129933 DOI: 10.1074/jbc.m304131200] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Helicobacter pylori vacuolating toxin (VacA) is a secreted toxin that is reported to produce multiple effects on mammalian cells. In this study, we explored the relationship between VacA-induced cellular vacuolation and VacA-induced cytochrome c release from mitochondria. Within intoxicated cells, vacuolation precedes cytochrome c release and occurs at lower VacA concentrations, indicating that cellular vacuolation is not a downstream consequence of cytochrome c release. Conversely, bafilomycin A1 blocks VacA-induced vacuolation but not VacA-induced cytochrome c release, which indicates that cytochrome c release is not a downstream consequence of cellular vacuolation. Acid activation of purified VacA is required for entry of VacA into cells, and correspondingly, acid activation of the toxin is required for both vacuolation and cytochrome c release, which suggests that VacA must enter cells to produce these two effects. Single amino acid substitutions (P9A and G14A) that ablate vacuolating activity and membrane channel-forming activity render VacA unable to induce cytochrome c release. Channel blockers known to inhibit cellular vacuolation and VacA membrane channel activity also inhibit cytochrome c release. These data indicate that cellular vacuolation and mitochondrial cytochrome c release are two independent outcomes of VacA intoxication and that both effects are dependent on the formation of anion-selective membrane channels.
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Affiliation(s)
- David C Willhite
- Department of Biology and Biochemistry, University of Houston, 369 Science & Research Building II, Houston, Texas 77204-5001, USA
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Tsuji S. TRAILing gastrointestinal pathogenesis. J Gastroenterol Hepatol 2003; 18:753-5. [PMID: 12795744 DOI: 10.1046/j.1440-1746.2003.03036.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Sarafian TA, Kouyoumjian S, Khoshaghideh F, Tashkin DP, Roth MD. Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics. Am J Physiol Lung Cell Mol Physiol 2003; 284:L298-306. [PMID: 12533310 DOI: 10.1152/ajplung.00157.2002] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We have observed rapid and extensive depletion of cellular energy stores by Delta(9)-tetrahydrocannabinol (THC) in the pulmonary transformed cell line A549. ATP levels declined dose dependently with an IC(50) of 7.5 microg/ml of THC after 24-h exposure. Cell death was observed only at concentrations >10 microg/ml. Studies using JC-1, a fluorescent probe for mitochondrial membrane potential, revealed diminished mitochondrial function at THC concentrations as low as 0.5 microg/ml. At concentrations of 2.5 or 10 microg/ml of THC, a decrease in mitochondrial membrane potential was observed as early as 1 h after THC exposure. Mitochondrial function remained diminished for at least 30 h after THC exposure. Flow cytometry studies on cells exposed to particulate smoke extracts indicate that JC-1 red fluorescence was fivefold lower in cells exposed to marijuana smoke extract relative to cells exposed to tobacco smoke extract. Comparison with a variety of mitochondrial inhibitors demonstrates that THC produced effects similar to that of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, suggesting uncoupling of electron transport. Loss of red JC-1 fluorescence by THC was suppressed by cyclosporin A, suggesting mediation by the mitochondrial permeability transition pore. This disruption of mitochondrial function was sustained for at least 24 h after removal of THC by extensive washing. These results suggest that exposure of the bronchopulmonary epithelium to THC may have important health and physiological consequences.
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Affiliation(s)
- Theodore A Sarafian
- Department of Medicine, Division of Pulmonary and Critical Care, Center for Health Sciences, University of California-Los Angeles, Los Angeles, CA 90095, USA.
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Abstract
This review covers progress in identifying Helicobacter pylori-derived factors that are involved in survival and virulence of the organism and in elucidating host response pathways that can limit the infection but are also susceptible to dysregulation. Recent work has identified genes of the cytotoxin-associated gene (cag) pathogenicity island (PAI) involved in regulating signaling, interleukin-8 secretion, and phenotypic events in epithelial cells. New roles in pathogenesis have been recognized for vacuolating toxin A (VacA) and urease, H. pylori membrane and secreted factors, and host epithelial surface molecules. Molecular pathways involved in H. pylori-induced apoptosis in epithelial cells, T cells, and macrophages are being dissected. Activation of toll-like receptors and bacterial factors involved in nitric oxide (NO) and reactive oxygen species induction were also described. The ability of H. pylori to limit NO production by several mechanisms may be an important part of its ability to evade the host immune response.
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Affiliation(s)
- Purvi C Panchal
- University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, University of Maryland Medical Center, Baltimore, Maryland 21201, USA
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Lembo A, Caradonna L, Magrone T, Mastronardi ML, Caccavo D, Jirillo E, Amati L. Helicobacter pylori organisms induce expression of activation and apoptotic surface markers on human lymphocytes and AGS cells: a cytofluorimetric evaluation. Immunopharmacol Immunotoxicol 2002; 24:567-82. [PMID: 12510791 DOI: 10.1081/iph-120016036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Human peripheral blood mononuclear cells (PBMCs) were treated with Helicobacter pylori (Hp) organisms alone or with Hp-stimulated AGS cells (a gastric adenocarcinoma cell line). Hp organisms were able per se to increase the percentage of CD8 +/- CD95 +/- cells, while number of CD25+ cells and HLA-DR molecule expression increased following pretreatment with Hp-stimulated AGS cells. A comparison was made with a test system in which PBMCs were stimulated with Escherichia coli (Ec) organisms and colo-cells (a colon carcinoma cell line). In this case, CD95+ cells and CD25+ cells increased when the combination Ec organisms/colo-cells was present in the culture. On the other hand, Hp bacteria in combination with colo-cells were not able to induce activation and/or apoptotic surface markers on PBMCs, while Ec-stimulated AGS cells increased the expression of CD95 on PBMC. Finally, the direct interaction of AGS cells with Hp was able to induce higher expression of CD95 on gastric epithelial cells than Hp-stimulated PBMCs. Taken together, these data support the interplay between bacteria and epithelial cells in the course of Hp-mediated gastropathy.
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Affiliation(s)
- Annalisa Lembo
- Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari, Bari, Italy
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