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Lee Y, Lee SM, Choi J, Kang S, So S, Kim D, Ahn JY, Jung HY, Jeong JY, Kang E. Mitochondrial DNA Haplogroup Related to the Prevalence of Helicobacter pylori. Cells 2021; 10:cells10092482. [PMID: 34572132 PMCID: PMC8469812 DOI: 10.3390/cells10092482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 11/16/2022] Open
Abstract
Mitochondria are essential organelles that are not only responsible for energy production but are also involved in cell metabolism, calcium homeostasis, and apoptosis. Targeting mitochondria is a key strategy for bacteria to subvert host cells' physiology and promote infection. Helicobacter (H.) pylori targets mitochondria directly. However, mitochondrial genome (mtDNA) polymorphism (haplogroup) is not yet considered an important factor for H. pylori infection. Here, we clarified the association of mitochondrial haplogroups with H. pylori prevalence and the ability to perform damage. Seven mtDNA haplogroups were identified among 28 H. pylori-positive subjects. Haplogroup B was present at a higher frequency and haplotype D at a lower one in the H. pylori population than in that of the H. pylori-negative one. The fibroblasts carrying high-frequency haplogroup displayed a higher apoptotic rate and diminished mitochondrial respiration following H. pylori infection. mtDNA mutations were accumulated more in the H. pylori-positive population than in that of the H. pylori-negative one in old age. Among the mutations, 57% were located in RNA genes or nonsynonymous protein-coding regions in the H. pylori-positive population, while 35% were in the H. pylori-negative one. We concluded that gastric disease caused by Helicobacter virulence could be associated with haplogroups and mtDNA mutations.
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Affiliation(s)
- Yeonmi Lee
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
| | - Sun-Mi Lee
- Asan Medical Center, Asan Institute for Life Sciences, Seoul 05505, Korea;
| | - Jiwan Choi
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
| | - Seoon Kang
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
| | - Seongjun So
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Deokhoon Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Ji-Yong Ahn
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Hwoon-Yong Jung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Correspondence: (H.-Y.J.); (J.-Y.J.); (E.K.); Tel.: +82-2-3010-3197 (H.-Y.J.); +82-2-3010-4105 (J.-Y.J.); +82-31-881-7846 (E.K.)
| | - Jin-Yong Jeong
- Asan Medical Center, Asan Institute for Life Sciences, Seoul 05505, Korea;
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Correspondence: (H.-Y.J.); (J.-Y.J.); (E.K.); Tel.: +82-2-3010-3197 (H.-Y.J.); +82-2-3010-4105 (J.-Y.J.); +82-31-881-7846 (E.K.)
| | - Eunju Kang
- Department of Biomedical Science, College of Life Science and Center for Embryo and Stem Cell Research, CHA Advanced Research Institute, CHA University, Seongnam, Gyeonggi 13488, Korea; (Y.L.); (J.C.); (S.K.); (S.S.)
- Correspondence: (H.-Y.J.); (J.-Y.J.); (E.K.); Tel.: +82-2-3010-3197 (H.-Y.J.); +82-2-3010-4105 (J.-Y.J.); +82-31-881-7846 (E.K.)
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2
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Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol 2019; 20:175-193. [PMID: 30655609 PMCID: PMC7325303 DOI: 10.1038/s41580-018-0089-8] [Citation(s) in RCA: 1353] [Impact Index Per Article: 225.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The loss of vital cells within healthy tissues contributes to the development, progression and treatment outcomes of many human disorders, including neurological and infectious diseases as well as environmental and medical toxicities. Conversely, the abnormal survival and accumulation of damaged or superfluous cells drive prominent human pathologies such as cancers and autoimmune diseases. Apoptosis is an evolutionarily conserved cell death pathway that is responsible for the programmed culling of cells during normal eukaryotic development and maintenance of organismal homeostasis. This pathway is controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that balance the decision between cellular life and death. Recent insights into the dynamic interactions between BCL-2 family proteins and how they control apoptotic cell death in healthy and diseased cells have uncovered novel opportunities for therapeutic intervention. Importantly, the development of both positive and negative small-molecule modulators of apoptosis is now enabling researchers to translate the discoveries that have been made in the laboratory into clinical practice to positively impact human health.
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Affiliation(s)
- Rumani Singh
- John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Lab for Systems Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Anthony Letai
- Lab for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
- Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Kristopher Sarosiek
- John B. Little Center for Radiation Sciences, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
- Lab for Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
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3
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Yaseen A, Audette GF. Structural flexibility in the Helicobacter pylori peptidyl-prolyl cis,trans-isomerase HP0175 is achieved through an extension of the chaperone helices. J Struct Biol 2018; 204:261-269. [PMID: 30179659 DOI: 10.1016/j.jsb.2018.08.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 08/08/2018] [Accepted: 08/31/2018] [Indexed: 01/19/2023]
Abstract
Helicobacter pylori infects the gastric epithelium of half the global population, where infections can persist into adenocarcinomas and peptic ulcers. H. pylori secretes several proteins that lend to its pathogenesis and survival including VacA, CagA, γ-glutamyltransferase and HP0175. HP0175, also known as HpCBF2, classified as a peptidyl-prolyl cis,trans-isomerase, has been shown to induce apoptosis through a cascade of mechanisms initiated though its interaction with toll like receptor 4 (TLR4). Here, we report the structure of apo-HP0175 at 2.09 Å with a single monomer in the asymmetric unit. Chromatographic, light scattering and mass spectrometric analysis of HP0175 in solution indicate that the protein is mainly monomeric under low salt conditions, while increasing ionic interactions facilitates protein dimerization. A comparison of the apo-HP0175 structure to that of the indole-2-carboxylic acid-bound form shows movement of the N- and C-terminal helices upon interaction of the catalytic residues in the binding pocket. Helix extension of the N/C chaperone domains between apo and I2CA-bound HP0175 supports previous findings in parvulin PPIases for their role in protein stabilization (and accommodation of variable protein lengths) of those undergoing catalysis.
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Affiliation(s)
- Ayat Yaseen
- Department of Chemistry, York University, Toronto M3J 1P3, Canada
| | - Gerald F Audette
- Department of Chemistry, York University, Toronto M3J 1P3, Canada; Centre for Research of Biomolecular Interactions, York University, Toronto M3J 1P3, Canada.
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Som S, Dutta Banik G, Maity A, Chaudhuri S, Pradhan M. Exhaled nitric oxide as a potential marker for detecting non-ulcer dyspepsia and peptic ulcer disease. J Breath Res 2018; 12:026005. [PMID: 28947681 DOI: 10.1088/1752-7163/aa8efb] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nitric oxide (NO) plays a key role in the development of peptic ulcer disease (PUD). Conversely, the gastric pathogen Helicobacter pylori colonizes the human stomach and contributes to the development of non-ulcer dyspepsia (NUD) and PUD. However, the underlying relation between molecular NO in exhaled breath and H. pylori-associated NUD and PUD remains largely unknown. Here, we found that the excretion kinetics of NO profiles in exhaled breath are altered markedly in H. pylori-infected NUD and PUD subjects. In our observations, PUD led to considerably higher enrichments of NO in exhaled breath compared to NUD, thus revealing a potential link between exhaled NO and ulcer and non-ulcer complications. Our findings therefore suggest that molecular NO in exhaled breath could be used as a potential biomarker for non-invasive diagnosis and selective differentiation of NUD from PUD. Our observations also highlight that alterations of NO in the gastric environment can play an important role in the pathogenesis of peptic ulcers and thus may provide a new strategy for precise evolution of the actual disease state without the need for endoscopic biopsy, even after the eradication of H. pylori infection.
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Affiliation(s)
- Suman Som
- Department of Chemical, Biological and Macro-Molecular Sciences, S N Bose National Centre for Basic Sciences, Salt Lake, JD Block, Sector III, Kolkata-700106, India
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Manuka Honey Exerts Antioxidant and Anti-Inflammatory Activities That Promote Healing of Acetic Acid-Induced Gastric Ulcer in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 2017:5413917. [PMID: 28250794 PMCID: PMC5307292 DOI: 10.1155/2017/5413917] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 10/30/2016] [Accepted: 11/03/2016] [Indexed: 01/01/2023]
Abstract
Gastric ulcers are a major problem worldwide with no effective treatment. The objective of this study was to evaluate the use of manuka honey in the treatment of acetic acid-induced chronic gastric ulcers in rats. Different groups of rats were treated with three different concentrations of honey. Stomachs were checked macroscopically for ulcerative lesions in the glandular mucosa and microscopically for histopathological alterations. Treatment with manuka honey significantly reduced the ulcer index and maintained the glycoprotein content. It also reduced the mucosal myeloperoxidase activity, lipid peroxidation (MDA), and the inflammatory cytokines (TNF-α, IL-1β, and IL-6) as compared to untreated control group. In addition, honey-treated groups showed significant increase in enzymatic (GPx and SOD) and nonenzymatic (GSH) antioxidants besides levels of the anti-inflammatory cytokine IL-10. Flow cytometry studies showed that treatment of animals with manuka honey has normalized cell cycle distribution and significantly lowered apoptosis in gastric mucosa. In conclusion, the results indicated that manuka honey is effective in the treatment of chronic ulcer and preservation of mucosal glycoproteins. Its effects are due to its antioxidant and anti-inflammatory properties that resulted in a significant reduction of the gastric mucosal MDA, TNF-α, IL-1β, and IL-6 and caused an elevation in IL-10 levels.
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Maity A, Pal M, Maithani S, Ghosh B, Chaudhuri S, Pradhan M. Molecular hydrogen in human breath: a new strategy for selectively diagnosing peptic ulcer disease, non-ulcerous dyspepsia and
Helicobacter pylori
infection. J Breath Res 2016; 10:036007. [DOI: 10.1088/1752-7155/10/3/036007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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7
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Ghalehnoei H, Ahmadzadeh A, Farzi N, Alebouyeh M, Aghdaei HA, Azimzadeh P, Molaei M, Zali MR. Relationship between ureB Sequence Diversity, Urease Activity and Genotypic Variations of Different Helicobacter pylori Strains in Patients with Gastric Disorders. Pol J Microbiol 2016; 65:153-159. [PMID: 30015438 DOI: 10.5604/17331331.1204761] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/03/2015] [Indexed: 12/13/2022] Open
Abstract
Association of the severity of Helicobacter pylori induced diseases with virulence entity of the colonized strains was proven in some studies. Urease has been demonstrated as a potent virulence factor for H. pylori. The main aim of this study was investigation of the relationships of ureB sequence diversity, urease activity and virulence genotypes of different H. pylori strains with histopathological changes of gastric tissue in infected patients suffering from different gastric disorders. Analysis of the virulence genotypes in the isolated strains indicated significant associations between the presence of severe active gastritis and cagA+ (P = 0.039) or cagA/iceA1 genotypes (P = 0.026), and intestinal metaplasia and vacA m1 (P = 0.008) or vacA s1/m2 (P = 0.001) genotypes. Our results showed a 2.4-fold increased risk of peptic ulcer (95% CI: 0.483-11.93), compared with gastritis, in the infected patients who had dupA positive strains; however this association was not statistically significant. The results of urease activity showed a significant mean difference between the isolated strains from patients with PUD and NUD (P = 0.034). This activity was relatively higher among patients with intestinal metaplasia. Also a significant associa-tion was found between the lack of cagA and increased urease activity among the isolated strains (P = 0.036). While the greatest sequencevariation of ureB was detected in a strain from a patient with intestinal metaplasia, the sole determined amino acid change in UreB sequence (Ala201Thr, 30%), showed no influence on urease activity. In conclusion, the supposed role of H. pylori urease to form peptic ulcer and advancing of intestinal metaplasia was postulated in this study. Higher urease activity in the colonizing H. pylori strains that present specific virulence factors was indicated as a risk factor for promotion of histopathological changes of gastric tissue that advance gastric malignancy.
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Affiliation(s)
- Hossein Ghalehnoei
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Ahmadzadeh
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nastaran Farzi
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Alebouyeh
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pedram Azimzadeh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Molaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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8
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CXC chemokine CXCL12 tissue expression and circulating levels in peptic ulcer patients with Helicobacter pylori infection. Cytokine 2016; 85:1-4. [PMID: 27269177 DOI: 10.1016/j.cyto.2016.05.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 05/25/2016] [Accepted: 05/27/2016] [Indexed: 02/08/2023]
Abstract
Helicobacter pylori (H. pylori) infection is among the most prevalent human infections. CXCL12 is a well-known CXC chemokine involved in inflammation and play major roles in angiogenesis. There is currently very limited data on the role of CXCL12 in peptic ulcer disease. Hence, we aimed to explore whether CXCL12 is involved in the pathogenesis of peptic ulcer induced by H. pylori. In this study, we enrolled 102 H. pylori-infected patients, including 51 with active ulcer (GA) and 51 with healing ulcer (GH). We also recruited 50 healthy subjects as control, which did not show any sign or symptoms of chronic inflammatory diseases, infection, or immune-related disorders. Endoscopy was performed to determine the stage of the disease. ELISA was used for detection of H. pylori infection and CXCL12 measurement. We also employed western blotting to detect CXCL12 in ulcerative lesions of H. pylori. Demographic data were also collected by questionnaire. Our results demonstrated that CXCL12 serum levels in GA group (151.8±18.31pg/mL) were significantly higher than those in GH (36.89±6.78pg/mL) and control groups (33.77±9.12pg/mL) (P<0.0001). However, we did not observe a significant difference between GH and control groups. Moreover, overexpression of CXCL12 in gastric lesions of patients in GA group was confirmed by Western blot analysis. According to the result of the present study, it could be concluded that CXCL12 is involved in the pathogenesis and healing of H. pylori-induced peptic ulcer. CXCL12 serum levels may also be used to distinguish between GA and GH phases of the disease.
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Mohammad N, Karsabet MT, Amani J, Ardjmand A, Zadeh MR, Gholi MK, Saffari M, Ghasemi A. In Silico Design of a Chimeric Protein Containing Antigenic Fragments of Helicobacter pylori; A Bioinformatic Approach. Open Microbiol J 2016; 10:97-112. [PMID: 27335622 PMCID: PMC4899534 DOI: 10.2174/1874285801610010097] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 01/21/2016] [Accepted: 01/25/2016] [Indexed: 12/20/2022] Open
Abstract
Helicobacter pylori is a global health problem which has encouraged scientists to find new ways to diagnose, immunize and eradicate the H. pylori infection. In silico studies are a promising approach to design new chimeric antigen having the immunogenic potential of several antigens. In order to obtain such benefit in H. pylori vaccine study, a chimeric gene containing four fragments of FliD sequence (1-600 bp), UreB (327-334 bp),VacA (744-805 bp) and CagL(51-100 bp) which have a high density of B- and T-cell epitopes was designed. The secondary and tertiary structures of the chimeric protein and other properties such as stability, solubility and antigenicity were analyzed. The in silico results showed that after optimizing for the purpose of expression in Escherichia coli BL21, the solubility and antigenicity of the construct fragments were highly retained. Most regions of the chimeric protein were found to have a high antigenic propensity and surface accessibility. These results would be useful in animal model application and accounted for the development of an epitope-based vaccine against the H. pylori.
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Affiliation(s)
- Nazanin Mohammad
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mehrnaz Taghipour Karsabet
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Jafar Amani
- Applied Microbiology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abolfazl Ardjmand
- Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohsen Razavi Zadeh
- Gastroenterology Department, Beheshti Hospital, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Khalifeh Gholi
- Department of Microbiology and Immunology, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Mahmood Saffari
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Amir Ghasemi
- Department of Microbiology and Immunology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
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10
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Chen XY, Chen HM, Liu YH, Zhang ZB, Zheng YF, Su ZQ, Zhang X, Xie JH, Liang YZ, Fu LD, Lai XP, Su ZR, Huang XQ. The gastroprotective effect of pogostone from Pogostemonis Herba against indomethacin-induced gastric ulcer in rats. Exp Biol Med (Maywood) 2015; 241:193-204. [PMID: 26290140 DOI: 10.1177/1535370215600099] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 07/20/2015] [Indexed: 12/23/2022] Open
Abstract
Pogostemonis Herba, known as "Guang-Huo-Xiang" in Chinese, has been widely used in the treatment of gastrointestinal dysfunction. Pogostone is one of the major constituents of Pogostemonis Herba. The aim was to scientifically evaluate the possible gastroprotective effect and the underlying mechanisms of pogostone against indomethacin-induced gastric ulcer in rats. Rats were orally treated with vehicle, lansoprazole (30 mg/kg) or pogostone (10, 20 and 40 mg/kg) and subsequently exposed to acute gastric lesions induced by indomethacin. Gross evaluation, histological observation, gastric mucosal superoxide dismutase activity, glutathione content, catalase activity, malonaldehyde level and prostaglandin E2 production were performed. Immunohistochemistry and reverse transcription polymerase chain reaction for cyclooxygenase-1 and cyclooxygenase-2, as well as terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, immunohistochemistry for heat-shock protein 70, B-cell lymphoma-2 and Bax were conducted. Results indicated that rats pretreated with pogostone showed remarkable protection from the gastric mucosa damage compared to vehicle-treated rats based on the ulcer index and inhibition percentage. Histologically, oral administration of pogostone resulted in observable improvement of gastric injury, characterized by reduction of necrotic lesion, flattening of gastric mucosa and alleviation of submucosal edema with hemorrhage. Pogostone pretreatment significantly raised the depressed activities of superoxide dismutase, glutathione and catalase, while reduced the elevated malonaldehyde level compared with indomethacin-induced group. Pogostone-pretreated group induced a significant increase in gastric mucosal prostaglandin E2 level and obvious up-regulation of protein levels and mRNA expressions of cyclooxygenase-1 and cyclooxygenase-2. Furthermore, antiapoptotic effect of pogostone was verified by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, and the apoptotic process triggered by pogostone involved the up-expression of heat-shock protein70 and B-cell lymphoma-2 protein, and suppression of Bax protein expressions in the ulcerated tissues. It is speculated that the gastroprotective effect of pogostone against indomethacin-induced gastric ulceration might be associated with its stimulation of cyclooxygenase-mediated prostaglandin E2, antioxidant and antiapoptotic effect.
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Affiliation(s)
- Xiao-Ying Chen
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China
| | - Hai-Ming Chen
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510120, People's Republic of China Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510120, People's Republic of China
| | - Yu-Hong Liu
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China
| | - Zhen-Biao Zhang
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China
| | - Yi-Feng Zheng
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China
| | - Zu-Qing Su
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510120, People's Republic of China
| | - Xie Zhang
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China
| | - Jian-Hui Xie
- The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510120, People's Republic of China
| | - Yong-Zhuo Liang
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China Patent Examination Cooperation Center of the Patent Office, SIPO, Guangdong, Guangzhou, 510530, People's Republic of China
| | - Lu-Di Fu
- Laboratory Animal Center of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan 523808, People's Republic of China
| | - Xiao-Ping Lai
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan 523808, People's Republic of China
| | - Zi-Ren Su
- College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan 523808, People's Republic of China
| | - Xiao-Qi Huang
- The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, People's Republic of China
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Tsukanov VV, Shtygasheva OV, Vasyutin AV, Amel'chugova OS, Butorin NN, Ageeva ES. Parameters of proliferation and apoptosis of epithelial cells in the gastric mucosa in indigenous and non-indigenous residents of Khakassia with Helicobacter pylori positive duodenal ulcer disease. Bull Exp Biol Med 2015; 158:431-433. [PMID: 25711663 DOI: 10.1007/s10517-015-2778-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Indexed: 12/26/2022]
Abstract
We evaluated parameters of apoptosis in the mucosa of the gastric antrum and body of indigenous and non-indigenous residents of Khakassia with duodenal ulcer disease associated with Helicobacter pylori infection. In the gastric antrum, apoptotic index was significantly increased in patients with ulcer disease in comparison with healthy individuals in both populations. The ratio of proliferation index to apoptotic index was lower in patients with ulcer disease in comparison with healthy individuals in both populations. Similar, but less pronounced processes were recorded in the body of the stomach. Significant changes in the parameters of proliferation and apoptosis were noted in the gastric antrum and body of the stomach in both populations, but they were more pronounced in Caucasians in comparison with Khakasses.
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Affiliation(s)
- V V Tsukanov
- Research Institute for Medical Northern Problems, Siberian Division of Russian Academy of Medical Sciences, Krasnoyarsk, Russia,
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12
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Deep-sea water containing selenium provides intestinal protection against duodenal ulcers through the upregulation of Bcl-2 and thioredoxin reductase 1. PLoS One 2014; 9:e96006. [PMID: 24984066 PMCID: PMC4077573 DOI: 10.1371/journal.pone.0096006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 04/02/2014] [Indexed: 02/06/2023] Open
Abstract
Deep-sea water (DSW), which is rich in micronutrients and minerals and with antioxidant and anti-inflammatory qualities, may be developed as marine drugs to provide intestinal protection against duodenal ulcers. We determined several characteristics in the modified DSW. We explored duodenal pressure, oxygenation, microvascular blood flow, and changes in pH and oxidative redox potential (ORP) values within the stomach and duodenum in response to tap water (TW, hardness: 2.48 ppm), DSW600 (hardness: 600 ppm), and DSW1200 (hardness: 1200 ppm) in Wistar rats and analyzed oxidative stress and apoptosis gene expressions by cDNA and RNA microarrays in the duodenal epithelium. We compared the effects of drinking DSW, MgCl2, and selenium water on duodenal ulcers using pathologic scoring, immunohistochemical analysis, and Western blotting. Our results showed DSW has a higher pH value, lower ORP value, higher scavenging H2O2 and HOCl activity, higher Mg2+ concentrations, and micronutrients selenium compared with TW samples. Water infusion significantly increased intestinal pressure, O2 levels, and microvascular blood flow in DSW and TW groups. Microarray showed DSW600, DSW1200, selenium water upregulated antioxidant and anti-apoptotic genes and downregulated pro-apoptotic gene expression compared with the TW group. Drinking DSW600, DSW1200, and selenium water but not Mg2+ water significantly enhanced Bcl-2 and thioredoxin reductase 1 expression. Bax/Bcl-2/caspase 3/poly-(ADP-ribose)-polymerase signaling was activated during the pathogenesis of duodenal ulceration. DSW drinking reduced ulcer area as well as apoptotic signaling in acetic acid-induced duodenal ulcers. DSW, which contains selenium, provides intestinal protection against duodenal ulcers through the upregulation of Bcl-2 and thioredoxin reductase 1.
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Sequence and apoptotic activity of VacA cytotoxin cloned from a Helicobacter pylori Thai clinical isolate. BIOMED RESEARCH INTERNATIONAL 2014; 2014:398350. [PMID: 24963483 PMCID: PMC4052787 DOI: 10.1155/2014/398350] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Revised: 03/06/2014] [Accepted: 03/08/2014] [Indexed: 02/07/2023]
Abstract
The vacuolating cytotoxin VacA produced by Helicobacter pylori induces the formation of large cytoplasmic vacuoles in host gastric epithelial cells as well as a release of cytochrome C from mitochondria resulting in cell apoptosis. Considerable sequence diversity in VacA relating to different degrees of disease severity is observed with clinical samples from a multitude of geographic places. In this study we describe expression in Escherichia coli, purification to homogeneity and in vitro assay of its apoptotic activity of a VacA toxin from a H. pylori isolate of a Thai patient with gastrointestinal lymphoma. Sequencing revealed that the deduced amino acid sequence of the cloned Thai isolate VacA is similar to H. pylori s1/m2 type strains. The percent sequence similarity to the model strain 60190 was lower due to the presence of extra amino acids in the mid (m) region. The purified VacA toxin exhibited significant apoptotic activity on both T84 and MDCK epithelial cell lines, as revealed by DAPI staining, whereby the observed activity was significantly higher on MDCK cells. These findings could relate to a modulation of VacA activity on host cells in the Thai isolate-VacA toxin that may differ from those of the model strain.
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Ma YJ, Duan GC, Zhang RG, Fan QT, Zhang WD. Mutation of iceA in Helicobacter pylori compromised IL-8 induction from human gastric epithelial cells. J Basic Microbiol 2010; 50 Suppl 1:S83-8. [DOI: 10.1002/jobm.200900410] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Accepted: 04/19/2010] [Indexed: 01/30/2023]
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Machado AMD, Figueiredo C, Seruca R, Rasmussen LJ. Helicobacter pylori infection generates genetic instability in gastric cells. Biochim Biophys Acta Rev Cancer 2010; 1806:58-65. [PMID: 20122996 DOI: 10.1016/j.bbcan.2010.01.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2009] [Revised: 01/16/2010] [Accepted: 01/24/2010] [Indexed: 01/02/2023]
Abstract
The discovery that Helicobacter pylori is associated with gastric cancer has led to numerous studies that investigate the mechanisms by which H. pylori induces carcinogenesis. Gastric cancer shows genetic instability both in nuclear and mitochondrial DNA, besides impairment of important DNA repair pathways. As such, this review highlights the consequences of H. pylori infection on the integrity of DNA in the host cells. By down-regulating major DNA repair pathways, H. pylori infection has the potential to generate mutations. In addition, H. pylori infection can induce direct changes on the DNA of the host, such as oxidative damage, methylation, chromosomal instability, microsatellite instability, and mutations. Interestingly, H. pylori infection generates genetic instability in nuclear and mitochondrial DNA. Based on the reviewed literature we conclude that H. pylori infection promotes gastric carcinogenesis by at least three different mechanisms: (1) a combination of increased endogenous DNA damage and decreased repair activities, (2) induction of mutations in the mitochondrial DNA, and (3) generation of a transient mutator phenotype that induces mutations in the nuclear genome.
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Altonsy MO, Andrews SC, Tuohy KM. Differential induction of apoptosis in human colonic carcinoma cells (Caco-2) by Atopobium, and commensal, probiotic and enteropathogenic bacteria: mediation by the mitochondrial pathway. Int J Food Microbiol 2009; 137:190-203. [PMID: 20036023 DOI: 10.1016/j.ijfoodmicro.2009.11.015] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2009] [Revised: 09/29/2009] [Accepted: 11/22/2009] [Indexed: 12/20/2022]
Abstract
The induction of apoptosis in mammalian cells by bacteria is well reported. This process may assist infection by pathogens whereas for non-pathogens apoptosis induction within carcinoma cells protects against colon cancer. Here, apoptosis induction by a major new gut bacterium, Atopobium minutum, was compared with induction by commensal (Escherichia coli K-12 strains), probiotic (Lactobacillus rhamnosus, Bifidobacterium latis) and pathogenic (E. coli: EPEC and VTEC) gut bacteria within the colon cancer cell line, Caco-2. The results show a major apoptotic effect for the pathogens, mild effects for the probiotic strains and A. minutum, but no effect for commensal E. coli. The mild apoptotic effects observed are consistent with the beneficial roles of probotics in protection against colon cancer and suggest, for the first time, that A. minutum possesses similar advantageous, anti-cancerous activity. Although bacterial infection increased Caco-2 membrane FAS levels, caspase-8 was not activated indicating that apoptosis is FAS independent. Instead, in all cases, apoptosis was induced through the mitochondrial pathway as indicated by BAX translocation, cytochrome c release, and caspase-9 and -3 cleavage. This suggests that an intracellular stimulus initiates the observed apoptosis responses.
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Affiliation(s)
- Mohammed O Altonsy
- The School of Biological Sciences, University of Reading, Reading, RG6 6AJ, UK
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Maity P, Biswas K, Chattopadhyay I, Banerjee RK, Bandyopadhyay U. The use of neem for controlling gastric hyperacidity and ulcer. Phytother Res 2009; 23:747-55. [PMID: 19140119 DOI: 10.1002/ptr.2721] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
H(2)-receptor blockers and proton pump inhibitors are now used extensively to control gastric and duodenal ulcer, inflammation and pain, but these drugs have limitations and are not always affordable. The development of novel nontoxic antiulcer drugs, including from medicinal plants, is therefore desirable, and Azadirachta indica A. Juss, commonly known as Neem, is known to have potent gastroprotective and antiulcer effects. This review deals with the pharmacological and biochemical studies carried out regarding the antiulcer activities of Neem extracts and their mechanism of action, including the inhibition of acid secretion. A comparison with ranitidine and omeprazole in some animal models has been included and clinical studies, where available, have also been incorporated, along with a safety evaluation. Neem bark extract has the potential for the development of novel medicines for the therapeutic control of gastric hyperacidity and ulcer.
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Affiliation(s)
- Pallab Maity
- Division of Infectious Disease and Immunology, Indian Institute of Chemical Biology, Kolkata-700032, West Bengal, India
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Zhang Z, Zhou Y, Zou YY, Wang L, Yang ZC, Guo R, Li D, Peng J, Li YJ. Detrimental effects of nicotine on the acute gastric mucosal injury induced by ethanol: role of asymmetric dimethylarginine. Can J Physiol Pharmacol 2009; 86:835-40. [PMID: 19088804 DOI: 10.1139/y08-093] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The aim of this study was to determine whether asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is responsible for the detrimental effects of nicotine on ethanol-induced gastric mucosal injury and its underlying mechanisms. Gastric mucosal injury was induced by an injection of ethanol in the stomach in rats. Animals were pretreated with nicotine for 28 days before ethanol injection. The gastric mucosal ulcer index (UI) and the levels of ADMA and NO in gastric juice were determined. In vitro, the cultured mucosal epithelial cells were treated with nicotine in the presence or absence of ethanol. The concentration of ADMA in the culture medium and the ratio of cell apoptosis were measured, and the effect of nicotine or ADMA alone on cell apoptosis was also examined. In rats treated with ethanol, the UI and ADMA levels were increased and the NO level was decreased, and these effects of ethanol were augmented by pretreatment with nicotine. Administration of nicotine alone did not show significant impact on UI, ADMA level, or NO level. In vitro, incubation of human epithelial cells with ethanol induced cell injury accompanied by increased ADMA levels in the culture medium, an effect which was amplified in the presence of nicotine. Similarly, ethanol was able to induce epithelial cell apoptosis that was exacerbated by nicotine. Incubation of epithelial cells with nicotine alone did not induce cell apoptosis, but administration of ADMA alone did induce cell apoptosis. The results suggest that the gastric mucosal injury induced by ethanol is augmented by nicotine, which is related to the increased ADMA level.
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Affiliation(s)
- Zhe Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, Changsha 410078, China
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Askarov MB, Vostrikova OF, Vorobjova NN, Onishenko NA. Effects of Autologous Bone Marrow Cells on Apoptosis and Regeneration of Non-Healing Autoimmune Gastric Ulcers. Bull Exp Biol Med 2009; 146:647-51. [DOI: 10.1007/s10517-009-0360-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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The aggravatory effect of nicotine on Helicobacter pylori-induced gastric mucosa injury: role of asymmetric dimethylarginine. J Clin Gastroenterol 2009; 43:261-6. [PMID: 18936714 DOI: 10.1097/mcg.0b013e3181624485] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND GOAL Nitric oxide (NO) is a well-known gastric mucosa protection factor. Recently, it has been reported that methylated arginine compound such as asymmetric dimethylarginine (ADMA), which inhibits nitric oxide synthesis, may be related to the development of gastric mucosa injury in patients with Helicobacter pylori infection. In the present study, we tested the relationship between endogenous ADMA and gastric mucosa injury in H. pylor- infected patients and cultured gastric epithelial cells. METHODS One hundred and fifty subjects with gastric diseases were entered in this study. The levels of ADMA in gastric juice and plasma were measured in both H. pylori+ and H. pylori- patients. We analyzed independent risk factors that contribute to ADMA levels by multiple linear regression analyses. Mucosal epithelium cells were treated with nicotine (10 microM) for 24 hours in the presence or absence of H. pylori. The concentrations of ADMA in the culture medium and the rate of cell apoptosis were determined. RESULTS The ADMA level in gastric juice was significantly increased in H. pylori+ patients (P<0.05), whereas there were no differences in the content of ADMA in the plasma between H. pylori+ patients and H. pylori- patients. Smoking and H. pylori infection were 2 independent risk factors contributing to ADMA levels, and in the population of H. pylori+ patients, the level of ADMA in smokers was higher compared with nonsmokers. Incubation of nicotine (10 microM) with epithelial cells for 24 hours further increased the elevated level of ADMA and the rate of cell apoptosis owing to H. pylori infection. CONCLUSIONS H. pylori infection caused an increase of ADMA levels in gastric juice, which was aggravated by smoking. Endogenous ADMA may be an important factor contributing to gastric mucosa injury.
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Narayan S, Veeraraghavan M, Devi CSS. Pterocarpus santalinus: an In Vitro study on its anti-Helicobacter pylori effect. Phytother Res 2007; 21:190-3. [PMID: 17128431 DOI: 10.1002/ptr.2047] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The anti-H. pylori activity of Pterocarpus santalinus (PS), a traditional herb, has been assessed and compared with that of bismuth subcitrate, through in vitro studies employing rat gastric epithelial cell cultures and H. pylori isolates from gastric mucosal biopsy patients. The MIC of PS was found to be 20 microg/mL. H. pylori was co-cultivated with rat gastric epithelial cells in the presence/absence of PS at its MIC. A reduction in the activity of urease, a normal appearance of the epithelial cells on electron microscopic examination, a decrease in lipid peroxidation and lactate dehydrogenase suggests the possible anti-H. pylori activity of PS.
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Affiliation(s)
- Shoba Narayan
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, India.
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Li X, Jiang HX, Chen G, Lei L, Qin SY. Correlations of Helicobacter pylori infection with the expression of basic fibroblast growth factor and fibroblast growth factor receptor-2 in gastric mucosa and their significances. Shijie Huaren Xiaohua Zazhi 2007; 15:964-969. [DOI: 10.11569/wcjd.v15.i9.964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-2 (FGFR-2) in gastric mucosal epithelia with H. pylori infection and their significances in the carcinogenesis of stomach cancer.
METHODS: A total of 30 patients with chronic superficial gastritis (CGS), 29 with intestinal metaplasia (IM), 31 with dysplasia (Dys) and 55 with gastric cancer (GC) were included in this study. The expression of bFGF and FGFR-2 were assessed by immunohistochemistry (SP method). Rapid urease test and histological examination with Warthin-Starry were used to determine the status of H. pylori infection.
RESULTS: The expression of bFGF and FGFR-2 in CSG patients were significantly lower than those in the other patients (IM: χ2 = 4.002, P < 0.05; χ2 = 4.163, P < 0.05; Dys: χ2 = 15.779, P = 0.000; χ2 = 15.949, P = 0.000; GC: χ2 = 24.110, P = 0.000; χ2 = 18.736, P = 0.000). The expression of bFGF and FGFR-2 in IM patients were significantly lower than those in Dys and GC patients (Dys: χ2 = 4.258, P < 0.05; χ2 = 4.212, P < 0.05; GC: χ2 = 7.786, P < 0.01; χ2 = 4.687, P < 0.05). But there was no significant difference between Dys and GC patients. The positive rates of bFGF and FGFR-2 expression were significantly higher in H. pylori-infected IM and Dys patients than those in the patients without H. pylori infection (IM: χ2 = 10.076, P < 0.01; χ2 = 7.535, P < 0.01; Dys: χ2 = 11.501, P < 0.01; χ2 = 8.330, P < 0.01). The positive rates of bFGF and FGFR-2 expression in H. pylori-infected Dys patients were significantly higher than those in GC group (bFGF: χ2 = 4.201, P < 0.05; FGFR-2: χ2 = 3.982, P < 0.05), while no significant difference was found between GC and IM patients. The expression of bFGF in Dys and IM patients without H. pylori infection were significantly lower than that in GC patients (Dys: χ2 = 5.736, P < 0.05; IM: χ2 = 17.113, P = 0.000), and FGFR-2 expression in H. pylori-negative IM patients was significant lower than that in GC patients (χ2 = 11.091, P < 0.05). No significant difference was found between H. pylori-negative Dys and GC patients.
CONCLUSION: H. pylori may induce over-expression of bFGF and FGFR-2 in gastric mucosal epithelia, which may play a vital role in the carcinogenesis of stomach cancer.
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Singh M, Prasad KN, Saxena A, Yachha SK. Helicobacter pylori induces apoptosis of T- and B-cell lines and translocates mitochondrial apoptosis-inducing factor to nucleus. Curr Microbiol 2006; 52:254-60. [PMID: 16528467 DOI: 10.1007/s00284-005-0103-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2005] [Accepted: 12/08/2005] [Indexed: 12/31/2022]
Abstract
Immune cell apoptosis may play a role in human persistent Helicobacter pylori infection. We planned to study the apoptosis of T and B cells by H. pylori strains. T (Jurkat) and B (Raji) cell lines were co-cultured with cagA-positive H. pylori strains carrying different vacA genotypes (s1a/m1, s1a/m2, and s2/m2). Apoptosis was detected by microscopy, DNA fragmentation assay, and flow cytometry. Apoptosis-inducing factor (AIF) transfer from mitochondria to nucleus was studied by immunoblot analysis. Apoptosis of T and B cells was significantly higher in H. pylori-infected cells than in uninfected controls (s1a/m1 80%, s1a/m2 78%, s2m2 69% vs. control 16% for T cells, P < 0.001; s1 a/m1 78%, s1a/m2 73%, s2m2 62% vs. control 24% for B cells, P < 0.001 by flow cytometry) with no difference among the genotypes. AIF transfer from mitochondria to nucleus was demonstrated in both apoptotic cell lines. Thus, H. pylori induces apoptosis in T- and B-cell lines and translocates AIF. T and B cells deletion through apoptosis may explain the persistence of H. pylori infection; its role in pathogenesis needs further research.
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Affiliation(s)
- Manisha Singh
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
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Liu DY, Gao AN, Tang GD, Yang WY, Qin J, Wu XG, Zhu DC, Wang GN, Liu JJ, Liang ZH. Relationship between onset of peptic ulcer and meteorological factors. World J Gastroenterol 2006; 12:1463-7. [PMID: 16552822 PMCID: PMC4124331 DOI: 10.3748/wjg.v12.i9.1463] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To discuss the relationship between onset of peptic ulcer (PU) and meteorological factors (MFs).
METHODS: A total of 24 252 patients were found with active PU in 104 121 samples of gastroscoic examination from 17 hospitals in Nanning from 1992 to 1997. The detectable rate of PU (DRPU) was calculated every month, every ten days and every five days. An analysis of DRPU and MFs was made in the same period of the year. A forecast model based on MFs of the previous month was established. The real and forecast values were tested and verified.
RESULTS: During the 6 years, the DRPU from November to April was 24.4 -28.8%. The peak value (28.8%) was in January. The DRPU from May to October was 20.0 -22.6%, with its low peak (20.0%) in June. The DRPU decreased from winter and spring to summer and autumn (P < 0.005). The correlated coefficient between DRPU and average temperature value was -0.8704, -0.6624, -0.5384 for one month, ten days , five days respectively (P < 0.01). The correlated coefficient between DRPU and average highest temperature value was -0.8000, -0.6470,-0.5167 respectively (P <0.01). The correlated coefficient between DRPU and average lowest temperature value was -0.8091, -0.6617, -0.5384 respectively (P <0.01). The correlated coefficient between DRPU and average dew point temperature was -0.7812, -0.6246, -0.4936 respectively (P <0.01). The correlated coefficient between DRPU and average air pressure value was 0.7320, 0.5777, 0.4579 respectively (P <0.01). The average temperature, average highest and lowest temperature, average air pressure and average dew point temperature value of the previous month, ten days and five days could forecast the onset of PU, with its real and forecast values corresponding to 71.8%, 67.9% and 66.6% respectively.
CONCLUSION: DRPU is closely related with the average temperature, average highest and lowest temperature, average air pressure and average dew point temperature of each month, every ten days and every five days for the same period. When MFs are changed, the human body produces a series of stress actions. A long-term and median-term based medical meteorological forecast of the onset of PU can be made more accurately according to this.
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Affiliation(s)
- Da-Yun Liu
- Department of Gastroenterology, Nanning First People's Hospital, Nannig 530022, Guangxi Zhuang Autonomous Region, China.
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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: 3] [Impact Index Per Article: 0.2] [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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N/A, 李 家. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:1864-1866. [DOI: 10.11569/wcjd.v13.i15.1864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Basak C, Pathak SK, Bhattacharyya A, Pathak S, Basu J, Kundu M. The secreted peptidyl prolyl cis,trans-isomerase HP0175 of Helicobacter pylori induces apoptosis of gastric epithelial cells in a TLR4- and apoptosis signal-regulating kinase 1-dependent manner. THE JOURNAL OF IMMUNOLOGY 2005; 174:5672-80. [PMID: 15843568 DOI: 10.4049/jimmunol.174.9.5672] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Apoptosis contributes to the pathology of gastric epithelial cell damage that characterizes Helicobacter pylori infection. The secreted peptidyl prolyl cis, trans-isomerase of H. pylori, HP0175 executed apoptosis of the gastric epithelial cell line AGS in a dose- and time-dependent manner. The effect of HP0175 was confirmed by generating an isogenic mutant of H. pylori disrupted in the HP0175 gene. The apoptosis-inducing ability of this mutant was impaired compared with that of the wild type. The effect of HP0175 was mediated through TLR4. Preincubation of the gastric epithelial cell line AGS with anti-TLR4 mAb inhibited apoptosis induced by HP0175. Downstream of TLR4, apoptosis signal-regulating kinase 1 activated MAPK p38, leading to the caspase 8-dependent cleavage of Bid, its translocation to the mitochondria, mitochondrial pore formation, cytochrome c release, and activation of caspases 9 and 3. We show for the first time that a secreted bacterial Ag with peptidyl prolyl cis,trans-isomerase activity signals through TLR4, and that this Ag executes gastric epithelial cell apoptosis through a signaling pathway in which TLR4 and apoptosis signal-regulating kinase 1 are central players.
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Kitsanta P, Triantafyllou K, Chatziargyriou M, Barbatzas C, Ladas SD. Gastric mucosa epithelial cell kinetics are differentiated by anatomic site and Helicobacter pylori infection. Dig Dis Sci 2005; 50:1087-1091. [PMID: 15986859 DOI: 10.1007/s10620-005-2709-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Changes in epithelial cell turnover related to Helicobacter pylori infection may contribute to gastric cancer development. The response of different anatomic sites of the gastric mucosa to H. pylori is not known. We studied apoptosis and cell proliferation at the grater and lesser curvature of the antrum and corpus, the fundus, and the cardia from 9 H. pylori gastritis patients and 11 H. pylori-negative controls with normal histology. Proliferation was highest at the major curve of the antrum and lowest at the fundus, and apoptosis was highest at the cardia and lowest at the major curve of the antrum in both H. pylori gastritis and normal mucosa. Proliferation was significantly higher at all anatomic sites, while apoptosis was significantly lower only at the major and lesser curve of the corpus in H. pylori gastritis compared with normal controls. Our data suggest that gastric mucosa epithelial cell kinetics is differentiated by the anatomic site and H. pylori infection.
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Affiliation(s)
- Panagiota Kitsanta
- Histopathology Department, Sheffield Teaching Hospitals, Sheffield, United Kingdom
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Chan FKL. NSAID-induced peptic ulcers and Helicobacter pylori infection: implications for patient management. Drug Saf 2005; 28:287-300. [PMID: 15783239 DOI: 10.2165/00002018-200528040-00002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The conflicting data about the influence of Helicobacter pylori infection on the ulcer risk in patients receiving NSAIDs can be accounted for by the heterogeneity of study designs and the diversified host response to H. pylori. Factors that will affect the outcome include the choice of H. pylori diagnostic tests, previous ulcer complications, concurrent use of acid suppressants, NSAID-naive versus long-term users, low-dose aspirin (acetylsalicylic acid) versus non-aspirin NSAIDs and whether the result was derived from a pre-specified endpoint or post hoc subgroup analysis. Current evidence suggests that H. pylori eradication reduces the ulcer risk for patients who are about to start receiving NSAIDs but not for those who are already on long-term NSAID therapy. Since treatment with a proton pump inhibitor (PPI) worsens H. pylori-associated corpus gastritis, H. pylori should be tested for, and eradicated if present, before starting long-term prophylaxis with PPIs. Patients with H. pylori infection and a history of ulcer complications who require NSAIDs should receive concomitant PPIs or misoprostol after curing the infection. Among patients receiving low-dose aspirin, who have H. pylori infection and previous ulcer complications, long-term treatment with a PPI further reduces the risk of complicated ulcers if H. pylori eradication fails or if patients use concomitant non-aspirin NSAIDs. Current data on the gastric safety of COX-2 selective NSAIDs in H. pylori-infected patients are conflicting. Limited data suggest that the gastroduodenal sparing effect of rofecoxib is negated by H. pylori infection in patients who have had prior upper gastrointestinal events. In light of potential cardiovascular risk with COX-2 selective NSAIDs, it is important to weigh the potential adverse effects against the benefits for an individual patient.
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Affiliation(s)
- Francis K L Chan
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Shatin, Hong Kong SAR.
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Sánchez-Fidalgo S, Martín-Lacave I, Illanes M, Motilva V. Angiogenesis, cell proliferation and apoptosis in gastric ulcer healing. Effect of a selective cox-2 inhibitor. Eur J Pharmacol 2005; 505:187-94. [PMID: 15556152 DOI: 10.1016/j.ejphar.2004.10.019] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2004] [Accepted: 10/04/2004] [Indexed: 02/08/2023]
Abstract
To elucidate the role of cyclooxygenase-2, we compared the effects of rofecoxib, a selective cyclooxygenase-2 inhibitor, and ibuprofen, a nonselective cyclooxygenase inhibitor, on the evolution of acetic-acid-induced gastric ulcers in rats, evaluating growth factor expression, the angiogenic process, cell proliferation and cell apoptosis. Levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), angiogenesis and cell proliferation were analysed by immunohistochemical methods, and apoptosis was evaluated by an enzyme immunoassay. Both growth factors and microvessels appeared to be abundant in the granulation tissue of the ulcer bed. Rofecoxib (2.5 mg/kg/day) and ibuprofen (100 mg/kg/day) delayed ulcer healing, but only rofecoxib treatment provoked a reduction of bFGF expression and inhibition of the development of new microvessels. No changes in VEGF expression were detected. Results also showed that proliferation and apoptosis were increased in control ulcerated animals. Rofecoxib reduced significantly both processes. These findings demonstrate that a reduction of bFGF expression and an antiangiogenic action, as well as proliferation/apoptosis inhibition, are some of the mechanisms possibly implicated in the delay in ulcer healing seen after the administration of the highly selective COX-2 inhibitor rofecoxib.
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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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Bandyopadhyay U, Biswas K, Sengupta A, Moitra P, Dutta P, Sarkar D, Debnath P, Ganguly CK, Banerjee RK. Clinical studies on the effect of Neem (Azadirachta indica) bark extract on gastric secretion and gastroduodenal ulcer. Life Sci 2004; 75:2867-78. [PMID: 15454339 DOI: 10.1016/j.lfs.2004.04.050] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2003] [Accepted: 04/07/2004] [Indexed: 01/27/2023]
Abstract
We have shown earlier that Neem (Azadirachta indica) bark aqueous extract has potent antisecretory and antiulcer effects in animal models and has no significant adverse effect (Bandyopadhyay et al., Life Sciences, 71, 2845-2865, 2002). The objective of the present study was to investigate whether Neem bark extract had similar antisecretory and antiulcer effects in human subjects. For this purpose, a group of patients suffering from acid-related problems and gastroduodenal ulcers were orally treated with the aqueous extract of Neem bark. The lyophilised powder of the extract when administered for 10 days at the dose of 30 mg twice daily caused a significant (p < 0.002) decrease (77%) in gastric acid secretion. The volume of gastric secretion and its pepsin activity were also inhibited by 63% and 50%, respectively. Some important blood parameters for organ toxicity such as sugar, urea, creatinine, serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, albumin, globulin, hemoglobin levels and erythrocyte sedimentation rate remained close to the control values. The bark extract when taken at the dose of 30-60 mg twice daily for 10 weeks almost completely healed the duodenal ulcers monitored by barium meal X-ray or by endoscopy. One case of esophageal ulcer (gastroesophageal reflux disease) and one case of gastric ulcer also healed completely when treated at the dose of 30 mg twice daily for 6 weeks. The levels of various blood parameters for organ toxicity after Neem treatment at the doses mentioned above remained more or less close to the normal values suggesting no significant adverse effects. Neem bark extract thus has therapeutic potential for controlling gastric hypersecretion and gastroesophageal and gastroduodenal ulcers.
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Affiliation(s)
- Uday Bandyopadhyay
- Department of Physiology, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata, 700032, India.
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Martin JH, Potthoff A, Ledig S, Cornberg M, Jandl O, Manns MP, Kubicka S, Flemming P, Athmann C, Beil W, Wagner S. Effect of H. pylori on the expression of TRAIL, FasL and their receptor subtypes in human gastric epithelial cells and their role in apoptosis. Helicobacter 2004; 9:371-86. [PMID: 15361075 DOI: 10.1111/j.1083-4389.2004.00269.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS In the human stomach expression of TNF-related apoptosis inducing ligand (TRAIL) and its receptors and the modulatory role of Helicobacter pylori are not well described. Therefore, we investigated the effect of H. pylori on the expression of TRAIL, FasL and their receptors (TRAIL-R1-R4, Fas) in gastric epithelial cells and examined their role in apoptosis. MATERIALS AND METHODS mRNA and protein expression of TRAIL, FasL and their receptors were analyzed in human gastric epithelial cells using RT-PCR, Western blot, and immunohistochemistry. Gastric epithelial cells were incubated with FasL, TRAIL and/or H. pylori, and effects on expression, cell viability and epithelial apoptosis were monitored. Apoptosis was analyzed by histone ELISA, DAPI staining and immunohistochemistry. RESULTS TRAIL, FasL and their receptor subtypes were expressed in human gastric mucosa, gastric epithelial cell primary cultures and gastric cancer cells. TRAIL, FasL and H. pylori caused a time- and concentration-dependent induction of DNA fragmentation in gastric cancer cells with synergistic effects. In addition, H. pylori caused a selective up-regulation of TRAIL, TRAIL-R1 and Fas mRNA and protein expression in gastric cancer cells. CONCLUSIONS Next to FasL and Fas, TRAIL and all of its receptor subtypes are expressed in the human stomach and differentially modulated by H. pylori. TRAIL, FasL and H. pylori show complex interaction mediating apoptosis in human gastric epithelial cells. These findings might be important for the understanding of gastric epithelial cell kinetics in patients with H. pylori infection.
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Affiliation(s)
- Jan Hendrik Martin
- Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Germany
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Maity P, Biswas K, Roy S, Banerjee RK, Bandyopadhyay U. Smoking and the pathogenesis of gastroduodenal ulcer--recent mechanistic update. Mol Cell Biochem 2004; 253:329-38. [PMID: 14619984 DOI: 10.1023/a:1026040723669] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Peptic ulcer is a common disorder of gastrointestinal system and its pathogenesis is multifactorial, where smoking and nicotine have significant adverse effects. Smoking and chronic nicotine treatment stimulate basal acid output which is more pronounced in the smokers having duodenal ulcer. This increased gastric acid secretion is mediated through the stimulation of H2-receptor by histamine released after mast cell degranulation and due to the increase of the functional parietal cell volume or secretory capacity in smokers. Smoking and nicotine stimulate pepsinogen secretion also by increasing chief cell number or with an enhancement of their secretory capacity. Long-term nicotine treatment in rats also significantly decreases total mucus neck cell population and neck-cell mucus volume. Smoking also increases bile salt reflux rate and gastric bile salt concentration thereby increasing duodenogastric reflux that raises the risk of gastric ulcer in smokers. Smoking and nicotine not only induce ulceration, but they also potentiate ulceration caused by H. pylori, alcohol, nonsteroidal anti-inflammatory drugs or cold restrain stress. Polymorphonuclear neutrophils (PMN) play an important role in ulcerogenesis through oxidative damage of the mucosa by increasing the generation of reactive oxygen intermediates (ROI), which is potentiated by nicotine and smoking. Nicotine by a cAMP-protein kinase A signaling system elevates the endogenous vasopressin level, which plays an aggressive role in the development of gastroduodenal lesions. Smoking increases production of platelet activating factor (PAF) and endothelin, which are potent gastric ulcerogens. Cigarette smoking and nicotine reduce the level of circulating epidermal growth factor (EGF) and decrease the secretion of EGF from the salivary gland, which are necessary for gastric mucosal cell renewal. Nicotine also decreases prostaglandin generation in the gastric mucosa of smokers, thereby making the mucosa susceptible to ulceration. ROI generation and ROI-mediated gastric mucosal cell apoptosis are also considered to be important mechanism for aggravation of ulcer by cigarette smoke or nicotine. Both smoking and nicotine reduce angiogenesis in the gastric mucosa through inhibition of nitric oxide synthesis thereby arresting cell renewal process. Smoking or smoke extract impairs both spontaneous and drug-induced healing of ulcer. Smoke extract also inhibits gastric mucosal cell proliferation by reducing ornithine decarboxylase activity, which synthesises growth-promoting polyamines. It is concluded that gastric mucosal integrity is maintained by an interplay of some aggressive and defensive factors controlling apoptotic cell death and cell proliferation and smoking potentiates ulcer by disturbing this balance.
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Affiliation(s)
- Pallab Maity
- Department of Physiology, Indian Institute of Chemical Biology, Kolkata, India
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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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Domhan S, Stremmel W, Rudi J. Role of apoptosis and CD95-receptor/ligand system in aspirin- and Helicobacter pylori-induced cell death. Eur J Clin Invest 2004; 34:422-8. [PMID: 15200494 DOI: 10.1111/j.1365-2362.2004.01358.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Helicobacter pylori and aspirin both induce gastric epithelial apoptosis. However, the apoptosis-inducing mechanism of aspirin is still unknown. MATERIAL AND METHODS Apoptosis induction was measured in several gastric epithelial cell lines after incubation with either aspirin or H. pylori supernatant or with a combination of both. CD95 expression was assessed by FACS analysis and CD95L mRNA was measured by reverse transcription polymerase chain reaction. RESULTS It could be demonstrated that aspirin- and H. pylori supernatant-induced apoptosis involves increased CD95 expression in three different gastric epithelial cell lines. The combined exposure of H. pylori supernatant and aspirin had synergistic effects on both apoptotic cell death and CD95 expression. Blockade of CD95 signalling with an antagonistic antibody was partially prevented from H. pylori- but not from aspirin-induced apoptosis. Furthermore, CD95L expression was detected after treatment with H. pylori only. CONCLUSIONS These data suggest that although aspirin-mediated CD95 up-regulation is not relevant for its direct apoptotic effect it may sensitize gastric epithelial cells for H. pylori-induced apoptosis. Collectively our data demonstrate the relation of aspirin- and H. pylori-induced apoptosis from a new perspective.
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Affiliation(s)
- S Domhan
- Department of Medicine, University of Heidelberg, Heidelberg, Germany
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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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Zhang H, Fang DC, Wang RQ, Yang SM, Liu HF, Luo YH. Effect of Helicobacter pylori infection on expression of Bcl-2 family members in gastric adenocarcinoma. World J Gastroenterol 2004; 10:227-30. [PMID: 14716828 PMCID: PMC4717009 DOI: 10.3748/wjg.v10.i2.227] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2003] [Revised: 08/09/2003] [Accepted: 08/16/2003] [Indexed: 12/15/2022] Open
Abstract
AIM To investigate the effect of Helicobacter pylori (H pylori) infection on the expressions of Bcl-2 family members in gastric adenocarcinoma. METHODS Gastric adenocarcinoma and resection margin tissues of 95 patients were studied. Semi-quantitative RT-PCR was used to measure Bid, Bax and Bcl-2 mRNA expressions. RESULTS Expressions of Bid and Bax in gastric adenocarcinoma tissues without H pylori infection, with cagA- H pylori infection and cagA+ H pylori infection increased significantly in turn (Bid, 0.304, 0.422 and 0.855 respectively, P<0.05; Bax, 0.309, 0.650 and 0.979 respectively, P<0.05). Bcl-2 mRNA levels increased significantly in gastric adenocarcinoma tissues with cagA- H pylori infection and cagA+ H pylori infection, compared with those without H pylori infection (0.696 and 0.849 vs 0.411, P<0.05). Expressions of Bid, Bax and Bcl-2 in resection margin tissues without H pylori infection, with cagA- H pylori infection and cagA+ H pylori infection increased significantly in turn (Bid, 0.377, 0.686 and 0.939 respectively, P<0.05; Bax, 0.353, 0.645 and 1.001 respectively, P<0.05; Bcl-2, 0.371, 0.487 and 0.619 respectively, P<0.05). In H pylori negative specimens, expressions of Bid and Bax correlated negatively with that of Bcl-2 respectively in adenocarcinoma tissues (Bid vs Bcl-2, r=-0.409, P<0.05; Bax vs Bcl-2, r=-0.451, P<0.05). In H pylori positive specimens, expressions of Bid and Bax did not correlate with that of Bcl-2 in adenocarcinoma tissues (Bid vs Bcl-2, r=0.187, P>0.05; Bax vs Bcl-2, r=0.201, P>0.05), but correlated positively with that of Bcl-2 respectively in resection margin tissues (Bid vs Bcl-2, r=0.331, P<0.05; Bax vs Bcl-2, r=0.295, P<0.05). CONCLUSION H pylori may enhance Bid, Bax and Bcl-2 mRNA levels and cause deregulation of these apoptosis-associated genes expressions, which may play a role during development of gastric adenocarcinoma induced by H pylori.
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Affiliation(s)
- Hao Zhang
- Department of Gastroenterology of Southwest Hospital, Third Military Medical University, Chongqing 400038, China
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Dandekar S, Reay E, Taylor JM, Solnick JV. Apoptosis of gastric lymphocytes in Helicobacter pylori-infected rhesus macaques. Dig Dis Sci 2003; 48:1073-80. [PMID: 12822865 DOI: 10.1023/a:1023756427046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In vitro studies suggest that H. pylori induces apoptosis in gastric epithelial cells and perhaps in gastric lymphocytes as well. However, the early effects of H. pylori infection on lymphocyte apoptosis have not been examined in experimental animal models, nor have studies been performed using markers specific for T cells and T-cell subsets. Gastric T-cell apoptosis and Fas ligand expression were examined by flow cytometry after experimental infection of rhesus macaques with H. pylori. Infection induced transient apoptosis of gastric CD4+ and CD8+ T-cells, which began as soon as three days after inoculation and declined to baseline within eight weeks. Fas ligand expression showed a similar transient induction, suggesting that it mediates gastric T-cell apoptosis. We propose that transient, Fas-mediated apoptosis in gastric lymphocytes is a compensatory response to the initial T-cell inflammatory response after acute H. pylori infection.
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Affiliation(s)
- Satya Dandekar
- Department of Medical Microbiology and Immunology, University of California, Davis, California 95616, USA
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Li XH, Zhang GY, Luo FJ, Mei-HuaXu, Li Q. Influence of expression of matrix metalloproteinase induced by H. pylori infection in gastric cancer cell line. Shijie Huaren Xiaohua Zazhi 2003; 11:544-546. [DOI: 10.11569/wcjd.v11.i5.544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To establish an animal model to study the effect of H. pylori on metastasis, and to explore the possible mechanism and the relationship between H. pylori and gastric cancer metastasis.
METHODS Using BGC-823 cell cocultured with H. pylori, the growth of tumors and metastasis were observed in 8-week nude mice after the first intraumoral injection of the group of H.pylori infection and the group of no infection. The expression of MMP-2, MMP-3, TIMP-2 and TIMP-3 were investigated by immunohistochemical staining.
RESULTS There was a significant difference in the weight of tumors between the group of H.pylori infection and the group without H.pylori infection in 8-week nude mice after the first intratumoral injection (P<0.05). There were two lung metastases in group of H. pylori infection. The positive rates of MMP-2, MMP-3, TIMP-2 and TIMP-3 in the group of H. pylori infection by immunohischemical staining were 77.8±9.6%, 64.5±6.9%, 57.6±12.2% and 40.0±9.2%, and 61.2±9.7%, 53.1±5.8%, 54.3±10.9% and 53.0±6.6% in the group without H.pylori infection, respectively. The expression of MMP-2, MMP-3 and TIMP-2 were significantly higher in the group of H. pylori infection than those in the group without H.pylori infection (P<0.05), but the expression of TIMP-3 has no significantly change.
CONCLUSION H.pylori infection can accelerate the tumor growth in nude mouse and lung metastasis. The expression of MMP-2 and MMP-3 increases and TIMP-2 decreases in H. pylori infection, suggesting H. pylori may enhance gastric cancer metastasis by regulating the expression of metastasis-correlated factors.
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Affiliation(s)
- Xin-Hua Li
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Gui-Ying Zhang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Fei-Jun Luo
- Cancer Research Institute, Xiangya Medical College, Central South University, Changsha 410078, Hunan Province, China
| | - Mei-HuaXu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Qian Li
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
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Biswas K, Bandyopadhyay U, Chattopadhyay I, Varadaraj A, Ali E, Banerjee RK. A novel antioxidant and antiapoptotic role of omeprazole to block gastric ulcer through scavenging of hydroxyl radical. J Biol Chem 2003; 278:10993-1001. [PMID: 12529378 DOI: 10.1074/jbc.m210328200] [Citation(s) in RCA: 212] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The mechanism of the antiulcer effect of omeprazole was studied placing emphasis on its role to block oxidative damage and apoptosis during ulceration. Dose-response studies on gastroprotection in stress and indomethacin-induced ulcer and inhibition of pylorus ligation-induced acid secretion indicate that omeprazole significantly blocks gastric lesions at lower dose (2.5 mg/kg) without inhibiting acid secretion, suggesting an independent mechanism for its antiulcer effect. Time course studies on gastroprotection and acid reduction also indicate that omeprazole almost completely blocks lesions at 1 h when acid inhibition is partial. The severity of lesions correlates well with the increased level of endogenous hydroxyl radical (*OH), which when scavenged by dimethyl sulfoxide causes around 90% reduction of the lesions, indicating that *OH plays a major role in gastric damage. Omeprazole blocks stress-induced increased generation of *OH and associated lipid peroxidation and protein oxidation, indicating that its antioxidant role plays a major part in preventing oxidative damage. Omeprazole also prevents stress-induced DNA fragmentation, suggesting its antiapoptotic role to block cell death during ulceration. The oxidative damage of DNA by *OH generated in vitro is also protected by omeprazole or its analogue, lansoprazole. Lansoprazole when incubated in a *OH-generating system scavenges *OH to produce four oxidation products of which the major one in mass spectroscopy shows a molecular ion peak at m/z 385, which is 16 mass units higher than that of lansoprazole (m/z 369). The product shows no additional aromatic proton signal for aromatic hydroxylation in (1)H NMR. The product absorbing at 278 nm shows no alkaline shift for phenols, thereby excluding the formation of hydroxylansoprazole. The product is assigned to lansoprazole sulfone formed by the addition of one oxygen atom at the sulfur center following attack by the *OH. Thus, omeprazole plays a significant role in gastroprotection by acting as a potent antioxidant and antiapoptotic molecule.
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Affiliation(s)
- Kaushik Biswas
- Department of Physiology, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700 032, India
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Yang Y, Deng CS, Peng JZ, Wong BCY, Lam SK, Xia HHX. Effect of Helicobacter pylori on apoptosis and apoptosis related genes in gastric cancer cells. Mol Pathol 2003; 56:19-24. [PMID: 12560457 PMCID: PMC1187283 DOI: 10.1136/mp.56.1.19] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2002] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Helicobacter pylori induces the apoptosis of gastric epithelial cells in vivo and in vitro. However, the molecular mechanism has not been clarified. The aim of this study was to investigate the effect of H pylori on the apoptosis of gastric epithelial cells and the expression of apoptosis related genes in vitro. METHODS Human gastric adenocarcinoma SGC-7901 cells were co-cultured with a cytotoxic H pylori strain, NCTC 11637, at various densities ranging from 3.2 x 10(4) to 1.0 x 10(8) colony forming units (CFU)/ml for 48 hours. Apoptosis in gastric cells was determined by transmission electron microscopy, Hoechst 33258 fluorochrome staining, and flow cytometry. The expression of apoptosis related proteins, Bcl-2, Bax, and c-Myc, was measured by an immunohistochemical method, and c-Myc mRNA expression was determined by the reverse transcription-polymerase chain reaction. RESULTS Helicobacter pylori induces morphological changes typical of apoptosis. Both fluorochrome staining and flow cytometry showed that the apoptotic index began to increase when H pylori were at a density of > 1.6 x 10(4) CFU/ml, and in a density dependent manner (p < 0.01; one way ANOVA). The expression of the Bax and c-Myc proteins and of c-Myc mRNA was increased, whereas Bcl-2 expression was decreased after co-culture for 48 hours. CONCLUSIONS Helicobacter pylori induced apoptosis in gastric epithelial cells is mediated by altered expression of the products of the Bcl-2, Bax, and c-Myc genes.
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Affiliation(s)
- Y Yang
- Department of Gastroenterology, Zhongnan Hospital, Wuhan University, China Faculty of Medicine, Wuhan Science and Technology University, Wuhan, China
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Guo DL, Dong M, Wang L, Sun LP, Yuan Y. Expression of gastric cancer-associated MG7 antigen in gastric cancer, precancerous lesions and H. pylori-associated gastric diseases. World J Gastroenterol 2002; 8:1009-13. [PMID: 12439915 PMCID: PMC4656370 DOI: 10.3748/wjg.v8.i6.1009] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between the antigen MG7 antigen expression and gastric cancer as well as precancerous condition; to study the relationship between the MG7 antigen expression and H. pylori infection in benign gastric lesions in order to find out the effect of H. pylori infection on the process of gastric cancer development.
METHODS: The level of MG7 antigen expression was determined by immunohistochemical method in 383 gastric biopsied materials. The intestinal metaplasia was determined by histochemistry method. The H. pylori infection was determined by HE stain, PCR and ELISA in 291 specimens, among which only 34 cases of H. pylori-associated gastric lesions were followed up.
RESULTS: The positive rate of MG7 expression in normal gastric mucosa, intestinal metaplasia, dysplasia and gastric cancer increased gradually in ascending order (P < 0.01). The positive rate of MG7 antigen expression in type III intestinal metaplasia of gastric mucosa was higher than that of type I and II intestinal metaplasia, being highly significant (P < 0.05). The positive rate of MG7 antigen expression in superficial gastritis, atrophic gastritis and gastric cancer increased gradually (11.9%, 64.8%, 91.2%, P < 0.01). There was no significant difference between H .pylori-negative and H. pylori-positive intestinal metaplasia, atrophic gastritis and dysplasia of gastric epithelium in the positive rate of MG7 antigen expression. There was no expression of MG7 antigen in H. pylori-negative superficial gastritis. The positive rate of MG7 expression in H. pylori-positive superficial gastritis was 20.5%, and the difference between them was significant (P < 0.05). During following up, one of the three H. pylori negative cases turned positive again, and its MG7 antigen expression turned to be stronger correspondingly. 3 of 31 H. pylori positive cases were detected as early gastric cancer, among which one with “+++” MG7 antigen expression was diminished after H. pylori eradication.
CONCLUSION: MG7 antigen expression is highly specific in gastric cancer and can be used as a good marker for screening of gastric cancer; type III intestinal metaplasia, atrophic gastritis and dysplasia should be followed up and MG7 antigen expression has high clinical value in the dynamic follow-up study; although the positive -MG7 in positive - H. pylori superficial gastritis show benign morphology in features, there is still the potential risk of developing into gastric cancer, hence special attention should be paid to those showing increasing MG7 antigen expression.
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Affiliation(s)
- Dong-Li Guo
- Cancer Institute, First Affiliated Hospital, China Medical University, Shenyang, 110001, Liaoning Province, China
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Nakamura E, Hagen SJ. Role of glutamine and arginase in protection against ammonia-induced cell death in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol 2002; 283:G1264-75. [PMID: 12388179 DOI: 10.1152/ajpgi.00235.2002] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Ammonia is a cytotoxic factor produced during Helicobacter pylori infection that may reduce the survival of surface epithelial cells. Here we examine whether ammonia kills cells and whether L-glutamine (L-Gln) protects against cell death by stimulating ammonia detoxification pathways. Cell viability and vacuolation were quantified in rat gastric epithelial (RGM1) cells incubated with ammonium chloride at pH 7.4 in the presence or absence of L-Gln. Incubation of RGM1 cells with ammonium chloride caused a dose-dependent increase in cell death and vacuolation, which were both inhibited by L-Gln. We show that RGM1 cells metabolize ammonia to urea via arginase, a process that is stimulated by L-Gln and results in reduced ammonia cytotoxicity. L-Gln also inhibits the uptake and facilitates the extrusion of ammonia from cells. Blockade of glutamine synthetase did not reduce the survival of RGM1 cells, demonstrating that the conversion of L-glutamate and ammonia to L-Gln is not involved in ammonia detoxification. Thus our data support a role for L-Gln and arginase in protection against ammonia-induced cell death in gastric epithelial cells.
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Affiliation(s)
- Eiji Nakamura
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA
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Bandyopadhyay U, Biswas K, Chatterjee R, Bandyopadhyay D, Chattopadhyay I, Ganguly CK, Chakraborty T, Bhattacharya K, Banerjee RK. Gastroprotective effect of Neem (Azadirachta indica) bark extract: possible involvement of H(+)-K(+)-ATPase inhibition and scavenging of hydroxyl radical. Life Sci 2002; 71:2845-65. [PMID: 12377267 DOI: 10.1016/s0024-3205(02)02143-4] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The antisecretory and antiulcer effects of aqueous extract of Neem (Azadirachta indica) bark have been studied along with its mechanism of action, standardisation and safety evaluation. The extract can dose dependently inhibit pylorus-ligation and drug (mercaptomethylimidazole)-induced acid secretion with ED(50) value of 2.7 and 2 mg Kg(-1) b.w. respectively. It is highly potent in dose-dependently blocking gastric ulcer induced by restraint-cold stress and indomethacin with ED(50) value of 1.5 and 1.25 mg Kg(-1) b.w. respectively. When compared, bark extract is equipotent to ranitidine but more potent than omeprazole in inhibiting pylorus-ligation induced acid secretion. In a stress ulcer model, it is more effective than ranitidine but almost equipotent to omeprazole. Bark extract inhibits H(+)-K(+)-ATPase activity in vitro in a concentration dependent manner similar to omeprazole. It offers gastroprotection against stress ulcer by significantly preventing adhered mucus and endogenous glutathione depletion. It prevents oxidative damage of the gastric mucosa by significantly blocking lipid peroxidation and by scavenging the endogenous hydroxyl radical ((z.rad;)OH)-the major causative factor for ulcer. The (z.rad;)OH-mediated oxidative damage of human gastric mucosal DNA is also protected by the extract in vitro. Bark extract is more effective than melatonin, vitamin E, desferrioxamine and alpha-phenyl N-tert butylnitrone, the known antioxidants having antiulcer effect. Standardisation of the bioactive extract by high pressure liquid chromatography indicates that peak 1 of the chromatogram coincides with the major bioactive compound, a phenolic glycoside, isolated from the extract. The pharmacological effects of the bark extract are attributed to a phenolic glycoside which is apparently homogeneous by HPLC and which represents 10% of the raw bark extract. A single dose of 1g of raw extract per kg b.w. (mice) given in one day and application of 0.6g raw extract per kg b.w. per day by oral route over 15 days to a cumulative dose of 9g per kg was well tolerated and was below the LD(50). It is also well tolerated by rats with no significant adverse effect. It is concluded that Neem bark extract has therapeutic potential for the control of gastric hyperacidity and ulcer.
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Affiliation(s)
- Uday Bandyopadhyay
- Department of Physiology, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick road, Kolkata 700032, India
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Hasumi K, Tanaka K, Saitoh S, Takagi A, Miwa T, Mine T, Koga Y. Roles of tumor necrosis factor-alpha-receptor type 1 and Fas in the Helicobacter pylori-induced apoptosis of gastric epithelial cells. J Gastroenterol Hepatol 2002; 17:651-658. [PMID: 12100609 DOI: 10.1046/j.1440-1746.2002.02757.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVES Helicobacter pylori (HP) infection has been reported to accelerate the apoptosis of gastric epithelial cells. This bacteria has also been known to enhance the expression levels of molecules such as Fas antigen and a receptor for tumor necrosis factor-alpha-receptor type 1 (TNF-R1). However, whether Fas and/or TNF-R1 is actually involved in HP-mediated apoptosis has yet to be evaluated. The purpose of this study was therefore to examine the roles of Fas and TNF-R1 in HP-mediated apoptosis. METHODS Biopsy samples were collected from 10 HP-negative healthy volunteers and from 39 HP-positive ulcer patients. Gastric epithelial cells were obtained from the samples. The cells were then stained with anti-Fas, anti-TNF-R1 and Annexin V, which detected apoptotic cells. The findings were analyzed by three-color flow cytometry. RESULTS The percentages of apoptotic cells were significantly higher in HP-positive patients than in the controls. In HP-negative controls, almost all of the apoptotic cells lacked both Fas and TNF-R1. On the other hand, in HP-positive patients, HP upregulated the expression levels of Fas and TNF-R1 and, consequently, enhanced the apoptosis mediated by receptors such as Fas and TNF-R1. However, even in HP-positive patients, apoptosis was also observed in the cells that lacked both Fas and TNF-R1. CONCLUSIONS Fas and TNF-R1 expressed on gastric epithelial cells from HP-infected patients were responsible for the accelerated apoptosis of the cells.
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Affiliation(s)
- Keizo Hasumi
- Department of Infectious Diseases, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
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Jones NL, Day AS, Jennings H, Shannon PT, Galindo-Mata E, Sherman PM. Enhanced disease severity in Helicobacter pylori-infected mice deficient in Fas signaling. Infect Immun 2002; 70:2591-2597. [PMID: 11953400 PMCID: PMC127915 DOI: 10.1128/iai.70.5.2591-2597.2002] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2001] [Revised: 11/28/2001] [Accepted: 01/22/2002] [Indexed: 11/20/2022] Open
Abstract
Recent evidence suggests that immune-mediated gastric epithelial cell apoptosis through Fas-Fas ligand interactions participates in Helicobacter pylori disease pathogenesis. To define the role of Fas signaling in vivo, H. pylori strain SS1 infection in C57BL/6 mice was compared to that in mice deficient in the Fas ligand (gld). gld mice had a degree of gastritis similar to that of C57BL/6 mice after 6 weeks (gastritis score, 5.2 +/- 0.6 [mean +/- standard error] versus 3.5 +/- 0.8) and 12 weeks (4.0 +/- 0.7 versus 3.4 +/- 0.5) of infection. Bacterial colonization was comparable in each group of mice at 12 weeks of infection (2.1 +/- 0.3 versus 1.6 +/- 0.3 for gld and C57BL/6, respectively; the difference is not significant). Sixty-seven percent of H. pylori-infected gld mice displayed atrophic changes in the gastric mucosa, compared with 37% of infected C57BL/6 mice, at 12 weeks. In addition, atrophic changes were more severe in H. pylori-infected gld mice (P < 0.05). Splenocytes isolated from H. pylori-infected C57BL/6 mice had a twofold increase in production of the Th1 cytokine gamma interferon (IFN-gamma) in response to H. pylori antigens at both 6 and 12 weeks compared to controls (143 +/- 65 versus 69 +/-26 pg/ml and 336 +/- 73 versus 172 +/- 60, respectively). In contrast, there was a lack of detectable IFN-gamma in gld mice infected with the bacterium. H. pylori-infected C57BL/6 mice had increased epithelial cell apoptosis compared with sham-infected C57BL/6 mice (35.0 +/- 8.9 versus 12.3 +/- 6.9; P < 0.05). Epithelial cell apoptosis did not differ between H. pylori-infected and control gld mice (5.2 +/- 1.6 versus 6.5 +/- 2.9 [not significant]). These data demonstrate that mice with mutations in the Fas ligand develop more severe premalignant mucosal changes in response to infection with H. pylori in association with both an impaired gastric epithelial cell apoptotic response and IFN-gamma production. The Fas death pathway modulates disease pathophysiology following murine infection with H. pylori. Deregulation of the Fas pathway could be involved in the transition from gastritis to gastric cancers during H. pylori infection.
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Affiliation(s)
- Nicola L Jones
- Department of Physiology, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
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Abstract
Although gastric adenocarcinoma is associated with the presence of Helicobacter pylori in the stomach, only a small fraction of colonized individuals develop this common malignancy. H. pylori strain and host genotypes probably influence the risk of carcinogenesis by differentially affecting host inflammatory responses and epithelial-cell physiology. Understanding the host-microbial interactions that lead to neoplasia will improve cancer-targeted therapeutics and diagnostics, and provide mechanistic insights into other malignancies that arise within the context of microbially initiated inflammatory states.
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Affiliation(s)
- Richard M Peek
- Division of Gastroenterology, Vanderbilt University School of Medicine, Medical Center North, Nashville, Tennessee 37232-2279, USA.
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Sumie A, Yamashiro T, Nakashima K, Nasu M, Watanabe M, Nishizono A. Comparison of genomic structures and antigenic reactivities of orthologous 29-kilodalton outer membrane proteins of Helicobacter pylori. Infect Immun 2001; 69:6846-52. [PMID: 11598058 PMCID: PMC100063 DOI: 10.1128/iai.69.11.6846-6852.2001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
We purified a 29-kDa Helicobacter pylori outer membrane protein (Omp29 protein) and cloned the gene encoding the protein from H. pylori strain ATCC 43504. The Omp29 gene corresponded to the reported JHP73 and the HP78-79 genes of H. pylori strains. A corresponding nucleotide fragment was detected in all 150 tested H. pylori clinical isolates by PCR or Southern blotting. The amplified Omp29-corresponding fragments were categorized into a ca. 770-bp-long group and a larger-fragment group. Sequence analysis indicated that the larger fragments were likely synthesized from the 770-bp fragments by insertion of an irrelevant fragment via 17-bp-long repeat sequences. Immunoblot analysis implies that the ca. 770-bp fragment is responsible for the protein homologous to Omp29, whereas the larger fragments are not responsible for those proteins or encoding antigenically distinct proteins. We postulate that the H. pylori outer membrane protein Omp29 can alter its antigenicity through gene modifications mediated by nucleotide transfer.
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Affiliation(s)
- A Sumie
- Department of Microbiology, Oita Medical University, Oita, Japan
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Kuck D, Kolmerer B, Iking-Konert C, Krammer PH, Stremmel W, Rudi J. Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect Immun 2001; 69:5080-7. [PMID: 11447189 PMCID: PMC98603 DOI: 10.1128/iai.69.8.5080-5087.2001] [Citation(s) in RCA: 137] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Helicobacter pylori induces cell death by apoptosis. However, the apoptosis-inducing factor is still unknown. The virulence factor vacuolating cytotoxin A (VacA) is a potential candidate, and thus its role in apoptosis induction was investigated in the human gastric epithelial cell line AGS. The supernatant from the vacA wild-type strain P12 was able to induce apoptotic cell death, whereas the supernatant from its isogenic mutant strain P14 could not. That VacA was indeed the apoptosis-inducing factor was demonstrated further by substantial reduction of apoptosis upon treatment of AGS cells with a supernatant specifically depleted of native VacA. Furthermore, a recombinant VacA produced in Escherichia coli was also able to induce apoptosis in AGS cells but failed to induce cellular vacuolation. These findings demonstrate that the vacuolating cytototoxin of H. pylori is a bacterial factor capable of inducing apoptosis in gastric epithelial cells.
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Affiliation(s)
- D Kuck
- Department of Medicine, University of Heidelberg, 69115 Heidelberg, Germany
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