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
The GECAM series of satellites utilizes LaBr_(3)(Ce),LaBr_(3)(Ce,Sr),and NaI(Tl)crystals as sensitive materials for gamma-ray detectors(GRDs).To investigate the nonlinearity in the detection of low-energy gamma rays a...The GECAM series of satellites utilizes LaBr_(3)(Ce),LaBr_(3)(Ce,Sr),and NaI(Tl)crystals as sensitive materials for gamma-ray detectors(GRDs).To investigate the nonlinearity in the detection of low-energy gamma rays and address the errors in the calibration of the E-C relationship,comprehensive tests and comparative studies of the three aforementioned crystals were conducted using Compton electrons,radioactive sources,and mono-energetic X-rays.The nonlinearity test results of the Compton electrons and X-rays demonstrated substantial differences,with all three crystals presenting a higher nonlinearity for X/-rays than for Compton electrons.Despite the LaBr_(3)(Ce)and LaBr_(3)(Ce,Sr)crystals having higher absolute light yields,they exhibited a noticeable nonlinear decrease in the light yield,especially at energies below 400 keV.The NaI(Tl)crystal demonstrated an"excess"light output in the 6-200 keV range,reaching a maximum"excess"of 9.2%at 30 keV in the X-ray testing and up to 15.5%at 14 keV during Compton electron testing,indicating a significant advantage in the detection of low-energy gamma rays.Furthermore,we explored the underlying causes of the observed nonlinearity in these crystals.This study not only elucidates the detector responses of GECAM,but also initiates a comprehensive investigation of the nonlinearity of domestically produced lanthanum bromide and sodium iodide crystals.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This work was supported by the National Key Research and Development Program(Nos.2022YFB3503600 and 2021YFA0718500)Strategic Priority Research Program of the Chinese Academy of Sciences(Nos.XDA15360102)National Natural Science Foundation of China(Nos.12273042 and 12075258).
文摘The GECAM series of satellites utilizes LaBr_(3)(Ce),LaBr_(3)(Ce,Sr),and NaI(Tl)crystals as sensitive materials for gamma-ray detectors(GRDs).To investigate the nonlinearity in the detection of low-energy gamma rays and address the errors in the calibration of the E-C relationship,comprehensive tests and comparative studies of the three aforementioned crystals were conducted using Compton electrons,radioactive sources,and mono-energetic X-rays.The nonlinearity test results of the Compton electrons and X-rays demonstrated substantial differences,with all three crystals presenting a higher nonlinearity for X/-rays than for Compton electrons.Despite the LaBr_(3)(Ce)and LaBr_(3)(Ce,Sr)crystals having higher absolute light yields,they exhibited a noticeable nonlinear decrease in the light yield,especially at energies below 400 keV.The NaI(Tl)crystal demonstrated an"excess"light output in the 6-200 keV range,reaching a maximum"excess"of 9.2%at 30 keV in the X-ray testing and up to 15.5%at 14 keV during Compton electron testing,indicating a significant advantage in the detection of low-energy gamma rays.Furthermore,we explored the underlying causes of the observed nonlinearity in these crystals.This study not only elucidates the detector responses of GECAM,but also initiates a comprehensive investigation of the nonlinearity of domestically produced lanthanum bromide and sodium iodide crystals.
