幽门螺杆菌dupA基因在胃十二指肠疾病中的研究进展

幽门螺杆菌感染是一个主要的全球公共卫生问题,在发展中国家更为普遍。最近的一项系统回顾显示,全球幽门螺杆菌感染率约为48.5%,约有44亿人为幽门螺杆菌阳性。幽门螺杆菌感染是慢性胃炎和消化性溃疡的主要病因,同时也是胃癌和胃黏膜相关淋巴组织淋巴瘤的危险因素,幽门螺杆菌具有遗传多样性,不同菌株引起的临床症状存在差异,其与宿主的遗传易感性和生存环境有关,主要与细菌毒力因子有关。目前关于幽门螺杆菌dupA基因的研究取得了一定的进展,本文就幽门螺杆菌dupA基因相关研究的最新进展作一综述。

Novel virulence factor dupA of Helicobacter pylori as an important risk determinant for disease manifestation:An overview

Helicobacter pylori(H.pylori)is a microaerophilic,Gram-negative,human gastric pathogen found usually in the mucous lining of stomach.It infects more than 50%of the world’s population and leads to gastroduodenal diseases.The outcome of disease depends on mainly three factors:Host genetics,environment and bacterial factors.Among these,bacterial virulence factors such as cagA,vacA are well known for their role in disease outcomes.However,based on the global epidemiological results,none of the bacterial virulence(gene)factors was found to be associated with particular diseases like duodenal ulcer(DU)in all populations.Hence,substantial importance has been provided for research in strain-specific genes outside the cag pathogenicity island,especially genes located within the plasticity regions.dupA found within the plasticity regions was first demonstrated in 2005 and was proposed for duodenal ulcer development and reduced risk of gastric cancer in certain geographical regions.Due to the discrepancies in report from different parts of the world in DU development related to H.pylori virulence factor,dupA became an interesting area of research in elucidating the role of this gene in the disease progression.In this review,we shed light on the detailed information available on the polymorphisms in dupA and their clinical relevance.We have critically appraised several pertinent studies on dupA and discussed their merits and shortcomings.This review also highlights dupA gene as an important biomarker for DU in certain populations.

Prevalence of Helicobacter pylori vacA,cagA,dupA and oipA Genotypes in Patients with Gastric Disease

Gastric diseases such as chronic gastritis and gastric cancer are most commonly caused by virulence factors of Helicobacter pylori (H. pylori), such as the vacA, cagA, dupA and oipA genes. Therefore, this study investigated the prevalence and the combination of these virulence factors from patients with gastric diseases. The endoscopic biopsies were obtained from 516 patients with gastric symptoms, 101 of which were from patients with normal gastric tissue, 365 of which were from patients with chronic gastritis, and 50 of which were from patients with gastric cancer. H. pylori and the virulence factors were detected by PCR. The oipA gene exhibited an increased risk for chronic gastritis (p = 0.0296), and the vacA gene demonstrated a risk for gastric cancer from chronic gastritis (p = 0.0002). Based on the combination of the virulence factors, cagA, vacA, dupA and oipA genes exhibited a high prevalence in patients with chronic gastritis and gastric cancer. The cagA+/dupA+ genotype demonstrated a significant correlation in patients with normal gastric mucosa (p = 0.0278). In the chronic gastritis group, a significant association was observed between the cagA+ and the vacA s1m1 genotypes (p cagA+/dupA+ genotypes (p = 0.0183), the dupA+/oipA+ genotypes (p cagA, vacA, dupA, and oipA genes, which contributed to the risk of developing gastroduodenal diseases. Furthermore, this is the first study to reveal a high prevalence of the oipA gene in H. pylori isolates in Brazil.

幽门螺杆菌dupA基因与十二指肠溃疡关系的Meta分析

目的探讨幽门螺杆菌(H.pylori)dupA基因与十二指肠溃疡的关系。方法检索国内万方数据库、中国知网、维普中文科技期刊数据库及国外Science Direct、Pubmed等数据库,根据纳入与排除标准筛选文献,提取资料和评价质量后采用Revman 5.3软件对纳入研究的文献进行Meta分析。结果共纳入24篇文献,合计疾病组1 499例,对照组1 827例。Meta分析结果显示幽门螺杆菌dupA基因阳性率与十二指肠溃疡呈正相关(合并OR值为1.82,95%CI:1.37~2.42)。亚组分析显示,亚洲地区dupA基因与十二指肠溃疡的相关性(合并OR值为2.14,95%CI:1.52~3.02)高于西方国家(合并OR值为1.16,95%CI:0.82~1.64)。结论幽门螺杆菌dupA基因与十二指肠溃疡呈正相关,在亚洲人种中相关性比西方国家人种更显著。

Helicobacter pylori and gastric cancer in the Middle East: A new enigma?

The Middle East is the home of ethnic groups from three main backgrounds: Semitic (Arabs and Jews), Indo-European (Persians and Kurdish) and Turkic (Turkish and Turkmens). Its geographic location, which has been under continuous influences from Asia, Europe and Africa, has made it an ideal site for epidemiological studies on Helicobacter pylori (H. pylori) infection and genotyping. The gastric cancer rate differs in this region from very high in Iran (26.1/105) to low in Israel (12.5/105) and very low in Egypt (3.4/105). Epidemiological studies showed that the prevalence of H. pylori is almost similar in those countries with a high level of infection in childhood. Importantly, the frequency of vacA s1 and m1 regions and cagA+ genotypes were higher in non Semitic populations who inhabit the North than Semitic populations, the inhabitants of Southern parts of the Middle East. H. pylori infection prevalence, distribution pattern of virulence factors, diet and smoking could not have explained the difference in cancer rate. This reflects the multifactorial aetiology of gastric cancer and suggests that H. pylori infection does not always directly correlate with the risk for gastrointestinal disease, such as gastric cancer. Further detailed investigations and international comparative studies of each risk factor needto be performed to investigate whether this represents a true enigma.

Role of dup A in virulence of Helicobacter pylori

Helicobacter pylori(H. pylori) is a gastric human pathogen associated with acute and chronic gastritis, 70% of all gastric ulcers, 85% of all duodenal ulcers, and both forms of stomach cancer, mucosal-associated lymphoid tissue(MALT) lymphoma and adenocarcinoma. Recently, attention has focused on possible relationship between presence of certain virulence factor and H. pylori-associated diseases. Some contradictory data between this bacterium and related disorders has been observed since not all the colonized individuals develop to severe disease. The reported diseases plausibility related to H. pylori specific virulence factors became an interesting story about this organism. Although a number of putative virulence factors have been identified including cytotoxin-associated gene a(cag A) and vac A, there are conflicting data about their actual participation as specific risk factor for H. pylori-related diseases. Duodenal ulcer promoting gene a(dup A) is a virulence factor of H. pylori that is highly associated with duodenal ulcer development and reduced risk of gastric cancer. The prevalence of dup A in H. pylori strains isolated from western countries is relatively higher than in H. pylori strains from Asian countries. Current confusing epidemiological reports will continue unless future sophisticated and molecular studies provide data on functional and complete dup A cluster in H. pylori infected individuals. This paper elucidates available knowledge concerning role of dup A in virulence of H. pylori after a decade of its discovery.

Evaluation of the reducing potential of PSMA-containing endosomes by FRET imaging

Aim:Ligand-targeted therapeutics are experiencing increasing use for treatment of human diseases due to their ability to concentrate a desired drug at a pathologic site while reducing accumulation in healthy tissues.For many ligand-targeted drug conjugates,a critical aspect of conjugate design lies in engineering release of the therapeutic payload to occur only after its internalization by targeted cells.Because disulfide bond reduction is frequently exploited to ensure intracellular drug release,an understanding of the redox properties of endocytic compartments can be critical to ligand-targeted drug design.While the redox properties of folate receptor trafficking endosomes have been previously reported,little is known about the trafficking of prostate-specific membrane antigen(PSMA),a receptor that is experiencing increasing use for drug targeting in humans.Methods:To obtain this information,we have constructed a PSMA-targeted fluorescence resonance energy transfer pair that reports on disulfide bond reduction by changing fluorescence from red to green.Results:We show here that this reporter exhibits rapid and selective uptake by PSMA-positive cells,and that reduction of its disulfide bond proceeds steadily but incompletely following internalization.The fact that maximal disulfide reduction reaches only~50%,even after 24 h incubation,suggests that roughly half of the conjugates must traffic through endosomes that display no reducing capacity.Conclusion:As the level of disulfide reduction differs between PSMA trafficked and previously published folate trafficked conjugates,it also follows that not all internalizing receptors are translocated through similar intracellular compartments.Taken together,these data suggest that the efficiency of disulfide bond reduction must be independently analyzed for each receptor trafficking pathway when disulfide bond reduction is exploited for intracellular drug release.