AIM： To study the role of advanced glycation end products （AGE） and their specific receptor （RAGE） in the pathogenesis of liver fibrogenesis. METHODS： In vitro RAGE expression and extracellular matrix-related ge...AIM： To study the role of advanced glycation end products （AGE） and their specific receptor （RAGE） in the pathogenesis of liver fibrogenesis. METHODS： In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells （HSC） were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin （AGE- BSA） and N＇-（carboxymethyl） lysine （CML）-BSA, or with tumor necrosis factor-α （TNF-α）. In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS： In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1（ I ） mRNA by AGE-BSA. CONCLUSION： Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.展开更多
Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms un...Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.展开更多
Advanced glycation end products lead to cell apoptosis, and cause cell death by increasing endoplasmic reticulum stress. Advanced glycation end products alone may also directly cause damage to tissues and cells, but t...Advanced glycation end products lead to cell apoptosis, and cause cell death by increasing endoplasmic reticulum stress. Advanced glycation end products alone may also directly cause damage to tissues and cells, but the precise mechanism remains unknown. This study used primary cultures of rat cerebral cortex neurons, and treated cells with different concentrations of glycation end products （50, 100, 200, 400 mg/L）, and with an antibody for the receptor of advanced glycation end products before and after treatment with advanced glycation end products. The results showed that with increasing concentrations of glycation end products, free radical content increased in neurons, and the number of apoptotic cells increased in a dose-dependent manner. Before and after treatment of advanced glycation end products, the addition of the antibody against advanced glycation end-products markedly reduced hydroxyl free radicals, malondialdehyde levels, and inhibited cell apoptosis. This result indicated that the antibody for receptor of advanced glycation end-products in neurons from the rat cerebral cortex can reduce glycation end product-induced oxidative stress damage by suppressing glycation end product receptors. Overall, our study confirms that the advanced glycation end products-advanced glycation end products receptor pathway may be the main signaling pathway leading to neuronal damage.展开更多
目的:探究外周血高迁移率族蛋白-1(high mobility group box protein 1,HMGB1)、糖基化终产物受体(receptor for advanced glycation endproducts,RAGE)和快速顺序器官功能衰竭评估(quick sequential organ failure assessment,qSOFA)...目的:探究外周血高迁移率族蛋白-1(high mobility group box protein 1,HMGB1)、糖基化终产物受体(receptor for advanced glycation endproducts,RAGE)和快速顺序器官功能衰竭评估(quick sequential organ failure assessment,qSOFA)评分在急性呼吸衰竭并发心肌损伤评估中的应用价值。方法:选择2020年1月-2022年12月就诊于兴山县人民医院的129例急性呼吸衰竭患者作为观察对象,根据患者是否并发心肌损伤将其分为心肌损伤组(n=43)和非心肌损伤组(n=86)。收集所有研究对象入组时的年龄、性别、体重指数等一般资料;评估受试者qSOFA评分,检测受试者外周血HMGB1和RAGE水平;logistic回归分析急性呼吸衰竭并发心肌损伤的影响因素;受试者工作特性曲线(receiver operator characteristic curve,ROC)分析HMGB1、RAGE联合qSOFA评分对急性呼吸衰竭并发心肌损伤的评估价值。结果:心肌损伤组一秒率[第1秒用力呼气容积(forced expiratory volume in one second,FEV1)/用力肺活量(forced vital capacity,FVC)%]和动脉血氧分压(arterial partial pressure of oxygen,PaO2)显著低于非心肌损伤组,动脉血二氧化碳分压(arterial carbon dioxide partial pressure,PaCO_(2))显著高于非心肌损伤组,差异有统计学意义(P<0.05);心肌损伤组外周血HMGB1、RAGE水平和q SOFA评分均显著高于非心肌损伤组,差异有统计学意义(P<0.05);logistic回归分析显示,HMGB1、RAGE水平和qSOFA评分升高均为急性呼吸衰竭患者并发心肌损伤的独立危险因素(P<0.05);ROC分析显示,HMGB1、RAGE水平、qSOFA评分联合检测ROC曲线下面积(AUC)明显高于各指标单独检测,差异有统计学意义(P<0.05)。结论:HMGB1、RAGE水平和qSOFA评分升高均为急性呼吸衰竭患者并发心肌损伤的独立危险因素;HMGB1、RAGE水平和qSOFA评分均可对急性呼吸衰竭患者心肌损伤的发生进行评估,且联合评估的价值更高。展开更多
目的探讨通络救脑口服液对快速老化模型(SAMP8)小鼠晚期糖基化终末产物受体(RAGE)和淀粉样蛋白β(Aβ)表达的影响。方法 24只SAMP8小鼠随机分为模型组、通络救脑高、低剂量组(9,6 m L·kg^(-1)·d^(-1)),另设抗快速衰老亚系1(SA...目的探讨通络救脑口服液对快速老化模型(SAMP8)小鼠晚期糖基化终末产物受体(RAGE)和淀粉样蛋白β(Aβ)表达的影响。方法 24只SAMP8小鼠随机分为模型组、通络救脑高、低剂量组(9,6 m L·kg^(-1)·d^(-1)),另设抗快速衰老亚系1(SAMR1)小鼠对照组(正常对照组),连续灌胃给药21 d。取海马区脑组织,分别采用酶联免疫吸附法(ELISA)和免疫组织化学法检测小鼠大脑海马内Aβ以及RAGE的表达。结果与模型组比较,通络救脑高、低剂量组海马区脑组织RAGE和Aβ表达降低(P<0.01),RAGE蛋白含量明显降低(P<0.01)。结论通络救脑口服液可通过抑制海马区脑组织RAGE和Aβ的表达,以减轻RAGE和Aβ介导的神经病理损伤作用。展开更多
晚期糖基化终末产物受体(receptor for advanced glycation end product,RAGE)是免疫球蛋白受体,能够与多种配体结合,研究发现RAGE参与了非专职吞噬细胞对组蛋白修饰的微米颗粒的吞噬过程,但目前没有研究证明组蛋白是RAGE的配体。该研...晚期糖基化终末产物受体(receptor for advanced glycation end product,RAGE)是免疫球蛋白受体,能够与多种配体结合,研究发现RAGE参与了非专职吞噬细胞对组蛋白修饰的微米颗粒的吞噬过程,但目前没有研究证明组蛋白是RAGE的配体。该研究对组蛋白分子能否直接激活RAGE及其下游信号通路进行探究。使用共聚焦显微镜和流式细胞仪检测哺乳动物细胞对可溶性组蛋白分子的内化;采用钙黄绿素乙酰氧基甲酯/碘化丙啶染色法检测细胞活性;通过荧光探针2′,7′-二氯二氢荧光素二乙酸酯检测胞内活性氧水平;利用酶联免疫吸附剂测定法(enzyme-linked immunosorbent assay,ELISA)测定炎症因子的释放。结果表明,组蛋白分子能够被野生型HEK293T细胞内化并于胞内溶酶体中聚集,RAGE-敲除细胞则无法内化组蛋白;培养基组蛋白质量浓度在100μg/mL时对细胞无明显毒性,细胞活性正常;组蛋白能够通过RAGE刺激细胞活性氧水平升高,并释放炎症因子肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)和白细胞介素-6(interleukin-6,IL-6);组蛋白与DNA结合能够增强对RAGE的刺激。以上结果表明,组蛋白能够激活RAGE及其下游炎症通路。展开更多
基金Supported by Grants from the Interdisciplinary Center for Clinical Research(IZKF,Project B39)the Johannes and Frieda Marohn Foundation of the University of Erlangen-Nuremberg,Germany
文摘AIM： To study the role of advanced glycation end products （AGE） and their specific receptor （RAGE） in the pathogenesis of liver fibrogenesis. METHODS： In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells （HSC） were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin （AGE- BSA） and N＇-（carboxymethyl） lysine （CML）-BSA, or with tumor necrosis factor-α （TNF-α）. In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS： In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1（ I ） mRNA by AGE-BSA. CONCLUSION： Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.
文摘Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.
文摘Advanced glycation end products lead to cell apoptosis, and cause cell death by increasing endoplasmic reticulum stress. Advanced glycation end products alone may also directly cause damage to tissues and cells, but the precise mechanism remains unknown. This study used primary cultures of rat cerebral cortex neurons, and treated cells with different concentrations of glycation end products （50, 100, 200, 400 mg/L）, and with an antibody for the receptor of advanced glycation end products before and after treatment with advanced glycation end products. The results showed that with increasing concentrations of glycation end products, free radical content increased in neurons, and the number of apoptotic cells increased in a dose-dependent manner. Before and after treatment of advanced glycation end products, the addition of the antibody against advanced glycation end-products markedly reduced hydroxyl free radicals, malondialdehyde levels, and inhibited cell apoptosis. This result indicated that the antibody for receptor of advanced glycation end-products in neurons from the rat cerebral cortex can reduce glycation end product-induced oxidative stress damage by suppressing glycation end product receptors. Overall, our study confirms that the advanced glycation end products-advanced glycation end products receptor pathway may be the main signaling pathway leading to neuronal damage.
文摘目的:探究外周血高迁移率族蛋白-1(high mobility group box protein 1,HMGB1)、糖基化终产物受体(receptor for advanced glycation endproducts,RAGE)和快速顺序器官功能衰竭评估(quick sequential organ failure assessment,qSOFA)评分在急性呼吸衰竭并发心肌损伤评估中的应用价值。方法:选择2020年1月-2022年12月就诊于兴山县人民医院的129例急性呼吸衰竭患者作为观察对象,根据患者是否并发心肌损伤将其分为心肌损伤组(n=43)和非心肌损伤组(n=86)。收集所有研究对象入组时的年龄、性别、体重指数等一般资料;评估受试者qSOFA评分,检测受试者外周血HMGB1和RAGE水平;logistic回归分析急性呼吸衰竭并发心肌损伤的影响因素;受试者工作特性曲线(receiver operator characteristic curve,ROC)分析HMGB1、RAGE联合qSOFA评分对急性呼吸衰竭并发心肌损伤的评估价值。结果:心肌损伤组一秒率[第1秒用力呼气容积(forced expiratory volume in one second,FEV1)/用力肺活量(forced vital capacity,FVC)%]和动脉血氧分压(arterial partial pressure of oxygen,PaO2)显著低于非心肌损伤组,动脉血二氧化碳分压(arterial carbon dioxide partial pressure,PaCO_(2))显著高于非心肌损伤组,差异有统计学意义(P<0.05);心肌损伤组外周血HMGB1、RAGE水平和q SOFA评分均显著高于非心肌损伤组,差异有统计学意义(P<0.05);logistic回归分析显示,HMGB1、RAGE水平和qSOFA评分升高均为急性呼吸衰竭患者并发心肌损伤的独立危险因素(P<0.05);ROC分析显示,HMGB1、RAGE水平、qSOFA评分联合检测ROC曲线下面积(AUC)明显高于各指标单独检测,差异有统计学意义(P<0.05)。结论:HMGB1、RAGE水平和qSOFA评分升高均为急性呼吸衰竭患者并发心肌损伤的独立危险因素;HMGB1、RAGE水平和qSOFA评分均可对急性呼吸衰竭患者心肌损伤的发生进行评估,且联合评估的价值更高。
文摘目的探讨通络救脑口服液对快速老化模型(SAMP8)小鼠晚期糖基化终末产物受体(RAGE)和淀粉样蛋白β(Aβ)表达的影响。方法 24只SAMP8小鼠随机分为模型组、通络救脑高、低剂量组(9,6 m L·kg^(-1)·d^(-1)),另设抗快速衰老亚系1(SAMR1)小鼠对照组(正常对照组),连续灌胃给药21 d。取海马区脑组织,分别采用酶联免疫吸附法(ELISA)和免疫组织化学法检测小鼠大脑海马内Aβ以及RAGE的表达。结果与模型组比较,通络救脑高、低剂量组海马区脑组织RAGE和Aβ表达降低(P<0.01),RAGE蛋白含量明显降低(P<0.01)。结论通络救脑口服液可通过抑制海马区脑组织RAGE和Aβ的表达,以减轻RAGE和Aβ介导的神经病理损伤作用。
文摘晚期糖基化终末产物受体(receptor for advanced glycation end product,RAGE)是免疫球蛋白受体,能够与多种配体结合,研究发现RAGE参与了非专职吞噬细胞对组蛋白修饰的微米颗粒的吞噬过程,但目前没有研究证明组蛋白是RAGE的配体。该研究对组蛋白分子能否直接激活RAGE及其下游信号通路进行探究。使用共聚焦显微镜和流式细胞仪检测哺乳动物细胞对可溶性组蛋白分子的内化;采用钙黄绿素乙酰氧基甲酯/碘化丙啶染色法检测细胞活性;通过荧光探针2′,7′-二氯二氢荧光素二乙酸酯检测胞内活性氧水平;利用酶联免疫吸附剂测定法(enzyme-linked immunosorbent assay,ELISA)测定炎症因子的释放。结果表明,组蛋白分子能够被野生型HEK293T细胞内化并于胞内溶酶体中聚集,RAGE-敲除细胞则无法内化组蛋白;培养基组蛋白质量浓度在100μg/mL时对细胞无明显毒性,细胞活性正常;组蛋白能够通过RAGE刺激细胞活性氧水平升高,并释放炎症因子肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)和白细胞介素-6(interleukin-6,IL-6);组蛋白与DNA结合能够增强对RAGE的刺激。以上结果表明,组蛋白能够激活RAGE及其下游炎症通路。
