目的:通过观察丹芍化纤胶囊对肝纤维化大鼠PDGFR-β和p-ERK1/2的影响,探索其抗肝纤维化的可能机制.方法:♂SD大鼠55只,体质量180-220g,随机分为正常组、模型组、预防组.除正常组外,其余均采用四氯化碳、高脂饮食及乙醇复合因素复制肝纤...目的:通过观察丹芍化纤胶囊对肝纤维化大鼠PDGFR-β和p-ERK1/2的影响,探索其抗肝纤维化的可能机制.方法:♂SD大鼠55只,体质量180-220g,随机分为正常组、模型组、预防组.除正常组外,其余均采用四氯化碳、高脂饮食及乙醇复合因素复制肝纤维化模型,造模同时预防组每日一次予以0.8 g/kg丹芍化纤自来水悬液灌胃,模型组、正常组予以等体积自来水灌胃,持续8 wk.造模结束后肝组织HE染色病理检查,免疫组化检测肝组织PDGFR-β、蛋白印迹检测肝组织p-ERK1/2在各组表达,生化法检测各组血清透明质酸(HA)、层黏蛋白(LN)、Ⅲ型前胶原(PⅢP)、白蛋白(ALB)、总蛋白(TP),计算白球比(A/G).结果:造模8 wk后经病理学证实模型大鼠形成典型的肝纤维化,模型成功.与正常组相比,模型组肝组织PDGFR-β、p-ERK1/2及血清HA、LN、PⅢP均有显著升高,ALB、A/G显著降低(PDGFR-β:184.6±8.5 vs 89.6±5.8,P<0.05;p-ERK1/2:360.0±14.5 vx 15.4±2.1,P<0.05;HA:517.5±91.5μg/L vs 254.4±33.1μg/L,P<0.05;LN:58.4±11.3μg/L vs 37.3±9.8μg/L,P<0.05:PⅢP:36.9±5.6μg/L vs 4.7±1.5μg/L,P<0.05;ALB:27.4±4.9 g/L vs 42.1±1.6 g/L,P<0.05;A/G:0.89±0.08 vs 1.38±0.09,P<0.05);与模型组相比,预防组肝组织PDGFR-β、p-ERK1/2及血清HA、LN、PⅢP均有显著降低,ALB、A/G显著升高(PDGFR-β:91.1±6.3 vs 184.6±8.5,P<0.05;p-ERK1/2:253.8±18.2 vs 360.0±14.5,P<0.05;HA:322.9±41.4μg/L vs 517.5±91.5μg/L,P<0.05;LN:46.0±9.4μg/L vs 58.4±11.3μg/L,P<0.05;PⅢP:14.5±2.4μg/L vs 36.9±5.6μg/L,P<0.05;ALB:37.2±2.8g/L vs 27.4±4.9g/L,P<0.05;A/G:1.18±0.13 vs 0.89±0.08,P<0.05).结论:PDGFR-β及p-ERK1/2在肝纤维化形成中起重要作用,丹芍化纤胶囊具有良好的预防肝纤维化形成的作用,其降低PDGFR-β及p-ERK1/2在肝组织的表达可能是其作用机制之一.展开更多
Objective： Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colon...Objective： Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colonic fibroblasts. Methods： Cell cycle analysis and cell proliferation assays were performed to evaluate the inhibitory effect of sunitinib in vitro. Western-blot analysis was performed to evaluate variations in the levels of phosphorylated plateletderived growth factor receptor β （PDGFR-β）, Akt, and ERK proteins. Co-injection of SW620 cells and colonic fibreblasts in nude mice was employed to test anti-growth efficacy in vivo. Results： Sunitinib was found to effectively inhibit the growth of primary colonic fibroblasts. Low-dose sunitinib blocked the PDGF-BB-induced cell proliferation and PDGFR-β signaling. Co-injection of SW620 cells and colonic fibroblasts in nude mice generated greater tumor volumes than single injection of SW620 cells. Sunitinib treatment inhibited the SW620 cell＋colonic fibroblast tumor growth more effectively than treatment of 5-fluorouracil. Conclusions： Sunitinib mesylate inhibited the proliferation of primary human colonic fibroblasts through target-inhibited PDGFR signaling in vitro and in vivo.展开更多
文摘目的:通过观察丹芍化纤胶囊对肝纤维化大鼠PDGFR-β和p-ERK1/2的影响,探索其抗肝纤维化的可能机制.方法:♂SD大鼠55只,体质量180-220g,随机分为正常组、模型组、预防组.除正常组外,其余均采用四氯化碳、高脂饮食及乙醇复合因素复制肝纤维化模型,造模同时预防组每日一次予以0.8 g/kg丹芍化纤自来水悬液灌胃,模型组、正常组予以等体积自来水灌胃,持续8 wk.造模结束后肝组织HE染色病理检查,免疫组化检测肝组织PDGFR-β、蛋白印迹检测肝组织p-ERK1/2在各组表达,生化法检测各组血清透明质酸(HA)、层黏蛋白(LN)、Ⅲ型前胶原(PⅢP)、白蛋白(ALB)、总蛋白(TP),计算白球比(A/G).结果:造模8 wk后经病理学证实模型大鼠形成典型的肝纤维化,模型成功.与正常组相比,模型组肝组织PDGFR-β、p-ERK1/2及血清HA、LN、PⅢP均有显著升高,ALB、A/G显著降低(PDGFR-β:184.6±8.5 vs 89.6±5.8,P<0.05;p-ERK1/2:360.0±14.5 vx 15.4±2.1,P<0.05;HA:517.5±91.5μg/L vs 254.4±33.1μg/L,P<0.05;LN:58.4±11.3μg/L vs 37.3±9.8μg/L,P<0.05:PⅢP:36.9±5.6μg/L vs 4.7±1.5μg/L,P<0.05;ALB:27.4±4.9 g/L vs 42.1±1.6 g/L,P<0.05;A/G:0.89±0.08 vs 1.38±0.09,P<0.05);与模型组相比,预防组肝组织PDGFR-β、p-ERK1/2及血清HA、LN、PⅢP均有显著降低,ALB、A/G显著升高(PDGFR-β:91.1±6.3 vs 184.6±8.5,P<0.05;p-ERK1/2:253.8±18.2 vs 360.0±14.5,P<0.05;HA:322.9±41.4μg/L vs 517.5±91.5μg/L,P<0.05;LN:46.0±9.4μg/L vs 58.4±11.3μg/L,P<0.05;PⅢP:14.5±2.4μg/L vs 36.9±5.6μg/L,P<0.05;ALB:37.2±2.8g/L vs 27.4±4.9g/L,P<0.05;A/G:1.18±0.13 vs 0.89±0.08,P<0.05).结论:PDGFR-β及p-ERK1/2在肝纤维化形成中起重要作用,丹芍化纤胶囊具有良好的预防肝纤维化形成的作用,其降低PDGFR-β及p-ERK1/2在肝组织的表达可能是其作用机制之一.
基金supported by the National Natural Science Foundation of China(Nos.81071801 and 81272455)the Zhejiang Provincial Natural Science Foundation of China(No.R2100071)
文摘Objective： Cancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colonic fibroblasts. Methods： Cell cycle analysis and cell proliferation assays were performed to evaluate the inhibitory effect of sunitinib in vitro. Western-blot analysis was performed to evaluate variations in the levels of phosphorylated plateletderived growth factor receptor β （PDGFR-β）, Akt, and ERK proteins. Co-injection of SW620 cells and colonic fibreblasts in nude mice was employed to test anti-growth efficacy in vivo. Results： Sunitinib was found to effectively inhibit the growth of primary colonic fibroblasts. Low-dose sunitinib blocked the PDGF-BB-induced cell proliferation and PDGFR-β signaling. Co-injection of SW620 cells and colonic fibroblasts in nude mice generated greater tumor volumes than single injection of SW620 cells. Sunitinib treatment inhibited the SW620 cell＋colonic fibroblast tumor growth more effectively than treatment of 5-fluorouracil. Conclusions： Sunitinib mesylate inhibited the proliferation of primary human colonic fibroblasts through target-inhibited PDGFR signaling in vitro and in vivo.
