scholarly journals Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses

2012 ◽  
Vol 109 (38) ◽  
pp. E2543-E2550 ◽  
Author(s):  
Jinxiong Wei ◽  
Jennifer Noto ◽  
Elena Zaika ◽  
Judith Romero-Gallo ◽  
Pelayo Correa ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Expression Profile ◽  
P53 Protein ◽  
Pathogenic Bacterium ◽  
Protein Isoforms ◽  
Cellular Damage ◽  
Mongolian Gerbils ◽  
Cellular Stresses ◽  
H Pylori ◽  
P53 Isoforms

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 ∆133p53 and ∆160p53 isoforms in human cells. Induction of an orthologous p53 isoform, ∆153p53, 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 ∆133p53, 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.

scholarly journals Multiple in vivo passages enhance the ability of a clinical Helicobacter pylori isolate to colonize the stomach of Mongolian gerbils and to induce gastritis

2005 ◽  
Vol 39 (2) ◽  
pp. 221-229 ◽  
Author(s):  
A Bleich ◽  
I Köhn ◽  
S Glage ◽  
W Beil ◽  
S Wagner ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Bacterial Colonization ◽  
Underlying Mechanism ◽  
Mongolian Gerbils ◽  
Histopathological Changes ◽  
Genetic Changes ◽  
Colonization Ability ◽  
Colonization Factors ◽  
H Pylori

The Mongolian gerbil is an excellent animal model for Helicobacter pylori-induced gastritis in humans. In this study, initially low colonization rates of the H. pylori strains ATCC 43504, SS1, or HP87 inoculated into gerbils caused difficulties in establishing this model. In order to increase the colonization ability and pathogenicity, the clinical HP87 isolate was selected for adaptation to the gerbil stomach by multiple in vivo passages through gerbils. Development of gastritis was examined histologically at 4–52 weeks after infection. The proportion of gerbils which tested positive for H. pylori by culture at four weeks after inoculation gradually increased from 11.1% of gerbils inoculated with HP87 without prior in vivo passage (P0) to 100% of gerbils inoculated with HP87 with seven in vivo passages (P7). In addition, adaptation of HP87 resulted in more severe histopathological changes. Gerbils infected with adapted HP87 (P7) exhibited severe infiltration by monomorphonuclear and polymorphonuclear leukocytes in the mucosa, submucosa, and subserosa of the gastric antrum, as well as epithelial changes consisting of hyperplasia, erosion, and ulceration. Histopathological changes increased in severity from four to 52 weeks after infection. Adaptation of HP87 during its passages through gerbils could be due to genetic changes in bacterial colonization factors. Identification of these changes might be useful to understand the underlying mechanism of gastric adaptation and pathogenesis of H. pylori.

scholarly journals Mucoadhesive Microspheres Containing Amoxicillin for Clearance of Helicobacter pylori

1998 ◽  
Vol 42 (10) ◽  
pp. 2492-2494 ◽  
Author(s):  
Naoki Nagahara ◽  
Yohko Akiyama ◽  
Masafumi Nakao ◽  
Mayumi Tada ◽  
Megumi Kitano ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastrointestinal Tract ◽  
Oral Administration ◽  
Antimicrobial Agent ◽  
Extended Period ◽  
Mongolian Gerbils ◽  
Polymer Powder ◽  
Hydrogenated Castor Oil ◽  
H Pylori

ABSTRACT In an effort to augment the anti-Helicobacter pylorieffect of amoxicillin, mucoadhesive microspheres, which have the ability to reside in the gastrointestinal tract for an extended period, were prepared. The microspheres contained the antimicrobial agent and an adhesive polymer (carboxyvinyl polymer) powder dispersed in waxy hydrogenated castor oil. The percentage of amoxicillin remaining in the stomach both 2 and 4 h after oral administration of the mucoadhesive microspheres to Mongolian gerbils under fed conditions was about three times higher than that after administration in the form of a 0.5% methylcellulose suspension. The in vivo clearance ofH. pylori following oral administration of the mucoadhesive microspheres and the 0.5% methylcellulose suspension to infected Mongolian gerbils was examined under fed conditions. The mucoadhesive microspheres and the 0.5% methylcellulose suspension both showed anti-H. pylori effects in this experimental model of infection, but the required dose of amoxicillin was effectively reduced by a factor of 10 when the mucoadhesive microspheres were used. In conclusion, the mucoadhesive microspheres more effectively cleared H. pylori from the gastrointestinal tract than the 0.5% methylcellulose suspension due to the prolonged gastrointestinal residence time resulting from mucoadhesion. A dosage form consisting of mucoadhesive microspheres containing an appropriate antimicrobial agent should be useful for the eradication of H. pylori.

scholarly journals Targeting cellular senescence in cancer and aging: roles of p53 and its isoforms

2020 ◽  
Vol 41 (8) ◽  
pp. 1017-1029 ◽  
Author(s):  
Jessica Beck ◽  
Casmir Turnquist ◽  
Izumi Horikawa ◽  
Curtis Harris
Keyword(s):  
Cellular Senescence ◽  
Therapeutic Potential ◽  
P53 Protein ◽  
Tp53 Gene ◽  
Suppressor Gene ◽  
Cellular Reprogramming ◽  
Protein Isoforms ◽  
Age Related ◽  
Alternative Mrna Splicing ◽  
P53 Isoforms

Abstract Cellular senescence and the associated secretory phenotype (SASP) promote disease in the aged population. Targeting senescent cells by means of removal, modulation of SASP or through cellular reprogramming represents a novel therapeutic avenue for treating cancer- and age-related diseases such as neurodegeneration, pulmonary fibrosis and renal disease. Cellular senescence is partly regulated by the TP53 gene, a critical tumor suppressor gene which encodes 12 or more p53 protein isoforms. This review marks a significant milestone of 40 years of Carcinogenesis publication history and p53 research and 15 years of p53 isoform research. The p53 isoforms are produced through initiation at alternative transcriptional and translational start sites and alternative mRNA splicing. These truncated p53 isoform proteins are endogenously expressed in normal human cells and maintain important functional roles, including modulation of full-length p53-mediated cellular senescence, apoptosis and DNA repair. In this review, we discuss the mechanisms and functions of cellular senescence and SASP in health and disease, the regulation of cellular senescence by p53 isoforms, and the therapeutic potential of targeting cellular senescence to treat cancer- and age-associated diseases.

scholarly journals Helicobacter pylori AdaptationIn Vivoin Response to a High-Salt Diet

2015 ◽  
Vol 83 (12) ◽  
pp. 4871-4883 ◽  
Author(s):  
John T. Loh ◽  
Jennifer A. Gaddy ◽  
Holly M. Scott Algood ◽  
Silvana Gaudieri ◽  
Simon Mallal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Helicobacter Pylori ◽  
High Salt ◽  
Mongolian Gerbils ◽  
High Salt Diet ◽  
Salt Diet ◽  
Content Type ◽  
Regular Diet ◽  
H Pylori ◽  
And Oxidative Stress

Helicobacter pyloriexhibits a high level of intraspecies genetic diversity. In this study, we investigated whether the diversification ofH. pyloriis influenced by the composition of the diet. Specifically, we investigated the effect of a high-salt diet (a known risk factor for gastric adenocarcinoma) onH. pyloridiversification within a host. We analyzedH. pyloristrains 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 infur(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 inH. pylori-infected animals and that these conditions, along with the high intraluminal concentrations of sodium chloride, lead to selection ofH. pyloristrains that are most fit for growth in this environment.

scholarly journals Colonization and Inflammation Deficiencies in Mongolian Gerbils Infected by Helicobacter pylori Chemotaxis Mutants

2005 ◽  
Vol 73 (3) ◽  
pp. 1820-1827 ◽  
Author(s):  
David J. McGee ◽  
Melanie L. Langford ◽  
Emily L. Watson ◽  
J. Elliot Carter ◽  
Yu-Ting Chen ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Immune Cell ◽  
Response Regulator ◽  
Critical Role ◽  
Mongolian Gerbils ◽  
Wild Type ◽  
In The Wild ◽  
H Pylori

ABSTRACT Helicobacter pylori causes disease in the human stomach and in mouse and gerbil stomach models. Previous results have shown that motility is critical for H. pylori to colonize mice, gerbils, and other animal models. The role of chemotaxis, however, in colonization and disease is less well understood. Two genes in the H. pylori chemotaxis pathway, cheY and tlpB, which encode the chemotaxis response regulator and a methyl-accepting chemoreceptor, respectively, were disrupted. The cheY mutation was complemented with a wild-type copy of cheY inserted into the chromosomal rdxA gene. The cheY mutant lost chemotaxis but retained motility, while all other strains were motile and chemotactic in vitro. These strains were inoculated into gerbils either alone or in combination with the wild-type strain, and colonization and inflammation were assessed. While the cheY mutant completely failed to colonize gerbil stomachs, the tlpB mutant colonized at levels similar to those of the wild type. With the tlpB mutant, there was a substantial decrease in inflammation in the gerbil stomach compared to that with the wild type. Furthermore, there were differences in the numbers of each immune cell in the tlpB-mutant-infected stomach: the ratio of lymphocytes to neutrophils was about 8 to 1 in the wild type but only about 1 to 1 in the mutant. These results suggest that the TlpB chemoreceptor plays an important role in the inflammatory response while the CheY chemotaxis regulator plays a critical role in initial colonization. Chemotaxis mutants may provide new insights into the steps involved in H. pylori pathogenesis.

scholarly journals Functional association between the Helicobacter pylori virulence factors VacA and CagA

2008 ◽  
Vol 57 (2) ◽  
pp. 145-150 ◽  
Author(s):  
Richard H. Argent ◽  
Rachael J. Thomas ◽  
Darren P. Letley ◽  
Michael G. Rittig ◽  
Kim R. Hardie ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Epithelial Cells ◽  
Virulence Factors ◽  
Cellular Damage ◽  
Gastric Epithelial Cells ◽  
Wild Type ◽  
Functional Association ◽  
H Pylori ◽  
Vacuolated Cells ◽  
Type Strains

The Helicobacter pylori virulence factors CagA and VacA are implicated in the development of gastroduodenal diseases. Most strains possessing CagA also possess the more virulent vacuolating form of VacA. This study assessed the significance of possession of both virulence factors in terms of their effect on gastric epithelial cells, using a set of minimally passaged, isogenic VacA, CagA and CagE mutants in H. pylori strains 60190 and 84-183. The cagA and cagE mutants were found to significantly increase VacA-induced vacuolation of epithelial cells, and the vacA mutants significantly increased CagA-induced cellular elongations, compared with wild-type strains, indicating that CagA reduces vacuolation and VacA reduces hummingbird formation. Although epithelial cells incubated with the wild-type H. pylori strains may display both vacuolation and hummingbird formation, it was found that (i) hummingbird length was significantly reduced in vacuolated cells compared with those without vacuolation; (ii) the number of vacuoles was significantly reduced in vacuolated cells with hummingbird formation compared with those without hummingbirds; and (iii) cells displaying extensive vacuolation did not subsequently form hummingbirds and vice versa. VacA did not affect the phosphorylation of CagA. These data show that VacA and CagA downregulate each other's effects on epithelial cells, potentially allowing H. pylori interaction with cells whilst avoiding excessive cellular damage.

scholarly journals Natural History of Gastric Mucosal Cytokine Expression in Helicobacter pylori Gastritis in Mongolian Gerbils

2005 ◽  
Vol 73 (4) ◽  
pp. 2205-2212 ◽  
Author(s):  
Yoshio Yamaoka ◽  
Kazuyoshi Yamauchi ◽  
Hiroyoshi Ota ◽  
Atsushi Sugiyama ◽  
Satoshi Ishizone ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Ulcers ◽  
Mongolian Gerbils ◽  
Mrna Levels ◽  
Hyperplastic Polyps ◽  
Fundic Mucosa ◽  
Reverse Transcription Pcr ◽  
Pyloric Mucosa ◽  
Ifn Γ ◽  
H Pylori

ABSTRACT Data regarding the chronological changes in gastric mucosal cytokines in the different phases of Helicobacter pylori infection are unavailable. We examined Mongolian gerbils for up to 52 weeks after H. pylori (ATCC 43504) inoculation. Levels of mRNAs of mucosal cytokines (interleukin-1β [IL-1β], gamma interferon [IFN-γ], IL-4, IL-6, and IL-10) were assessed using real-time reverse transcription-PCR. Starting 26 weeks after H. pylori inoculation, two clinicohistologic patterns appeared: gastric ulcers in 32% and hyperplastic polyps in 68% of gerbils. High levels of mucosal IL-1β mRNA were observed early in the infection, reaching maximum at 4 weeks and then rapidly declining. Mucosal IFN-γ mRNA also reached maximal levels at 4 weeks but remained high thereafter. Both IL-1β and IFN-γ mRNA levels were consistently higher in the pyloric mucosa than in the fundic mucosa. In contrast, IL-4, IL-6, and IL-10 mRNA levels peaked at 8 to 26 weeks and levels were similar in the pyloric mucosa and the fundic mucosa. IFN-γ mRNA levels were significantly higher in gerbils with ulcers than in those with hyperplastic polyps (median IFN-γ/glyceraldehyde-3-phosphate dehydrogenase ratio × 100,000 = 650 versus 338, respectively [antrum], and 172 versus 40, respectively [corpus]) (P < 0.05). We propose that the different outcomes (e.g., ulcers or hyperplastic polyps) might relate to imbalances among cytokines.

scholarly journals Detection and variability analyses of CRISPR-like loci in the H. pylori genome

2018 ◽  
Author(s):  
Jerson Alexander Garcia-Zea ◽  
Roberto de la Herrán ◽  
Francisca Robles Rodríguez ◽  
Rafael Navajas-Pérez ◽  
Carmelo Ruiz Rejón
Keyword(s):  
Helicobacter Pylori ◽  
Geographical Area ◽  
Pathogenic Bacterium ◽  
Gene Location ◽  
Phylogenetic Marker ◽  
Genomic Plasticity ◽  
Human Pathogenic Bacterium ◽  
H Pylori ◽  
Different Strains ◽  
Genomic Locations

Helicobacter pylori is a human pathogenic bacterium with a high genomic plasticity. Although the functional CRISPR-Cas system has not been found in its genome, CRISPR like loci have been recently identified. In this work, 53 genomes from different geographical areas are analyzed for the search and analysis of variability of this type of structure. We confirm the presence of a locus that was previously described in the VlpC gene in al lgenomes, and we characterize new CRISPR-like loci in other genomic locations. By studying the variability and gene location of these loci, the evolution and the possible roles of these sequences are discussed. Additionally, the usefulness of this type of sequences as a phylogenetic marker has been demonstrated, associating the different strains by geographical area.

Anti-Helicobacter pylori (H. pylori) urease immunoglobulin Y (IgY)-containing egg yolk prevented H. pylori colonization in mongolian gerbils

2003 ◽  
Vol 124 (4) ◽  
pp. A12
Author(s):  
Sachiko Nomura ◽  
Hidekazu Suzuki ◽  
Tatsuhiro Masaoka ◽  
Kumiko Kurabayashi ◽  
Yuriko Minegishi ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Egg Yolk ◽  
Mongolian Gerbils ◽  
Immunoglobulin Y ◽  
H Pylori

scholarly journals Virulence Factors of Helicobacter pylori Responsible for Gastric Diseases in Mongolian Gerbil

2000 ◽  
Vol 192 (11) ◽  
pp. 1601-1610 ◽  
Author(s):  
Keiji Ogura ◽  
Shin Maeda ◽  
Masafumi Nakao ◽  
Takeshi Watanabe ◽  
Mayumi Tada ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Ulcer ◽  
Secretion System ◽  
Mongolian Gerbils ◽  
Wild Type ◽  
Gastric Diseases ◽  
Type Iv ◽  
H Pylori ◽  
Isogenic Mutants

Helicobacter pylori infection induces various gastroduodenal diseases. We examined the role of two genes, vacA and cagE, in the gastric pathogenesis induced by H. pylori using a long-term (62 wk) animal model. Reportedly, both genes are associated with the virulence of H. pylori: vacA encodes vacuolating cytotoxin, and cagE, with other genes in the cag pathogenicity islands, encodes a type IV secretion system. Mongolian gerbils were challenged in this study by a wild-type TN2 strain and its isogenic mutants of cagE or vacA. The wild-type and vacA mutants induced severe gastritis, whereas cagE mutants induced far milder changes. Gastric ulcer was induced at the highest rate (22/23) by the wild-type TN2, followed by the vacA mutant (19/28). No ulcer was found in the gerbils infected with the cagE mutant (0/27) or in controls (0/27). Intestinal metaplasia was also found in the gerbils infected with the wild-type (14/23) or vacA mutant (15/28). Gastric cancer developed in one gerbil with wild-type infection and in one with vacA mutant infection. In conclusion, the knocking out of the cagE gene deprived wild-type H. pylori of the pathogenicity for gastritis and gastric ulcer, suggesting that the secretion system encoded by cag pathogenicity island genes plays an essential role.

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