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Biochemical and Biophysical Characterization of the Enolase from Helicobacter pylori.
López-López, MJ, Rodríguez-Luna, IC, Lara-Ramírez, EE, López-Hidalgo, M, Benítez-Cardoza, CG, Guo, X
BioMed research international. 2018;:9538193
Abstract
Enolase, which catalyses the conversion of 2-phospho-D-glycerate to phosphoenolpyruvate, is an important enzyme in the classic glycolysis pathway in cells. Enolase is highly conserved in organisms from bacteria to humans, indicating its importance in cells. Thus, enolase is a good target for developing new drugs. In the last decade, new functions of this enzyme have been found. Helicobacter pylori is a common human pathogen that causes gastric diseases and even gastric cancer. In this study, the sequence of H. pylori enolase (HpEno) was analysed; the conservation (at least partial) of binding sites for cofactor, plasminogen, and host extracellular RNA, as well as catalytic site, indicates that HpEno should be capable of performing the functions. Recombinant HpEno was overexpressed and purified from E. coli. Compared to the enolases from other species, HpEno had similar characteristics for its secondary structure. The temperature-induced profiles indicate that HpEno is quite stable to temperature, compared to other homologs. Regarding the kinetics of the unfolding reaction, we found that the activation enthalpy associated with the thermal unfolding reaction is equivalent to the reported activation enthalpy for yeast enolase, indicating a similar scaffold and kinetic stability. Although a wide range of experimental conditions were assayed, it was not possible to detect any enzymatic activity of HpEno. To prove the lack of activity, still a much wider range of experiments should be carried out.
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Helicobacter pylori and extragastric diseases.
Ražuka-Ebela, D, Giupponi, B, Franceschi, F
Helicobacter. 2018;:e12520
Abstract
Many studies have been performed in the last year concerning the potential role of Helicobacter pylori in different extragastric diseases, reinforcing the idea that specific microorganisms may cause diseases even far from the primary site of infection. While the role of H. pylori on idiopathic thrombocytopenic purpura, sideropenic anemia, and vitamin B12 deficiency has been well established, there is a growing interest in other conditions, such as cardiovascular, neurologic, dermatologic, obstetric, immunologic, and metabolic diseases. Concerning neurologic diseases, there is a great interest in cognitive impairment and neurodegeneration. The aim of this review was to summarize the results of the most relevant studies published over the last year on this fascinating topic.
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H. pylori infection and extra-gastroduodenal diseases.
Tsay, FW, Hsu, PI
Journal of biomedical science. 2018;(1):65
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Abstract
Helicobacter pylori infection is the principal cause of peptic ulcer disease, gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue lymphoma. Recent studies have shown that it may interfere with many biological processes and determine or influence the occurrence of many diseases outside the stomach. Currently, the role of H. pylori in idiopathic thrombocytopenic purpura and iron deficiency anemia is well documented. Emerging evidence suggests that it may also contribute to vitamin B12 deficiency, insulin resistance, metabolic syndrome, diabetes mellitus and non-alcoholic liver disease. Additionally, it may increase the risk of acute coronary syndrome, cerebrovascular disease, neurodegenerative disease and other miscellaneous disorders. Different pathogenic mechanisms have been hypothesized, including the occurrence of molecular mimicry and the induction of a low-grade inflammation. This review summarizes the results of the most relevant studies on the extra-gastroduodenal manifestations of H. pylori infection.
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Safety of first-line triple therapy with a potassium-competitive acid blocker for Helicobacter pylori eradication in children.
Kusano, C, Gotoda, T, Suzuki, S, Ikehara, H, Moriyama, M
Journal of gastroenterology. 2018;(6):718-724
Abstract
BACKGROUND Helicobacter pylori infection is a risk factor for gastric cancer, and it has been reported that eradication of H. pylori is effective for preventing such cancer. Recently, H. pylori eradication has been performed in children as first-line therapy against gastric cancer. Here, we report use of triple therapy with a potassium-competitive acid blocker (P-CAB) for H. pylori eradication in children. METHODS H. pylori infection testing and eradication therapy began in fiscal year 2015 in junior high school students located in Yurihonjo city and Nikaho city, Akita prefecture, Japan. Urine-based immunochromatography, stool antigen enzyme-linked immunosorbent assay tests, and serum antibody tests were performed as the initial screening examination. Those who tested positive on one of the three examinations then underwent a urea breath test (13C-UBT). Those who tested positive on 13C-UBT and expressed the desire to undergo H. pylori eradication then received eradication therapy comprising 20 mg P-CAB, 750 mg amoxicillin, and 200 mg clarithromycin twice a day for 7 days. At least 8 weeks after treatment, eradication success was evaluated using 13C-UBT. RESULTS A total of 118 students received eradication therapy. Eradication rates were 81.3% (95% confidence interval: 74.3-88.4, 96/118) in ITT analysis and 85.7% (95% confidence interval: 79.1-92.9 96/112) in PP analysis. Adverse effects associated with eradication therapy were observed in 25 of 118 subjects (21.1%), seven of whom required hospital treatment (rash in five, vomiting in two). All seven subjects either discontinued therapy or were administered anti-allergy drugs, which resulted in swift alleviation of symptoms. CONCLUSIONS First-line triple therapy with a P-CAB for H. pylori eradication in children was found to be safe.
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Biological properties and pathogenicity factors of Helicobacter pylori.
Isaeva, GS, Fagoonee, S
Minerva gastroenterologica e dietologica. 2018;(3):255-266
Abstract
The unexpected discovery of Helicobacter pylori (H. pylori) has revolutionised the history of microbiology as well as of gastroenterology in the last 30 years, with an invaluable benefit for millions of persons worldwide. The confirmation that this Gram-negative spiral bacterium could live in the stomach has rendered out-of-date the concept of inhospitality of micro-organisms in the gastric environment, after a long history of unheard reports on the presence of spiral bacteria in the stomach. The pathogenicity of H. pylori depends on its ability to colonize as well as the capability to survive in the harsh gastric environment. This is possible by a coevolution between the pathogen itself and the host. Any perturbation of this equilibrium disrupts the host-pathogen interaction, promoting the pathological effects. H. pylori has a wide range of pathogenicity factors, in particular cytotoxins, enzymes of aggression, and factors providing protection against human defense systems. The most well-characterized cytotoxins contributing to epithelial cell damage are the vacuolating cytotoxin A (VacA) and the cytotoxin-associated gene A (CagA). Only detailed knowledge of the microbiology and genomics of H. pylori infection will allow a vaccine to be produced. Today, we know that H. pylori induces strong humoral and cellular immune responses, but these are incapable of eliminating the bacterium, raising doubts about the possibility of developing an effective vaccine easily. This review highlights microbiological findings concerning H. pylori infection, focusing on colonization, survival and pathogenicity.
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Correlation between serum vitamin B12 level and peripheral neuropathy in atrophic gastritis.
Yang, GT, Zhao, HY, Kong, Y, Sun, NN, Dong, AQ
World journal of gastroenterology. 2018;(12):1343-1352
Abstract
AIM: To explore the correlation between serum vitamin B12 level and peripheral neuropathy in patients with chronic atrophic gastritis (CAG). METHODS A total of 593 patients diagnosed with chronic gastritis by gastroscopy and pathological examination from September 2013 to September 2016 were selected for this study. The age of these patients ranged within 18- to 75-years-old. Blood pressure, height and weight were measured in each patient, and the body mass index value was calculated. Furthermore, gastric acid, serum gastrin, serum vitamin and serum creatinine tests were performed, and peripheral nerve conduction velocity and Helicobacter pylori (H. pylori) were detected. In addition, the type of gastritis was determined by gastroscopy. The above factors were used as independent variables to analyze chronic gastritis with peripheral neuropathy and vitamin B12 deficiency risk factors, and to analyze the relationship between vitamin B12 levels and peripheral nerve conduction velocity. In addition, in the treatment of CAG on the basis of vitamin B12, patients with peripheral neuropathy were observed. RESULTS Age, H. pylori infection, CAG, vitamin B9 and vitamin B12 were risk factors for the occurrence of peripheral nerve degeneration. Furthermore, CAG and H. pylori infection were risk factors for chronic gastritis associated with vitamin B12 deficiency. Serum vitamin B12 level was positively correlated with sensory nerve conduction velocity in the tibial nerve (R = 0.463). After vitamin B12 supplementation, patients with peripheral neuropathy improved. CONCLUSION Serum vitamin B12 levels in patients with chronic gastritis significantly decreased, and the occurrence of peripheral neuropathy had a certain correlation. CAG and H. pylori infection are risk factors for vitamin B12 deficiency and peripheral neuropathy. When treating CAG, vitamin B12 supplementation can significantly reduce peripheral nervous system lesions. Therefore, the occurrence of peripheral neuropathy associated with vitamin B12 deficiency may be considered in patients with CAG. Furthermore, the timely supplementation of vitamin B12 during the clinical treatment of CAG can reduce or prevent peripheral nervous system lesions.
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Serum pepsinogen 1 and anti-Helicobacter pylori IgG antibodies as predictors of gastric cancer risk in Finnish males.
Song, M, Camargo, MC, Weinstein, SJ, Murphy, G, Freedman, ND, Koshiol, J, Stolzenberg-Solomon, RZ, Abnet, CC, Männistö, S, Albanes, D, et al
Alimentary pharmacology & therapeutics. 2018;(4):494-503
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Abstract
BACKGROUND Serum pepsinogen 1 (SPG1) and anti-Helicobacter pylori serology have been used for gastric risk stratification in Asia. AIM: To assess utility of these markers in a Western population. METHODS SPG1 measurements were available for 21 895 Finnish male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. We used Cox proportional hazards models adjusted for potential confounders to estimate gastric cancer hazard ratios (HR) and 95% confidence intervals (95% CI) for low SPG1 (<25 μg/L). In a subset (n = 3555) with anti-H. pylori serology, these markers jointly defined the following: Group A (H. pylori[-], SPG1[normal]; reference group), Group B (H. pylori[+], SPG1[normal]), Group C (H. pylori[+], SPG1[low]) and Group D (H. pylori[-], SPG1[low]). Odds ratios (ORs) and 95% CI were calculated using multivariate logistic regression. RESULTS There were 329 gastric cancers diagnosed an average of 13.9 years after baseline. Pre-diagnostic low SPG1 was significantly associated with increased gastric cancer risk (HR 2.68, 95% CI 1.99-3.61). Among subjects with both SPG1 and H. pylori serology, groups B, C and D had increased gastric cancer ORs (95% CI) of 1.79 (1.21-2.64), 3.85 (2.36-6.28) and 6.35 (2.20-18.34), respectively. CagA seropositives had significantly higher ORs than CagA seronegatives within group B (Pheterogeneity = 0.01). For groups B and C, repeat SPG1 level at 3 years did not further stratify gastric cancer risk. CONCLUSIONS Low SPG1 was associated with increased gastric cancer risk in our large Finnish cohort. A single measurement of SPG1 along with H. pylori whole cell and CagA serology provides potentially useful prediction of gastric cancer risk.
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Helicobacter pylori therapy and clinical perspective.
Talebi Bezmin Abadi, A, Yamaoka, Y
Journal of global antimicrobial resistance. 2018;:111-117
Abstract
Helicobacter pylori induces chronic gastritis and duodenal ulcer in a small fraction of the colonised population. Three decades after the discovery of H. pylori and disclosure of an urgent need for eliminating the bacterium in patients, it seems that we are still in the first steps of dealing with this mysterious organism. Treatment of H. pylori is a complex dilemma for clinicians, a repeating sentence by many scientists who spend years on this research topic. Apart from many modifications in initial first-line treatment of H. pylori, gastroenterologists are unable to overcome the problem of therapeutic failure. Choosing the best regimen in any region depends on many factors, which have been the focus of many randomised clinical trials. A potential increase in efficacy of future therapies may be influenced by adding the novel potassium-competitive acid blocker vonoprazan. Undeniably, in-depth analysis is necessary to propose more effective therapeutic regimens. Meanwhile, we recommend the performance of antimicrobial susceptibility testing before any antimicrobial prescription.
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Structure and dynamics of Helicobacter pylori nickel-chaperone HypA: an integrated approach using NMR spectroscopy, functional assays and computational tools.
Spronk, CAEM, Żerko, S, Górka, M, Koźmiński, W, Bardiaux, B, Zambelli, B, Musiani, F, Piccioli, M, Basak, P, Blum, FC, et al
Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 2018;(8):1309-1330
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Abstract
Helicobacter pylori HypA (HpHypA) is a metallochaperone necessary for maturation of [Ni,Fe]-hydrogenase and urease, the enzymes required for colonization and survival of H. pylori in the gastric mucosa. HpHypA contains a structural Zn(II) site and a unique Ni(II) binding site at the N-terminus. X-ray absorption spectra suggested that the Zn(II) coordination depends on pH and on the presence of Ni(II). This study was performed to investigate the structural properties of HpHypA as a function of pH and Ni(II) binding, using NMR spectroscopy combined with DFT and molecular dynamics calculations. The solution structure of apo,Zn-HpHypA, containing Zn(II) but devoid of Ni(II), was determined using 2D, 3D and 4D NMR spectroscopy. The structure suggests that a Ni-binding and a Zn-binding domain, joined through a short linker, could undergo mutual reorientation. This flexibility has no physiological effect on acid viability or urease maturation in H. pylori. Atomistic molecular dynamics simulations suggest that Ni(II) binding is important for the conformational stability of the N-terminal helix. NMR chemical shift perturbation analysis indicates that no structural changes occur in the Zn-binding domain upon addition of Ni(II) in the pH 6.3-7.2 range. The structure of the Ni(II) binding site was probed using 1H NMR spectroscopy experiments tailored to reveal hyperfine-shifted signals around the paramagnetic metal ion. On this basis, two possible models were derived using quantum-mechanical DFT calculations. The results provide a comprehensive picture of the Ni(II) mode to HpHypA, important to rationalize, at the molecular level, the functional interactions of this chaperone with its protein partners.
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Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016).
Jones, NL, Koletzko, S, Goodman, K, Bontems, P, Cadranel, S, Casswall, T, Czinn, S, Gold, BD, Guarner, J, Elitsur, Y, et al
Journal of pediatric gastroenterology and nutrition. 2017;(6):991-1003
Abstract
BACKGROUND Because of the changing epidemiology of Helicobacter pylori infection and low efficacy of currently recommended therapies, an update of the European Society for Paediatric Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations for the diagnosis and management of H pylori infection in children and adolescents is required. METHODS A systematic review of the literature (time period: 2009-2014) was performed. Representatives of both societies evaluated the quality of evidence using GRADE (Grading of Recommendation Assessment, Development, and Evaluation) to formulate recommendations, which were voted upon and finalized using a Delphi process and face-to-face meeting. RESULTS The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasizing strict adherence. Clarithromycin-containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high-dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth-based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests. CONCLUSIONS The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first-line therapies and broader availability of culture or molecular-based testing to tailor treatment to the individual child.