Acute lung injury(ALI)is a critical respiratory disorder with a high mortality rate and is caused by several factors.Addressing oxidative stress and infiammation is a pivotal strategy for ALI treatment.In this study,w...Acute lung injury(ALI)is a critical respiratory disorder with a high mortality rate and is caused by several factors.Addressing oxidative stress and infiammation is a pivotal strategy for ALI treatment.In this study,we introduced a novel nanotherapeutic approach involving a curcumin-loaded ceria nanoenzyme delivery system tailored to counteract the multifaceted aspects of ALI.This system leverages the individual and combined effects of the components to provide a comprehensive therapeutic solution.The dual-action capability of this nanosystem was manifested by mitigating mitochondrial oxidative stress in lung epithelial cells and inhibiting the transient receptor potential melanosome-associated protein 2(TRPM2)-NOD-like receptor thermal protein domain associated protein 3(NLRP3)signaling pathway,offering a highly effective therapeutic approach to ALI.Our findings reveal the underlying mechanisms of this innovative nanodelivery system,showcasing its potential as a versatile strategy for ALI treatment and encouraging further exploration of nanoenzyme-based therapies for ALI.展开更多
Alzheimer's disease(AD),the most prevalent form of dementia,disproportionately affects the elderly population.While aging is widely recognized as a major risk factor for AD,the precise mechanisms by which aging co...Alzheimer's disease(AD),the most prevalent form of dementia,disproportionately affects the elderly population.While aging is widely recognized as a major risk factor for AD,the precise mechanisms by which aging contributes to the pathogenesis of AD remain poorly understood.In our previous work,the neuropathological changes in the brains of aged cynomolgus monkeys(≥18 years old)following parenchymal cerebral injection of amyloid-β oligomers(AβOs)have been characterized.Here,we extend our investigation to middle-aged cynomolgus monkeys(≤15 years old)to establish an AD model.Surprisingly,immunohistochemical analysis reveals no detectable AD-related pathology in the brains of middle-aged monkeys,even after AβOs injection.In a comprehensive pathological analysis of 38 monkeys,we observe that the amyloid-β(Aβ)burden increases significantly with advancing age.Notably,the density of Aβ plaques is markedly higher in the ventral regions compared with the dorsal regions of aged monkey brains.Furthermore,we demonstrate that tau phosphorylation coincides with the accumulation of extensive Aβplaques and exhibits a positive correlation with Aβ burden in aged monkeys.Collectively,these findings underscore the critical role of the aged brain in providing the necessary conditions for AβO-induced AD pathologies in cynomolgus monkeys.展开更多
BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(...BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(mGluR5)may alleviate hepatic steatosis.However,the precise mechanism warrants further exploration.AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.METHODS Free fatty acids(FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG.Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content.Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II,as well as the expression of the key signaling molecules AMPK and ULK1,in the treated cells.To further elucidate the contributions of autophagy and AMPK,we used chloroquine(CQ)to inhibit autophagy and compound C(CC)to inhibit AMPK activity.In parallel,wild-type mice and mGluR5 knockout(KO)mice fed a normal chow diet or a high-fat diet(HFD)were used to evaluate the effect of mGluR5 inhibition in vivo.RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression.The autophagy inhibitor CQ reversed the effects of MPEP.In addition,MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs.MPEP treatment led to the nuclear translocation of transcription factor EB,which is known to promote p62 expression.This effect was negated by the AMPK inhibitor CC.mGluR5 KO mice presented reduced body weight,improved glucose tolerance and reduced hyperlipidemia when fed a HFD.Additionally,the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway.These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.展开更多
目的探讨法医毒物分析中液相色谱-串联质谱(liquid chromatography-tandem mass spectrome⁃try,LC-MS/MS)法检测血液中毒品类(甲基苯丙胺、吗啡、氯胺酮)、苯二氮蓝卓类(艾司唑仑、咪达唑仑、地西泮、氯硝西泮)和巴比妥类(苯巴比妥)共3...目的探讨法医毒物分析中液相色谱-串联质谱(liquid chromatography-tandem mass spectrome⁃try,LC-MS/MS)法检测血液中毒品类(甲基苯丙胺、吗啡、氯胺酮)、苯二氮蓝卓类(艾司唑仑、咪达唑仑、地西泮、氯硝西泮)和巴比妥类(苯巴比妥)共3大类8种常见药(毒)物的保留时间和离子丰度比的最大允许偏差。方法在2根色谱柱、3种色谱条件下,经液液萃取后采用LC-MS/MS进行检测,分析质量浓度在检出限(limit of detection,LOD)、2倍检出限(2LOD)、定量限(limit of quantitation,LOQ)、1.5倍定量限(1.5LOQ)、2倍定量限(2LOQ)、4倍定量限(4LOQ)和6倍定量限(6LOQ)共7个较低质量浓度时保留时间和离子丰度比的偏差。结果血液添加样品中8种药(毒)物绝对保留时间的偏差在±0.05 min范围内的占98.11%,相对保留时间的偏差在±0.4%范围内的占96.21%。离子丰度比的最大偏差与质量浓度存在高度关联:药(毒)物质量浓度为LOQ及以上时,离子丰度比的绝对偏差和相对偏差都有95%以上分别在±25%和±40%范围内;质量浓度为LOQ以下时,范围可分别扩大至±35%和±50%。结论建议8种常见药(毒)物绝对保留时间的偏差判定范围为±0.1min,相对保留时间的偏差判定范围为±1.0%。质量浓度在LOQ及以上时离子丰度比的绝对偏差判定范围为±25%,相对偏差为±40%,质量浓度在LOQ以下时偏差判定范围可分别扩大至±35%和±50%。展开更多
基金funded by the National Natural Science Foundation of China(Nos.82103885,81871521,82273672)Natural Science Foundation of Shanghai(Nos.21ZR1477700,20ZR1470300)+1 种基金the Shanghai Municipal Health Commission-Outstanding Youth Foundation of Public Health(No.GWV-10.2-YQ48)Sci Tech Funding by CSPFTZ Lingang Special Area Marine Biomedical Innovation Platform。
文摘Acute lung injury(ALI)is a critical respiratory disorder with a high mortality rate and is caused by several factors.Addressing oxidative stress and infiammation is a pivotal strategy for ALI treatment.In this study,we introduced a novel nanotherapeutic approach involving a curcumin-loaded ceria nanoenzyme delivery system tailored to counteract the multifaceted aspects of ALI.This system leverages the individual and combined effects of the components to provide a comprehensive therapeutic solution.The dual-action capability of this nanosystem was manifested by mitigating mitochondrial oxidative stress in lung epithelial cells and inhibiting the transient receptor potential melanosome-associated protein 2(TRPM2)-NOD-like receptor thermal protein domain associated protein 3(NLRP3)signaling pathway,offering a highly effective therapeutic approach to ALI.Our findings reveal the underlying mechanisms of this innovative nanodelivery system,showcasing its potential as a versatile strategy for ALI treatment and encouraging further exploration of nanoenzyme-based therapies for ALI.
基金supported in part by the National Key Basic Research and Development Program of China(2019YFA0801402,2018YFA0107200,2018YFA0801402,2018YFA0800100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16020501 and XDA16020404)the National Natural Science Foundation of China(32130030,31900454,32470866,32471010,32100800)。
文摘Alzheimer's disease(AD),the most prevalent form of dementia,disproportionately affects the elderly population.While aging is widely recognized as a major risk factor for AD,the precise mechanisms by which aging contributes to the pathogenesis of AD remain poorly understood.In our previous work,the neuropathological changes in the brains of aged cynomolgus monkeys(≥18 years old)following parenchymal cerebral injection of amyloid-β oligomers(AβOs)have been characterized.Here,we extend our investigation to middle-aged cynomolgus monkeys(≤15 years old)to establish an AD model.Surprisingly,immunohistochemical analysis reveals no detectable AD-related pathology in the brains of middle-aged monkeys,even after AβOs injection.In a comprehensive pathological analysis of 38 monkeys,we observe that the amyloid-β(Aβ)burden increases significantly with advancing age.Notably,the density of Aβ plaques is markedly higher in the ventral regions compared with the dorsal regions of aged monkey brains.Furthermore,we demonstrate that tau phosphorylation coincides with the accumulation of extensive Aβplaques and exhibits a positive correlation with Aβ burden in aged monkeys.Collectively,these findings underscore the critical role of the aged brain in providing the necessary conditions for AβO-induced AD pathologies in cynomolgus monkeys.
基金Supported by National Natural Science Foundation of China,No.81800771 and No.81300702.
文摘BACKGROUND The global prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has continued to increase annually.Recent studies have indicated that inhibition of metabotropic glutamate receptor 5(mGluR5)may alleviate hepatic steatosis.However,the precise mechanism warrants further exploration.AIM To investigate the potential mechanism by which mGluR5 attenuates hepatocyte steatosis in vitro and in vivo.METHODS Free fatty acids(FFAs)-stimulated HepG2 cells were treated with the mGluR5 antagonist MPEP and the mGluR5 agonist CHPG.Oil Red O staining and a triglyceride assay kit were used to evaluate lipid content.Western blot analysis was conducted to detect the expression of the autophagy-associated proteins p62 and LC3-II,as well as the expression of the key signaling molecules AMPK and ULK1,in the treated cells.To further elucidate the contributions of autophagy and AMPK,we used chloroquine(CQ)to inhibit autophagy and compound C(CC)to inhibit AMPK activity.In parallel,wild-type mice and mGluR5 knockout(KO)mice fed a normal chow diet or a high-fat diet(HFD)were used to evaluate the effect of mGluR5 inhibition in vivo.RESULTS mGluR5 inhibition by MPEP attenuated hepatocellular steatosis and increased LC3-II and p62 protein expression.The autophagy inhibitor CQ reversed the effects of MPEP.In addition,MPEP promoted AMPK and ULK1 expression in HepG2 cells exposed to FFAs.MPEP treatment led to the nuclear translocation of transcription factor EB,which is known to promote p62 expression.This effect was negated by the AMPK inhibitor CC.mGluR5 KO mice presented reduced body weight,improved glucose tolerance and reduced hyperlipidemia when fed a HFD.Additionally,the livers of HFD-fed mGluR5 KO mice presented increases in LC3-II and p62.CONCLUSION Our results suggest that mGluR5 inhibition promoted autophagy and reduced hepatocyte steatosis through activation of the AMPK signaling pathway.These findings reveal a new functional mechanism of mGluR5 as a target in the treatment of MASLD.
文摘目的探讨法医毒物分析中液相色谱-串联质谱(liquid chromatography-tandem mass spectrome⁃try,LC-MS/MS)法检测血液中毒品类(甲基苯丙胺、吗啡、氯胺酮)、苯二氮蓝卓类(艾司唑仑、咪达唑仑、地西泮、氯硝西泮)和巴比妥类(苯巴比妥)共3大类8种常见药(毒)物的保留时间和离子丰度比的最大允许偏差。方法在2根色谱柱、3种色谱条件下,经液液萃取后采用LC-MS/MS进行检测,分析质量浓度在检出限(limit of detection,LOD)、2倍检出限(2LOD)、定量限(limit of quantitation,LOQ)、1.5倍定量限(1.5LOQ)、2倍定量限(2LOQ)、4倍定量限(4LOQ)和6倍定量限(6LOQ)共7个较低质量浓度时保留时间和离子丰度比的偏差。结果血液添加样品中8种药(毒)物绝对保留时间的偏差在±0.05 min范围内的占98.11%,相对保留时间的偏差在±0.4%范围内的占96.21%。离子丰度比的最大偏差与质量浓度存在高度关联:药(毒)物质量浓度为LOQ及以上时,离子丰度比的绝对偏差和相对偏差都有95%以上分别在±25%和±40%范围内;质量浓度为LOQ以下时,范围可分别扩大至±35%和±50%。结论建议8种常见药(毒)物绝对保留时间的偏差判定范围为±0.1min,相对保留时间的偏差判定范围为±1.0%。质量浓度在LOQ及以上时离子丰度比的绝对偏差判定范围为±25%,相对偏差为±40%,质量浓度在LOQ以下时偏差判定范围可分别扩大至±35%和±50%。
