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
目的探讨核因子相关因子2/抗氧化反应元件(Nrf2/ARE)信号通路关键因子与妊娠期肝内胆汁淤积症(ICP)孕妇肝功能和预后的关联性。方法选取2020年1月至2023年6月新乡医学院第一附属医院收治的89例ICP孕妇作为研究组,另按照1∶1配对原则选...目的探讨核因子相关因子2/抗氧化反应元件(Nrf2/ARE)信号通路关键因子与妊娠期肝内胆汁淤积症(ICP)孕妇肝功能和预后的关联性。方法选取2020年1月至2023年6月新乡医学院第一附属医院收治的89例ICP孕妇作为研究组,另按照1∶1配对原则选择孕周、年龄等因素匹配的正常妊娠期女性作为对照组。统计两组孕妇入院当天Nrf2/ARE信号通路关键因子[Nrf2蛋白、血红素加氧酶-1(HO-1)蛋白、醌氧化还原酶1(NQO1)蛋白]、肝功能指标[总胆红素(TBIL)、天冬氨酸氨基转氨酶(AST)、总胆汁酸(TBA)],采用Spearman分析Nrf2/ARE信号通路关键因子与ICP孕妇肝功能指标相关性,同时以不良母婴结局为预后判定标准,比较预后良好和不良孕妇Nrf2/ARE信号通路关键因子、肝功能指标,采用受试者工作特征(ROC)曲线及曲线下面积(AUC)、净重新分类指数(NRI)、整体鉴别指数(IDI)分析上述指标单一及联合预测预后效能。结果研究组孕妇的Nrf2、HO-1、NQO1蛋白表达及TBIL、AST、TBA含量明显高于对照组,差异均有统计学意义(P<0.05);ICP孕妇Nrf2、HO-1、NQO1蛋白表达与TBIL、AST、TBA呈正相关(r_(1)=0.592、0.587、0.624,r_(2)=0.571、0.599、0.611,r_(3)=0.566、0.576、0.598,P<0.05);预后不良组孕妇的Nrf2、HO-1、NQO1蛋白表达及TBIL、AST、TBA含量分别为1.70±0.39、1.59±0.33、1.75±0.44、(24.46±7.34)μmol/L、(50.51±16.11)U/L、(61.77±13.38)μmol/L,明显高于预后不良组1.40±0.33、1.35±0.30、1.34±0.36、(16.24±4.88)μmol/L、(41.24±12.34)U/L、(49.68±8.89)μmol/L,差异均有统计学意义(P<0.05);Nrf2+HO-1+NQO1蛋白预测ICP孕妇预后效能近似TBIL+AST+TBA(AUC:0.924 vs 0.929);Nrf2+HO-1+NQO1蛋白、TBIL+AST+TBA较单一指标可显著提升ICP孕妇预后预测能力,IDI分别为0.714(0.448~0.970)、0.709(0.423~1.457)、NRI分别为0.077(0.021~0.119)、0.089(0.018~0.027)。结论Nrf2/ARE信号通路关键因子与ICP孕妇肝功能密切相关,三者联合检测有助于提高预后预测效能,为本病鉴别诊治提供依据。展开更多
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.
文摘目的探讨核因子相关因子2/抗氧化反应元件(Nrf2/ARE)信号通路关键因子与妊娠期肝内胆汁淤积症(ICP)孕妇肝功能和预后的关联性。方法选取2020年1月至2023年6月新乡医学院第一附属医院收治的89例ICP孕妇作为研究组,另按照1∶1配对原则选择孕周、年龄等因素匹配的正常妊娠期女性作为对照组。统计两组孕妇入院当天Nrf2/ARE信号通路关键因子[Nrf2蛋白、血红素加氧酶-1(HO-1)蛋白、醌氧化还原酶1(NQO1)蛋白]、肝功能指标[总胆红素(TBIL)、天冬氨酸氨基转氨酶(AST)、总胆汁酸(TBA)],采用Spearman分析Nrf2/ARE信号通路关键因子与ICP孕妇肝功能指标相关性,同时以不良母婴结局为预后判定标准,比较预后良好和不良孕妇Nrf2/ARE信号通路关键因子、肝功能指标,采用受试者工作特征(ROC)曲线及曲线下面积(AUC)、净重新分类指数(NRI)、整体鉴别指数(IDI)分析上述指标单一及联合预测预后效能。结果研究组孕妇的Nrf2、HO-1、NQO1蛋白表达及TBIL、AST、TBA含量明显高于对照组,差异均有统计学意义(P<0.05);ICP孕妇Nrf2、HO-1、NQO1蛋白表达与TBIL、AST、TBA呈正相关(r_(1)=0.592、0.587、0.624,r_(2)=0.571、0.599、0.611,r_(3)=0.566、0.576、0.598,P<0.05);预后不良组孕妇的Nrf2、HO-1、NQO1蛋白表达及TBIL、AST、TBA含量分别为1.70±0.39、1.59±0.33、1.75±0.44、(24.46±7.34)μmol/L、(50.51±16.11)U/L、(61.77±13.38)μmol/L,明显高于预后不良组1.40±0.33、1.35±0.30、1.34±0.36、(16.24±4.88)μmol/L、(41.24±12.34)U/L、(49.68±8.89)μmol/L,差异均有统计学意义(P<0.05);Nrf2+HO-1+NQO1蛋白预测ICP孕妇预后效能近似TBIL+AST+TBA(AUC:0.924 vs 0.929);Nrf2+HO-1+NQO1蛋白、TBIL+AST+TBA较单一指标可显著提升ICP孕妇预后预测能力,IDI分别为0.714(0.448~0.970)、0.709(0.423~1.457)、NRI分别为0.077(0.021~0.119)、0.089(0.018~0.027)。结论Nrf2/ARE信号通路关键因子与ICP孕妇肝功能密切相关,三者联合检测有助于提高预后预测效能,为本病鉴别诊治提供依据。
