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Lin Y, Liu K, Lu F, Zhai C, Cheng F. Programmed cell death in Helicobacter pylori infection and related gastric cancer. Front Cell Infect Microbiol 2024; 14:1416819. [PMID: 39145306 PMCID: PMC11322058 DOI: 10.3389/fcimb.2024.1416819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 07/08/2024] [Indexed: 08/16/2024] Open
Abstract
Programmed cell death (PCD) plays a crucial role in maintaining the normal structure and function of the digestive tract in the body. Infection with Helicobacter pylori (H. pylori) is an important factor leading to gastric damage, promoting the Correa cascade and accelerating the transition from gastritis to gastric cancer. Recent research has shown that several PCD signaling pathways are abnormally activated during H. pylori infection, and the dysfunction of PCD is thought to contribute to the development of gastric cancer and interfere with treatment. With the deepening of studies on H. pylori infection in terms of PCD, exploring the interaction mechanisms between H. pylori and the body in different PCD pathways may become an important research direction for the future treatment of H. pylori infection and H. pylori-related gastric cancer. In addition, biologically active compounds that can inhibit or induce PCD may serve as key elements for the treatment of this disease. In this review, we briefly describe the process of PCD, discuss the interaction between different PCD signaling pathways and the mechanisms of H. pylori infection or H. pylori-related gastric cancer, and summarize the active molecules that may play a therapeutic role in each PCD pathway during this process, with the expectation of providing a more comprehensive understanding of the role of PCD in H. pylori infection.
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Affiliation(s)
- Yukun Lin
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Kunjing Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Fang Lu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Changming Zhai
- Department of Rheumatism, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China
| | - Fafeng Cheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Singh V, Rai R, Mathew BJ, Chourasia R, Singh AK, Kumar A, Chaurasiya SK. Phospholipase C: underrated players in microbial infections. Front Cell Infect Microbiol 2023; 13:1089374. [PMID: 37139494 PMCID: PMC10149971 DOI: 10.3389/fcimb.2023.1089374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/21/2023] [Indexed: 05/05/2023] Open
Abstract
During bacterial infections, one or more virulence factors are required to support the survival, growth, and colonization of the pathogen within the host, leading to the symptomatic characteristic of the disease. The outcome of bacterial infections is determined by several factors from both host as well as pathogen origin. Proteins and enzymes involved in cellular signaling are important players in determining the outcome of host-pathogen interactions. phospholipase C (PLCs) participate in cellular signaling and regulation by virtue of their ability to hydrolyze membrane phospholipids into di-acyl-glycerol (DAG) and inositol triphosphate (IP3), which further causes the activation of other signaling pathways involved in various processes, including immune response. A total of 13 PLC isoforms are known so far, differing in their structure, regulation, and tissue-specific distribution. Different PLC isoforms have been implicated in various diseases, including cancer and infectious diseases; however, their roles in infectious diseases are not clearly understood. Many studies have suggested the prominent roles of both host and pathogen-derived PLCs during infections. PLCs have also been shown to contribute towards disease pathogenesis and the onset of disease symptoms. In this review, we have discussed the contribution of PLCs as a determinant of the outcome of host-pathogen interaction and pathogenesis during bacterial infections of human importance.
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Affiliation(s)
- Vinayak Singh
- Molecular Signalling Lab, Department of Biological Science and Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
| | - Rupal Rai
- Molecular Signalling Lab, Department of Biological Science and Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
| | - Bijina J. Mathew
- Molecular Signalling Lab, Department of Biological Science and Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
| | - Rashmi Chourasia
- Department of Chemistry, IES University, Bhopal, Madhya Pradesh, India
| | - Anirudh K. Singh
- School of Sciences, SAM Global University, Raisen, Madhya Pradesh, India
| | - Awanish Kumar
- Department of Biotechnology, National Institute of Technology, Raipur, Chhattisgarh, India
| | - Shivendra K. Chaurasiya
- Molecular Signalling Lab, Department of Biological Science and Engineering, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh, India
- *Correspondence: Shivendra K. Chaurasiya,
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Chen M, Liu C, Huan H, Hu RW, Wu H, Deng K. A comparative study on Helicobacter pylori infection in Tibetan and Han people from Tibet and Sichuan province. Shijie Huaren Xiaohua Zazhi 2018; 26:1402-1407. [DOI: 10.11569/wcjd.v26.i23.1402] [Citation(s) in RCA: 1] [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 compare the prevalence of Helicobacter pylori (H. pylori) infection in Tibetan and Han subjects from Tibet and Sichuan province.
METHODS A retrospective study for investigating H. pylori infection was performed among Tibetan and Han subjects who underwent the 14C-urea breath test at the Tibetan Chengdu Branch Hospital and West China Hospital. The clinical characteristics (residential address, H. pylori infection status, etc.) were collected and recorded.
RESULTS A total of 2163 subjects from Tibet (Tibetan/Han, 547/297) and Sichuan province (Tibetan/Han, 308/1011) were enrolled in this retrospective study. The overall H. pylori positive rate in Tibet was significantly lower than that in Sichuan province (50.8% vs 39.3%, P < 0.001). The H. pylori positive rate in Tibetan subjects from both Tibet and Sichuan was significantly higher than that in Han people (56.9% vs 39.7%, P < 0.001; 52.3% vs 35.4%, P < 0.001). No significant difference was observed in the H. pylori positive rate between Tibetan subjects from Tibet and Sichuan (P = 0.196) or Han subjects from Tibet and Sichuan (P = 0.192). The H. pylori positive rate of Han ethnic subjects significantly increased in the older age group (age < 45 vs age ≥ 45: 32.3% vs 40.5%, P = 0.002). However, the H. pylori positive rate of Tibetan subjects significantly decreased in the older age group (age < 45 vs age ≥ 45: 61.5% vs 50.0%, P = 0.001).
CONCLUSION The H. pylori prevalence rate is higher in Tibetan subjects than in Han subjects from Sichuan province and Tibet. The H. pylori prevalence rate is positively correlated with age in Han subjects, but is negatively correlated with age in Tibetan subjects.
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Affiliation(s)
- Mo Chen
- Department of Gastroenterology, Tibetan Chengdu Branch of West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Chao Liu
- Department of Gastroenterology, Tibetan Chengdu Branch of West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hui Huan
- Department of Gastroenterology, Tibetan Chengdu Branch of West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ren-Wei Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Kai Deng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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Slomiany BL, Slomiany A. Role of LPS-elicited signaling in triggering gastric mucosal inflammatory responses to H. pylori: modulatory effect of ghrelin. Inflammopharmacology 2017; 25:415-429. [PMID: 28516374 DOI: 10.1007/s10787-017-0360-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 05/05/2017] [Indexed: 12/14/2022]
Abstract
Infection with Helicobacter pylori is a primary culprit in the etiology of gastric disease, and its cell-wall lipopolysaccharide (LPS) is recognized as a potent endotoxin responsible for triggering a pattern of the mucosal inflammatory responses. The engagement by the LPS of gastric mucosal Toll-like receptor 4 (TLR4) leads to initiation of signal transduction events characterized by the activation of mitogen-activated protein kinase (MAPK) cascade, induction of phosphoinositide-specific phospholipase C (PLC)/protein kinase C (PKC)/phosphatidylinositol 3-kinase (PI3K) pathway, and up-regulation in Src/Akt. These signaling events in turn exert their influence over H. pylori-elicited excessive generation of NO and PGE2 caused by the disturbances in nitric oxide synthase and cyclooxygenase isozyme systems, increase in epidermal growth factor receptor transactivation, and the induction in matrix metalloproteinase-9 (MMP-9) release. Interestingly, the extent of gastric mucosal inflammatory response to H. pylori is influenced by a peptide hormone, ghrelin, the action of which relays on the growth hormone secretagogue receptor type 1a (GHS-R1a)-mediated mobilization of G-protein dependent transduction pathways. Yet, the signals triggered by TLR-4 activation as well as those arising through GHS-R1a stimulation converge at MAPK and PLC/PKC/PI3K pathways that form a key integration node for proinflammatory signals generated by H. pylori LPS as well as for those involved in modulation of inflammation by ghrelin. Hence, therapeutic targeting these signals' convergence and integration node could provide a novel and attractive opportunities for developing more effective treatments of H. pylori-related gastric disease.
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Affiliation(s)
- B L Slomiany
- Research Center, C855, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA
| | - A Slomiany
- Research Center, C855, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA.
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Slomiany BL, Slomiany A. Helicobacter pylori-induced changes in microtubule dynamics conferred by α-tubulin phosphorylation on Ser/Tyr mediate gastric mucosal secretion of matrix metalloproteinase-9 (MMP-9) and its modulation by ghrelin. Inflammopharmacology 2016; 24:197-205. [PMID: 27613723 DOI: 10.1007/s10787-016-0278-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 08/27/2016] [Indexed: 12/18/2022]
Abstract
Regulation of matrix metalloproteinase-9 (MMP-9) secretion in response to proinflammatory challenge remains under a strict control of factors that affect the stability dynamics of the major cytoskeleton polymeric structures, microtubules (MTs). In this study, we report that H. pylori LPS-elicited induction gastric mucosal MMP-9 secretion is accompanied by the enhancement in MT stabilization as evidenced by the increase in α-tubulin acetylation and detyrosination while the modulatory influence of hormone, ghrelin, is associated with MT destabilization and reflected in a decrease in α-tubulin acetylation and detyrosination. Further, we reveal that the LPS-induced enhancement in MT stabilization and up-regulation in MMP-9 secretion as well as the modulatory influence of ghrelin occur with the involvement of PKCδ and SFK. The LPS effect is reflected in a marked increase in PKCδ-mediated α-tubulin phosphorylation on Ser, while the modulatory effect of ghrelin on MT dynamics and MMP-9 secretion is manifested by the SFK-dependent phosphorylation of α-tubulin on Tyr. Moreover, the changes in α-tubulin phosphorylation and MT stabilization dynamics occur in concert with the Golgi recruitment and activation of PKD2 and Arf-GEF. The findings demonstrate that the enhancement in gastric mucosal MMP-9 secretion in response to H. pylori and its modulation by ghrelin are the result of changes in MT dynamics conferred by PKCδ/SFK- mediated α-tubulin Ser/Tyr phosphorylation.
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Affiliation(s)
- B L Slomiany
- Research Center, C875 Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA.
| | - A Slomiany
- Research Center, C875 Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA
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Slomiany B, Piotrowski J, Slomiany A. Effect of ebrotidine on Helicobacter pylori lipopolysaccharide-induced up-regulation of endothelin-1 in gastric mucosa. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519990050050401] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Helicobacter pylori is recognized as a primary etiologic factor in the development of gastric disease. We applied the animal model of H. pylori lipopolysaccharide-induced acute gastritis to study the effect of the anti-ulcer agent, ebrotidine, on the course of mucosal inflammatory responses by analyzing over a period of 10 days the extent of epithelial cell apoptosis and the mucosal expression of endothelin-1 (ET-1), tumor necrosis factor α (TNFα), and the activity of constitutive (cNOS) and inducible (NOS-2) nitric oxide synthase. Rats, pretreated twice daily for 3 days with ebrotidine at 100 mg/kg or the vehicle, were subjected to intragastric application of H. pylori lipopolysaccharide at 50 µg/animal, and after 2, 4, and 10 additional days on the drug or vehicle regimen their mucosal tissue was used for histological and biochemical assessment. In the absence of ebrotidine, H. pylori lipopolysaccharide elicited within 2 days extensive mucosal inflammation accompanied by a significant increase in epithelial cell apoptosis (13.5-fold) and the mucosal expression of TNFα (11.7-fold), NOS-2 (9.3-fold), and ET-1 (2.9-fold), while cNOS activity showed a 5.5-fold decrease. The extent of mucosal inflammatory involvement reached a maximum by the 4th day and showed a decline by the 10th day. This was reflected in a marked reduction in epithelial cell apoptosis, a decrease in the mucosal expression of ET-1, TNFα and NOS-2, and the recovery in cNOS activity. Treatment with ebrotidine caused a reduction in the extent of mucosal inflammatory involvement elicited by the lipopolysaccharide and this effect of ebrotidine was reflected at the end of a 10 day period in a 61.3% reduction in inflammation, and a decrease in apoptosis (83%), TNFα (51.8%), ET-1 (27.6%) and NOS-2 (62.9%), while the expression of cNOS increased by 78.6%. The findings indicate that an increase in the ET-1 level elicited by H. pylori lipopolysaccharide, combined with a decline in cNOS, trigger the induction of TNFα which propagates the inflammatory process. We also show that ebrotidine is capable of suppressing the H. pylori-induced gastric mucosal inflammatory responses.
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Affiliation(s)
- B.L. Slomiany
- Research Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA,
| | - J. Piotrowski
- Research Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
| | - A. Slomiany
- Research Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
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Durkin E, Moran AP, Hanson PJ. Apoptosis induction in gastric mucous cells in vitro: lesser potency of Helicobacter pylori than Escherichia coli lipopolysaccharide, but positive interaction with ibuprofen. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519060120010501] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) cause peptic ulcer disease, but whether they interact with Helicobacter pylori to promote damage is controversial. Moreover, the reported induction of apoptosis in gastric cells by H. pylori lipopolysaccharide (LPS) (10—9 g/ml) contrasts with studies showing low immunological potency of this LPS. Therefore, the effects of LPS from H. pylori NCTC 11637 and Escherichia coli O111:B4 on apoptosis in a primary culture of guinea-pig gastric mucous cells were investigated in the presence and absence of the NSAID, ibuprofen. Cell loss was estimated by a crystal violet assay, and apoptosis determined from caspase activity and from condensation and fragmentation of nuclei. Exposure to E. coli LPS for 24 h caused cell loss and enhanced apoptotic activity at concentrations ≥ 10—9 g/ml, but similar effects were only obtained with H. pylori LPS at concentrations ≥ 10— 6 g/ml. Although ibuprofen (250 µM) caused cell loss and apoptosis, addition of either E. coli or H. pylori LPSs further enhanced these effects. In conclusion, LPS and ibuprofen interact to enhance gastric cell loss and apoptosis. In such interactions, E. coli LPS is more potent than that of H. pylori. The low potency of H. pylori LPS may contribute to a chronic low-grade gastritis that can be enhanced by the use of NSAIDs.
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Affiliation(s)
- Emma Durkin
- School of Life and Health Sciences, Aston University, Birmingham, UK
| | - Anthony P. Moran
- Department of Microbiology, National University of Ireland, Galway, Ireland
| | - Peter J. Hanson
- School of Life and Health Sciences, Aston University, Birmingham, UK,
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Role of protein kinase D2 phosphorylation on Tyr in modulation by ghrelin of Helicobacter pylori-induced up-regulation in gastric mucosal matrix metalloproteinase-9 (MMP-9) secretion. Inflammopharmacology 2016; 24:119-26. [PMID: 27209313 DOI: 10.1007/s10787-016-0267-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/10/2016] [Indexed: 01/26/2023]
Abstract
Matrix metalloproteinas-9 (MMP-9) is a glycosylated endopeptidase associated with host reaction to microbial endotoxins and also characterizes gastric mucosal inflammatory response to H. pylori infection. Here, we report on the factors involved in gastric mucosal MMP-9 secretion in response to H. pylori LPS, and the effect of hormone, ghrelin. We show that both the LPS-elicited induction in MMP-9 secretion and also the modulatory influence of ghrelin occur at the level of MMP-9 processing between the endoplasmic reticulum (ER) and Golgi. Further, we demonstrate that the LPS effect is associated with up-regulation in the activation of Arf1, a small GTPase of the ADP-ribosylation factor family, and the recruitment and phosphorylation of protein kinase D2 (PKD2), involved in the secretory cargo processing in the Golgi. Moreover, we reveal that the LPS-induced up-regulation in MMP-9 secretion is reflected in a marked increase in PKCδ-mediated PKD2 phosphorylation on Ser, while the modulatory effect of ghrelin is manifested by the SFK-PTKs-dependent phosphorylation of PKD2 on Tyr. Thus, our findings demonstrate the role of Arf1/PKD2 in mediation of H. pylori LPS-induced up-regulation in gastric mucosal MMP-9 secretion and suggest the modulatory mechanism of ghrelin action.
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Helicobacter pylori-elicited induction in gastric mucosal matrix metalloproteinase-9 (MMP-9) release involves ERK-dependent cPLA2 activation and its recruitment to the membrane-localized Rac1/p38 complex. Inflammopharmacology 2016; 24:87-95. [PMID: 26886372 DOI: 10.1007/s10787-016-0261-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 02/04/2016] [Indexed: 01/23/2023]
Abstract
Matrix metalloproteinases (MMPs) are a family of endopeptidases implicated in a wide rage of degenerative and inflammatory diseases, including Helicobacter pylori-associated gastritis, and gastric and duodenal ulcer. As gastric mucosal inflammatory responses to H. pylori are characterized by the rise in MMP-9 production, as well as the induction in mitogen-activated protein kinase (MAPK) and Rac1 activation, we investigated the role of Rac1/MAPK in the processes associated with the release of MMP-9. We show that H. pylori LPS-elicited induction in gastric mucosal MMP-9 release is associated with MAPK, ERK and p38 activation, and occurs with the involvement of Rac1 and cytosolic phospholipase A2 (cPLA2). Further, we demonstrate that the LPS-induced MMP-9 release requires ERK-mediated phosphorylation of cPLA2 on Ser(505) that is essential for its membrane localization with Rac1, and that this process necessitates p38 participation. Moreover, we reveal that the activation and membrane translocation of p38 to the Rac1-GTP complex plays a pivotal role in cPLA2-dependent enhancement in MMP-9 release. Hence, our findings provide a strong evidence for the role of ERK/cPLA2 and Rac1/p38/cPLA2 cascade in H. pylori LPS-induced up-regulation in gastric mucosal MMP-9 release.
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Slomiany BL, Slomiany A. Helicobacter pylori-induced gastric mucosal TGF-α ectodomain shedding and EGFR transactivation involves Rac1/p38 MAPK-dependent TACE activation. Inflammopharmacology 2015; 24:23-31. [PMID: 26658844 DOI: 10.1007/s10787-015-0254-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 11/11/2015] [Indexed: 01/26/2023]
Abstract
Infection of gastric mucosa by H. pylori triggers a pattern of inflammatory responses characterized by the rise in proinflammatory cytokine production, up-regulation in mitogen-activated protein kinase (MAPK) cascade, and the induction in epidermal growth factor receptor (EGFR) activation. In this study, we report on the role of MAPK/p38 and Rac1 in the regulation of H. pylori LPS-induced TGF-α ectodomain shedding and EGFR transactivation. We show that stimulation of gastric mucosal cells with the LPS, reflected in p38 phosphorylation, guanine nucleotide exchange factor Dock180 activation and the rise in Rac1-GTP level, is accompanied by the activation of membrane-associated metalloprotease, (TACE) also known as ADAM17, responsible for soluble TGF-α release. Further, we reveal that the LPS-induced TGF-α shedding and EGFR transactivation involves the TACE activation through phosphorylation by p38 that requires Rac1 participation. Moreover, we demonstrate that up-regulation in H. pylori LPS-elicited Rac1-GTP membrane translocation plays a pivotal role in recruitment of the activated p38 to the membrane for TACE activation through phosphorylation on Thr(735). Taken together, our findings provide strong evidence as to the essential function of Rac1 in TACE activation, TGF-α ectodomain shedding, and the EGFR transactivation.
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Affiliation(s)
- B L Slomiany
- Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103 2400, USA.
| | - A Slomiany
- Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103 2400, USA
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Ramakrishna YG, Savithri K, Kist M, Devaraj SN. Aegle marmelos fruit extract attenuates Helicobacter pylori Lipopolysaccharide induced oxidative stress in Sprague Dawley rats. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 15:375. [PMID: 26482072 PMCID: PMC4615325 DOI: 10.1186/s12906-015-0915-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 10/13/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Bael (Aegle marmelos (L.) Corr.) has been widely used in indigenous systems of Indian medicine to exploit its medicinal properties including astringent, antidiarrheal, antidysenteric, demulcent, antipyretic, antiulcer, anti-inflammatory and anti cancer activities. The present study aims to evaluate the antioxidative and antiulcer effect of methanolic extract of unripe fruit of Aegle marmelos (MEAM) against Helicobacter pylori-Lipopolysaccharide (HP-LPS) induced gastric ulcer in Sprague Dawley (SD) rats. METHODS Dose and duration of HP-LPS and MEAM were fixed based on ulcer index of gastric tissue of experimental animals. Various gastric secretory parameters such as volume of gastric juice, free and total acidity, acid output, pepsin concentration were analyzed. The activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase), non-enzymatic antioxidants (reduced glutathione, vitamin C and vitamin E) and the levels of lipid peroxidation products were measured. Histological analysis was performed to evaluate the effect of Aegle marmelos on HP-LPS induced gastric ulcer. RESULTS Oral administration of HP-LPS (50 μg per animal) for four consecutive days resulted in induction of ulcer with the increase in gastric secretory parameters such as volume of gastric juice, free and total acidity, acid output, pepsin concentration. Oral administration of methanolic extract of Aegle marmelos fruit (MEAM) (25, 50, 100, 250 and 500 mg/kg) reduced the gastric ulcer by 2.8 %, 52.4 %, 73 %, 93 % and 93.98 %, respectively, compared to 89.2 % reduction by sucralfate (100 mg/kg). MEAM treatment significantly (p < 0.05) inhibited the increase in gastric secretory parameters in ulcerated rats, and it also prevented the reduction of enzymatic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase) and non-enzymatic antioxidants (reduced glutathione, vitamin C and vitamin E) after HP-LPS induction. In addition, lipid peroxidation was inhibited by MEAM in HP-LPS induced rats. Results of histological analysis correlated well with biochemical parameters. CONCLUSION These observations explored the antioxidant properties of MEAM contributing to the gastroprotective effect in HP-LPS induced gastric ulcer model.
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Affiliation(s)
| | - Kumarasamy Savithri
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600025, India.
| | - Manfred Kist
- Institut fur Medizinische, Mekrobiologie und Hygiene, Freiburg, Germany.
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Slomiany BL, Slomiany A. Mechanism of Rac1-induced amplification in gastric mucosal phospholipase Cγ2 activation in response to Helicobacter pylori: modulatory effect of ghrelin. Inflammopharmacology 2015; 23:101-9. [PMID: 25796615 DOI: 10.1007/s10787-015-0231-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 03/04/2015] [Indexed: 12/27/2022]
Abstract
Membrane recruitment followed by targeted phosphorylation of specific Tyr and Ser residues and the interaction with Rac GTPases are the crucial parts of an elaborate mechanism of PLCγ2 activation essential for its role in linking the specific receptor responses to a variety of hormones and bacterial endotoxins with the intended intracellular targets. Here, we explored the involvement of Rac in mediation of PLCγ2 activation associated with gastric mucosal inflammatory responses to H. pylori LPS and the hormone, ghrelin. We show that stimulation of gastric mucosal cells with the LPS leads to the membrane translocation of Rac1 as well as PLCγ2, while the effect of ghrelin is manifested by elevation in the membrane PLCγ2 activation and suppression in Rac1 translocation. However, blocking the LPS-induced Rac1 translocation, while detrimental to the PLCγ2 activation, has no effect on its membrane translocation. We reveal further that PLCγ2, localized in the membrane in association with Rac1 following the LPS stimulation, exhibits a marked increase in phosphorylation on Ser, while the modulatory effect of ghrelin, manifested by a drop in Rac1 translocation, is associated with a distinct decrease in PLCγ2 phosphorylation on Ser. Thus, the results suggest that H. pylori-elicited increase in gastric mucosal PLCγ2 phosphorylation on Ser serves as an essential platform for Rac1 colocalization and amplification in PLCγ2 activation.
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Affiliation(s)
- B L Slomiany
- Research Center C875, Rutgers School of Dental Medicine Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA,
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Role of amplification in phospholipase Cγ2 activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori: effect of ghrelin. Inflammopharmacology 2014; 23:37-45. [PMID: 25362585 DOI: 10.1007/s10787-014-0220-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 10/18/2014] [Indexed: 12/21/2022]
Abstract
Phosphoinositide-specific phospholipase C (PLC) enzymes are crucial elements of signal transduction pathways that provide a common link of communication integrating specific receptor responses to a variety of hormones, growth factors, and bacterial endotoxins with the intended intracellular targets. Here, we examined the involvement of PLC in modulation of gastric mucosal inflammatory responses to Helicobacter pylori LPS by peptide hormone, ghrelin. We show that stimulation of gastric mucosal cells with the LPS leads to the activation and membrane translocation of the γ2 isoform of PLC, phosphorylated on Tyr as well as Ser, while the effect of ghrelin is reflected in the translocation and phosphorylation of membrane-associated PLCγ2 on Tyr mainly. Moreover, we demonstrate that PLCγ2 phosphorylation on Tyr remains under the control of the Src family protein tyrosine kinases (SFK-PTKs), and is intimately linked to PLCγ2 membrane localization, while the LPS-induced phosphorylation of membrane-recruited PLCγ2 on Ser displays dependence on protein kinase Cδ (PKCδ) and leads to the amplification in PLCγ2 activation. Thus, our findings link the extent of H. pylori-elicited gastric mucosal inflammatory involvement to the PKCδ-mediated amplification in PLCγ2 activation through phosphorylation on Ser.
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14
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Ahmed AU, Sarvestani ST, Gantier MP, Williams BRG, Hannigan GE. Integrin-linked kinase modulates lipopolysaccharide- and Helicobacter pylori-induced nuclear factor κB-activated tumor necrosis factor-α production via regulation of p65 serine 536 phosphorylation. J Biol Chem 2014; 289:27776-93. [PMID: 25100717 DOI: 10.1074/jbc.m114.574541] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Integrin-linked kinase (ILK) is a ubiquitously expressed and highly conserved serine-threonine protein kinase that regulates cellular responses to a wide variety of extracellular stimuli. ILK is involved in cell-matrix interactions, cytoskeletal organization, and cell signaling. ILK signaling has also been implicated in oncogenesis and progression of cancers. However, its role in the innate immune system remains unknown. Here, we show that ILK mediates pro-inflammatory signaling in response to lipopolysaccharide (LPS). Pharmacological or genetic inhibition of ILK in mouse embryonic fibroblasts and macrophages selectively blocks LPS-induced production of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α). ILK is required for LPS-induced activation of nuclear factor κB (NF-κB) and transcriptional induction of TNF-α. The modulation of LPS-induced TNF-α synthesis by ILK does not involve the classical NF-κB pathway, because IκB-α degradation and p65 nuclear translocation are both unaffected by ILK inhibition. Instead, ILK is involved in an alternative activation of NF-κB signaling by modulating the phosphorylation of p65 at Ser-536. Furthermore, ILK-mediated alternative NF-κB activation through p65 Ser-536 phosphorylation also occurs during Helicobacter pylori infection in macrophages and gastric cancer cells. Moreover, ILK is required for H. pylori-induced TNF-α secretion in macrophages. Although ILK-mediated phosphorylation of p65 at Ser-536 is independent of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway during LPS stimulation, upon H. pylori infection this event is dependent on the PI3K/Akt pathway. Our findings implicate ILK as a critical regulatory molecule for the NF-κB-mediated pro-inflammatory signaling pathway, which is essential for innate immune responses against pathogenic microorganisms.
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Affiliation(s)
- Afsar U Ahmed
- From the Centre for Cancer Research, MIMR-PHI Institute of Medical Research, and Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| | - Soroush T Sarvestani
- From the Centre for Cancer Research, MIMR-PHI Institute of Medical Research, and Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| | - Michael P Gantier
- From the Centre for Cancer Research, MIMR-PHI Institute of Medical Research, and Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| | - Bryan R G Williams
- From the Centre for Cancer Research, MIMR-PHI Institute of Medical Research, and Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
| | - Gregory E Hannigan
- From the Centre for Cancer Research, MIMR-PHI Institute of Medical Research, and Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia
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15
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Role of ghrelin-induced phosphatidylinositol 3-kinase activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori. Inflammopharmacology 2013; 22:169-77. [PMID: 24057979 DOI: 10.1007/s10787-013-0190-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 09/10/2013] [Indexed: 12/14/2022]
Abstract
A peptide hormone, ghrelin, is recognized as an important modulator of gastric mucosal inflammatory responses to Helicobacter pylori through the regulation of Src/Akt-dependent activation of constitutive nitric oxide synthase (cNOS) by phosphorylation. In this study, we report on the role of phosphatidylinositol 3-kinase (PI3K) in the processes of Src/Akt activation in gastric mucosal cells exposed to H. pylori LPS. We demonstrate that cNOS activation through phosphorylation induced by ghrelin is associated with PI3K activation which occurs upstream of cSrc, and that PI3K is required for cSrc activation of Akt. We show further that ghrelin-induced activation of PI3K, as well as that of Src and Akt, was susceptible to suppression by the inhibitors of phospholipase C (U73122) and protein kinase C (BIM). Both these inhibitors also blocked the ghrelin-induced membrane translocation of PI3K and cSrc, whereas the inhibitor of PI3K (LY294002) blocked only the membrane translocation of cSrc. Collectively, our findings suggest that the modulatory influence of ghrelin in countering gastric mucosal responses to H. pylori LPS relies on PI3K activation that depends on PLC/PKC signaling pathway, and that PI3K activity is required for the induction of cSrc/Akt activation.
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16
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Lee JM, Kim SS, Cho YS. The Role of PPARγ in Helicobacter pylori Infection and Gastric Carcinogenesis. PPAR Res 2012; 2012:687570. [PMID: 22936949 PMCID: PMC3425866 DOI: 10.1155/2012/687570] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Accepted: 07/16/2012] [Indexed: 11/17/2022] Open
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is important in many physiological and pathological processes, such as lipid metabolism, insulin sensitivity, inflammation, cell proliferation, and carcinogenesis. Several studies have shown that PPARγ plays an important role in gastric mucosal injury due to Helicobacter pylori (H. pylori). As H. pylori infection is the main etiologic factor in chronic gastritis and gastric cancer, understanding of the potential roles of PPARγ in H. pylori infection may lead to the development of a therapeutic target. In this paper, the authors discuss the current knowledge on the role of PPARγ in H. pylori infection and its related gastric carcinogenesis.
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Affiliation(s)
- Jong-Min Lee
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480717, Republic of Korea
| | - Sung Soo Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480717, Republic of Korea
| | - Young-Seok Cho
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480717, Republic of Korea
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17
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The protective of hydrogen on stress-induced gastric ulceration. Int Immunopharmacol 2012; 13:197-203. [PMID: 22543062 DOI: 10.1016/j.intimp.2012.04.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 03/24/2012] [Accepted: 04/09/2012] [Indexed: 02/08/2023]
Abstract
Stress ulceration frequently occurs as a result of major stressful events and hydroxyl radical (⋅OH) is one of the major causative factors for it. Recently, it has been proved that hydrogen, a potent selectively ⋅OH scavenger, can effectively protect animals against ROS-induced tissue damage. In like manner, we hypothesize that hydrogen may have a protective effect against stress ulceration. Gastric ulceration was induced by the method of cold restraint stress. Rats in the hydrogen treatment group received hydrogen-rich saline (10 mL/kg body weight) 5 min before the stress. At 6h post-stress, gastric corpus mucosa was harvested for the measurement of malondialdehyde, protein carbonyl, 8-hydroxy-desoxyguanosine, glutathione, superoxide dismutase, myeloperoxidase, TNF-α, IL-1β and cytokine-induced neutrophils chemoattractant-1. In addition, western blotting was used to determine the expression of p38 MAPK, P-p38 MAPK, P-JNk, JNK, Bcl-xl, Bax and cleaved caspase-3. Nuclear translocation of NF-κB was assessed by electrophoretic mobility shift assay. Gastric mucosa structure and mucosal epithelial cells apoptosis were measured at 12h post-stress. Our present study showed that hydrogen treatment lessened the stress-induced lipid peroxidation, protein carbonyl and DNA oxidant and improved tissue antioxidant potential. In addition, hydrogen mitigated inflammatory response and neutrophils infiltration with suppressing the activity of P-p38 MAPK, P-JNk and NF-κB. Importantly, hydrogen ameliorated gastric mucosa damage with preventing cell apoptosis. Furthermore, the up-regulation of cleaved caspase-3, Bax and down-regulation of Bcl-xl expression were blocked by hydrogen treatment. In conclusion, hydrogen treatment effectively ameliorated stress-associated gastric mucosa damage via its anti-oxidant, anti-inflammatory and anti-apoptotic effects.
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18
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In silico quest for putative drug targets in Helicobacter pylori HPAG1: molecular modeling of candidate enzymes from lipopolysaccharide biosynthesis pathway. J Mol Model 2011; 18:1855-66. [PMID: 21850571 DOI: 10.1007/s00894-011-1204-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Accepted: 07/26/2011] [Indexed: 01/05/2023]
Abstract
Aimed at identification and structural characterization of novel putative therapeutic targets in H. pylori, the etiological agent of numerous gastrointestinal diseases including peptic ulcer and gastric cancer, the present study comprised of three phases. First, through subtractive analysis of metabolic pathways of Helicobacter pylori HPAG1 and human, as documented in the KEGG database, 11 pathogen-specific pathways were identified. Next, all proteins involved in these pathogen-specific pathways were scrutinized in search of promising targets and the study yielded 25 candidate target proteins that are likely to be essential for the pathogen viability, but have no homolog in human. The lipopolysaccharide (LPS) biosynthesis pathway was found to be the largest contributor (nine proteins) to this list of candidate proteins. Considering the importance of LPS in H. pylori virulence, 3D structural models of three predicted target enzymes of this pathway, namely 2-dehydro-3-deoxy-phosphooctonate aldolase, UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase and Phosphoheptose isomerase, were then built up using the homology modeling approaches. Binding site analysis and docking of the known biological substrate PEP to 2-dehydro-3-deoxyphosphooctonate aldolase revealed the potential binding pocket present in the single monomeric form of the enzyme and identified 11 amino acid residues that might play the key roles in this protein-ligand interaction.
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19
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Slomiany BL, Slomiany A. Role of ghrelin-induced cSrc activation in modulation of gastric mucosal inflammatory responses to Helicobacter pylori. Inflammopharmacology 2011; 19:197-204. [PMID: 21516493 DOI: 10.1007/s10787-011-0083-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Accepted: 04/06/2011] [Indexed: 01/01/2023]
Abstract
A peptide hormone, ghrelin, is recognized as an important modulator of gastric mucosal inflammatory responses to H. pylori through the regulation of nitric oxide synthase (NOS) system. As cSrc kinase plays a major role in transduction of signals that regulate the activity of NOS isozyme system, we investigated the influence of H. pylori LPS on the processes associated with Src activation in gastric mucosal cells. The LPS-induced drop in constitutive (c) cNOS activity and up-regulation in inducible (i) iNOS was associated with the suppression in cSrc kinase activity that was reflected in a decrease in its phosphorylation at Tyr⁴¹⁶. Further, the countering effect of ghrelin on the LPS-induced changes in cSrc activity and the extent of its phosphorylation was accompanied by a marked reduction in the activity of iNOS and an increase in cNOS activation through phosphorylation at Ser¹¹⁷⁹. Moreover, the effect of ghrelin on cSrc activation and its Tyr⁴¹⁶ phosphorylation was associated with the kinase S-nitrosylation that was susceptible to the blockage by cNOS inhibition. Our findings suggest that up-regulation in iNOS with H. pylori infection leads to disturbances in cNOS phosphorylation that exerts the detrimental effect on the processes of cSrc activation through cNOS-mediated S-nitrosylation. We also show that ghrelin attenuation of H. pylori-induced gastric mucosal inflammatory responses involves the enhancement in cSrc activation, elicited by the kinase S-nitrosylation and the increase in its phosphorylation at Tyr⁴¹⁶.
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Affiliation(s)
- B L Slomiany
- UMDNJ-NJ Dental School, Research Center C875, University of Medicine and Dentistry of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ 07103-2400, USA.
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20
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Different antiulcer activities of pantoprazole in stress, alcohol and pylorus ligation-induced ulcer models. Lab Anim Res 2011; 27:47-52. [PMID: 21826160 PMCID: PMC3145982 DOI: 10.5625/lar.2011.27.1.47] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Revised: 02/27/2011] [Accepted: 03/04/2011] [Indexed: 11/25/2022] Open
Abstract
Antiulcer effects of pantoprazole, a proton-pump inhibitor, on water-immersion restraint stress (WIRS)-, alcohol (ethanol)- and pylorus ligation-induced gastric ulcers were investigated in male rats. Rats were orally administered with pantoprazole 30 min prior to exposure to various types of ulcer inducers. In stress-induced ulcer model, rats were subjected to WIRS at 22℃ for 4 hours, and the degree of ulcer (in mm) was evaluated. In alcohol-induced ulcer model, rats were orally administered with pure (100%) ethanol (1 mL/kg), and the ulcer lesions were measured 1 hour after ethanol challenge. In pylorus ligation-induced ulcer model, rats were subjected to pylorus ligation, and the degree of erosions and ulcers was scored 17 hours after the operation. Pantoprazole attenuated the ulcer lesions induced by WIRS in a dose-dependent manner, exhibiting a median effective dose (ED50) value of 0.78 mg/kg. By comparison, pantoprazole was effective at relatively-high doses for the improvement of ethanol-induced ulcers, showing an ED50 value of 20.5 mg/kg. Notably, pantoprazole was practically ineffective (ED50>50.0) in pylorus ligation model. Taken together, it was confirmed that pantoprazole showed inhibitory activity on gastric ulcers induced by stress and alcohol, but was ineffective on pylorus ligation-induced ulcer. Therefore, the results indicate that proton-pump inhibitors including pantoprazole might reveal highly-different effects according to the type of ulcer inducers, and that the prescription of antiulcer agents should be carefully selected.
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21
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Slomiany BL, Slomiany A. Ghrelin suppression of Helicobacter pylori-induced S-nitrosylation-dependent Akt inactivation exerts modulatory influence on gastric mucin synthesis. Inflammopharmacology 2011; 19:89-97. [PMID: 21279549 DOI: 10.1007/s10787-011-0078-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 01/06/2011] [Indexed: 01/27/2023]
Abstract
Loss of mucus coat integrity and the impairment in its mucin component as well as the disturbance in nitric oxide (NO) generation are well-recognized features of gastric disease associated with H. pylori infection. As ghrelin plays a major role in the regulation of nitric oxide synthase system, we investigated the influence of this hormone on H. pylori LPS-induced interference with gastric mucin synthesis. The results revealed that the LPS-induced impairment in mucin synthesis and accompanied induction in inducible nitric oxide synthase (iNOS) expression, were associated with the suppression in Akt kinase activity and the impairment in constitutive nitric oxide synthase (cNOS) phosphorylation. The LPS effect on Akt inactivation was manifested in the kinase protein S-nitrosylation and a decrease in its phosphorylation at Ser(473). Further, we show that the countering effect of ghrelin, on the LPS-induced impairment in mucin synthesis was reflected in the suppression of iNOS and the increase in Akt activation, associated with the loss in S-nitrosylation and the increase in phosphorylation, as well as cNOS activation through phosphorylation. Our findings demonstrate that up-regulation in iNOS with H. pylori infection and subsequent Akt kinase inactivation through S-nitrosylation exerts the detrimental effect on the processes dependent on Akt activation, including that of cNOS activation and mucin synthesis. We also show that ghrelin protection against H. pylori-induced impairment in mucin synthesis is intimately linked to the events of Akt activation and reflected in a decrease in the kinase S-nitrosylation and the increase in its phosphorylation.
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Affiliation(s)
- B L Slomiany
- Research Center, UMDNJ-NJ Dental School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400, USA.
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22
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Slomiany BL, Slomiany A. Role of constitutive nitric oxide synthase in regulation of <i>Helicobacter pylori</i>-induced gastric mucosal cyclooxygenase-2 ac-tivation through S-nitrosylation: mechanism of ghrelin action. ACTA ACUST UNITED AC 2011. [DOI: 10.4236/ojgas.2011.12003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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23
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Slomiany BL, Slomiany A. Helicobacter pylori Induces Disturbances in Gastric Mucosal Akt Activation through Inducible Nitric Oxide Synthase-Dependent S-Nitrosylation: Effect of Ghrelin. ISRN GASTROENTEROLOGY 2010; 2011:308727. [PMID: 21991502 PMCID: PMC3168387 DOI: 10.5402/2011/308727] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 10/21/2010] [Indexed: 12/13/2022]
Abstract
Gastric mucosal inflammatory response to H. pylori and its key virulence factor, lipopolysaccharide (LPS), are characterized by a massive rise in apoptosis and the disturbances in NO signaling pathways. Here, we report that H. pylori LPS-induced enhancement in the mucosal inducible nitric oxide synthase (iNOS) was associated with the suppression in Akt kinase activity and the impairment in constitutive nitric oxide synthase (cNOS) phosphorylation. Further, we demonstrate that the LPS effect on Akt inactivation, manifested in the kinase protein S-nitrosylation and a decrease in its phosphorylation at Ser473, was susceptible to suppression by iNOS inhibition. Moreover, the countering effect of hormone, ghrelin, on the LPS-induced changes in Akt activity was reflected in the loss in Akt S-nitrosylation and the increase in its phosphorylation at Ser473, as well as cNOS activation through phosphorylation. Our findings demonstrate that up-regulation in iNOS with H. pylori infection leads to Akt inactivation through S-nitrosylation that exerts the detrimental effect on the processes of cNOS activation through phosphorylation. We also report that ghrelin protection against H. pylori-induced disturbances is manifested in a marked increase in Akt activity and evoked by a decrease in the kinase S-nitrosylation and the increase in its phosphorylation at Ser473.
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Affiliation(s)
- Bronislaw L Slomiany
- Research Center, C875 University of Medicine and Dentistry of New Jersey Dental School, 110 Bergen Street, P.O. Box 1709, Newark, NJ 07103-2400, USA
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24
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Role of constitutive nitric oxide synthase S-nitrosylation in Helicobacter pylori-induced gastric mucosal cell apoptosis: effect of ghrelin. Inflammopharmacology 2010; 18:233-40. [PMID: 20596895 DOI: 10.1007/s10787-010-0051-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Accepted: 06/14/2010] [Indexed: 01/01/2023]
Abstract
Infection with H. pylori is a primary factor in the etiology of gastric disease, and the excessive NO generation and a massive rise in apoptosis are well recognized features that characterize the mucosal inflammatory responses to the bacterium and its lipopolysaccharide (LPS). Here, we report that H. pylori LPS-induced enhancement in gastric mucosal cell apoptosis and NO generation was associated with the suppression in constitutive nitric oxide synthase (cNOS) activity and a marked up-regulation in the activity of inducible nitric oxide synthase (iNOS). Further, we demonstrate that the detrimental effect of the LPS on cNOS was manifested in the enzyme protein S-nitrosylation, that was susceptible to suppression by iNOS inhibitor, 1400W. Moreover, we show that the countering effect of peptide hormone, ghrelin, on the LPS-induced changes in apoptosis and cNOS activity was reflected in the loss in cNOS S-nitrosylation and the increase in the enzyme phosphorylation. These findings demonstrate that the disturbances in gastric mucosal NO generation system caused by H. pylori result from the iNOS-derived NO suppression of cNOS activation through S-nitrosylation. We also report that ghrelin protection against H. pylori-induced gastric mucosal proapoptotic events involves cNOS activation manifested by the increase in enzyme protein phosphorylation and a decrease in its S-nitrosylation.
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25
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Ghrelin protection against lipopolysaccharide-induced gastric mucosal cell apoptosis involves constitutive nitric oxide synthase-mediated caspase-3 S-nitrosylation. Mediators Inflamm 2010; 2010:280464. [PMID: 20369000 PMCID: PMC2847901 DOI: 10.1155/2010/280464] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Accepted: 02/04/2010] [Indexed: 11/18/2022] Open
Abstract
Ghrelin, a peptide hormone produced mainly in the stomach, has emerged as an important modulator of the inflammatory responses that are of significance to the maintenance of gastric mucosal integrity. Here, we report on the role of ghrelin in controlling the apoptotic processes induced in gastric mucosal cells by H. pylori lipopolysaccharide (LPS). The countering effect of ghrelin on the LPS-induced mucosal cell apoptosis was associated with the increase in constitutive nitric oxide synthase (cNOS) activity, and the reduction in caspase-3 and inducible nitric oxide synthase (NOS-2). The loss in countering effect of ghrelin on the LPS-induced changes in apoptosis and caspase-3 activity was attained with Src kinase inhibitor, PP2, as well as Akt inhibitor, SH-5, and cNOS inhibitor, L-NAME. Moreover, the effect of ghrelin on the LPS-induced changes in cNOS activity was reflected in the increased cNOS phosphorylation that was sensitive to SH-5. Furthermore, the ghrelin-induced up-regulation in cNOS activity was associated with the increase in caspase-3 S-nitrosylation that was susceptible to the blockage by L-NAME. Therefore, ghrelin protection of gastric mucosal cells against H. pylori LPS-induced apoptosis involves Src/Akt-mediated up-regulation in cNOS activation that leads to the apoptotic signal inhibition through the NO-induced caspase-3 S-nitrosylation.
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26
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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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27
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Taylor JM, Ziman ME, Canfield DR, Vajdy M, Solnick JV. Effects of a Th1- versus a Th2-biased immune response in protection against Helicobacter pylori challenge in mice. Microb Pathog 2008; 44:20-7. [PMID: 17683897 PMCID: PMC2234601 DOI: 10.1016/j.micpath.2007.06.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2007] [Accepted: 06/13/2007] [Indexed: 12/16/2022]
Abstract
The roles that T helper type 1 (Th1) and T helper type 2 (Th2) Helicobacter pylori-specific immune responses play in protection from H. pylori challenge are poorly understood. It is expected that Th2 immune responses are required for protection against extracellular bacteria, such as H. pylori. However, recent studies have suggested that Th1 immunity is required for protection. The mechanisms by which this might occur are unknown. Our goal in this study was to more clearly define the effects of a Th1- versus a Th2-promoting H. pylori vaccine on immunity and protection. Therefore, we tested a Th1 vaccine consisting of an H. pylori sonicate and CpG oligonucleotides (CpG) and a Th2 vaccine consisting of a lipopolysaccharide (LPS)-depleted H. pylori sonicate combined with cholera toxin (CT). We demonstrate that although the Th2-promoting vaccine induced stronger systemic and local immune responses, only the Th1-promoting vaccine was protective.
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Affiliation(s)
- Jennifer M. Taylor
- Center for Comparative Medicine, University of California, Davis CA 95616
| | - Melanie E. Ziman
- Center for Comparative Medicine, University of California, Davis CA 95616
| | - Don R. Canfield
- Center for Comparative Medicine, University of California, Davis CA 95616
- California National Primate Research Center, University of California, Davis CA 95616
| | - Michael Vajdy
- Departments of Internal Medicine and Medical Microbiology and Immunology, University of California, Davis CA 95616
| | - Jay V. Solnick
- Center for Comparative Medicine, University of California, Davis CA 95616
- Departments of Internal Medicine and Medical Microbiology and Immunology, University of California, Davis CA 95616
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28
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Li L, Zhang YM, Qiao WL, Wang L, Zhang JF. Effects of hypothalamic paraventricular nuclei on apoptosis and proliferation of gastric mucosal cells induced by ischemia/reperfusion in rats. World J Gastroenterol 2007; 13:874-81. [PMID: 17352016 PMCID: PMC4065922 DOI: 10.3748/wjg.v13.i6.874] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [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 investigate the effects of electrical stimulation of hypothalamic paraventricular nuclei (PVN) on gastric mucosal cellular apoptosis and proliferation induced by gastric ischemia/reperfusion (I/R) injury.
METHODS: For different experimental purposes, stimulating electrode plantation or electrolytic destruction of the PVN was applied, then the animals’ GI/R injury model was established by clamping the celiac artery for 30 min and allowing reperfusing the artery for 30 min, 1 h, 3 h or 6 h respectively. Then histological, immunohistochemistry methods were used to assess the gastric mucosal damage index, the gastric mucosal cellular apoptosis and proliferation at different times.
RESULTS: The electrical stimulation of PVN significantly attenuated the GI/R injury at 30 min, 1 h and 3 h after reperfusion. The electrical stimulation of PVN decreased gastric mucosal apoptosis and increased gastric mucosal proliferation. The electrolytic destruction of the PVN could eliminate the protective effects of electrical stimulation of PVN on GI/R injury. These results indicated that the PVN participated in the regulation of GI/R injury as a specific area in the brain, exerting protective effects against the GI/R injury, and the protection was associated with the inhibition of cellular apoptosis and the promotion of gastric mucosal proliferation.
CONCLUSION: Stimulating PVN significantly inhibits the gastric mucosal cellular apoptosis and promots gastric mucosal cellular proliferation. This may explain the protective mechanisms of electrical stimulation of PVN against GI/R injury.
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Affiliation(s)
- Li Li
- Department of Pathophysiology, Xuzhou Medical College, Xuzhou 221002, Jiangsu Province, China
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29
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Lou LX, Geng B, Yu F, Zhang J, Pan CS, Chen L, Qi YF, Ke Y, Wang X, Tang CS. Endoplasmic reticulum stress response is involved in the pathogenesis of stress induced gastric lesions in rats. Life Sci 2006; 79:1856-64. [PMID: 16875701 DOI: 10.1016/j.lfs.2006.06.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2006] [Revised: 05/28/2006] [Accepted: 06/13/2006] [Indexed: 11/26/2022]
Abstract
Stress gastric ulcer is a serious complication, but the mechanism involved is not fully clarified. It is well known that mucosal cell apoptosis plays a crucial role in the pathogenesis of gastric ulceration. Recent studies have shown that endoplasmic reticulum (ER) stress is an important pathway leading to cellular apoptosis. To investigate the role of ER stress in the pathogenesis of stress gastric ulcer, we studied the alteration in the expression of ER stress markers GRP78 (glucose-regulated protein 78) and caspase-12 (an ER stress-specific proapoptotic molecule) and their relations with gastric mucosal apoptosis during development of stress gastric lesions in the water-immersion and restraint stress (WRS) model in rats. Rats developed severe gastric lesions after 6 h of WRS. Typical apoptosis was observed at the edge cells of WRS induced gastric lesions. Western blot analysis showed that GRP78 and activated caspase-12 were over-expressed in the gastric tissues of WRS rats. Immunohistochemical analysis demonstrated that increased GRP78 and caspase-12 were distributed only under the lesions. In addition, dithiothreitol and tunicamycin (ER stress inducers), which increased the expression of GRP78 and activated caspase-12, caused gastric mucosal injury and mucosal cell apoptosis in vitro. These findings suggest that ER stress might be involved in the development of stress gastric ulcer through an apoptotic mechanism.
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Affiliation(s)
- Li Xia Lou
- Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
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Taylor JM, Ziman ME, Huff JL, Moroski NM, Vajdy M, Solnick JV. Helicobacter pylori lipopolysaccharide promotes a Th1 type immune response in immunized mice. Vaccine 2006; 24:4987-94. [PMID: 16621176 DOI: 10.1016/j.vaccine.2006.03.043] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2006] [Revised: 03/13/2006] [Accepted: 03/16/2006] [Indexed: 12/20/2022]
Abstract
Helicobacter pylori (H. pylori) infection is prevalent worldwide and results in chronic gastritis, which may lead to peptic ulcer disease or gastric cancer. The goal of this study was to determine the role that H. pylori lipopolysaccharide (LPS) plays in stimulating host immune responses in the context of a vaccine. We compared H. pylori SS1 sonicate (LPS+) to a sonicate depleted of LPS (LPS-) in immunized BALB/c mice. Naïve splenocytes produced high levels of TNF-alpha and IL-10 after incubation with LPS+ sonicate, while cells incubated with LPS- sonicate did not. Mice immunized with LPS+ sonicate developed a prominent innate response characterized by increased TNF-alpha and IL-10, as well as a strong antigen specific Th1 response including, IFN-gamma, IL-2 and high IgG2a serum titers. Mice that received LPS- sonicate were strongly Th2 biased in their immune response, with significantly more IL-4 than IFN-gamma and serum IgG1 titers higher than IgG2a. Together these studies suggest that H. pylori LPS in a whole cell sonicate vaccine promotes a Th1 immune response that may aid in protection or clearance of H. pylori infection.
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Affiliation(s)
- Jennifer M Taylor
- Department of Internal Medicine, Center for Comparative Medicine, University of California, Davis, USA
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Aydemir S, Ozdemir BH, Gur G, Dogan I, Yilmaz U, Boyacioglu S. Effects of Helicobacter pylori infection on gastric epithelial cell kinetics in patients with chronic renal failure. World J Gastroenterol 2006; 11:7183-7. [PMID: 16437669 PMCID: PMC4725091 DOI: 10.3748/wjg.v11.i45.7183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [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 evaluate the effects of Helicobacter pylori infection on gastric epithelial cell kinetics in patients with chronic renal failure (CRF). METHODS Forty-four patients were enrolled in this study and divided into four groups with respect to their Helicobacter pylori (H pylori) and CRF status. Groups were labeled as follows: 1a: normal renal function, H pylori negative (n = 12), 1b: normal renal function, H pylori positive (n = 11), 2a: CRF, H pylori negative (n = 10), 2b: CRF, H pylori positive (n = 11). Upper gastrointestinal endoscopy was done in all the patients involved in the study. During endoscopical investigation, antral biopsy specimens were taken from each patient. In order to evaluate the cell apoptosis and proliferation in gastric epithelial cells, Bax and proliferating cell nuclear antigen (PCNA) labeling indexes (LI) were assessed with immunohistochemical staining method. RESULTS For groups 1a, 1b, 2a, and 2b, mean Bax LI was identified as 34.4+/-13.7, 44.1+/-16.5, 46.3+/-20.5, 60.7+/-13.8, respectively and mean PCNA LI was identified as 36.2+/-17.2, 53.6+/-25.6, 59.5+/-25.6, 67.2+/-22, respectively. When the one-way ANOVA test was applied, statistically significant differences were detected between the groups for both Bax LI (P = 0.004 <0.01) and PCNA LI (P = 0.009 <0.01). When groups were compared further in terms of Bax LI and PCNA LI with Tukeyos HSD test for multiple pairwise comparisons, statistically significant difference was observed only between groups 1a and 2b (P = 0.006 <0.01). CONCLUSION In gastric epithelial cells, expression of both the pre-apoptotic protein Bax and the proliferation marker PCNA increase with H pylori infection. This increase is more evident in patients with uremia. These findings suggest that uremia accelerates apoptosis and proliferation in gastric epithelial cells.
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Affiliation(s)
- Selim Aydemir
- Department of Gastroenterology, Zonguldak Karaelmas University Faculty of Medicine, Zonguldak 67800, Turkey.
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Slomiany BL, Slomiany A. Endothelin-1-dependent leptin induction in gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide. Biochem Biophys Res Commun 2005; 336:1106-11. [PMID: 16165095 DOI: 10.1016/j.bbrc.2005.08.236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2005] [Accepted: 08/27/2005] [Indexed: 10/25/2022]
Abstract
Leptin, a multifunctional hormone that regulates food intake and energy expenditure, has emerged recently as an important modulator of gastric mucosal responses to Helicobacter pylori infection. We applied the animal model of H. pylori LPS-induced gastritis to investigate the role of endothelin-1 (ET-1) in the mucosal leptin production. We show that the histologic pattern of inflammation reached a maximum on the fourth day following the LPS and was reflected in a marked increase in the mucosal level of ET-1 and leptin. Therapeutic administration of phosphoramidon, an inhibitor of ECE-1 activity, led to a 61.2% decline in the mucosal ET-1 level and a 64.1% reduction in leptin, while the severity of mucosal inflammatory involvement increased by 28.6%. A drop in the level of leptin and the increase in severity of the inflammatory involvement elicited by the LPS was also attained in the presence of ET(A) receptor antagonist BQ610, but not the ET(B) receptor antagonist BQ788. Moreover, administration of ERK inhibitor, PD98059, in the presence of ET(B) receptor antagonist, but not the ET(A) receptor antagonist, caused reduction in the mucosal leptin level. Our findings are the first to implicate ET-1 as a key factor in up-regulation of gastric mucosal leptin-associated H. pylori infection. We also show that the effect of ET-1 on leptin production is a consequence of ET(A) receptor activation.
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Affiliation(s)
- Bronislaw L Slomiany
- Research Center, University of Medicine and Dentistry of New Jersey, Newark, 07103-2400, USA.
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Yoshino N, Ishihara S, Rumi MAK, Ortega-Cava CF, Yuki T, Kazumori H, Takazawa S, Okamoto H, Kadowaki Y, Kinoshita Y. Interleukin-8 regulates expression of Reg protein in Helicobacter pylori-infected gastric mucosa. Am J Gastroenterol 2005; 100:2157-66. [PMID: 16181363 DOI: 10.1111/j.1572-0241.2005.41915.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIM Chronic inflammation induced by Helicobacter pylori infection is closely associated with epithelial cell proliferation and apoptosis, which are related to cellular turnover in gastric mucosa. Reg protein is a regenerating gene product and a potent growth factor for gastric mucosal cells, however, little is known regarding its association with the pathogenesis of H. pylori infection. The aim of this study was to investigate Reg protein production and its regulation in H. pylori-associated gastritis. METHODS Gastric fundic biopsy samples were taken from patients with and without H. pylori infection. In vivo expression of Reg protein was examined by Western blotting and immunohistochemistry methods. The effects of interleukin (IL)-8 on Reg protein expression and transcriptional activation of the Reg gene in ECC10 cells were investigated by Western blotting and luciferase assays, respectively. RESULTS Reg expression was found localized in the deeper part of gastric fundic glands and clearly shown in chromogranin A-positive cells in the gastric corpus. Semiquantitative immunohistochemistry and Western blotting results for Reg expression were significantly associated with polymorphonuclear neutrophil activity and chronic inflammation of gastric mucosa. IL-8 production in the gastric mucosa was significantly augmented by H. pylori infection, while IL-8 dose-dependently stimulated Reg protein production and Reg promoter activity in vitro in cultured ECC10 cells. CONCLUSION The present study showed for the first time that Reg protein may be a potent stimulator of gastric epithelial cells in H. pylori-infected human gastric mucosa stimulated by IL-8. Further, our findings provide evidence of a novel link between Reg protein and H. pylori infection, which may help explain the molecular mechanisms underlying H. pylori-associated diseases, including gastric cancer.
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Affiliation(s)
- Nagisa Yoshino
- Department of Gastroenterology and Hepatology, Shimane University, School of Medicine, Izumo, Japan
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Hiratsuka K, Logan SM, Conlan JW, Chandan V, Aubry A, Smirnova N, Ulrichsen H, Chan KHN, Griffith DW, Harrison BA, Li J, Altman E. Identification of a D-glycero-D-manno-heptosyltransferase gene from Helicobacter pylori. J Bacteriol 2005; 187:5156-65. [PMID: 16030209 PMCID: PMC1196013 DOI: 10.1128/jb.187.15.5156-5165.2005] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
We have identified a Helicobacter pylori d-glycero-d-manno-heptosyltransferase gene, HP0479, which is involved in the biosynthesis of the outer core region of H. pylori lipopolysaccharide (LPS). Insertional inactivation of HP0479 resulted in formation of a truncated LPS molecule lacking an alpha-1,6-glucan-, dd-heptose-containing outer core region and O-chain polysaccharide. Detailed structural analysis of purified LPS from HP0479 mutants of strains SS1, 26695, O:3, and PJ1 by a combination of chemical and mass spectrometric methods showed that HP0479 likely encodes alpha-1,2-d-glycero-d-manno-heptosyltransferase, which adds a d-glycero-d-manno-heptose residue (DDHepII) to a distal dd-heptose of the core oligosaccharide backbone of H. pylori LPS. When the wild-type HP0479 gene was reintegrated into the chromosome of strain 26695 by using an "antibiotic cassette swapping" method, the complete LPS structure was restored. Introduction of the HP0479 mutation into the H. pylori mouse-colonizing Sydney (SS1) strain and the clinical isolate PJ1, which expresses dd-heptoglycan, resulted in the loss of colonization in a mouse model. This indicates that H. pylori expressing a deeply truncated LPS is unable to successfully colonize the murine stomach and provides evidence for a critical role of the outer core region of H. pylori LPS in colonization.
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Affiliation(s)
- Koji Hiratsuka
- Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada
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Kusumoto K, Kawahara T, Kuwano Y, Teshima-Kondo S, Morita K, Kishi K, Rokutan K. Ecabet sodium inhibits Helicobacter pylori lipopolysaccharide-induced activation of NADPH oxidase 1 or apoptosis of guinea pig gastric mucosal cells. Am J Physiol Gastrointest Liver Physiol 2005; 288:G300-7. [PMID: 15458921 DOI: 10.1152/ajpgi.00274.2004] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Helicobacter pylori LPS activates a homolog of gp91(phox), NADPH oxidase 1 (Nox1), in guinea pig gastric mucosal cells cultured in 10% FBS-containing medium. RT-PCR and Northern hybridization demonstrated that H. pylori LPS stimulated expression of Nox1 and a novel p47(phox) homolog (Noxo1) mRNAs with a peak at 4 h, followed by upregulation of superoxide anion (O2-) generation. Pretreatment with 10 mg/ml of a nonabsorbable antigastric ulcer drug, ecabet sodium (ecabet), completely blocked these two mRNA expressions and the upregulation of O2- production. Under low (0.1%)-FBS conditions, H. pylori LPS predominantly caused apoptosis of the cells. Ecabet completely blocked the LPS-triggered phosphorylation of transforming growth factor-beta-activated kinase 1 (TAK1) and TAK1-binding protein 1, activation of caspase 8, loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase 3, and appearance of apoptotic cells. In contrast, ecabet had no effect on ethanol- or etoposide-initiated apoptosis. The ecabet-pretreated cells exhibited the responsiveness to H. pylori LPS, similarly as untreated control cells did, when ecabet was removed by washing before the addition of H. pylori LPS. Incubation of H. pylori LPS with ecabet eliminated the toxic effects of the LPS, and nondenatured polyacrylamide gel electrophoresis indicated the formation of higher molecular mass complexes between H. pylori LPS and ecabet, suggesting that ecabet may interact with H. pylori LPS and block the activation of Toll-like receptor 4 (TLR4). Our results suggest that ecabet may suppress TLR4-mediated inflammation or accelerated apoptosis caused H. pylori infection.
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Affiliation(s)
- Kenji Kusumoto
- Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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Cho SJ, Kang NS, Park SY, Kim BO, Rhee DK, Pyo S. Induction of apoptosis and expression of apoptosis related genes in human epithelial carcinoma cells by Helicobacter pylori VacA toxin. Toxicon 2004; 42:601-11. [PMID: 14602115 DOI: 10.1016/j.toxicon.2003.08.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Virulence factors produced by Helicobacter pylori have been known to be associated with serious gastroduodenal diseases. The aims of this study were to clarify the apoptosis-inducing properties of vacuolating cytotoxin (VacA) and examine the expression of apoptosis related proteins in human epithelial carcinoma cells expressing (AGS) or lacking (Kato III) p53. The midregion VacA homolog from H. pylori strain Q35 (Korean isolate) was cloned, expressed and sequenced. Recombinant VacA (VacA(418-799)) inhibited cell growth and induced apoptosis in gastric epithelial cells. Treatment with VacA(418-799) resulted in morphological changes and DNA fragmentation. Cell cycle analysis revealed subdiploid cells suggesting apoptosis, which was confirmed by the activation of caspase-3 and cleavage of PARP. VacA(418-799) also mediated a prolongation of the cell cycle progression in G1 phase. Furthermore, VacA(418-799) increased the expression of p53, p21(waf1/cip1) and Bax in AGS cells, but not in Kato III cells and did not affect the phosphorylation of Rb in both cell lines. These results indicate that recombinant VacA of H. pylori induces apoptosis in both Kato III and AGS cells, regardless of p53 status and suggest that VacA(418-799) mediate the development of gastric diseases through cell cycle arrest in the G1 phase. VacA(418-799) induction of apoptosis is associated with up-regulation of p53, p21(waf1/cip1), Bax in AGS cells and activation of caspase-3 in both cell lines.
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Affiliation(s)
- Seong-Jun Cho
- Division of Immunopharmacology, College of Pharmacy, Sungkyunkwan University, Suwon city, Kyunggi-do 440-746, South Korea
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Slomiany BL, Slomiany A. Peroxisome proliferator-activated receptor γ activation counters the detrimental effect of Helicobacter pylori lipopolysaccharide on gastric mucin synthesis. Inflammopharmacology 2003; 11:223-36. [PMID: 15035805 DOI: 10.1163/156856003322315578] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the subfamily of ligand-dependent nuclear transcription factors, plays a key role in the regulation of the expression of genes associated with inflammation. In this study, using gastric mucosal cells in culture, we assess the role of PPARgamma in the disturbances in gastric mucin synthesis and apoptotic processes evoked by Helicobacter pylori lipopolysaccharide (LPS). Exposure of gastric mucosal cells to the LPS led to a concentration-dependent decrease (up to 59.5%) in mucin synthesis, and this effect of the LPS was accompanied by a 6.5-fold increase in apoptosis, induction of COX-2 and NOS-2 protein expression, and the enhancement in PGE(2) generation (18.6-fold) and NOS-2 activity (24.1-fold). However, the expression of COX-1 protein was not affected. Activation of PPARgamma with a specific synthetic agonist, ciglitazone, countered (up to 90.2%) the LPS-induced reduction in mucin synthesis in a concentration-dependent manner, and this effect of the agent was reflected in a marked decrease in COX-2 and NOS-2 protein expression, reduction (up to 72.4%) in apoptosis and a decline (up to 84.1%) in PGE(2) generation and NOS-2 activity (up to 90%). A pronounced prevention (88.2%) in the LPS-induced PGE(2) release and the diminished COX-2 protein expression was also attained with the COX-2-selective inhibitor NS-398, but the effect was not associated with the impedance of the LPS inhibitory effect on mucin synthesis. Our findings thus demonstrate that the detrimental influence of H. pylori LPS on gastric mucin synthesis is closely linked to the increase in proapoptotic processes triggered by NOS-2 upregulation, and that PPARgamma activation obviates this detrimental effect. Hence, pharmacological manipulation of PPARgamma activation may provide therapeutic benefits in countering the disruptive effects of H. pylori on gastric mucosal mucus coat continuity.
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Affiliation(s)
- B L Slomiany
- Research Center, Room C875, University of Medicine and Dentistry of New Jersey, 110 Bergen Street, Newark, NJ 07103-2400, USA.
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Kim DH, Kim SW, Song YJ, Oh TY, Han SU, Kim YB, Joo HJ, Cho YK, Kim DY, Cho SW, Kim MW, Kim JH, Hahm KB. Long-term evaluation of mice model infected with Helicobacter pylori: focus on gastric pathology including gastric cancer. Aliment Pharmacol Ther 2003; 18 Suppl 1:14-23. [PMID: 12925137 DOI: 10.1046/j.1365-2036.18.s1.4.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Long-term evaluation of gastric pathology after H. pylori infection is very important in order to reveal its clinical implications, since debate still exists on the gastric carcinogenesis provoked by H. pylori infection in animal models. AIM Either to evaluate the long-term outcome of H. pylori infection or to determine how H. pylori could provoke gastric cancer in the mice model. METHODS Four-week-old specific pathogen free C57BL/6 mice (n = 115) were infected with SS1, the mouse-adapted H. pylori strain. After 4, 8, 16, 24, 36, 50 and 80 weeks of bacterial infection, the H. pylori-infected mice were sacrificed. RESULTS After 80 weeks of infection, almost all the H. pylori-infected mice developed hyperplastic gastritis, but did not show any evidence of gastric adenoma, dysplasia or carcinoma. PCNA positive cells were most abundant after 50 weeks and tended to decrease thereafter up to 80 weeks, whereas apoptosis began to be noted 8 weeks after H. pylori infection, showing 7-8 apoptotic cells/high power field, and tending to increase as time passed. Normally observed neutral mucin decreased during the experiment, showing the most marked decrease 50 weeks after H. pylori infection. In contrast, acidic mucin was noted from 50 weeks after infection. CONCLUSION The SS1-infected mouse seems to be a suitable animal model for H. pylori-related research, and H. pylori itself does not induce gastric cancer in normal wild-type mouse model following long-term exposure, which could be explained by the balance that exists between cell proliferation and apoptosis.
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Affiliation(s)
- D H Kim
- Genomic Research Center for Gastroenterology and Ajou Helicobacter pylori Research Group, Ajou University School of Medicine, Suwon, Korea
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Slomiany BL, Slomiany A. Platelet-activating factor modulates gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide. Biochem Biophys Res Commun 2003; 306:261-6. [PMID: 12788098 DOI: 10.1016/s0006-291x(03)00944-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Platelet-activating factor (PAF) is a phospholipid messenger implicated in mediation of inflammatory events associated with the resolution of inflammation. We applied the animal model of Helicobacter pylori LPS-induced gastritis in conjunction with prophylactic and therapeutic administration of a specific PAF antagonist, BN52020, to investigate the role of PAF in gastric mucosal responses to H. pylori infection. Prophylactic BN52020 administration produced up to 73.6% reduction in the severity of the LPS-induced inflammatory changes, whereas up to 38.4% increase in the severity of mucosal involvement occurred with BN52020 administered therapeutically. The prophylactic effects of BN52020 were accompanied by a drop in apoptosis and the expression of TNF-alpha and NOS-2, while BN52020 administered therapeutically caused a marked upregulation in apoptosis, TNF-alpha, and NOS-2. The untoward therapeutic effects of BN52020, moreover, were potentiated further in the presence of COX-2 inhibitor, whereas NOS-2 inhibitor caused a reduction in the extent of inflammatory changes. Our findings point to PAF as a key mediator of gastric mucosal inflammatory responses to H. pylori and suggest its modulatory role in the expression of COX-2 derived anti-inflammatory prostaglandins that are involved in controlling the extent of NOS-2 induction.
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Affiliation(s)
- Bronislaw L Slomiany
- Research Center, Room C 875, University of Medicine and Dentistry of New Jersey, 110 Bergen Street, P.O. Box 1709, Newark, NJ 07103-2400, USA.
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Tari A, Kodama K, Kitadai Y, Ohta M, Sumii K, Kajiyama G. Is apoptosis in antral mucosa correlated with serum nitrite concentration in Japanese Helicobacter pylori-infected patients? J Gastroenterol Hepatol 2003; 18:498-504. [PMID: 12702040 DOI: 10.1046/j.1440-1746.2003.03013.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND AIM Helicobacter pylori infection in gastric mucosa is a form of chronic active gastritis that leads to expression of inducible nitric oxide synthase in host macrophages and polymorphonuclear leukocytes. Nitric oxide produced by these cells infiltrating the gastric mucosa could damage DNA. We correlated apoptosis in H. pylori-infected antral tissue from peptic ulcer patients with serum nitrate-plus-nitrite. METHODS Biopsy specimens were obtained endoscopically from antrum and fundus in 17 peptic ulcer patients before and after H. pylori eradication. Tissue samples were subjected to rapid urease testing and histopathological scoring (updated Sydney system), as well as immunohistochemical detection of single-stranded DNA indicating apoptotic cells. Fasting serum samples were analyzed for combined nitrate and nitrite content. RESULTS In all cases atrophy was absent to mild in antral mucosa and H. pylori was eradicated successfully. A strong positive correlation was present between apoptosis and both inflammation and activity scores in infected antral mucosa. A significant positive correlation also was noted between apoptosis and H. pylori density. Serum nitrite concentrations were decreased significantly by successful eradication of H. pylori, and showed a strong positive correlation with H. pylori density. Serum nitrite concentrations showed a significant positive correlation with numbers of single-stranded DNA-positive cells. CONCLUSIONS High H. pylori density was associated with elevated serum nitrate-plus-nitrite (a marker of nitric oxide production in gastric mucosa). Increased apoptosis and abnormal gastric cell turnover are likely results.
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Affiliation(s)
- Akira Tari
- Department of Internal Medicine, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan.
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Sepulveda AR, Graham DY. Role of Helicobacter pylori in gastric carcinogenesis. Hematol Oncol Clin North Am 2003. [DOI: 10.1016/s0889-8588(03)00021-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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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: 210] [Impact Index Per Article: 9.5] [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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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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Affiliation(s)
- Colm Power
- Department of Academic Surgery, Cork University Hospital and University College Cork, Ireland
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Slomiany BL, Slomiany A. Disruption in gastric mucin synthesis by Helicobacter pylori lipopolysaccharide involves ERK and p38 mitogen-activated protein kinase participation. Biochem Biophys Res Commun 2002; 294:220-4. [PMID: 12051697 DOI: 10.1016/s0006-291x(02)00463-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Helicobacter pylori is a primary factor in the etiology of gastric disease, and its early pathogenic effects are manifested by up-regulation of inflammatory processes and the loss of mucus coat continuity. We investigated the role of extracellular signal-regulated kinase (ERK) and p38 mitogen activated protein kinase (MAPK) in the disturbances in gastric mucin synthesis and apoptotic processes evoked by H. pylori lipopolysaccharide (LPS). Exposure of gastric mucosal cells to the LPS led to a dose-dependent decrease (up to 59.5%) in mucin synthesis, accompanied by a marked increase in caspase-3 activity and apoptosis. Inhibition of ERK with PD98059 accelerated (up to 36.1%) the LPS-induced decrease in mucin synthesis, and caused further enhancement in caspase-3 activity and apoptosis. Blockade of p38 kinase with SB203580 produced reversal in the LPS-induced reduction in mucin synthesis, and substantially countered the LPS-induced increases in caspas-3 activity and apoptosis. Moreover, inhibition of caspase-3 blocked the LPS-induced increase in caspse-3 activity and produced an increase in mucin synthesis. Thus the detrimental influence of H. pylori LPS on gastric mucin synthesis is closely linked to caspase-3 activation and apoptosis, and involves ERK and p38 kinase participation.
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Affiliation(s)
- Bronislaw L Slomiany
- Research Center, University of Medicine and Dentistry of New Jersey, New Jersey Dental School, 110 Bergen Street, Newark, NJ 07103-2400, USA.
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Abstract
Peptic ulcers and gastric malignancies are the two major complication of the course of Helicobacter pylori-associated chronic gastritis. Both gastric adenocarcinomas and MALT lymphomas occur in association with H. pylori infection, and studies support an etiological association. This article discusses the natural history of H. pylori-related gastric carcinogenesis and criteria to identify people susceptible to H. pylori infection-associated gastric cancer. It then reviews the molecular and genetic mechanisms underlying the malignant transformation of the gastric mucosa associated with H. pylori.
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Affiliation(s)
- Antonia R Sepulveda
- Department of Pathology, PUH-A610, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213-2582, USA.
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Karhukorpi J, Yan Y, Niemela S, Valtonen J, Koistinen P, Joensuu T, Saikku P, Karttunen R. Effect of CD14 promoter polymorphism and H. pylori infection and its clinical outcomes on circulating CD14. Clin Exp Immunol 2002; 128:326-32. [PMID: 11985523 PMCID: PMC1906384 DOI: 10.1046/j.1365-2249.2002.01837.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
CD14 is a pattern recognition receptor on the membranes of monocytes and macrophages for several microbial products, of which lipopolysaccharide (LPS) is the best known. A shed form of CD14 is present in serum. As the CD14 gene promoter polymorphism -159C/T and some bacterial infections may affect the sCD14 levels, we compared the impact of both the CD14 promoter polymorphism and Helicobacter pylori infection on serum sCD14 levels in 201 dyspeptic patients (group 1) who had undergone gastroscopy, and 127 staff members (group 2) with no endoscopy. sCD14 was measured from the sera by a commercial enzyme immunoassay (EIA), and CD14 genotyping was carried out with PCR. Helicobacter pylori infection was detected by serology and/or culture or PCR. sCD14 levels were elevated in the subjects carrying the T allele (CT or TT genotype) in both groups when compared with subjects with the CC genotype. Overall, H. pylori-positive subjects tended to have higher sCD14 levels compared with H. pylori-negative subjects. In group 1 consisting of dyspeptic patients, those with gastric ulcer, gastric erosion or duodenal ulcer had significantly elevated levels of sCD14 compared with the patients with normal endoscopic findings or macroscopic gastritis. The recent use of NSAIDs was also associated with enhanced sCD14. Thus, we were able to show several factors, one genetic and the other environmental (H. pylori infection and mucosal lesion), to have an impact on sCD14.
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Affiliation(s)
- J Karhukorpi
- Department of Medical Microbiology, University of Oulu, Finland.
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Slomiany BL, Piotrowski J, Slomiany A. Up-regulation of gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide by aspirin but not indomethacin. ACTA ACUST UNITED AC 2002. [PMID: 11581571 DOI: 10.1177/09680519010070030201] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Infection with Helicobacter pylori and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are recognized as the two primary factors in the etiology of gastric disease. In this study, we applied the animal model of H. pylori-induced gastritis to assess the influence of NSAIDs on the course of mucosal inflammatory responses to H. pylori. Two days following intragastric application of H. pylori lipopolysaccharide, rats were divided into groups and administered daily for up to 8 days either indomethacin, aspirin or the vehicle, and their gastric mucosal tissue subjected to histological and biochemical assessment. H. pylori lipopolysaccharide elicited within 2 days a pattern of acute mucosal inflammatory responses accompanied by a massive epithelial cell apoptosis, and a marked increase in the expression of membrane-bound and soluble forms of TNF-alpha. The extent of mucosal inflammatory involvement reached a maximum by the 4th day and showed a decline by the 10th day; this was reflected in a 38.1% reduction in apoptosis, a 53.2% decline in membrane-bound TNF-alpha and a 63.8% decrease in soluble TNF-alpha. Compared to the vehicle controls, aspirin caused a 36.2% increase in the severity of the mucosal inflammatory involvement by the second day of administration and a 25.9% increase in the inflammatory involvement occurred by the 8th day; this effect of aspirin was accompanied by a significant (54.5%) induction in apoptosis, a 58.2% decline in membrane-bound TNF-alpha and a 61% increase in soluble TNF-alpha. In contrast, administration of indomethacin evoked only a marginal increase (5-7%) in apoptosis, and caused no discernible changes in the severity of gastric mucosal involvement and the expression of TNF-alpha forms elicited by H. pylori lipopolysaccharide. The findings indicate that aspirin, but not indomethacin, increases the severity of gastric mucosal inflammatory responses to H. pylori. This detrimental influence of aspirin appears to result from up-regulation in the mucosal expression of soluble form of TNF-alpha, which leads to the amplification of apoptotic events that potentiate gastric mucosal inflammatory reaction to H. pylori.
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Affiliation(s)
- B L Slomiany
- Research Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103-2400, USA.
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Ishihara S, Fukuda R, Kawashima K, Moriyama N, Suetsugu H, Ishimura N, Kazumori H, Kaji T, Sato H, Okuyama T, Rumi KM, Adachi K, Watanabe M, Kinoshita Y. T cell-mediated cytotoxicity via Fas/Fas ligand signaling in Helicobacter pylori-infected gastric corpus. Helicobacter 2001; 6:283-293. [PMID: 11843960 DOI: 10.1046/j.1523-5378.2001.00043.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Helicobacter pylori infection induces T helper-1 immune responses in inflamed mucosa. However, the role of T cell-mediated cytotoxicity in the induction of epithelial apoptosis is still unclear. The aim of this study was to investigate the involvement of the Fas/Fas ligand (Fas/Fas-L) system in the H. pylori-infected gastric corpus. MATERIALS AND METHODS Gastric fundic biopsy specimens were taken from patients with and without H. pylori infection. The expression of Fas and Fas-L was examined by immunohistochemistry and RT-PCR. Subsets of gastric infiltrating T cells in the biopsy specimens were studied by immunohistochemistry and flow cytometry. In histological sections, apoptosis was detected by the TUNEL method. We studied the in vitro expression of Fas-L in peripheral T cells after stimulation with H. pylori antigen and interferon-gamma (IFN-gamma). The Fas-mediated in vitro cytotoxicity of activated T cells was assessed by flow cytometry. RESULTS The numbers of CD4+ and CD8+ T cells were greater in H. pylori-infected subjects. Fas expression was abundantly increased on fundic gland epithelium, and Fas-L was detected on lamina propria mononuclear cells in H. pylori-infected mucosa. TUNEL-positive epithelial cells were also increased in H. pylori-infected subjects. H. pylori antigen and IFN-gamma induced Fas-L mRNA expression in both CD4+ and CD8+ T cells. In cytotoxic assay, activated T cells induced apoptosis in AGS cells, which could be significantly inhibited by neutralizing Fas-L antibody. CONCLUSIONS T cell-mediated cytotoxicity via Fas/Fas-L signaling may contribute to the induction of apoptosis in gastric epithelial cells during H. pylori infection.
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Affiliation(s)
- S Ishihara
- Department of Internal Medicine II, Shimane Medical University, Izumo, Shimane, Japan.
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