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Helicobacter pylori adaptation in vivo in response to a high-salt diet.
Loh JT, Gaddy JA, Algood HM, Gaudieri S, Mallal S, Cover TL
(2015) Infect Immun 83: 4871-83
MeSH Terms: Adaptation, Physiological, Animals, Bacterial Proteins, Base Sequence, Disease Models, Animal, Gastric Mucosa, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Genome, Bacterial, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Host-Pathogen Interactions, Humans, Iron, Molecular Sequence Data, Mutation, Oxidative Stress, Proteome, Repressor Proteins, Sodium Chloride, Dietary
Show Abstract · Added October 8, 2015
Helicobacter pylori exhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification of H. pylori is influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) on H. pylori diversification within a host. We analyzed H. pylori strains isolated from Mongolian gerbils fed either a high-salt diet or a regular diet for 4 months by proteomic and whole-genome sequencing methods. Compared to the input strain and output strains from animals fed a regular diet, the output strains from animals fed a high-salt diet produced higher levels of proteins involved in iron acquisition and oxidative-stress resistance. Several of these changes were attributable to a nonsynonymous mutation in fur (fur-R88H). Further experiments indicated that this mutation conferred increased resistance to high-salt conditions and oxidative stress. We propose a model in which a high-salt diet leads to high levels of gastric inflammation and associated oxidative stress in H. pylori-infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection of H. pylori strains that are most fit for growth in this environment.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
0 Communities
3 Members
0 Resources
21 MeSH Terms
Modification of Helicobacter pylori Peptidoglycan Enhances NOD1 Activation and Promotes Cancer of the Stomach.
Suarez G, Romero-Gallo J, Piazuelo MB, Wang G, Maier RJ, Forsberg LS, Azadi P, Gomez MA, Correa P, Peek RM
(2015) Cancer Res 75: 1749-59
MeSH Terms: Acetylation, Acetyltransferases, Adenocarcinoma, Aged, Amidohydrolases, Animals, Bacterial Proteins, Cell Transformation, Neoplastic, Cells, Cultured, Female, Gastritis, Gene Silencing, Gerbillinae, HEK293 Cells, Helicobacter pylori, Host-Pathogen Interactions, Humans, Male, Middle Aged, Nod1 Signaling Adaptor Protein, Organisms, Genetically Modified, Peptidoglycan, Stomach Neoplasms
Show Abstract · Added February 5, 2016
Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric carcinogenesis. One cancer-linked locus is the cag pathogenicity island, which translocates components of peptidoglycan into host cells. NOD1 is an intracellular immune receptor that senses peptidoglycan from Gram-negative bacteria and responds by inducing autophagy and activating NF-κB, leading to inflammation-mediated bacterial clearance; however chronic pathogens can evade NOD1-mediated clearance by altering peptidoglycan structure. We previously demonstrated that the H. pylori cag(+) strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. Using 2D-DIGE and mass spectrometry, we identified a novel mutation within the gene encoding the peptidoglycan deacetylase PgdA; therefore, we sought to define the role of H. pylori PgdA in NOD1-dependent activation of NF-κB, inflammation, and cancer. Coculture of H. pylori strain 7.13 or its pgdA(-) isogenic mutant with AGS gastric epithelial cells or HEK293 epithelial cells expressing a NF-κB reporter revealed that pgdA inactivation significantly decreased NOD1-dependent NF-κB activation and autophagy. Infection of Mongolian gerbils with an H. pylori pgdA(-) mutant strain led to significantly decreased levels of inflammation and malignant lesions in the stomach; however, preactivation of NOD1 before bacterial challenge reciprocally suppressed inflammation and cancer in response to wild-type H. pylori. Expression of NOD1 differs in human gastric cancer specimens compared with noncancer samples harvested from the same patients. These results indicate that peptidoglycan deacetylation plays an important role in modulating host inflammatory responses to H. pylori, allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche.
©2015 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
23 MeSH Terms
Helicobacter pylori bacteria alter the p53 stress response via ERK-HDM2 pathway.
Bhardwaj V, Noto JM, Wei J, Andl C, El-Rifai W, Peek RM, Zaika AI
(2015) Oncotarget 6: 1531-43
MeSH Terms: Animals, Cell Line, Tumor, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, MAP Kinase Signaling System, Proto-Oncogene Proteins c-mdm2, Stomach Neoplasms, Transfection, Tumor Suppressor Protein p53
Show Abstract · Added February 19, 2015
H. pylori infection is the strongest known risk factor for gastric cancer. Inhibition of host tumor suppressor mechanisms by the bacteria underlies the development of this disease. Among the tumor suppressors affected by H. pylori are p53 and E-cadherin, which inhibition has been shown to increase the risk of gastric cancer. In this report, we investigated the interaction between E-cadherin and p53 in H. pylori-infected cells. We found that downregulation of E-cadherin leads to cellular stress and activation of p53. In the setting of H. pylori infection, this mechanism, however, is disrupted. We found that although co-culture of gastric epithelial cells with H. pylori led to downregulation of E-cadherin and cellular stress, it resulted in inhibition of p53, which is mediated by intracellular Erk kinases and HDM2 protein induced by H. pylori. Experimental inhibition of HDM2/p53 interactions restored p53 activity, and decreased survival of infected cells. Collectively, our results revealed that regulation of p53 and E-cadherin is tightly linked through the p53 stress response mechanism that is inhibited by H. pylori via activation of Erk1/2-HDM2-p53 pathway leading to survival of damaged cells. This might be advantageous to the bacteria but may increase the cancer risk.
0 Communities
5 Members
0 Resources
11 MeSH Terms
Regulation of Helicobacter pylori Virulence Within the Context of Iron Deficiency.
Noto JM, Lee JY, Gaddy JA, Cover TL, Amieva MR, Peek RM
(2015) J Infect Dis 211: 1790-4
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Gene Knockout Techniques, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Interleukin-8, Iron, Stomach, Virulence
Show Abstract · Added January 20, 2015
Helicobacter pylori strains that harbor the oncoprotein CagA increase gastric cancer risk, and this risk is augmented under iron-deficient conditions. We demonstrate here that iron depletion induces coccoid morphology in strains lacking cagA. To evaluate the stability of augmented H. pylori virulence phenotypes stimulated by low-iron conditions, H. pylori isolated from iron-depleted conditions in vivo were serially passaged in vitro. Long-term passage decreased the ability of hypervirulent strains to translocate CagA or induce interleukin 8, indicating that hypervirulent phenotypes stimulated by low-level iron conditions are reversible. Therefore, rectifying iron deficiency may attenuate disease among H. pylori-infected persons with no response to antibiotics.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
0 Communities
4 Members
0 Resources
11 MeSH Terms
Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase.
Chaturvedi R, de Sablet T, Asim M, Piazuelo MB, Barry DP, Verriere TG, Sierra JC, Hardbower DM, Delgado AG, Schneider BG, Israel DA, Romero-Gallo J, Nagy TA, Morgan DR, Murray-Stewart T, Bravo LE, Peek RM, Fox JG, Woster PM, Casero RA, Correa P, Wilson KT
(2015) Oncogene 34: 3429-40
MeSH Terms: Adenocarcinoma, Adult, Animals, Cells, Cultured, Colombia, DNA Damage, Enzyme Induction, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Hydrogen Peroxide, Male, Middle Aged, Oxidative Stress, Oxidoreductases Acting on CH-NH Group Donors, Risk Factors, Stomach Neoplasms
Show Abstract · Added January 20, 2015
Helicobacter pylori infection causes gastric cancer, the third leading cause of cancer death worldwide. More than half of the world's population is infected, making universal eradication impractical. Clinical trials suggest that antibiotic treatment only reduces gastric cancer risk in patients with non-atrophic gastritis (NAG), and is ineffective once preneoplastic lesions of multifocal atrophic gastritis (MAG) and intestinal metaplasia (IM) have occurred. Therefore, additional strategies for risk stratification and chemoprevention of gastric cancer are needed. We have implicated polyamines, generated by the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric carcinogenesis. During H. pylori infection, the enzyme spermine oxidase (SMOX) is induced, which generates hydrogen peroxide from the catabolism of the polyamine spermine. Herein, we assessed the role of SMOX in the increased gastric cancer risk in Colombia associated with the Andean mountain region when compared with the low-risk region on the Pacific coast. When cocultured with gastric epithelial cells, clinical strains of H. pylori from the high-risk region induced more SMOX expression and oxidative DNA damage, and less apoptosis than low-risk strains. These findings were not attributable to differences in the cytotoxin-associated gene A oncoprotein. Gastric tissues from subjects from the high-risk region exhibited greater levels of SMOX and oxidative DNA damage by immunohistochemistry and flow cytometry, and this occurred in NAG, MAG and IM. In Mongolian gerbils, a prototype colonizing strain from the high-risk region induced more SMOX, DNA damage, dysplasia and adenocarcinoma than a colonizing strain from the low-risk region. Treatment of gerbils with either α-difluoromethylornithine, an inhibitor of ODC, or MDL 72527 (N(1),N(4)-Di(buta-2,3-dien-1-yl)butane-1,4-diamine dihydrochloride), an inhibitor of SMOX, reduced gastric dysplasia and carcinoma, as well as apoptosis-resistant cells with DNA damage. These data indicate that aberrant activation of polyamine-driven oxidative stress is a marker of gastric cancer risk and a target for chemoprevention.
0 Communities
6 Members
0 Resources
18 MeSH Terms
High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis.
Gaddy JA, Radin JN, Loh JT, Zhang F, Washington MK, Peek RM, Algood HM, Cover TL
(2013) Infect Immun 81: 2258-67
MeSH Terms: Achlorhydria, Adenocarcinoma, Animals, Antigens, Bacterial, Bacterial Proteins, Gastric Mucosa, Gene Expression Regulation, Gerbillinae, H(+)-K(+)-Exchanging ATPase, Helicobacter Infections, Helicobacter pylori, Humans, Hydrogen-Ion Concentration, Inflammation, Interleukin-1beta, Male, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Sodium Chloride, Dietary, Stomach, Stomach Neoplasms
Show Abstract · Added January 13, 2014
Persistent colonization of the human stomach with Helicobacter pylori is a risk factor for gastric adenocarcinoma, and H. pylori-induced carcinogenesis is dependent on the actions of a bacterial oncoprotein known as CagA. Epidemiological studies have shown that high dietary salt intake is also a risk factor for gastric cancer. To investigate the effects of a high-salt diet, we infected Mongolian gerbils with a wild-type (WT) cagA(+) H. pylori strain or an isogenic cagA mutant strain and maintained the animals on a regular diet or a high-salt diet. At 4 months postinfection, gastric adenocarcinoma was detected in 100% of the WT-infected/high-salt-diet animals, 58% of WT-infected/regular-diet animals, and none of the animals infected with the cagA mutant strain (P < 0.0001). Among animals infected with the WT strain, those fed a high-salt diet had more severe gastric inflammation, higher gastric pH, increased parietal cell loss, increased gastric expression of interleukin 1β (IL-1β), and decreased gastric expression of hepcidin and hydrogen potassium ATPase (H,K-ATPase) compared to those on a regular diet. Previous studies have detected upregulation of CagA synthesis in response to increased salt concentrations in the bacterial culture medium, and, concordant with the in vitro results, we detected increased cagA transcription in vivo in animals fed a high-salt diet compared to those on a regular diet. Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA(+) H. pylori strains.
1 Communities
6 Members
0 Resources
21 MeSH Terms
Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans.
Noto JM, Gaddy JA, Lee JY, Piazuelo MB, Friedman DB, Colvin DC, Romero-Gallo J, Suarez G, Loh J, Slaughter JC, Tan S, Morgan DR, Wilson KT, Bravo LE, Correa P, Cover TL, Amieva MR, Peek RM
(2013) J Clin Invest 123: 479-92
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Bacterial Secretion Systems, Cell Transformation, Neoplastic, Female, Ferritins, Genomic Islands, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Iron, Male, Risk Factors, Stomach Neoplasms
Show Abstract · Added January 13, 2014
Gastric adenocarcinoma is strongly associated with Helicobacter pylori infection; however, most infected persons never develop this malignancy. H. pylori strains harboring the cag pathogenicity island (cag+), which encodes CagA and a type IV secretion system (T4SS), induce more severe disease outcomes. H. pylori infection is also associated with iron deficiency, which similarly augments gastric cancer risk. To define the influence of iron deficiency on microbial virulence in gastric carcinogenesis, Mongolian gerbils were maintained on iron-depleted diets and infected with an oncogenic H. pylori cag+ strain. Iron depletion accelerated the development of H. pylori-induced premalignant and malignant lesions in a cagA-dependent manner. H. pylori strains harvested from iron-depleted gerbils or grown under iron-limiting conditions exhibited enhanced virulence and induction of inflammatory factors. Further, in a human population at high risk for gastric cancer, H. pylori strains isolated from patients with the lowest ferritin levels induced more robust proinflammatory responses compared with strains isolated from patients with the highest ferritin levels, irrespective of histologic status. These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer.
1 Communities
8 Members
0 Resources
16 MeSH Terms
Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses.
Wei J, Noto J, Zaika E, Romero-Gallo J, Correa P, El-Rifai W, Peek RM, Zaika A
(2012) Proc Natl Acad Sci U S A 109: E2543-50
MeSH Terms: Animals, Cell Line, Tumor, Cell Survival, Coculture Techniques, Gene Expression Profiling, Gene Expression Regulation, Gerbillinae, Helicobacter pylori, Humans, NF-kappa B, Protein Isoforms, Transcription Factor AP-1, Transcriptional Activation, Tumor Suppressor Protein p53
Show Abstract · Added September 3, 2013
The p53 protein plays a central role in the prevention of tumorigenesis. Cellular stresses, such as DNA damage and aberrant oncogene activation, trigger induction of p53 that halts cellular proliferation and allows cells to be repaired. If cellular damage is beyond the capability of the repair mechanisms, p53 induces apoptosis or cell cycle arrest, preventing damaged cells from becoming cancerous. However, emerging evidence suggests that the function of p53 needs to be considered as isoform-specific. Here, we report that the expression profile of p53 can be shifted toward inhibitory p53 isoforms by the pathogenic bacterium Helicobacter pylori, which is known for its strong association with gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. We found that interaction of H. pylori with gastric epithelial cells, mediated via the cag pathogenicity island, induces N-terminally truncated Δ133p53 and Δ160p53 isoforms in human cells. Induction of an orthologous p53 isoform, Δ153p53, was also found in H. pylori-infected Mongolian gerbils. The p53 isoforms inhibit p53 and p73 activities, induce NF-κB, and increase survival of infected cells. Expression of Δ133p53, in response to H. pylori infection, is regulated by phosphorylation of c-Jun and activation of activator protein-1-dependent transcription. Together, these results provide unique insights into the regulation of p53 protein and may contribute to the understanding of tumorigenesis associated with H. pylori.
0 Communities
6 Members
0 Resources
14 MeSH Terms
Spermine oxidase, a polyamine catabolic enzyme that links Helicobacter pylori CagA and gastric cancer risk.
Chaturvedi R, de Sablet T, Peek RM, Wilson KT
(2012) Gut Microbes 3: 48-56
MeSH Terms: Animals, Antigens, Bacterial, Apoptosis, Bacterial Proteins, DNA Damage, Epithelial Cells, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Hydrogen Peroxide, Mice, Oxidoreductases Acting on CH-NH Group Donors, Spermine, Stomach Neoplasms, Virulence Factors
Show Abstract · Added September 3, 2013
We have recently reported that Helicobacter pylori strains expressing the virulence factor cytotoxin-associated gene A (CagA) stimulate increased levels of spermine oxidase (SMO) in gastric epithelial cells, while cagA⁻ strains did not. SMO catabolizes the polyamine spermine and produces H₂O₂ that results in both apoptosis and DNA damage. Exogenous overexpression of CagA confirmed these findings, and knockdown or inhibition of SMO blocked CagA-mediated apoptosis and DNA damage. The strong association of SMO, apoptosis, and DNA damage was also demonstrated in humans infected with cagA⁺, but not cagA⁻ strains. In infected gerbils and mice, DNA damage was CagA-dependent and only present in epithelial cells that expressed SMO. We also discovered SMO (high) gastric epithelial cells from infected animals with dysplasia that are resistant to apoptosis despite high levels of DNA damage. Inhibition of polyamine synthesis or SMO could abrogate the development of this cell population that may represent precursors for neoplastic transformation.
0 Communities
4 Members
0 Resources
16 MeSH Terms
An essential role for modulation of hyperpolarization-activated current in the development of binaural temporal precision.
Khurana S, Liu Z, Lewis AS, Rosa K, Chetkovich D, Golding NL
(2012) J Neurosci 32: 2814-23
MeSH Terms: Age Factors, Analysis of Variance, Androstadienes, Animals, Biophysical Phenomena, Bucladesine, Colforsin, Cyclic Nucleotide-Gated Cation Channels, Electric Stimulation, Enzyme Inhibitors, Female, Gene Expression Regulation, Developmental, Gerbillinae, Imidazoles, In Vitro Techniques, Ion Channel Gating, Male, Neurons, Olivary Nucleus, Patch-Clamp Techniques, Pyridines, Pyrimidines, Wortmannin
Show Abstract · Added April 2, 2019
In sensory circuits of the brain, developmental changes in the expression and modulation of voltage-gated ion channels are a common occurrence, but such changes are often difficult to assign to clear functional roles. We have explored this issue in the binaural neurons of the medial superior olive (MSO), whose temporal precision in detecting the coincidence of binaural inputs dictates the resolution of azimuthal sound localization. We show that in MSO principal neurons of gerbils during the first week of hearing, a hyperpolarization-activated current (I(h)) progressively undergoes a 13-fold increase in maximal conductance, a >10-fold acceleration of kinetics, and, most surprisingly, a 30 mV depolarizing shift in the voltage dependence of activation. This period is associated with an upregulation of the hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel subunits HCN1, HCN2, and HCN4 in the MSO, but only HCN1 and HCN4 were expressed strongly in principal neurons. I(h) recorded in nucleated patches from electrophysiologically mature MSO neurons (>P18) exhibited kinetics and an activation range nearly identical to the I(h) found in whole-cell recordings before hearing onset. These results indicate that the developmental changes in I(h) in MSO neurons can be explained predominantly by modulation from diffusible intracellular factors, and not changes in channel subunit composition. The exceptionally large modulatory changes in I(h), together with refinements in synaptic properties transform the coding strategy from one of summation and integration to the submillisecond coincidence detection known to be required for transmission of sound localization cues.
0 Communities
1 Members
0 Resources
MeSH Terms