Background:Nonalcoholic fatty liver disease(NAFLD)is a global health concern with the acid sphingomyelinase(ASM)/ceramide(CE)pathway and the NOD-like receptor family,pyrin domain-containing protein 3(NLRP3)inflammasom...Background:Nonalcoholic fatty liver disease(NAFLD)is a global health concern with the acid sphingomyelinase(ASM)/ceramide(CE)pathway and the NOD-like receptor family,pyrin domain-containing protein 3(NLRP3)inflammasome identified as pivotal players in lipid disorders and inflammation.This study explores the interaction mechanism between the ASM/CE pathway and NLRP3 in NAFLD cell models,aiming to understand the impact of amitriptyline(Ami),an ASM inhibitor,on lipid deposition and hepatocyte injury by regulating the ASM/CE-NLRP3 pathway.Methods:HepG2 and HL-7702 cells were exposed to free fatty acids(FFAs)to establish the NAFLD model.The cells were divided into 5 groups:control group,model group,Ami group,tumor necrosis factoralpha(TNF-α)group,and Ami+TNF-αgroup.Intracellular lipid droplets were visualized using Oil Red O staining,and Western blot analysis quantified ASM,NLRP3,and caspase 1 protein expression.Enzyme linked immunosorbent assay(ELISA)was measured CE and ASM levels,while qRT-PCR assessed mRNA expression.The apoptotic rate was evaluated by flow cytometry(FCM).Results:Following FFAs incubation,significant increases in ASM and CE levels were observed in HepG2 and HL-7702 cells,accompanied by elevated expression of NLRP3,and caspase 1,and IL-1β.TNF-αtreatment further amplified these indicators.Ami demonstrated a reduction in lipid deposition,suppressed ASM/CE pathway activation,downregulated NLRP3 and caspase 1 expression,and improved apoptosis.Additionally,MCC950,a selective inhibitor of the NLRP3,mitigated NLRP3,caspase 1,and IL-1βexpression,alleviating lipid deposition and apoptosis in the NAFLD cell model.Conclusion:The ASM/CE-NLRP3 pathway in NAFLD cells promotes hepatocyte steatosis,inflammation,and cell damage.Ami emerges as a promising therapeutic agent by inhibiting the ASM/CE-NLRP3 pathway,underscoring its potential as a key target for NAFLD treatment.展开更多
With the analysis of experiment and theory on GaN HEMT devices under DC sweep,an improved model for kink effect based on advanced SPICE model for high electron mobility transistors(ASM-HEMT)is pro⁃posed,considering th...With the analysis of experiment and theory on GaN HEMT devices under DC sweep,an improved model for kink effect based on advanced SPICE model for high electron mobility transistors(ASM-HEMT)is pro⁃posed,considering the relationship between the drain/gate-source voltage and kink effect.The improved model can not only accurately describe the trend of the drain-source current with the current collapse and kink effect,but also precisely fit different values of drain-source voltages at which the kink effect occurs under different gatesource voltages.Furthermore,it well characterizes the DC characteristics of GaN devices in the full operating range,with the fitting error less than 3%.To further verify the accuracy and convergence of the improved model,a load-pull system is built in ADS.The simulated result shows that although both the original ASM-HEMT and the improved model predict the output power for the maximum power matching of GaN devices well,the im⁃proved model predicts the power-added efficiency for the maximum efficiency matching more accurately,with 4%improved.展开更多
基金supported by the Initial Scientific Research Fund of the Talents Introduced in Nanjing Lishui People’s Hospital(Project 2021YJ02).
文摘Background:Nonalcoholic fatty liver disease(NAFLD)is a global health concern with the acid sphingomyelinase(ASM)/ceramide(CE)pathway and the NOD-like receptor family,pyrin domain-containing protein 3(NLRP3)inflammasome identified as pivotal players in lipid disorders and inflammation.This study explores the interaction mechanism between the ASM/CE pathway and NLRP3 in NAFLD cell models,aiming to understand the impact of amitriptyline(Ami),an ASM inhibitor,on lipid deposition and hepatocyte injury by regulating the ASM/CE-NLRP3 pathway.Methods:HepG2 and HL-7702 cells were exposed to free fatty acids(FFAs)to establish the NAFLD model.The cells were divided into 5 groups:control group,model group,Ami group,tumor necrosis factoralpha(TNF-α)group,and Ami+TNF-αgroup.Intracellular lipid droplets were visualized using Oil Red O staining,and Western blot analysis quantified ASM,NLRP3,and caspase 1 protein expression.Enzyme linked immunosorbent assay(ELISA)was measured CE and ASM levels,while qRT-PCR assessed mRNA expression.The apoptotic rate was evaluated by flow cytometry(FCM).Results:Following FFAs incubation,significant increases in ASM and CE levels were observed in HepG2 and HL-7702 cells,accompanied by elevated expression of NLRP3,and caspase 1,and IL-1β.TNF-αtreatment further amplified these indicators.Ami demonstrated a reduction in lipid deposition,suppressed ASM/CE pathway activation,downregulated NLRP3 and caspase 1 expression,and improved apoptosis.Additionally,MCC950,a selective inhibitor of the NLRP3,mitigated NLRP3,caspase 1,and IL-1βexpression,alleviating lipid deposition and apoptosis in the NAFLD cell model.Conclusion:The ASM/CE-NLRP3 pathway in NAFLD cells promotes hepatocyte steatosis,inflammation,and cell damage.Ami emerges as a promising therapeutic agent by inhibiting the ASM/CE-NLRP3 pathway,underscoring its potential as a key target for NAFLD treatment.
基金Supported by the National Key R&D Program of China(2022YFF0707800,2022YFF0707801)Primary Research&Development Plan of Jiangsu Province(BE2022070,BE2022070-2)。
文摘With the analysis of experiment and theory on GaN HEMT devices under DC sweep,an improved model for kink effect based on advanced SPICE model for high electron mobility transistors(ASM-HEMT)is pro⁃posed,considering the relationship between the drain/gate-source voltage and kink effect.The improved model can not only accurately describe the trend of the drain-source current with the current collapse and kink effect,but also precisely fit different values of drain-source voltages at which the kink effect occurs under different gatesource voltages.Furthermore,it well characterizes the DC characteristics of GaN devices in the full operating range,with the fitting error less than 3%.To further verify the accuracy and convergence of the improved model,a load-pull system is built in ADS.The simulated result shows that although both the original ASM-HEMT and the improved model predict the output power for the maximum power matching of GaN devices well,the im⁃proved model predicts the power-added efficiency for the maximum efficiency matching more accurately,with 4%improved.
