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灰暗的星星灰暗的星星灰暗的星星灰暗的星星灰暗的星星
 
杨友鹏
杨友鹏
主治医师
航天中心医院

1. 黄芩苷和黄芩素作为幽门螺杆菌尿素酶抑制剂的生物学评价和分子对接

   黄芩苷和黄芩素是作用于幽门螺杆菌尿素酶活性位点周围巯基尤其是Cys321的非竞争性抑制剂,将来可对其作为尿素酶抑制剂用于治疗幽门螺杆菌感染的可能性进一步研究。此外,本文对于在中药中应用黄芩治疗胃肠道疾病给出了额外的科学支持。

Biological evaluation and molecular docking of baicalin and scutellarin asHelicobacter pylori urease inhibitors.Yu XD1, Zheng RB2, Xie JH1, Su JY1, Huang XQ3, Wang YH4, Zheng YF1, Mo ZZ1, Wu XL1, Wu DW1, Liang YE1,Zeng HF5, Su ZR6, Huang P7.JEthnopharmacol. 2014 Dec 31. pii: S0378-8741(14)00945-3. doi: 10.1016/j.jep.2014.12.041.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Baicalin and scutellarin are the principal bioactive components of Scutellaria baicalensis Georgi which has extensively been incorporated into heat-clearing and detoxification formulas for the treatment of Helicobacter pylori-related gastrointestinal disorders in traditional Chinese medicine. However, the mechanism of action remained to be defined.

AIM OF THE STUDY:

To explore the inhibitory effect, kinetics and mechanism of Helicobacter pylori urease (the vital pathogenetic factor for Helicobacter pylori infection) inhibition by baicalin and scutellarin, for their therapeutic potential.

MATERIALS AND METHODS:

The ammonia formations, indicator of urease activity, were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. The inhibitory effect of baicalin and scutellarin was characterized with IC50 values, compared to acetohydroxamic acid (AHA), a well knownHelicobacter pylori urease inhibitor. Lineweaver-Burk and Dixon plots for the Helicobacter pylori urease inhibition of baicalin and scutellarin was constructed from the kinetic data. SH-blocking reagents and competitive active site Ni2+ binding inhibitors were employed for mechanism study. Molecular docking technique was used to provide some information on binding conformations as well as confirm the inhibition mode. Moreover, cytotoxicity experiment using Gastric Epithelial Cells (GES-1) was evaluated.

RESULTS:

Baicalin and scutellarin effectively suppressed Helicobacter pylori urease in dose-dependent and time-independent manner with IC50 of 0.82±0.07mM and 0.47±0.04mM, respectively, compared to AHA (IC50=0.14±0.05mM). Structure-activity relationship disclosed 4'-hydroxyl gave flavones an advantage to binding with Helicobacter pylori urease. Kinetic analysis revealed that the types of inhibition were non-competitive and reversible with inhibition constant Ki of 0.14±0.01mM and 0.18±0.02mM for baicalin and scutellarin, respectively. The mechanism of urease inhibition was considered to be blockage of the SH groups of Helicobacter pylori urease, since thiol reagents (l,d-dithiothreitol, l-cysteine and glutathione) abolished the inhibitory action and competitive active site Ni2+ binding inhibitors (boric acid and sodium fluoride) carried invalid effect. Molecular docking study further supported the structure-activity analysis and indicated that baicalin and scutellarin interacted with the key residues Cys321 located on the mobile flap through SH·πinteraction, but did not interact with active site Ni2+. Moreover, Baicalin (at 0.59-1.05mM concentrations) and scutellarin (at 0.23-0.71mM concentrations) did not exhibit significant cytotoxicity to GES-1.

CONCLUSIONS:

Baicalin and scutellarin were non-competitive inhibitors targeting sulfhydryl groups especially Cys321 around the active site of Helicobacter pylori urease, representing potential to be good candidate for future research as urease inhibitor for treatment of Helicobacter pylori infection. Furthermore, our work gave additional scientific support to the use of Scutellaria baicalensis in traditional Chinese medicine (TCM) to treat gastrointestinal disorders.

KEYWORDS:

Baicalin; Helicobacter pylori; Molecular docking; Non-competitive inhibitior; Scutellarin; Urease

 

2、预测胃酸分泌状态的内镜发现

本研究发现,无论有无幽门螺杆菌感染,可根据内镜发现预测胃酸分泌状态,可在一定程度上帮助判断酸相关疾病的风险。

Endoscopic findings for predicting gastric acid secretion status.Hatta W1, Iijima KKoike TKondo YAra NAsanuma KUno KAsano NImatani AShimosegawa T.Dig Endosc. 2014 Dec 30. doi: 10.1111/den.12427.

Abstract

OBJECTIVES:

Gastric acidic abnormalities are related to various kinds of diseases in each Helicobacter pylori(H. pylori) infection status. However, no studies have shown correlations between many tiny endoscopic finding and the acid secretion level simultaneously. In this study, we investigated predictive tiny endoscopic findings of hyperchlorhydria and hypochlorhydria.

METHODS:

A total of 223 subjects without organic diseases who underwent esophagogastroduodenoscopy and the endoscopic gastrin test (EGT) for estimating the gastrin-stimulated gastric acid secretory response between 1999 and 2011 at our institution were retrospectively analyzed. Two blinded expert endoscopists reviewed the images independently and recorded the endoscopic findings.

RESULTS:

According to the EGT values, the enrolled subjects were categorized into hyperchlorhydria, normal acid secretion, and hypochlorhydria groups. In all subjects, hematin (odds ratio [95% confidence interval] = 3.32 [1.40-7.84]) and antral erosion (2.88 [1.24-6.70]) were the predictive endoscopic findings for hyperchlorhydria, and swelling of areae gastricae (14.4 [5.74-36.1]) and open-type atrophy (15.1 [7.35-31.1]) were those for hypochlorhydria. In addition, the predictive endoscopic findings for hyperchlorhydria differed according to the H. pylori infection status, hematin in H. pylori-positive subjects and antral erosion in H. pylori-negative subjects, in contrast to those for hypochlorhydria, which were the same irrespective of the H. pyloriinfection status.

CONCLUSIONS:

In this study, we could predict the acid secretion status based on the endoscopic findings regardless of the H. pylori infection status, which would be of some help for evaluating the risk for acid-related diseases.

This article is protected by copyright. All rights reserved.

KEYWORDS:

Helicobacter pylori; endoscopy; gastric acid; hyperchlorhydria; hypochlorhydria

 

3、一种新型幽门螺杆菌唾液抗原一步检测法

   幽门螺杆菌唾液抗原一步检测法(HPS)与其他检测方法相比,敏感性高,特异性低,提示其不适合在临床中用于检测幽门螺杆菌感染。但是,该方法操作简单(仅需要唾液标本)、便宜且无创,可以考虑用于人群幽门螺杆菌感染的流行病学筛查。

A novel one-step Helicobacter pylori saliva antigen test.Yang BLYeh CKwong WGLee SD.J Chin Med Assoc. 2014 Dec 30. pii: S1726-4901(14)00314-1. doi: 10.1016/j.jcma.2014.11.004.

Abstract

BACKGROUND:

A rapid, reliable, and sufficiently accurate test for diagnosing Helicobacter pylori infection is required for screening dyspeptic patients before a referral for endoscopy. The purpose of this article is two-fold: first, to evaluate the accuracy of a one-step H. pylori saliva antigen (HPS) test; and second, to compare noninvasive and invasive H. pylori tests in Taiwanese population.

METHODS:

A total of 104 consecutive dyspeptic patients admitted for gastroenterology into the outpatient department underwent a one-step HPS test, rapid urease test, histology, and (13)C-urea breath test (13)C-UBT (proto C-13 urea kit). The accuracy of the HPS test was compared with a gold standard defined by at least two positive H. pylori test results from three H. pylori tests (histology, rapid urease test, and (13)C-UBT).

RESULTS:

The 104 patients eligible for analysis (mean age: 58 years, range 22-87 years), 21 (20%) were gold standard positive. Among them, the positive of the one-step H. pylori saliva Ag test, rapid urease test, (13)C-UBT, histology were (52; 50%), (17; 16%), (27; 25%) and (22; 21%) respectively. The sensitivity and specificity of the HPS tests, rapid urease test, (13)C-UBTs, and histology were 71.43% and 55.42%, 76.19% and 98.80%, 100% and 92.77%, and 85.71% and 95.18%, respectively, relative to the gold standard. The one-step HPS test exhibited a sensitivity of 71.43%, nearly equivalent to that of the rapid urea test.

CONCLUSION:

The one-step HPS test exhibited a high sensitivity and low specificity compared with the other tests, indicating that it is not sufficiently accurate for use in a clinical setting for diagnosing H. pylori infection. However, the test is simple to use (requiring only a saliva sample), inexpensive, and noninvasive in its application, and thus appealing for use in population-based prevalence surveys of the epidemiology of H. pylori infection.

4、抗氧化剂在预防感染相关癌症的发生及治疗感染驱动的肿瘤中有作用吗?

   本文简述了致癌作用与三种主要感染相关肿瘤,人乳头瘤病毒所致宫颈癌、乙型肝炎病毒阳性肝癌及幽门螺杆菌阳性胃癌的相关机制。

Is there a Role For Antioxidants in the Prevention of Infection-Associated Carcinogenesis and in the Treatment of Infection-Driven Tumors?De Luca CKharaeva ZKorkina L.Curr Top Med Chem. 2014 Dec 29.

Abstract

Causative connections between infections and cancer are ascertained for several types of viruses, bacteria, and parasites. The mechanisms of cancer induction in chronically infected inflamed tissues strongly implicate oxygen- and nitrogen-centered reactive species, and an impairment of redox-sensitive molecular pathways involved in the tumorigenic transformation, tumor growth, altered immune defense, and in the mechanisms of tumor cell death and survival. Here, we briefly reviewed mechanistic data on carcinogenesis and tumor progression of three major infection-associated tumors, human papillomavirus-induced cervical cancer, hepatitis B virus-positive hepatocarcinoma, and Helicobacter pylori-positive gastric cancer. Notwithstanding the contradictory results of clinical studies on cancer chemoprevention with long-term, high dosage antioxidant vitamin/micronutrient supplementation, natural and synthetic agents with proven capacity to affect redox-dependent molecular pathways still hold the promise for preventing/delaying carcinogenesis initiation, as well as the overt malignancy evolution from dysplastic/aplastic stages. Novel directions for a targeted antioxidant-based approach to the reduction of persistent infection-driven cancer risk stems from the current knowledge of critical factors in the host-microbe interaction leading to oncogenesis. An emerging role of redox active substances in the chemotherapy of tumors relies on their stimulating effects towards TRAIL-related apoptosis and the induction of intracellular oxidative stress.

 

自α氨基酸提取的铋(III)复合物的水溶物对对幽门螺杆菌具有较明显的体外抗菌活性。

Bismuth(III) complexes derived from α-amino acids: the impact of hydrolysis and oxido-cluster formation on their activity against Helicobacter pylori.Busse M1, Border EJunk PCFerrero RLAndrews PC.Dalton Trans. 2014 Dec 28;43(48):17980-90. doi: 10.1039/c4dt02505a. Epub 2014 Oct 14.

Abstract

Eight bismuth(III) complexes derived from a variety of α-amino acids covering a range of physico-chemical properties (L-phenylalanine (Phe), L-proline (Pro), L-methionine (Met), L-cysteine (Cys), D,L-serine (Ser), L-tyrosine (Tyr), l-aspartic acid (Asp) and L-glutamic acid (Glu)) have been synthesised, characterised, and evaluated for their activity against Helicobacter pylori. The optimal synthetic procedure utilises [Bi(O(t)Bu)3], giving the complexes [BiL3] (L = Phe 1, Pro 2, Met 3, Ser 5, Tyr 6) and [Bi2L3] (L = Cys 4, Asp 7, Glu 8) cleanly and in good yield. However, the synthesis is sensitive to both temperature and moisture. The solubility and stability of the bismuth(III) complexes was investigated using ESI-MS. Almost all compounds (except for [Bi(Phe)3] and [Bi(Pro)3]) were found to be partially or completely soluble in aqueous solution giving a pH 2.5-5.0, indicating the presence of free α-amino acid and hydrolysis of the bismuth(III) complexes to polynuclear bismuth oxido-clusters. The results of the bactericidal studies against Helicobacter pylori demonstrate that this hydrolysis process impacts significantly on the observed Minimum Inhibitory Concentration (MICs) which are increased substantially, often by many orders of magnitude, when the complexes are initially prepared in water rather than DMSO.

 

5、幽门螺杆菌在慢性扁桃体炎患者扁桃体的定植:系统综述及Meta分析

无论是在慢性还是反复感染扁桃体炎患者,幽门螺杆菌在其扁桃体组织中的定植率与非感染对照组无差异。

Tonsillar Helicobacter pylori Colonization in Chronic Tonsillitis: Systematic Review and Meta-analysis.Hwang MSForman SNKanter JAFriedman M4.JAMA Otolaryngol Head Neck Surg. 2014 Dec 26. doi: 10.1001/jamaoto.2014.3296.

Abstract

IMPORTANCE:

Helicobacter pylori colonization contributes significantly to multiple disease states, but its role in the development of tonsillar infection is unclear. Understanding the causes of chronic tonsillitis is important in clinical decision making of this commonly treated disease.

OBJECTIVE:

To assess the correlation between H pylori colonization of tonsillar tissue in chronic tonsillitis and in noninfectious hyperplastic tonsils.

DATA SOURCES:

We searched PubMed, MEDLINE, the Cochrane Trial Registry (through June 2014) and relevant article bibliographies.

STUDY SELECTION:

Systematic review and meta-analysis of studies assessing the correlation between Hpylori colonization in tonsillar tissues of patients undergoing tonsillectomy for either chronic tonsillitis or noninfectious causes. Included studies hypothesized that H pylori played a role in the development of chronic tonsillitis. All included studies investigated the presence of H pylori in tonsillar tissue removed for various indications. Included studies must have used an accepted method of testing for H pylori.

DATA EXTRACTION AND ANALYSIS:

Studies were systematically reviewed by 2 independent reviewers for inclusion. Reported results of H pylori testing between tissues removed for infectious or noninfectious causes were systematically reviewed. The odds ratio of Hpylori colonization in tissue removed for chronic tonsillitis compared with tissue removed for noninfectious causes was calculated using a random-effects model.

RESULTS:

Six studies met inclusion criteria and had suitable data for pooling (n = 436). Of these, 2 studies measured H pylori colonization of tonsillar tissue in pediatric populations. One study analyzed tissue in both adult and pediatric populations. Noninfectious indications for tonsillectomy included sleep apnea or sleep-related breathing disorder, obstruction, carcinoma, and tonsillar hypertrophy. Overall, tonsillar H pyloricolonization was found not to be significantly present more often in tissue samples removed secondary to recurrent infection rather than to noninfectious indications. The odds ratio of H pylori colonization in the tonsils of patients with chronic tonsillitis was 1.993 (95% CI, 0.909-4.371) (P = .09).

CONCLUSIONS AND RELEVANCE:

Helicobacter pylori colonization was not found to be more prevalent on tonsillar tissue with chronic or recurrent infections. The reviewed studies provide no evidence that H pyloriinfection plays a role in the pathogenesis or development of chronic tonsillitis.

 

6、在墨西哥人群中幽门螺杆菌CagAEPIYA-ABCC型 与消化性溃疡和胃癌相关。

   在南墨西哥,CagA阳性幽门螺杆菌感染率高,所有CagA均为西方型。编码EPIYA-ABCC的CagA位点与消化性溃疡和胃癌相关。

The EPIYA-ABCC motif pattern in CagA of Helicobacter pylori is associated with peptic ulcer and gastric cancer in Mexican population.Beltrán-Anaya FPoblete TRomán-Román AReyes Sde Sampedro JPeralta-Zaragoza ORodríguez MDel Moral-Hernández OIllades-Aguiar BFernández-Tilapa G.BMC Gastroenterol. 2014 Dec 24;14(1):2.

Abstract

Background Helicobacter pylori chronic infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. Cytotoxin-associated gene A (cagA)-positive H. pylori strains increase the risk of gastric pathology. The carcinogenic potential of CagA is linked to its polymorphic EPIYA motif variants. The goals of this study were to investigate the frequency of cagA-positive Helicobacter pylori in Mexican patients with gastric pathologies and to assess the association of cagA EPIYA motif patterns with peptic ulcer and gastric cancer.MethodsA total of 499 patients were studied; of these, 402 had chronic gastritis, 77 had peptic ulcer, and 20 had gastric cancer. H. pylori DNA, cagA, and the EPIYA motifs were detected in total DNA from gastric biopsies by PCR. The type and number of EPIYA segments were determined by the electrophoretic patterns. To confirm the PCR results, 20 amplicons of the cagA 3¿ variable region were sequenced, and analyzed in silico, and the amino acid sequence was predicted with MEGA software, version 5. The odds ratio (OR) was calculated to determine the associations between the EPIYA motif type and gastric pathology and between the number of EPIYA-C segments and peptic ulcers and gastric cancer.Results H. pylori DNA was found in 287 (57.5%) of the 499 patients, and 214 (74%) of these patients were cagA-positive. The frequency of cagA-positive H. pylori was 74.6% (164/220) in chronic gastritis patients, 73.6% (39/53) in peptic ulcer patients, and 78.6% (11/14) in gastric cancer patients. The EPIYA-ABC pattern was more frequently observed in chronic gastritis patients (79.3%, 130/164), while the EPIYA-ABCC sequence was more frequently observed in peptic ulcer (64.1%, 25/39) and gastric cancer patients (54.5%, 6/11). However, the risks of peptic ulcer (OR¿=¿7.0, 95% CI¿=¿3.3¿15.1; p¿<¿0.001) and gastric cancer (OR¿=¿5.9, 95% CI¿=¿1.5¿22.1) were significantly increased in individuals who harbored the EPIYA-ABCC cagA gene pattern.Conclusions cagA-positive H. pylori is highly prevalent in southern Mexico, and all CagA variants were of the western type. The cagA alleles that code for EPIYA-ABCC motif patterns are associated with peptic ulcers and gastric cancer.

 

7、比较以左氧氟沙星或莫西沙星为基础的三联疗法与标准疗法一线治疗幽门螺杆菌感染的疗效。

这项在土耳其进行的研究结果显示,以左氧氟沙星或莫西沙星为基础的三联疗法与标准疗法相比,三组的根除率分别为92%, 91.8%和82.4%,但应注意幽门螺杆菌对喹诺酮类的耐药问题。

Comparison of Levofloxacin- and Moxifloxacin-Based Triple Therapies with Standard Treatment in Eradication of Helicobacter Pylori as First-Line Therapy.Rakici HAyaz TAkdogan RABedir R.Digestion. 2014 Dec 24;90(4):261-264.

Abstract

Aim: It is recommended that treatments that include clarithromycin should be avoided in eradication ofHelicobacter pylori (HP) in cases where clarithromycin resistance is higher than 20%. We aimed to compare levofloxacin- and moxifloxacin-based triple therapies with standard treatment and with each other in eradication of helicobacter pylori as first-line therapy. Materials and Methods: Patients were randomized prospectively as three groups. There were 102 patients in the levofloxacin group, 101 patients in the moxifloxacin group, and 103 patients in the standard treatment group. The patients received levofloxacin 500 mg daily, amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. for ten days (LAL) in the levofloxacin group; moxifloxacin 400 mg daily, amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. (MAL) in the moxifloxacin group; and clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d. and lansoprazole 30 mg b.i.d. (CAL) in the standard treatment group. At post-treatment week 6, HP was checked by using stool antigen test. Results: In the eradication of Helicobacter pylori, the success rate as determined by per protocol (PP) analysis was 92% in the LAL group, 91.8% in the MAL group, and 82.4% in the CAL group. A statistically significant difference was found in the LAL and MAL groups compared to the CAL group (p < 0.05). There was no difference between the LAL and MAL groups. Conclusions: It was determined that levofloxacin- and moxifloxacin-based triple therapies were more effective than the standard treatment in first-line setting in the eradication of Helicobacter pylori. In addition, no difference was found between levofloxacin- and moxifloxacin-based triple therapies. Currently observed high efficacy may be evaluated in treatment. Although quinolon resistance is not considered a major problem, it appears to be a factor that may reduce treatment success over a period of time.

 

9、体外模拟幽门螺杆菌感染的一种新型人胃黏膜元代细胞培养系统

 

A novel human gastric primary cell culture system for modelling Helicobacter pyloriinfection in vitro.Schlaermann PToelle BBerger HSchmidt SCGlanemann MOrdemann JBartfeld SMollenkopf HJ,Meyer TF.Gut. 2014 Dec 24. pii: gutjnl-2014-307949. doi: 10.1136/gutjnl-2014-307949.

Abstract

BACKGROUND AND AIMS:

Helicobacter pylori is the causative agent of gastric diseases and the main risk factor in the development of gastric adenocarcinoma. In vitro studies with this bacterial pathogen largely rely on the use of transformed cell lines as infection model. However, this approach is intrinsically artificial and especially inappropriate when it comes to investigating the mechanisms of cancerogenesis. Moreover, common cell lines are often defective in crucial signalling pathways relevant to infection and cancer. A long-lived primary cell system would be preferable in order to better approximate the human in vivo situation.

METHODS:

Gastric glands were isolated from healthy human stomach tissue and grown in Matrigel containing media supplemented with various growth factors, developmental regulators and apoptosis inhibitors to generate long-lasting normal epithelial cell cultures.

RESULTS:

Culture conditions were developed which support the formation and quasi-indefinite growth of three dimensional (3D) spheroids derived from various sites of the human stomach. Spheroids could be differentiated to gastric organoids after withdrawal of Wnt3A and R-spondin1 from the medium. The 3D cultures exhibit typical morphological features of human stomach tissue. Transfer of sheared spheroids into 2D culture led to the formation of dense planar cultures of polarised epithelial cells serving as a suitable in vitro model of H.pylori infection.

CONCLUSIONS:

A robust and quasi-immortal 3D organoid model has been established, which is considered instrumental for future research aimed to understand the underlying mechanisms of infection, mucosal immunity and cancer of the human stomach.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

KEYWORDS:

GASTRIC CANCER; HELICOBACTER PYLORI

 

10、日本非幽门螺杆菌非NSAIDs特发性消化性溃疡多中心前瞻性研究

日本消化性溃疡患者中特发性消化性溃疡(IPU)的发生率为12%,明显高于之前的报道(0.9-2.6%)。存在的多种合并疾病,而不是衰老本身,是IPU的重要危险因素。

A multicenter prospective study on the prevalence of Helicobacter pylori-negative and NSAIDs-negative idiopathic peptic ulcers in Japan.

Kanno TIijima KAbe YYagi MAsonuma SOhyauchi MIto HKoike TShimosegawa T.J Gastroenterol Hepatol. 2014 Dec 23. doi: 10.1111/jgh.12876.

 

 

Abstract

BACKGROUND AND AIM:

The prevalence of Helicobacter pylori-negative and non-steroidal anti-inflammatory drug (NSAID)-negative peptic ulcers, commonly known as idiopathic peptic ulcers (IPUs), has been reported to be very low (0.9-2.6%) in Japan based on data from the 1990s. However, recent trends have yet to be been reported. Herein, we present a multicenter prospective analysis between 2012 and 2013 investigating current trends in the prevalence and characteristics of IPUs in Japan.

METHODS:

Clinical data of all peptic ulcer subjects detected via endoscopy at four participating hospitals were prospectively collected between April 2012 and March 2013. Enrolled subjects were classified according to H. pylori infection status and intake of NSAIDs. Multiple logistic regression analyses were used to determine the risk factors for IPUs.

RESULTS:

Of 382 enrolled patients with peptic ulcers, 46 (12%) were judged to have IPUs. Compared to those with simple H. pylori-positive ulcers, patients with IPUs were significantly older (p < 0.02), and more often had underlying comorbidities such as hypertension (p < 0.02) and hyperlipidemia (p < 0.05). Multivariate regression analysis indicated that the presence of multiple underlying diseases was the only significant risk factor for IPUs, with an odds ratio of 3.8 (95% confidence interval, 1.3-11.1).

CONCLUSIONS:

This study revealed that the prevalence of IPUs in patients with peptic ulcers in Japan is 12%, much higher than previously reported. Presence of multiple underlying comorbid diseases, rather than aging itself, is an important risk factor for IPUs.

This article is protected by copyright. All rights reserved.

KEYWORDS:

Helicobacter pylori; Idiopathic peptic ulcers; non-steroidal anti-inflammatory drug; risk factors

 

 

Abstract

BACKGROUND AND AIMS:

Helicobacter pylori is the causative agent of gastric diseases and the main risk factor in the development of gastric adenocarcinoma. In vitro studies with this bacterial pathogen largely rely on the use of transformed cell lines as infection model. However, this approach is intrinsically artificial and especially inappropriate when it comes to investigating the mechanisms of cancerogenesis. Moreover, common cell lines are often defective in crucial signalling pathways relevant to infection and cancer. A long-lived primary cell system would be preferable in order to better approximate the human in vivo situation.

METHODS:

Gastric glands were isolated from healthy human stomach tissue and grown in Matrigel containing media supplemented with various growth factors, developmental regulators and apoptosis inhibitors to generate long-lasting normal epithelial cell cultures.

RESULTS:

Culture conditions were developed which support the formation and quasi-indefinite growth of three dimensional (3D) spheroids derived from various sites of the human stomach. Spheroids could be differentiated to gastric organoids after withdrawal of Wnt3A and R-spondin1 from the medium. The 3D cultures exhibit typical morphological features of human stomach tissue. Transfer of sheared spheroids into 2D culture led to the formation of dense planar cultures of polarised epithelial cells serving as a suitable in vitro model of H.pylori infection.

CONCLUSIONS:

A robust and quasi-immortal 3D organoid model has been established, which is considered instrumental for future research aimed to understand the underlying mechanisms of infection, mucosal immunity and cancer of the human stomach.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

KEYWORDS:

GASTRIC CANCER; HELICOBACTER PYLORI

 

11、一种新型组蛋白样DNA连接蛋白HP119对幽门螺杆菌在宿主体内的抗逆性和生存发挥重要作用

A novel DNA-binding protein plays an important role in Helicobacter pylori stress tolerance and survival in the host.Wang GMaier RJ.J Bacteriol. 2014 Dec 22. pii: JB.02489-14.

Abstract

The gastric pathogen Helicobacter pylori must combat chronic acid and oxidative stress. It does so via many mechanisms including macromolecule repair and gene regulation. Mitomycin-C sensitive clones from a transposon mutagenesis library were screened. One sensitive strain contained the insertion element at the hp119 locus, a hypothetical gene. No homologous gene exists in any (non-H. pylori) organism. Nevertheless, the predicted protein has some features characteristic of histone-like proteins, and we showed that purified HP119 protein is a DNA-binding protein. An Δhp119 strain was markedly more sensitive (viability loss) to acid or to air exposure, and these phenotypes were restored to wild type (WT) attributes upon complementing the mutant with the wild type version of hp119 at a separate chromosomal locus. The mutant strain was approximately10-fold more sensitive to macrophage-mediated killing than the parent or the complemented strain. Of 12 mice inoculated with wild type, all contained H. pylori, whereas 5 of 12 mice contained the mutant strain; and the mean colonization numbers were 158 fold less for the mutant strain. A proteomic (2D-PAGE with MS analysis) comparison between Δhp119 and the WT strain under oxidative stress conditions revealed a number of important antioxidant protein differences; SodB, Tpx, TrxR, NapA, as well as the peptidoglycan deacetylase PgdA, were significantly less expressed in Δhp119 than in the WT strain. This study identified HP119 as a putative histone-like DNA-binding protein, and showed that it plays an important role in Helicobacter pylori stress tolerance and survival in the host.

 

12、幽门螺杆菌、γ谷氨酰转肽酶和癌:更深层的的联系。

近期已经发表的文献表明细菌GGT的分泌以类外泌体囊泡的形式发生。人癌细胞可产生非常类似的富含GGT的外泌体,因此,提出了在恶性肿瘤细胞的耐药型和侵袭型中,此种囊泡/外泌体型GGT在幽门螺杆菌感染中发挥作用,因此对癌症的转移有重要意义。

 

Helicobacter, gamma-glutamyltransferase and cancer: Further intriguing connections.Franzini MCorti AFierabracci VPompella A.World J Gastroenterol. 2014 Dec 21;20(47):18057-8. doi: 10.3748/wjg.v20.i47.18057.

Abstract

Virulence of Helicobacter pylori, Helicobacter suis and other bacteria appears to be partly mediated through a release of gamma-glutamyltransferase (GGT), an enzyme activity capable of promoting biochemical reactions ultimately resulting in damage to gastric epithelium and suppression of immune response. Recently published studies show that secretion of bacterial GGT occurs in the form of exosome-like vesicles. Very similar GGT-rich exosomes have been described to originate from human cancer cells, and the hypothesis is thus forwarded that in the resistant and invasive phenotype of malignant cells such vesicular/exosomal GGT may play roles akin to those described for Helicobacter infection, thus providing a significant contribution to the establishment of cancer metastases.

KEYWORDS:

Cancer metastasis; Gamma-glutamyltransferase; Helicobacter pylori; Helicobacter suis; Immunosuppression; Virulence

 

13、益生菌在幽门螺杆菌根除治疗中有效性的Meta分析

在幽门螺杆菌标准三联疗法中添加益生菌制剂可改善根除率,尤其是在亚洲患者中,且不良反应发生率降低。

Meta-analysis of the efficacy of probiotics in Helicobacter pylori eradication therapy.Zhu RChen KZheng YYZhang HWWang JSXia YJDai WQWang FShen MCheng PZhang Y,Wang CFYang JLi JJLu JZhou YQGuo CY.World J Gastroenterol. 2014 Dec 21;20(47):18013-21. doi: 10.3748/wjg.v20.i47.18013.

Abstract

AIM:

To evaluate the role of probiotics in the standard triple Helicobacter pylori therapy.

METHODS:

In this meta-analysis, we investigated the efficacy of probiotics in a standard triple H. pyloritherapy in adults. Searches were mainly conducted in MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Fourteen studies met our criteria, and the quality of these studies was assessed using the Jadad scale. We used STATA version 12.0 to extract data and to calculate the odds ratios (ORs), which are presented with the corresponding 95% confidence intervals (CIs). The data are presented as forest plots.

RESULTS:

The pooled ORs for the eradication rates calculated by intention-to-treat analysis and per-protocol analysis in the probiotic group vs the control group were 1.67 (95%CI: 1.38-2.02) and 1.68 (95%CI: 1.35-2.08), respectively, using the fixed-effects model. The sensitivity of the Asian studies was greater than that of the Caucasian studies (Asian: OR = 1.78, 95%CI: 1.40-2.26; Caucasian: OR = 1.48, 95%CI: 1.06-2.05). The pooled OR for the incidence of total adverse effects was significantly lower in the probiotic group (OR = 0.49, 95%CI: 0.26-0.94), using the random effects model, with significant heterogeneity (I (2) = 85.7%). The incidence of diarrhea was significantly reduced in the probiotic group (OR = 0.21, 95%CI: 0.06-0.74), whereas the incidence of taste disorders, metallic taste, vomiting, nausea, and epigastric pain did not differ significantly between the probiotic group and the control group.

CONCLUSION:

Supplementary probiotic preparations during standard triple H. pylori therapy may improve the eradication rate, particularly in Asian patients, and the incidence of total adverse effects.

KEYWORDS:

Adult; Eradication; Helicobacter pylori; Meta-analysis; Probiotics

 

14、海尔曼螺杆菌:在人类中感染的概述。

尽管海尔曼螺杆菌属在人类的感染率很低,但其与胃部病变相关,包括黏膜相关淋巴组织淋巴瘤。本文对海尔曼螺杆菌属感染的生物学分类、流行病学、微生物学、诊断和治疗进行了概述。

Helicobacter heilmannii sensu lato: An overview of the infection in humans.Bento-Miranda MFigueiredo C.World J Gastroenterol. 2014 Dec 21;20(47):17779-17787.

Abstract

Helicobacter heilmannii sensu lato (H. heilmannii s.l.) is a group of gastric non-Helicobacter pyloriHelicobacter species that are morphologically indistinguishable from each other. H. heilmannii s.l. infect the stomach of several animals and may have zoonotic potential. Although the prevalence of these infections in humans is low, they are associated with gastric pathology, including mucosa-associated lymphoid tissue lymphoma, making them a significant health issue. Here, the taxonomy, epidemiology, microbiology, diagnosis, and treatment of these infections will be reviewed. The gastric pathology associated with H. heilmannii s.l. infections in humans will also be addressed. Finally, the features of the complete bacterial genomes available and studies on species-specific pathogenesis will be reviewed. The understanding of the mechanisms that underlie gastric disease development mediated by the different bacterial species that constitute H. heilmannii s.l. is essential for developing strategies for prevention and treatment of these infections.

KEYWORDS:

Diagnosis; Gastric non-Helicobacter pylori; Genomes; Helicobacter heilmannii sensu lato;Helicobacter species; Pathogenesis; Treatment

 

15、抗LeY抗体通过下调MAPKs/COX-2信号通路增强塞来昔布抗胃癌的疗效:与临床研究的关系。

    本研究发现胃癌中幽门螺杆菌、COX-2、CA724和GRN的表达与胃溃疡和慢性胃炎相比显著升高。幽门螺杆菌的水平与COX-2、LeY、CA724和GRN存在显著相关性。采用塞来昔布和抗-LeY抗体的联合治疗可明显抑制胃癌细胞的增殖,且通过下调MAPKs/COX-2通路降低COX-2、CA724和GRN的表达。

Anti-LeY antibody enhances therapeutic efficacy of celecoxib against gastric cancer by downregulation of MAPKs/COX-2 signaling pathway: correlation with clinical study.Aziz FYang XWang XYan Q.J Cancer Res Clin Oncol. 2014 Dec 20.

 

INTRODUCTION:Helicobacter pylori (H. pylori) is a major causative agent for the induction of chronic gastritis, gastric ulcer and gastric cancer. Celecoxib (COX-2 inhibitor) inhibits gastric cancer cell proliferation, but with low treatment efficacy, limiting its applications. It is important to develop a better strategy to improve the efficacy of celecoxib. Lewis Y (LeY) is a difucosylated oligosaccharide, highly expressed in 60-90 % of human epithelial cancers, including gastric cancer. We previously found that H. pylori infection was associated with high level of LeY in gastric cancer.

MATERIAL AND METHODS:

Herein, we analyzed the correlation between H. pylori and cyclo-oxygenase-2 (COX-2), LeY, gastric markers (CA724 and GRN) in gastric patient's tissue and serum samples by IHC and ELISA. Furthermore, we treated the primary gastric cancer cells with celecoxib, anti-LeY antibody or the combination, and analyzed their therapeutic efficacy on CA724, GRN and COX-2 expression by Western blot, flow cytometry and ELISA.

RESULTS:

We found that gastric cancer had significantly high expression of H. pylori, COX-2, CA724, and GRN compared to gastric ulcers and chronic gastritis (P < 0.0001). H. pylori level showed significant correlation with COX-2 (R-0.552), LeY (R-0.861), CA724 (R-0.714) and GRN (R-0.664) (P < 0.0001). Additionally, the combination therapy led to impressive inhibition of gastric cancer cell proliferation, with decreased expression of COX-2, CA724 and GRN through downregulation of MAPKs/COX-2 pathway (P < 0.01).

CONCLUSIONS:

Our findings suggest that anti-LeY antibody enhances the cancer cell proliferation inhibitory effects of celecoxib, which might be a new feasible way for gastric cancer therapy.

 

16、趋化因子受体CXCR7在胃癌组织和细胞系中的表达

    CXCR7在胃癌组织中高度表达,在5个胃癌细胞系中表达强度不同,提示其在胃癌进展中具有重要作用。

Expression of chemokine receptor CXCR7 in gastric cancer tissues and cell lines. Shi AMDong LShi HTJia MGuo XYJiang JQin B.Nan Fang Yi Ke Da Xue Xue Bao. 2014 Dec 20;34(12):1780-4.

Abstract

OBJECTIVE:

To investigate the expression status of CXCR7 in gastric cancer tissues and cell lines.

METHODS:

The expression status of CXCR7 was detected in 35 primary gastric cancer tissues and matched adjacent tissues by immunohistochemistry and RT-PCR. The correlation of CXCR7 expression with the clinicopathological parameters and risk factors of gastric cancer was analyzed. The expression of CXCR7 in gastric cell lines (HGC-27, MGC-803, BGC-823, SGC-7901 and MKN-28) was also detected by immunofluorescence assay.

RESULTS:

The expression of CXCR7 was significantly higher in gastric cancer tissues than in adjacent tissues (P<0.01). CXCR7 expression was not correlated with age, gender, smoking history, Helicobacter pyloriinfection, tumor location or the pathological type, but showed a higher expression level in patients with a alcohol-drinking history than in those without (P<0.05). CXCR7 was expressed with variable intensities in the 5 gastric cancer cell lines without correlation with the degrees of cell differentiation; its expression was the highest in SGC-7901 cells, a moderately differentiated human gastric adenocarcinoma cell line.

CONCLUSIONS:

CXCR7 is highly expressed in gastric cancer tissues with variable intensities in 5 gastric cancer cell lines, suggesting its important role in gastric cancer progression.

 

17、在应用鲁比前列酮治疗慢性便秘患者时粘蛋白、粘液和粘度的刺激可能增加润滑作用。

    慢性便秘患者用鲁比前列醇治疗期间胃液粘蛋白和粘液的含量显著增加,表明了在其分泌过程中鲁比前列醇可能的主导作用及CIC-2的刺激作用。刺激的增加导致粘度显著增加,反过来促进和/或加速的不消化食物的传输和排泄。

Stimulation of Mucin, Mucus, and Viscosity during Lubiprostone in Patients with Chronic Constipation may Potentially Lead to Increase of Lubrication.Majewski MSarosiek IWallner GEdlavitch SASarosiek J.Clin Transl Gastroenterol. 2014 Dec 18;5:e66. doi: 10.1038/ctg.2014.19.

Abstract

OBJECTIVES:

The purpose of this clinical trial was to explore whether lubiprostone increases the rate of mucus and mucin secretion and its viscosity in chronic constipation (CC) patients. The secretion of chloride (CS) into the gastrointestinal tract lumen is pivotal in the body's ability to process non-digestible food components. CS sets the optimal rate of hydration for non-digestible food components, their fluidity, and their adequate propulsion along the alimentary tract. Chloride is also instrumental in the secretion of alimentary tract mucus, and the formation of a gel-like, viscous mucus-buffer layer. This layer acts as the first line and vanguard of the mucosal barrier. This barrier is essential in mucosal lubrication and protection. Lubiprostone, a novel chloride channel stimulator ClC-2, is currently approved for the treatment of CC. Its impact on mucus, mucus secretion, and viscosity is not established.

METHODS:

A double-blind, crossover trial was approved by the IRBs at the Kansas University Medical Center (Kansas City, KS) (study site) and at the Texas Tech University HSC (El Paso, TX) (analysis site). The study included 20 patients (17 females (F); mean age: 37 years) with symptoms of CC diagnosed according to the Rome III criteria. Patients were randomized to 1 week of therapy with lubiprostone or placebo followed by a 1 week washout and