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
Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced...Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI.展开更多
类风湿关节炎(rheumatoid arthritis,RA)发病机制复杂,晚期糖基化终末产物受体(receptor for advanced glycation end product,RAGE)及其配体在RA的发生发展中扮演着重要角色,也是近年来研究的热点。中药复方治疗RA具有明显的优势,研究...类风湿关节炎(rheumatoid arthritis,RA)发病机制复杂,晚期糖基化终末产物受体(receptor for advanced glycation end product,RAGE)及其配体在RA的发生发展中扮演着重要角色,也是近年来研究的热点。中药复方治疗RA具有明显的优势,研究表明多种中药复方及其活性成分可以通过干预RAGE信号轴的活性,以减轻RAGE及其配体对关节的损伤,减轻滑膜炎症,抑制血管翳的形成等,从而改善RA的临床症状,延缓疾病进展。应用中药复方及其活性成分干预自身免疫性疾病中的RAGE信号通路,提供了一种新的、安全、有效的治疗方法,将具有广阔的发展前景。展开更多
目的探究晚期糖基化终末产物(Receptor for Advanced Glycation End Products,RAGE)受体阻断剂对癫痫幼鼠脑电图、神经元损伤及S100B蛋白表达的影响。方法选取40只无特定病原体级SD雄性幼鼠,随机分为正常组(N组)、模型组(M组)、苯妥英钠...目的探究晚期糖基化终末产物(Receptor for Advanced Glycation End Products,RAGE)受体阻断剂对癫痫幼鼠脑电图、神经元损伤及S100B蛋白表达的影响。方法选取40只无特定病原体级SD雄性幼鼠,随机分为正常组(N组)、模型组(M组)、苯妥英钠组(P组)、RAGE受体阻断剂组(R组),每组10只。M组、P组、R组腹腔注射戊四氮建立癫痫模型,N组不建立该模型,建模成功后,对P组腹腔注射20 mg/kg苯妥英钠,对R组腹腔注射1 mg/kg RAGE受体阻断剂FPS-ZM,N组、M组同期腹腔注射同体积0.9%氯化钠溶液。观察各组幼鼠模型行为学,记录脑电图,采用FJB染色和尼氏染色检测神经元损伤情况,免疫酶标法检测S100B蛋白表达。结果与N组比较,M组、P组、R组幼鼠Racine评分、发作持续时间、发作次数明显升高(P<0.05);与M组比较,P组、R组幼鼠Racine评分、发作持续时间、发作次数明显降低(P<0.05);且与P组相比,R组上述指标显著降低(P<0.05)。与N组比较,M组、P组、R组幼鼠波幅明显升高(P<0.05);频率明显降低(P<0.05);与M组比较,P组、R组幼鼠波幅明显降低(P<0.05),频率明显升高(P<0.05);且与P组相比,R组上述指标变化显著(P<0.05)。与M组相比,P组、R组神经元损伤明显减轻,神经元数量有所增加,神经元形态有所改善,神经元细胞及尼氏小体数目明显增加。与N组比较,M组、P组、R组海马、中脑、额叶皮层S100B蛋白表达显著升高(P<0.05);与M组比较,P组、R组海马、中脑、额叶皮层S100B蛋白表达显著降低(P<0.05);且与P组相比,R组上述指标显著降低(P<0.05)。结论RAGE受体阻断剂可显著改善癫痫幼鼠脑电图和神经元损伤,并抑制S100B蛋白表达。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.
基金Scientific Research Project of Heilongjiang Provincial Education Department(No.12531608)。
文摘Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI.
文摘类风湿关节炎(rheumatoid arthritis,RA)发病机制复杂,晚期糖基化终末产物受体(receptor for advanced glycation end product,RAGE)及其配体在RA的发生发展中扮演着重要角色,也是近年来研究的热点。中药复方治疗RA具有明显的优势,研究表明多种中药复方及其活性成分可以通过干预RAGE信号轴的活性,以减轻RAGE及其配体对关节的损伤,减轻滑膜炎症,抑制血管翳的形成等,从而改善RA的临床症状,延缓疾病进展。应用中药复方及其活性成分干预自身免疫性疾病中的RAGE信号通路,提供了一种新的、安全、有效的治疗方法,将具有广阔的发展前景。
文摘目的探究晚期糖基化终末产物(Receptor for Advanced Glycation End Products,RAGE)受体阻断剂对癫痫幼鼠脑电图、神经元损伤及S100B蛋白表达的影响。方法选取40只无特定病原体级SD雄性幼鼠,随机分为正常组(N组)、模型组(M组)、苯妥英钠组(P组)、RAGE受体阻断剂组(R组),每组10只。M组、P组、R组腹腔注射戊四氮建立癫痫模型,N组不建立该模型,建模成功后,对P组腹腔注射20 mg/kg苯妥英钠,对R组腹腔注射1 mg/kg RAGE受体阻断剂FPS-ZM,N组、M组同期腹腔注射同体积0.9%氯化钠溶液。观察各组幼鼠模型行为学,记录脑电图,采用FJB染色和尼氏染色检测神经元损伤情况,免疫酶标法检测S100B蛋白表达。结果与N组比较,M组、P组、R组幼鼠Racine评分、发作持续时间、发作次数明显升高(P<0.05);与M组比较,P组、R组幼鼠Racine评分、发作持续时间、发作次数明显降低(P<0.05);且与P组相比,R组上述指标显著降低(P<0.05)。与N组比较,M组、P组、R组幼鼠波幅明显升高(P<0.05);频率明显降低(P<0.05);与M组比较,P组、R组幼鼠波幅明显降低(P<0.05),频率明显升高(P<0.05);且与P组相比,R组上述指标变化显著(P<0.05)。与M组相比,P组、R组神经元损伤明显减轻,神经元数量有所增加,神经元形态有所改善,神经元细胞及尼氏小体数目明显增加。与N组比较,M组、P组、R组海马、中脑、额叶皮层S100B蛋白表达显著升高(P<0.05);与M组比较,P组、R组海马、中脑、额叶皮层S100B蛋白表达显著降低(P<0.05);且与P组相比,R组上述指标显著降低(P<0.05)。结论RAGE受体阻断剂可显著改善癫痫幼鼠脑电图和神经元损伤,并抑制S100B蛋白表达。
