AIM:To investigate whether tumor necrosis factor-α(TNF-α)mediates ischemia-reperfusion(I/R)-induced intestinal mucosal injury through c-Jun N-terminal kinase(JNK)activation.METHODS:In this study,intestinal I/R was i...AIM:To investigate whether tumor necrosis factor-α(TNF-α)mediates ischemia-reperfusion(I/R)-induced intestinal mucosal injury through c-Jun N-terminal kinase(JNK)activation.METHODS:In this study,intestinal I/R was induced by 60-min occlusion of the superior mesenteric artery in rats followed by 60-min reperfusion,and the rats were pretreated with a TNF-α inhibitor,pentoxifylline,or the TNF-α antibody infliximab.After surgery,part of the intestine was collected for histological analysis.The mucosal layer was harvested for RNA and protein extraction,which were used for further real-time polymerase chain reaction,enzyme-linked immunosorbent assay and Western blotting analyses.The TNF-α expression,intestinal mucosal injury,cell apoptosis,activation of apoptotic protein and JNK signaling pathway were analyzed.RESULTS:I/R significantly enhanced expression of mucosal TNF-α at both the mRNA and protein levels,induced severe mucosal injury and cell apoptosis,activated caspase-9/caspase-3,and activated the JNK signaling pathway.Pretreatment with pentoxifylline markedly downregulated TNF-α at both the mRNA and protein levels,whereas infliximab pretreatment did not affect the expression of TNF-α induced by I/R.However,pretreatment with pentoxifylline or infliximab dramatically suppressed I/R-induced mucosal injury and cell apoptosis and significantly inhibited the activation of caspase-9/3 and JNK signaling.CONCLUSION:The results indicate there was a TNFα-mediated JNK activation response to intestinal I/R injury.展开更多
In the present work,comparative molecular field analysis(CoMFA)techniques were used to perform three-dimensional quantitative structure-activity relationship(3D-QSAR)studies on the anti-tumor activity(pHi,i=1,2,3,4)of...In the present work,comparative molecular field analysis(CoMFA)techniques were used to perform three-dimensional quantitative structure-activity relationship(3D-QSAR)studies on the anti-tumor activity(pHi,i=1,2,3,4)of N-aryl-salicylamide derivatives against four cancer cell lines,including A549,MCF-7,SGC-7901,and Bel-7402.12 compounds were randomly selected as the training set to establish the prediction models,which were verified by the test set of 5 compounds containing template molecule.The contributions of steric and electrostatic fields to pH1,pH2,pH3,and pH4 were 23.8% and 76.2%,20.1% and 79.9%,18.7% and 81.3%,and 14.3%and 85.7%,respectively.The cross-validation(Rcv 2)and non-cross-validation coefficients(R2)were 0.826 and 0.963 for pH1,0.867 and 0.974 for pH2,0.941 and 0.989 for pH3,and 0.797 and 0.961 for pH4,respectively.The CoMFA models were then used to predict the activities of the compounds,and it was found that the models had strong stability and good predictability.Based on the CoMFA contour maps,some key structural factors responsible for the anticancer activity of the series of compounds were revealed.The results provide some useful theoretical references for understanding the mechanism of action,designing new N-aryl-salicylamide derivatives with high anti-tumor activity,and predicting their activities.展开更多
目的:探究益肾通癃汤对前列腺癌(PCa)皮下种植瘤模型裸鼠N-钙黏蛋白(N-cadherin)、波形蛋白(Vimentin)表达的影响。方法:用前列腺癌PC-3细胞悬液建立PCa皮下种植瘤模型裸鼠,造模成功后将其随机分为模型组、益肾通癃汤低剂量组、益肾通...目的:探究益肾通癃汤对前列腺癌(PCa)皮下种植瘤模型裸鼠N-钙黏蛋白(N-cadherin)、波形蛋白(Vimentin)表达的影响。方法:用前列腺癌PC-3细胞悬液建立PCa皮下种植瘤模型裸鼠,造模成功后将其随机分为模型组、益肾通癃汤低剂量组、益肾通癃汤中剂量组、益肾通癃汤高剂量组,每组10只。各给药组灌胃给予相应药物,模型组灌胃给予等体积生理盐水,2次/d,连续3周。给药结束后,观察裸鼠一般状态,测量体质量及瘤体大小,称重并计算抑瘤率;运用HE染色观察各组裸鼠种植瘤病理学改变;ELISA法检测各组裸鼠血清中N-cadherin、Vimentin的水平;Western blotting检测各组裸鼠种植瘤组织中N-cadherin、Vimentin蛋白表达情况;PCR检测各组裸鼠种植瘤组织中N-cadherin m RNA、Vimentin m RNA表达情况。结果:与模型组比较,益肾通癃汤低、中、高剂量组裸鼠状态均可,瘤体质量,血清中N-cadherin、Vimentin水平,种植瘤组织中N-cadherin、Vimentin的蛋白及m RNA相对表达量均降低(P<0.05),瘤体细胞少量坏死;与益肾通癃汤低剂量组比较,益肾通癃汤中、高剂量组裸鼠一般状态可,瘤体质量,血清中N-cadherin、Vimentin水平、种植瘤组织中N-cadherin、Vimentin蛋白及mRNA相对表达量均降低(P<0.05),瘤体细胞部分坏死;与益肾通癃汤中剂量组比较,益肾通癃汤高剂量组裸鼠一般状态良好,瘤体质量,血清中N-cadherin水平,种植瘤组织中N-cadherin、Vimentin蛋白相对表达量,种植瘤组织中Vimentin mRNA相对表达量均降低(P<0.05),瘤体细胞坏死多;益肾通癃汤高剂量组裸鼠血清中Vimentin水平、种植瘤组织中N-cadherin mRNA相对表达量与益肾通癃汤中剂量组比较,差异无统计学意义(P>0.05);益肾通癃汤低、中、高剂量组裸鼠抑瘤率分别为26.67%、42.45%、66.26%。结论:益肾通癃汤对人前列腺癌PC-3细胞皮下种植瘤模型裸鼠N-cadherin、Vimentin蛋白的表达具有一定的抑制作用,其机制可能与抑制肿瘤上皮间质转化(EMT)过程相关。展开更多
Objective： To investigate the methylation status of CpG island in E-cadherin（CDHl）, P16^INK4a（ P16）promoter region ,and to analyze their role in gastrointestinal stromal rumor （GISTs）. Methods： A total of 56 s...Objective： To investigate the methylation status of CpG island in E-cadherin（CDHl）, P16^INK4a（ P16）promoter region ,and to analyze their role in gastrointestinal stromal rumor （GISTs）. Methods： A total of 56 surgically resected GISTs were obtained from January 2003 to December 2005. The routine H＆E-stained sections and CD117, CD34-immunoreactions were reviewed to verify the morphologic diagnosis. Methylation status of the CDH1, P16^INK4a promoter region was analyzed by methylation specific polymerase chain reaction （MSP） from chemically modified DNA after Na-bisulfite treatment. Results： The frequency of CDHlgene methylation was 32% （18 of 56） in GISTs. The rate was 9% （1 of 11）, 21% （4 of 19）, 41.6% （5 of 12）, and 57% （8 of 14） for very low risk, low risk, intermediate risk, and high risk GISTs; P16^INK4a methylation was found in 19 of 56（34%） cases. The rate was 0% （0 of 11）, 16% （3 of 19）, 50% （6 of 12）, and 71% （10 of 14） for very low risk, low risk, intermediate risk, and high risk GISTs. Statistical analysis indicated that of the 56 cases, there was significant association of CDH^INK4a and/or P16^INK4a methylation status with tumor malignant behavior （methylation rate 23/56, 41%, P〈0.01） and site （P〈0.05）. Conclusion： E-cadherin （CDHI） and/or P16^INK4a promoter hypermethylation is strongly associated with risk grade, may be a useful biomarker for GISTs risk assessment, and may shed light on new therapeutic options to treat GISTs展开更多
目的研究恶性肿瘤患者骨转移及其他脏器转移时血清骨唾液酸蛋白(bone sialoprotein,BSP)、I型胶原氨基末端肽(N-terminal telopeptide of type I collagen,NTx)的水平变化。方法收集天津市第四中心医院肿瘤血液科2013年9月至2014年9月...目的研究恶性肿瘤患者骨转移及其他脏器转移时血清骨唾液酸蛋白(bone sialoprotein,BSP)、I型胶原氨基末端肽(N-terminal telopeptide of type I collagen,NTx)的水平变化。方法收集天津市第四中心医院肿瘤血液科2013年9月至2014年9月间收治的资料完整的恶性肿瘤患者49例,其中无转移组(CO组)17例,其他脏器转移组(CM组)15例,骨转移组(CB组)17例,酶联免疫吸附法(enzyme-linked immunosorbent assay,ELISA)试剂盒检测BSP、NTx血清水平。结果1)CB组BSP水平明显高于CO及CM组[分别为(4305.45±964.83)pg/mL、(3302.50±748.67)pg/mL、(3326.34±920.94)pg/mL],且组间差异有统计学意义(P值分别为0.002、0.007)。2)CB组NTx水平明显高于CO及CM组[分别为(58.66±14.33)ng/mL、(39.24±12.62)ng/mL、(47.71±15.49)ng/mL],且组间差异有统计学意义(P值分别为<0.001、0.047)。3)CO与CM组之间BSP及NTx水平近似,组间差异无统计学意义(P值分别为0.963、0.099)。结论血清BSP及NTX水平测定可以作为临床早期监测恶性肿瘤骨转移的特异性指标,试验方法简单,操作方便,有利于临床上广泛开展。展开更多
皮肤黑色素瘤免疫原性高,对传统治疗抵抗,免疫治疗是皮肤黑色素瘤治疗方案中的新兴手段,而疗效的差异性是亟待解决的问题,引发了对皮肤黑色素瘤免疫调控机制的探索。RNA N 6-甲基腺苷(m^(6)A)甲基化修饰在皮肤黑色素瘤的发生、发展、转...皮肤黑色素瘤免疫原性高,对传统治疗抵抗,免疫治疗是皮肤黑色素瘤治疗方案中的新兴手段,而疗效的差异性是亟待解决的问题,引发了对皮肤黑色素瘤免疫调控机制的探索。RNA N 6-甲基腺苷(m^(6)A)甲基化修饰在皮肤黑色素瘤的发生、发展、转移中发挥了重要作用。目前皮肤黑色素瘤主要通过肿瘤微环境、免疫检查点分子及其下游通路进行免疫调控,而m^(6)A调节因子参与其中。探索RNA m^(6)A甲基化修饰与皮肤黑色素瘤免疫调控机制的关系将有助于皮肤黑色素瘤免疫治疗的精准靶向,提高免疫治疗效果。展开更多
基金Supported by Grants-in-Aid from the Major Projects Incubator Program of the National Key Basic Research Program of China,No. 2012CB526700National Natural Science Foundation of China,No. 30971357+2 种基金Natural Science Foundation of Guangdong Province,No. S2011020002348Science and Technology Planning Project of Guangdong Province,No. 2009B060300001Major Projects Incubator Program of SunYat-Sen University,No.10ykjc25
文摘AIM:To investigate whether tumor necrosis factor-α(TNF-α)mediates ischemia-reperfusion(I/R)-induced intestinal mucosal injury through c-Jun N-terminal kinase(JNK)activation.METHODS:In this study,intestinal I/R was induced by 60-min occlusion of the superior mesenteric artery in rats followed by 60-min reperfusion,and the rats were pretreated with a TNF-α inhibitor,pentoxifylline,or the TNF-α antibody infliximab.After surgery,part of the intestine was collected for histological analysis.The mucosal layer was harvested for RNA and protein extraction,which were used for further real-time polymerase chain reaction,enzyme-linked immunosorbent assay and Western blotting analyses.The TNF-α expression,intestinal mucosal injury,cell apoptosis,activation of apoptotic protein and JNK signaling pathway were analyzed.RESULTS:I/R significantly enhanced expression of mucosal TNF-α at both the mRNA and protein levels,induced severe mucosal injury and cell apoptosis,activated caspase-9/caspase-3,and activated the JNK signaling pathway.Pretreatment with pentoxifylline markedly downregulated TNF-α at both the mRNA and protein levels,whereas infliximab pretreatment did not affect the expression of TNF-α induced by I/R.However,pretreatment with pentoxifylline or infliximab dramatically suppressed I/R-induced mucosal injury and cell apoptosis and significantly inhibited the activation of caspase-9/3 and JNK signaling.CONCLUSION:The results indicate there was a TNFα-mediated JNK activation response to intestinal I/R injury.
基金supported by the National Natural Science Foundation of China(21075138)the special fund of State Key Laboratory of Structural Chemistry(20160028)
文摘In the present work,comparative molecular field analysis(CoMFA)techniques were used to perform three-dimensional quantitative structure-activity relationship(3D-QSAR)studies on the anti-tumor activity(pHi,i=1,2,3,4)of N-aryl-salicylamide derivatives against four cancer cell lines,including A549,MCF-7,SGC-7901,and Bel-7402.12 compounds were randomly selected as the training set to establish the prediction models,which were verified by the test set of 5 compounds containing template molecule.The contributions of steric and electrostatic fields to pH1,pH2,pH3,and pH4 were 23.8% and 76.2%,20.1% and 79.9%,18.7% and 81.3%,and 14.3%and 85.7%,respectively.The cross-validation(Rcv 2)and non-cross-validation coefficients(R2)were 0.826 and 0.963 for pH1,0.867 and 0.974 for pH2,0.941 and 0.989 for pH3,and 0.797 and 0.961 for pH4,respectively.The CoMFA models were then used to predict the activities of the compounds,and it was found that the models had strong stability and good predictability.Based on the CoMFA contour maps,some key structural factors responsible for the anticancer activity of the series of compounds were revealed.The results provide some useful theoretical references for understanding the mechanism of action,designing new N-aryl-salicylamide derivatives with high anti-tumor activity,and predicting their activities.
文摘目的:探究益肾通癃汤对前列腺癌(PCa)皮下种植瘤模型裸鼠N-钙黏蛋白(N-cadherin)、波形蛋白(Vimentin)表达的影响。方法:用前列腺癌PC-3细胞悬液建立PCa皮下种植瘤模型裸鼠,造模成功后将其随机分为模型组、益肾通癃汤低剂量组、益肾通癃汤中剂量组、益肾通癃汤高剂量组,每组10只。各给药组灌胃给予相应药物,模型组灌胃给予等体积生理盐水,2次/d,连续3周。给药结束后,观察裸鼠一般状态,测量体质量及瘤体大小,称重并计算抑瘤率;运用HE染色观察各组裸鼠种植瘤病理学改变;ELISA法检测各组裸鼠血清中N-cadherin、Vimentin的水平;Western blotting检测各组裸鼠种植瘤组织中N-cadherin、Vimentin蛋白表达情况;PCR检测各组裸鼠种植瘤组织中N-cadherin m RNA、Vimentin m RNA表达情况。结果:与模型组比较,益肾通癃汤低、中、高剂量组裸鼠状态均可,瘤体质量,血清中N-cadherin、Vimentin水平,种植瘤组织中N-cadherin、Vimentin的蛋白及m RNA相对表达量均降低(P<0.05),瘤体细胞少量坏死;与益肾通癃汤低剂量组比较,益肾通癃汤中、高剂量组裸鼠一般状态可,瘤体质量,血清中N-cadherin、Vimentin水平、种植瘤组织中N-cadherin、Vimentin蛋白及mRNA相对表达量均降低(P<0.05),瘤体细胞部分坏死;与益肾通癃汤中剂量组比较,益肾通癃汤高剂量组裸鼠一般状态良好,瘤体质量,血清中N-cadherin水平,种植瘤组织中N-cadherin、Vimentin蛋白相对表达量,种植瘤组织中Vimentin mRNA相对表达量均降低(P<0.05),瘤体细胞坏死多;益肾通癃汤高剂量组裸鼠血清中Vimentin水平、种植瘤组织中N-cadherin mRNA相对表达量与益肾通癃汤中剂量组比较,差异无统计学意义(P>0.05);益肾通癃汤低、中、高剂量组裸鼠抑瘤率分别为26.67%、42.45%、66.26%。结论:益肾通癃汤对人前列腺癌PC-3细胞皮下种植瘤模型裸鼠N-cadherin、Vimentin蛋白的表达具有一定的抑制作用,其机制可能与抑制肿瘤上皮间质转化(EMT)过程相关。
基金This work was supported by the NaturaScience Foundation of Shanxi Province (No. 2006011122)
文摘Objective： To investigate the methylation status of CpG island in E-cadherin（CDHl）, P16^INK4a（ P16）promoter region ,and to analyze their role in gastrointestinal stromal rumor （GISTs）. Methods： A total of 56 surgically resected GISTs were obtained from January 2003 to December 2005. The routine H＆E-stained sections and CD117, CD34-immunoreactions were reviewed to verify the morphologic diagnosis. Methylation status of the CDH1, P16^INK4a promoter region was analyzed by methylation specific polymerase chain reaction （MSP） from chemically modified DNA after Na-bisulfite treatment. Results： The frequency of CDHlgene methylation was 32% （18 of 56） in GISTs. The rate was 9% （1 of 11）, 21% （4 of 19）, 41.6% （5 of 12）, and 57% （8 of 14） for very low risk, low risk, intermediate risk, and high risk GISTs; P16^INK4a methylation was found in 19 of 56（34%） cases. The rate was 0% （0 of 11）, 16% （3 of 19）, 50% （6 of 12）, and 71% （10 of 14） for very low risk, low risk, intermediate risk, and high risk GISTs. Statistical analysis indicated that of the 56 cases, there was significant association of CDH^INK4a and/or P16^INK4a methylation status with tumor malignant behavior （methylation rate 23/56, 41%, P〈0.01） and site （P〈0.05）. Conclusion： E-cadherin （CDHI） and/or P16^INK4a promoter hypermethylation is strongly associated with risk grade, may be a useful biomarker for GISTs risk assessment, and may shed light on new therapeutic options to treat GISTs
文摘目的研究恶性肿瘤患者骨转移及其他脏器转移时血清骨唾液酸蛋白(bone sialoprotein,BSP)、I型胶原氨基末端肽(N-terminal telopeptide of type I collagen,NTx)的水平变化。方法收集天津市第四中心医院肿瘤血液科2013年9月至2014年9月间收治的资料完整的恶性肿瘤患者49例,其中无转移组(CO组)17例,其他脏器转移组(CM组)15例,骨转移组(CB组)17例,酶联免疫吸附法(enzyme-linked immunosorbent assay,ELISA)试剂盒检测BSP、NTx血清水平。结果1)CB组BSP水平明显高于CO及CM组[分别为(4305.45±964.83)pg/mL、(3302.50±748.67)pg/mL、(3326.34±920.94)pg/mL],且组间差异有统计学意义(P值分别为0.002、0.007)。2)CB组NTx水平明显高于CO及CM组[分别为(58.66±14.33)ng/mL、(39.24±12.62)ng/mL、(47.71±15.49)ng/mL],且组间差异有统计学意义(P值分别为<0.001、0.047)。3)CO与CM组之间BSP及NTx水平近似,组间差异无统计学意义(P值分别为0.963、0.099)。结论血清BSP及NTX水平测定可以作为临床早期监测恶性肿瘤骨转移的特异性指标,试验方法简单,操作方便,有利于临床上广泛开展。
文摘皮肤黑色素瘤免疫原性高,对传统治疗抵抗,免疫治疗是皮肤黑色素瘤治疗方案中的新兴手段,而疗效的差异性是亟待解决的问题,引发了对皮肤黑色素瘤免疫调控机制的探索。RNA N 6-甲基腺苷(m^(6)A)甲基化修饰在皮肤黑色素瘤的发生、发展、转移中发挥了重要作用。目前皮肤黑色素瘤主要通过肿瘤微环境、免疫检查点分子及其下游通路进行免疫调控,而m^(6)A调节因子参与其中。探索RNA m^(6)A甲基化修饰与皮肤黑色素瘤免疫调控机制的关系将有助于皮肤黑色素瘤免疫治疗的精准靶向,提高免疫治疗效果。
