BACKGROUND Approximately 90%of new cases of noncardiac gastric cancer(GC)are related to Helicobacter pylori(H.pylori),and cytotoxin-associated gene A(CagA)is one of the main pathogenic factors.Recent studies have show...BACKGROUND Approximately 90%of new cases of noncardiac gastric cancer(GC)are related to Helicobacter pylori(H.pylori),and cytotoxin-associated gene A(CagA)is one of the main pathogenic factors.Recent studies have shown that the pharmacological effects of cryptotanshinone(CTS)can be used to treat a variety of tumors.However,the effects of CTS on H.pylori,especially CagA+strain-induced gastric mucosal lesions,on the development of GC is unknown.AIM To assess the role of CTS in CagA-induced proliferation and metastasis of GC cells,and determine if CagA+H.pylori strains causes pathological changes in the gastric mucosa of mice.METHODS The effects of CTS on the proliferation of GC cells were assessed using the Cell Counting Kit-8(CCK-8)assay,and the abnormal growth,migration and invasion caused by CagA were detected by CCK-8 and transwell assays.After transfection with pSR-HA-CagA and treatment with CTS,proliferation and metastasis were evaluated by CCK-8 and transwell assays,respectively,and the expression of Src homology 2(SH2)domain–containing phosphatase 2(SHP2)and phosphorylated SHP2(p-SHP2)was detected using western blotting in AGS cells.The enzymelinked immunosorbent assay was used to determine the immunoglobulin G(IgG)level against CagA in patient serum.Mice were divided into four groups and administered H.pylori strains(CagA+or CagA-)and CTS(or PBS)intragastrically,and establishment of the chronic infection model was verified using polymerase chain reaction and sequencing of isolated strains.Hematoxylin and eosin staining was used to assess mucosal erosion in the stomach and toxicity to the liver and kidney.RESULTS CTS inhibited the growth of GC cells in dose-and time-dependent manners.Overexpression of CagA promoted the growth,migration,and invasion of GC cells.Importantly,we demonstrated that CTS significantly inhibited the CagAinduced abnormal proliferation,migration,and invasion of GC cells.Moreover,the expression of p-SHP2 protein in tumor tissue was related to the expression of IgG against CagA in the serum of GC patients.Additionally,CTS suppressed the protein expression levels of both SHP2 and p-SHP2 in GC cells.CTS suppressed CagA+H.pylori strain-induced mucosal erosion in the stomach of mice but had no obvious effects on the CagA-H.pylori strain group.CONCLUSION CTS inhibited CagA-induced proliferation and the epithelial-mesenchymal transition of GC cells in vitro,and CagA+H.pylori strains caused mucosal erosions of the stomach in vivo by decreasing the protein expression of SHP2.展开更多
Helicobacter pylori(H.pylori)infection might initiate and contribute to the progression of lymphoma from gastric mucosa-associated lymphoid tissue(MALT).Increasing evidence shows that eradication of H.pylori with anti...Helicobacter pylori(H.pylori)infection might initiate and contribute to the progression of lymphoma from gastric mucosa-associated lymphoid tissue(MALT).Increasing evidence shows that eradication of H.pylori with antibiotic therapy can lead to regression of gastric MALT lymphoma and can result in a 10-year sustained remission.The eradication of H.pylori is the standard care for patients with gastric MALT lymphoma.Cytotoxin-associated gene A(CagA)protein,one of the most extensively studied H.pylori virulence factors,is strongly associated with the gastric MALT lymphoma.CagA possesses polymorphisms according to its C-terminal structure and displays different functions among areas and races.After being translocated into B lymphocytes via typeⅣsecretion system,CagA deregulates intracellular signaling pathways in both tyrosine phosphorylation-dependent and-independent manners and/or some other pathways,and thereby promotes lymphomagenesis.A variety of proteins including p53and protein tyrosine phosphatases-2 are involved in the malignant transformation induced by CagA.Mucosal inflammation is the foundational mechanism underlying the occurrence and development of gastric MALT lymphoma.展开更多
OBJECTIVE： To assess the role of cytotoxin-associated gene-A （CagA） positive strains of Helicobacter pylori （Hp） in ischemic stroke （IS） subtypes. DATA SOURCES： A computer-based online search of PubMed, EMBASE...OBJECTIVE： To assess the role of cytotoxin-associated gene-A （CagA） positive strains of Helicobacter pylori （Hp） in ischemic stroke （IS） subtypes. DATA SOURCES： A computer-based online search of PubMed, EMBASE, the Cochrane Collaboration database, the CNKI database and the VIP database, from January 1997 to July 2010, was performed to find relevant studies. DATA SELECTION： Case-control studies relevant to CagA with IS and IS subtypes were selected. Data regarding related factors in the case group and control group were acquired using the same approach. All patients had been diagnosed as exhibiting IS using skull CT or MRI, and were etiologically typed according to the 1993 TOAST diagnosis criteria. Two investigators independently performed the same search and study selection. Meta-analyses were then performed for the selected studies using RevMan 5.0 software （Cochrane Collaboration） after strict screening. Heterogeneity tests, sensitivity analyses and publication bias assessments were then conducted. MAIN OUTCOME MEASURES： Relationship of CagA with IS and IS subtypes. RESULTS： Eight studies were selected, involving data from 879 patients with IS, and 849 healthy controls. Five out of eight of the selected studies were related to large artery atherosclerosis （461 patients with IS and 497 health controls）. The results of our meta-analysis revealed a significant association between prior infection with CagA-positive strains and increased risk of IS （odds ratio （OR） = 2.31,95% confidence interval （C/）： 1.89-2.82, P 〈 0.01）, In addition, we found an association between infection with CagA-negative strains and IS （OR = 0.57, 95%C1：0.47 0.70, P 〈 0.01）. CagA positive and negative strains were found to correlate with large artery atherosclerosis （CagA-positive strains： OR = 2.87, 95%C/： 2.19-3.77, P 〈 0.01; CagA-negative strains： OR = 0.51, 95%CL 0.39 0.67, P 〈 0.01）. Because of the diversity of etiological factors in the case-control study, we conducted further analyses after correcting for confounding factors, and the overall effects were recalculated. The results revealed significant relationships between CagA-positive strains and IS （OR = 2.36, 95%C1： 1.84-3.02, P 〈 0.01）, and between CagA-positive strains and large artery atherosclerosis （OR = 3.10, 95%C1： 2.29-4.19, P 〈 0.01 ）. A heterogeneity test of CagA-positive strains in IS and its subtypes revealed good homogeneity （f = 0%; f = 0%） and we adopted a fixed-effects model to calculate OR. Sensitivity analysis confirmed that the results of the meta-analysis were reliable. However, the funnel plot suggested that the experimental results may be affected by bias, possibly resulting from a lack of published studies reporting negative outcomes in the meta-analysis. CONCLUSION： Infection with CagA-positive strains is a risk factor for IS, especially the large artery atherosclerosis subtype. However, the evidence from case-control studies is weak, and more prospective studies are required to conclusively determine whether infection by CagA-positive strains should be considered a novel risk factor for IS and its subtypes.展开更多
Objective A systematic meta-analysis was performed to explore the role of cytotoxin-associated gene-A （CagA） seropositive strains of Helicobacter pylori （H. pylon） in the pathogenesis of atherosclerotic diseases. ...Objective A systematic meta-analysis was performed to explore the role of cytotoxin-associated gene-A （CagA） seropositive strains of Helicobacter pylori （H. pylon） in the pathogenesis of atherosclerotic diseases. Data sources Data from Medline, EMBASE, CBMdisc, CNKI and the Cochrane Collaboration database were searched. Similar search strategies were applied to each of these databases. Study selection The review was restricted to the case-control studies on infective, chronic virulent CagA strains of H. pylori, involving the risk of ischemic stroke and coronary heart disease, ineligible studies were excluded. Two reviewers independently extracted the data and assessed study quality. Results Totally 26 case-control studies （11 studies on ischemic stroke and 15 studies on coronary heart disease） were retrieved and considered. The combined data revealed that the chronic seropositive virulent strains of H. pylori infection had a trend of increasing the risk of ischemic strokes and coronary heart diseases, yielding pooled ORs of 2.68 （95% CI： 2.20, 3.27） and 2.11 （95% CI： 1.70, 2.62）, respectively. We also performed subgroup analyses, dividing the total population into Caucasian and Chinese subgroups. Through the subgroup analysis, no significant difference was found between the subgroups. Conclusions Our results support the hypothesis that CagA-seropositive strains infection is significantly associated with susceptibility to ischemic strokes and coronary heart diseases. The magnitude of the association with atherosclerotic diseases needs to be confirmed by prospective studies and the studies on CagA-seropositive strains eradication are more important.展开更多
目的:比较研究幽门螺杆菌毒素相关蛋白A(Cag A)不同分型对胃上皮细胞AGS形态及IL-8表达影响的差异。方法:设计、人工合成并优化不同cag A基因型,构建相应表达载体,转染胃上皮细胞AGS后观察不同型Cag A对细胞形态及IL-8表达的影响。结果...目的:比较研究幽门螺杆菌毒素相关蛋白A(Cag A)不同分型对胃上皮细胞AGS形态及IL-8表达影响的差异。方法:设计、人工合成并优化不同cag A基因型,构建相应表达载体,转染胃上皮细胞AGS后观察不同型Cag A对细胞形态及IL-8表达的影响。结果:转染后每6 h进行细胞形态观察,于24、36 h对形成蜂鸟状细胞的数量进行统计分析,结果表明,各型Cag A均能引起发生蜂鸟状改变的细胞数量增加;较空载体对照,Cag A的6种型别皆有非常显著差异,Cag A ABCCC与其余5种Cag A型别有非常显著差异。同时于转染后12、36 h对细胞分泌的IL-8进行检测,统计分析表明,转染后12 h,转染各型Cag A细胞的IL-8表达量开始出现差异;转染后36 h,较空载体对照,Cag AABD、Cag A J-Western、Cag A ABDD和Cag A ABCCC存在非常显著差异,Cag A ABDD和Cag A ABCCC分别与Cag AABD、Cag A ABC存在非常显著差异。结论:幽门螺杆菌Cag A可引起转染后的AGS细胞发生蜂鸟状改变及IL-8表达增加,EPIYA基序C数目的增加与细胞蜂鸟状改变呈正相关,EPIYA基序C和D数目的增加与IL-8表达呈正相关。展开更多
基金National Natural Science Foundation of China,No.81572350。
文摘BACKGROUND Approximately 90%of new cases of noncardiac gastric cancer(GC)are related to Helicobacter pylori(H.pylori),and cytotoxin-associated gene A(CagA)is one of the main pathogenic factors.Recent studies have shown that the pharmacological effects of cryptotanshinone(CTS)can be used to treat a variety of tumors.However,the effects of CTS on H.pylori,especially CagA+strain-induced gastric mucosal lesions,on the development of GC is unknown.AIM To assess the role of CTS in CagA-induced proliferation and metastasis of GC cells,and determine if CagA+H.pylori strains causes pathological changes in the gastric mucosa of mice.METHODS The effects of CTS on the proliferation of GC cells were assessed using the Cell Counting Kit-8(CCK-8)assay,and the abnormal growth,migration and invasion caused by CagA were detected by CCK-8 and transwell assays.After transfection with pSR-HA-CagA and treatment with CTS,proliferation and metastasis were evaluated by CCK-8 and transwell assays,respectively,and the expression of Src homology 2(SH2)domain–containing phosphatase 2(SHP2)and phosphorylated SHP2(p-SHP2)was detected using western blotting in AGS cells.The enzymelinked immunosorbent assay was used to determine the immunoglobulin G(IgG)level against CagA in patient serum.Mice were divided into four groups and administered H.pylori strains(CagA+or CagA-)and CTS(or PBS)intragastrically,and establishment of the chronic infection model was verified using polymerase chain reaction and sequencing of isolated strains.Hematoxylin and eosin staining was used to assess mucosal erosion in the stomach and toxicity to the liver and kidney.RESULTS CTS inhibited the growth of GC cells in dose-and time-dependent manners.Overexpression of CagA promoted the growth,migration,and invasion of GC cells.Importantly,we demonstrated that CTS significantly inhibited the CagAinduced abnormal proliferation,migration,and invasion of GC cells.Moreover,the expression of p-SHP2 protein in tumor tissue was related to the expression of IgG against CagA in the serum of GC patients.Additionally,CTS suppressed the protein expression levels of both SHP2 and p-SHP2 in GC cells.CTS suppressed CagA+H.pylori strain-induced mucosal erosion in the stomach of mice but had no obvious effects on the CagA-H.pylori strain group.CONCLUSION CTS inhibited CagA-induced proliferation and the epithelial-mesenchymal transition of GC cells in vitro,and CagA+H.pylori strains caused mucosal erosions of the stomach in vivo by decreasing the protein expression of SHP2.
基金Supported by Foundation of Scientific Technology Bureau of Zhejiang Province,No.2010C33118
文摘Helicobacter pylori(H.pylori)infection might initiate and contribute to the progression of lymphoma from gastric mucosa-associated lymphoid tissue(MALT).Increasing evidence shows that eradication of H.pylori with antibiotic therapy can lead to regression of gastric MALT lymphoma and can result in a 10-year sustained remission.The eradication of H.pylori is the standard care for patients with gastric MALT lymphoma.Cytotoxin-associated gene A(CagA)protein,one of the most extensively studied H.pylori virulence factors,is strongly associated with the gastric MALT lymphoma.CagA possesses polymorphisms according to its C-terminal structure and displays different functions among areas and races.After being translocated into B lymphocytes via typeⅣsecretion system,CagA deregulates intracellular signaling pathways in both tyrosine phosphorylation-dependent and-independent manners and/or some other pathways,and thereby promotes lymphomagenesis.A variety of proteins including p53and protein tyrosine phosphatases-2 are involved in the malignant transformation induced by CagA.Mucosal inflammation is the foundational mechanism underlying the occurrence and development of gastric MALT lymphoma.
基金School-level Foundation,No. 200503Ministry Youth Innovation Fund Project,No. 200901
文摘OBJECTIVE： To assess the role of cytotoxin-associated gene-A （CagA） positive strains of Helicobacter pylori （Hp） in ischemic stroke （IS） subtypes. DATA SOURCES： A computer-based online search of PubMed, EMBASE, the Cochrane Collaboration database, the CNKI database and the VIP database, from January 1997 to July 2010, was performed to find relevant studies. DATA SELECTION： Case-control studies relevant to CagA with IS and IS subtypes were selected. Data regarding related factors in the case group and control group were acquired using the same approach. All patients had been diagnosed as exhibiting IS using skull CT or MRI, and were etiologically typed according to the 1993 TOAST diagnosis criteria. Two investigators independently performed the same search and study selection. Meta-analyses were then performed for the selected studies using RevMan 5.0 software （Cochrane Collaboration） after strict screening. Heterogeneity tests, sensitivity analyses and publication bias assessments were then conducted. MAIN OUTCOME MEASURES： Relationship of CagA with IS and IS subtypes. RESULTS： Eight studies were selected, involving data from 879 patients with IS, and 849 healthy controls. Five out of eight of the selected studies were related to large artery atherosclerosis （461 patients with IS and 497 health controls）. The results of our meta-analysis revealed a significant association between prior infection with CagA-positive strains and increased risk of IS （odds ratio （OR） = 2.31,95% confidence interval （C/）： 1.89-2.82, P 〈 0.01）, In addition, we found an association between infection with CagA-negative strains and IS （OR = 0.57, 95%C1：0.47 0.70, P 〈 0.01）. CagA positive and negative strains were found to correlate with large artery atherosclerosis （CagA-positive strains： OR = 2.87, 95%C/： 2.19-3.77, P 〈 0.01; CagA-negative strains： OR = 0.51, 95%CL 0.39 0.67, P 〈 0.01）. Because of the diversity of etiological factors in the case-control study, we conducted further analyses after correcting for confounding factors, and the overall effects were recalculated. The results revealed significant relationships between CagA-positive strains and IS （OR = 2.36, 95%C1： 1.84-3.02, P 〈 0.01）, and between CagA-positive strains and large artery atherosclerosis （OR = 3.10, 95%C1： 2.29-4.19, P 〈 0.01 ）. A heterogeneity test of CagA-positive strains in IS and its subtypes revealed good homogeneity （f = 0%; f = 0%） and we adopted a fixed-effects model to calculate OR. Sensitivity analysis confirmed that the results of the meta-analysis were reliable. However, the funnel plot suggested that the experimental results may be affected by bias, possibly resulting from a lack of published studies reporting negative outcomes in the meta-analysis. CONCLUSION： Infection with CagA-positive strains is a risk factor for IS, especially the large artery atherosclerosis subtype. However, the evidence from case-control studies is weak, and more prospective studies are required to conclusively determine whether infection by CagA-positive strains should be considered a novel risk factor for IS and its subtypes.
文摘Objective A systematic meta-analysis was performed to explore the role of cytotoxin-associated gene-A （CagA） seropositive strains of Helicobacter pylori （H. pylon） in the pathogenesis of atherosclerotic diseases. Data sources Data from Medline, EMBASE, CBMdisc, CNKI and the Cochrane Collaboration database were searched. Similar search strategies were applied to each of these databases. Study selection The review was restricted to the case-control studies on infective, chronic virulent CagA strains of H. pylori, involving the risk of ischemic stroke and coronary heart disease, ineligible studies were excluded. Two reviewers independently extracted the data and assessed study quality. Results Totally 26 case-control studies （11 studies on ischemic stroke and 15 studies on coronary heart disease） were retrieved and considered. The combined data revealed that the chronic seropositive virulent strains of H. pylori infection had a trend of increasing the risk of ischemic strokes and coronary heart diseases, yielding pooled ORs of 2.68 （95% CI： 2.20, 3.27） and 2.11 （95% CI： 1.70, 2.62）, respectively. We also performed subgroup analyses, dividing the total population into Caucasian and Chinese subgroups. Through the subgroup analysis, no significant difference was found between the subgroups. Conclusions Our results support the hypothesis that CagA-seropositive strains infection is significantly associated with susceptibility to ischemic strokes and coronary heart diseases. The magnitude of the association with atherosclerotic diseases needs to be confirmed by prospective studies and the studies on CagA-seropositive strains eradication are more important.
文摘目的:探讨幽门螺旋杆菌细胞毒素相关基因A(cytotoxin associated gene A,CagA)与胃黏膜中TET2(ten-eleventranslocation 2)蛋白表达的关系,以及TET2在CagA致癌过程中可能的作用。方法:Real-time PCR检测人胃黏膜上皮细胞株GES-1和胃癌细胞株MGC-803中TET2 mRNA的表达水平,细胞免疫染色法检测TET2蛋白的细胞定位及表达。将pEGFP-CagA通过脂质体介导转染GES-1细胞,用200μmol/L H2O2处理GES-1细胞建立氧化应激模型,流式细胞仪检测细胞中活性氧(reactive oxygen species,ROS)和细胞周期的变化。结果:TET2 mRNA在GES-1细胞的表达水平低于胃癌MGC-803细胞(1.00±0.08 vs 1.68±0.07,P<0.05),TET2蛋白在GES-1细胞表达水平低于胃癌MGC-803细胞(8.09±3.57 vs14.60±2.31,P<0.05)。与阴性对照组pEGFP-N1相比,pEGFP-CagA转染组GES-1细胞中TET2 mRNA表达水平升高(1.00±0.04 vs 0.06±0.00,P<0.05),TET2蛋白表达水平也升高(16.45±4.40 vs 10.82±3.39,P<0.05),ROS积累水平升高(18.39±4.52 vs 15.31±4.40,P<0.05),细胞周期检测出现明显的凋亡峰。氧化应激(H2O2处理)模型中GES-1细胞与空白对照GES-1细胞相比,TET2 mRNA水平升高(1.44±0.02 vs 1.00±0.04,P<0.05),TET2蛋白表达水平增高(15.72±4.52vs 11.74±4.34,P<0.05)。结论:幽门螺旋杆菌毒力因子CagA可诱导GES-1细胞ROS增高和细胞周期的失衡,氧化应激可以诱导TET2表达上调,TET2可能参与CagA的致癌过程。
文摘目的:比较研究幽门螺杆菌毒素相关蛋白A(Cag A)不同分型对胃上皮细胞AGS形态及IL-8表达影响的差异。方法:设计、人工合成并优化不同cag A基因型,构建相应表达载体,转染胃上皮细胞AGS后观察不同型Cag A对细胞形态及IL-8表达的影响。结果:转染后每6 h进行细胞形态观察,于24、36 h对形成蜂鸟状细胞的数量进行统计分析,结果表明,各型Cag A均能引起发生蜂鸟状改变的细胞数量增加;较空载体对照,Cag A的6种型别皆有非常显著差异,Cag A ABCCC与其余5种Cag A型别有非常显著差异。同时于转染后12、36 h对细胞分泌的IL-8进行检测,统计分析表明,转染后12 h,转染各型Cag A细胞的IL-8表达量开始出现差异;转染后36 h,较空载体对照,Cag AABD、Cag A J-Western、Cag A ABDD和Cag A ABCCC存在非常显著差异,Cag A ABDD和Cag A ABCCC分别与Cag AABD、Cag A ABC存在非常显著差异。结论:幽门螺杆菌Cag A可引起转染后的AGS细胞发生蜂鸟状改变及IL-8表达增加,EPIYA基序C数目的增加与细胞蜂鸟状改变呈正相关,EPIYA基序C和D数目的增加与IL-8表达呈正相关。
