Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk ...Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease(NAFLD),retinopathy,critical limb ischemia,and impaired angiogenesis.Sterile inflammation driven by high-fat diet,increased formation of reactive oxygen species,alteration of intracellular calcium level and associated release of inflammatory mediators,are the main common underlying forces in the pathophysiology of NAFLD,ischemic retinopathy,stroke,and aging brain.This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein(TXNIP)to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states.Finally,the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.展开更多
Objective:To explore the regulatory role of thioredoxin-interacting protein(TXNIP) in Wnt/β-catenin signaling pathway and therefore to elucidate its function in diabetic myocardial infarction.Methods:Diabetic myocard...Objective:To explore the regulatory role of thioredoxin-interacting protein(TXNIP) in Wnt/β-catenin signaling pathway and therefore to elucidate its function in diabetic myocardial infarction.Methods:Diabetic myocardial infarction models were generated in mice.The expression levels of TXNIP and β-catenin and level of reactive oxygen species(ROS) were determined and compared with those in control group.Human umbilical vein endothelial cells were treated with high-eoncentration glucose and/or silencing TXNIP and/or H_2O_2.After 24 h,expression levels of TXNIP、β-catenin and its downstream protein Cyclin D1,and C-myc gene were determined by real-time PCR,Western blot and immunofluorescence method.The cell proliferation and ROS production capability in different groups were determined by methyl thiazolyl tetrazolium assay.Results:Compared with control group,hyperglycemia significantly up-regulated TXNIP expression and ROS level in the myocardium and endothelial cells of myocardial infarction area,whereas the β-catenin expression was down-regulated,and the difference was statistically significant(P<0.05).In comparison with Human umbilical vein endothelial cells in the control group,high glucose level increased the levels of TXNIP expression and ROS level in cells,but reduced cell proliferation as well as migration capability and expression levels of β-catenin,Cyclin D1 and C-myc;the difference was statistically significant(P<0.05).However,this trend can be partially reversed by silencing TXNIP.Conclusions:Diabetic myocardial ischemia could up-regulate levels of TXNIP expression and ROS production in endothelial cells of myocardial infarction area.The regulation effect of TXNIP on β-catenin was partially achieved by changing ROS levels.展开更多
文摘Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis.Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease(NAFLD),retinopathy,critical limb ischemia,and impaired angiogenesis.Sterile inflammation driven by high-fat diet,increased formation of reactive oxygen species,alteration of intracellular calcium level and associated release of inflammatory mediators,are the main common underlying forces in the pathophysiology of NAFLD,ischemic retinopathy,stroke,and aging brain.This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein(TXNIP)to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states.Finally,the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.
基金Supported by Fund Project.National Natural Science Foundation of China with Grant No.81500290
文摘Objective:To explore the regulatory role of thioredoxin-interacting protein(TXNIP) in Wnt/β-catenin signaling pathway and therefore to elucidate its function in diabetic myocardial infarction.Methods:Diabetic myocardial infarction models were generated in mice.The expression levels of TXNIP and β-catenin and level of reactive oxygen species(ROS) were determined and compared with those in control group.Human umbilical vein endothelial cells were treated with high-eoncentration glucose and/or silencing TXNIP and/or H_2O_2.After 24 h,expression levels of TXNIP、β-catenin and its downstream protein Cyclin D1,and C-myc gene were determined by real-time PCR,Western blot and immunofluorescence method.The cell proliferation and ROS production capability in different groups were determined by methyl thiazolyl tetrazolium assay.Results:Compared with control group,hyperglycemia significantly up-regulated TXNIP expression and ROS level in the myocardium and endothelial cells of myocardial infarction area,whereas the β-catenin expression was down-regulated,and the difference was statistically significant(P<0.05).In comparison with Human umbilical vein endothelial cells in the control group,high glucose level increased the levels of TXNIP expression and ROS level in cells,but reduced cell proliferation as well as migration capability and expression levels of β-catenin,Cyclin D1 and C-myc;the difference was statistically significant(P<0.05).However,this trend can be partially reversed by silencing TXNIP.Conclusions:Diabetic myocardial ischemia could up-regulate levels of TXNIP expression and ROS production in endothelial cells of myocardial infarction area.The regulation effect of TXNIP on β-catenin was partially achieved by changing ROS levels.
