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Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis.
Feichtinger RG, Neureiter D, Skaria T, Wessler S, Cover TL, Mayr JA, Zimmermann FA, Posselt G, Sperl W, Kofler B
(2017) Oxid Med Cell Longev 2017: 1320241
MeSH Terms: Electron Transport Complex I, Female, Gastritis, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Helicobacter Infections, Helicobacter pylori, Humans, Male, Neoplasm Proteins, Oxidative Phosphorylation, Stomach Neoplasms
Show Abstract · Added March 21, 2018
Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.
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12 MeSH Terms
Epidermal growth factor receptor inhibition downregulates -induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis.
Sierra JC, Asim M, Verriere TG, Piazuelo MB, Suarez G, Romero-Gallo J, Delgado AG, Wroblewski LE, Barry DP, Peek RM, Gobert AP, Wilson KT
(2018) Gut 67: 1247-1260
MeSH Terms: Animals, Antineoplastic Agents, Cell Culture Techniques, Epithelial Cells, ErbB Receptors, Gastritis, Gefitinib, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Mice, Mice, Inbred C57BL, Quinazolines, Stomach Neoplasms
Show Abstract · Added June 29, 2017
OBJECTIVE - Gastric cancer is the third leading cause of cancer death worldwide and infection by is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the -induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis.
DESIGN - We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of -induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of ( mice) were also used.
RESULTS - In C57BL/6 mice, gefitinib decreased and expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected versus control mice. In -infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked ri-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from versus mice. Epithelial EGFR activation persisted in humans and mice after eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics.
CONCLUSIONS - These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in -infected individuals.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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14 MeSH Terms
Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications.
Hardbower DM, Asim M, Luis PB, Singh K, Barry DP, Yang C, Steeves MA, Cleveland JL, Schneider C, Piazuelo MB, Gobert AP, Wilson KT
(2017) Proc Natl Acad Sci U S A 114: E751-E760
MeSH Terms: Animals, Cell Line, Citrobacter rodentium, Colitis, Colon, Cytokines, Enterobacteriaceae Infections, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Histones, Humans, Macrophage Activation, Macrophages, Male, Mice, NLR Family, Pyrin Domain-Containing 3 Protein, Ornithine Decarboxylase, Putrescine
Show Abstract · Added January 19, 2017
Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection. Myeloid-specific Odc deletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add-back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function. Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms.
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20 MeSH Terms
TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection.
Beceiro S, Radin JN, Chatuvedi R, Piazuelo MB, Horvarth DJ, Cortado H, Gu Y, Dixon B, Gu C, Lange I, Koomoa DL, Wilson KT, Algood HM, Partida-Sánchez S
(2017) Mucosal Immunol 10: 493-507
MeSH Terms: Animals, Calcium Signaling, Cell Differentiation, Cells, Cultured, Cytokines, Gastritis, Helicobacter Infections, Helicobacter pylori, Inflammation Mediators, Macrophage Activation, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, NADP, Oxidative Stress, Reactive Oxygen Species, TRPM Cation Channels
Show Abstract · Added July 30, 2016
Calcium signaling in phagocytes is essential for cellular activation, migration, and the potential resolution of infection or inflammation. The generation of reactive oxygen species (ROS) via activation of NADPH (nicotinamide adenine dinucleotide phosphate)-oxidase activity in macrophages has been linked to altered intracellular calcium concentrations. Because of its role as an oxidative stress sensor in phagocytes, we investigated the function of the cation channel transient receptor potential melastatin 2 (TRPM2) in macrophages during oxidative stress responses induced by Helicobacter pylori infection. We show that Trpm2/ mice, when chronically infected with H. pylori, exhibit increased gastric inflammation and decreased bacterial colonization compared with wild-type (WT) mice. The absence of TRPM2 triggers greater macrophage production of inflammatory mediators and promotes classically activated macrophage M1 polarization in response to H. pylori. TRPM2-deficient macrophages upon H. pylori stimulation are unable to control intracellular calcium levels, which results in calcium overloading. Furthermore, increased intracellular calcium in TRPM2/ macrophages enhanced mitogen-activated protein kinase and NADPH-oxidase activities, compared with WT macrophages. Our data suggest that augmented production of ROS and inflammatory cytokines with TRPM2 deletion regulates oxidative stress in macrophages and consequently decreases H. pylori gastric colonization while increasing inflammation in the gastric mucosa.
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Genetic Evolution of a Helicobacter pylori Acid-Sensing Histidine Kinase and Gastric Disease.
Krishna U, Romero-Gallo J, Suarez G, Azah A, Krezel AM, Varga MG, Forsyth MH, Peek RM
(2016) J Infect Dis 214: 644-8
MeSH Terms: Achlorhydria, Acids, Animals, Bacterial Proteins, Evolution, Molecular, Gastritis, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Histidine Kinase, Humans, Male, Mice, Inbred C57BL, Microbial Viability, Mutation, Missense
Show Abstract · Added April 6, 2017
Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, which develops within a hypochlorhydric environment. We sequentially isolated H. pylori (strain J99) from a patient who developed corpus-predominant gastritis and hypochlorhydia over a 6-year interval. Archival J99 survived significantly better under acidic conditions than recent J99 strains. H. pylori arsRS encodes a 2-component system critical for stress responses; recent J99 isolates harbored 2 nonsynonymous arsS mutations, and arsS inactivation abolished acid survival. In vivo, acid-resistant archival, but not recent J99, successfully colonized high-acid-secreting rodents. Thus, genetic evolution of arsS may influence progression to hypochlorhydia and gastric cancer.
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
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15 MeSH Terms
BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation.
Chen J, Wang Z, Hu X, Chen R, Romero-Gallo J, Peek RM, Chen LF
(2016) J Immunol 196: 4132-42
MeSH Terms: Azepines, Cell Line, Tumor, Enhancer Elements, Genetic, Gastritis, Gene Expression Regulation, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation Mediators, NF-kappa B, Nuclear Proteins, Promoter Regions, Genetic, Protein Binding, RNA Polymerase II, RNA, Messenger, Transcription Factors, Triazoles
Show Abstract · Added April 6, 2017
Helicobacter pylori infection causes chronic gastritis and peptic ulceration. H. pylori-initiated chronic gastritis is characterized by enhanced expression of many NF-κB-regulated inflammatory cytokines. Brd4 has emerged as an important NF-κB regulator and regulates the expression of many NF-κB-dependent inflammatory genes. In this study, we demonstrated that Brd4 was not only actively involved in H. pylori-induced inflammatory gene mRNA transcription but also H. pylori-induced inflammatory gene enhancer RNA (eRNA) synthesis. Suppression of H. pylori-induced eRNA synthesis impaired H. pylori-induced mRNA synthesis. Furthermore, H. pylori stimulated NF-κB-dependent recruitment of Brd4 to the promoters and enhancers of inflammatory genes to facilitate the RNA polymerase II-mediated eRNA and mRNA synthesis. Inhibition of Brd4 by JQ1 attenuated H. pylori-induced eRNA and mRNA synthesis for a subset of NF-κB-dependent inflammatory genes. JQ1 also inhibited H. pylori-induced interaction between Brd4 and RelA and the recruitment of Brd4 and RNA polymerase II to the promoters and enhancers of inflammatory genes. Finally, we demonstrated that JQ1 suppressed inflammatory gene expression, inflammation, and cell proliferation in H. pylori-infected mice. These studies highlight the importance of Brd4 in H. pylori-induced inflammatory gene expression and suggest that Brd4 could be a potential therapeutic target for the treatment of H. pylori-triggered inflammatory diseases and cancer.
Copyright © 2016 by The American Association of Immunologists, Inc.
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Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer.
Murray-Stewart T, Sierra JC, Piazuelo MB, Mera RM, Chaturvedi R, Bravo LE, Correa P, Schneider BG, Wilson KT, Casero RA
(2016) Oncogene 35: 5480-5488
MeSH Terms: 3' Untranslated Regions, Biopsy, DNA Methylation, Down-Regulation, Epigenesis, Genetic, Gastritis, Gene Expression Regulation, Gene Silencing, Helicobacter Infections, Helicobacter pylori, Humans, MicroRNAs, Oxidoreductases Acting on CH-NH Group Donors, Stomach Neoplasms
Show Abstract · Added April 11, 2016
Chronic inflammation contributes to the development of various forms of cancer. The polyamine catabolic enzyme spermine oxidase (SMOX) is induced in chronic inflammatory conditions, including Helicobacter pylori-associated gastritis, where its production of hydrogen peroxide contributes to DNA damage and subsequent tumorigenesis. MicroRNA expression levels are also altered in inflammatory conditions; specifically, the tumor suppressor miR-124 becomes silenced by DNA methylation. We sought to determine if this repression of miR-124 is associated with elevated SMOX activity and concluded that miR-124 is indeed a negative regulator of SMOX. In gastric adenocarcinoma cells harboring highly methylated and silenced mir-124 gene loci, 5-azacytidine treatment allowed miR-124 re-expression and decreased SMOX expression. Overexpression of an exogenous miR-124-3p mimic repressed SMOX mRNA and protein expression as well as HO production by >50% within 24 h. Reporter assays indicated that direct interaction of miR-124 with the 3'-untranslated region of SMOX mRNA contributes to this negative regulation. Importantly, overexpression of miR-124 before infection with H. pylori prevented the induction of SMOX believed to contribute to inflammation-associated tumorigenesis. Compelling human in vivo data from H. pylori-positive gastritis tissues indicated that the mir-124 gene loci are more heavily methylated in a Colombian population characterized by elevated SMOX expression and a high risk for gastric cancer. Furthermore, the degree of mir-124 methylation significantly correlated with SMOX expression throughout the population. These results indicate a protective role for miR-124 through the inhibition of SMOX-mediated DNA damage in the etiology of H. pylori-associated gastric cancer.
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14 MeSH Terms
The Immune Battle against Helicobacter pylori Infection: NO Offense.
Gobert AP, Wilson KT
(2016) Trends Microbiol 24: 366-376
MeSH Terms: Animals, Chronic Disease, Gastric Mucosa, Gastritis, Helicobacter Infections, Helicobacter pylori, Host-Pathogen Interactions, Humans, Nitric Oxide, Nitric Oxide Synthase Type II, Stomach Neoplasms
Show Abstract · Added March 13, 2016
Helicobacter pylori is a successful pathogen of the human stomach. Despite a vigorous immune response by the gastric mucosa, the bacterium survives in its ecological niche, thus favoring diseases ranging from chronic gastritis to adenocarcinoma. The current literature demonstrates that high-output of nitric oxide (NO) production by the inducible enzyme NO synthase-2 (NOS2) plays major functions in host defense against bacterial infections. However, pathogens have elaborated several strategies to counteract the deleterious effects of NO; this includes inhibition of host NO synthesis and transcriptional regulation in response to reactive nitrogen species, allowing the bacteria to face the nitrosative stress. Moreover, NO is also a critical mediator of inflammation and carcinogenesis. In this context, we review the recent findings on the expression of NOS2 in H. pylori-infected gastric tissues and epithelial cells, the role of NO in H. pylori-related diseases and H. pylori gene expression, and the mechanisms whereby H. pylori regulates NO synthesis by host cells.
Published by Elsevier Ltd.
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11 MeSH Terms
IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori.
Dixon BR, Radin JN, Piazuelo MB, Contreras DC, Algood HM
(2016) PLoS One 11: e0148514
MeSH Terms: Animals, Anti-Infective Agents, CD4-Positive T-Lymphocytes, Epithelial Cells, Epithelium, Gastritis, Gastrointestinal Tract, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Interleukin-17, Interleukin-8, Interleukins, Leukocyte L1 Antigen Complex, Lipocalins, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Stomach
Show Abstract · Added April 28, 2016
Helicobacter pylori colonization of the human stomach can lead to adverse clinical outcomes including gastritis, peptic ulcers, or gastric cancer. Current data suggest that in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. Specifically, CD4+ T cell responses impact the pathology elicited in response to H. pylori. Because gastritis is believed to be the initiating host response to more detrimental pathological outcomes, there has been a significant interest in pro-inflammatory T cell cytokines, including the cytokines produced by T helper 17 cells. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22. While these cytokines have been linked to inflammation, IL-17A and IL-22 are also associated with anti-microbial responses and control of bacterial colonization. The goal of this research was to determine the role of IL-22 in activation of antimicrobial responses in models of H. pylori infection using human gastric epithelial cell lines and the mouse model of H. pylori infection. Our data indicate that IL-17A and IL-22 work synergistically to induce antimicrobials and chemokines such as IL-8, components of calprotectin (CP), lipocalin (LCN) and some β-defensins in both human and primary mouse gastric epithelial cells (GEC) and gastroids. Moreover, IL-22 and IL-17A-activated GECs were capable of inhibiting growth of H. pylori in vitro. While antimicrobials were activated by IL-17A and IL-22 in vitro, using a mouse model of H. pylori infection, the data herein indicate that IL-22 deficiency alone does not render mice more susceptible to infection, change their antimicrobial gene transcription, or significantly change their inflammatory response.
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The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice.
Garay J, Piazuelo MB, Majumdar S, Li L, Trillo-Tinoco J, Del Valle L, Schneider BG, Delgado AG, Wilson KT, Correa P, Zabaleta J
(2016) Cancer Lett 371: 90-8
MeSH Terms: Animals, Antigens, Ly, Cells, Cultured, Chemotaxis, Leukocyte, Disease Models, Animal, Disease Progression, Female, Gastric Mucosa, Gastritis, Atrophic, Helicobacter Infections, Helicobacter pylori, Humans, Hyaluronan Receptors, Interferon-gamma, Macrophages, Peritoneal, Mice, Knockout, Neutrophil Infiltration, Neutrophils, Precancerous Conditions, Signal Transduction, Stomach Neoplasms, Time Factors
Show Abstract · Added February 15, 2016
Infection with Helicobacter pylori (H. pylori) leads to inflammatory events that can promote gastric cancer development. Immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied H. pylori-positive subjects with gastric lesions that ranged from multifocal atrophic gastritis to dysplasia to determine gene expression changes associated with disease progression over a period of 6 years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive H. pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. We present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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