Patients presenting with recurrence of anginal symptoms after saphenous vein bypass surgery pose an increasingly frequent challenge.In general,approximately 40%to 50%of saphenous vein graft(SVG)will become diseased or...Patients presenting with recurrence of anginal symptoms after saphenous vein bypass surgery pose an increasingly frequent challenge.In general,approximately 40%to 50%of saphenous vein graft(SVG)will become diseased or occluded within the first ten years after surgery.[1]Because adverse clinical outcomes,such as high restenosis rates and distal embolization,have been reported,percutaneous coronary intervention(PCI)for SVG is not recommended as a first-line strategy.[2]Distal embolization occurs in 2%–17%of patients despite advances in therapy,including the utilization of embolic protection device(EPD),which may lead to increased mortality at both short follow-up and midterm follow-up.[3]However,these patients often associated with inappropriate anatomic characteristics of native vessel intervention including calcification,tortuosity,abundant plaque burden,and complex chronic total occlusion(CTO)lesions.Moreover,repeat coronary bypass surgery is an option but is technically more demanding and is associated with a higher mortality.Therefore,it can sometimes result in SVG stenosis being the only intervention option.This is why the recanalization of SVG lesions,especially totally occluded lesions,remains one of the most challenging procedures in interventional cardiology.展开更多
The velocity distribution of sinter and gas in vertical cooling furnace(VCF)has an important influence on gas-solid heat transfer.Based on the slot model of single hopper in the VCF of Meishan Iron and Steel Co.,Ltd.,...The velocity distribution of sinter and gas in vertical cooling furnace(VCF)has an important influence on gas-solid heat transfer.Based on the slot model of single hopper in the VCF of Meishan Iron and Steel Co.,Ltd.,the velocity and particle size distribution of sinter and the velocity and pressure distribution of gas were studied using a computational fluid dynamics-discrete element method model to obtain the gas-solid flow rule in the VCF.The results showed that the velocity of sinter near the wall and the edge of vent cowl was lower than that in the rest of the same plane.Therefore,the rectangular section of the vertical cooling furnace can be divided into a quasi-static zone,a plug flow zone and a convergent flow zone according to the flow velocity of the sinter.The average particle size and the void fraction of sinter bed were distributed in"W"and"V"shape along the width direction,respectively.The distribution of gas velocity in the furnace cavity was uneven,and the high-velocity area gradually changed from the center to the edge of the furnace cavity with the rise of gas.Reducing the ratio of edge to center gas flow from 2.7∶1 to 0.7∶1 could improve the gas velocity,but could not change the gas velocity distribution.The gas velocity distribution was more affected by the average particle size distribution of the sinter bed.It was suggested that measures need be taken to adjust it to improve the gas velocity distribution in the VCF.展开更多
Alzheimer’s disease(AD)remains the most common neurodegenerative disease characterized by b-amyloid protein(Ab)deposition and memory loss.Studies have shown that mitochondrial dysfunction plays a crucial role in AD,w...Alzheimer’s disease(AD)remains the most common neurodegenerative disease characterized by b-amyloid protein(Ab)deposition and memory loss.Studies have shown that mitochondrial dysfunction plays a crucial role in AD,which involves oxidative stress-induced respiratory chain dysfunction,loss of mitochondrial biogenesis,defects of mitochondrial dynamics and mtDNA mutations.Thus mitochondria might serve as drug therapy target for AD.In this article,we first briefly discussed mitochondrial theory in the development of AD,and then we summarized recent advances of mitochondrial abnormalities in AD pathology and introduced a series of drugs and techniques targeting mitochondria.We think that maintaining mitochondrial function may provide a new way of thinking in the treatment of AD.展开更多
In vivo monitoring neuropathological changes in Alzheimer's disease(AD) animal model is critical for drug development. Here, by integrating blood-brain barrier penetrable peptide, we have developed a peptide probe...In vivo monitoring neuropathological changes in Alzheimer's disease(AD) animal model is critical for drug development. Here, by integrating blood-brain barrier penetrable peptide, we have developed a peptide probe which based on angiopep-2. Angiopep-based probe exhibited high binding affinity to Ab aggregates and labeled senile plaques in vivo. Remarkably, the in vivo near-infrared imaging data revealed that fluorescence signals of this probe were nearly 3-fold higher in the brains of 16-monthold APP/PS1 transgenic mice compared to C57 mice and exhibited linear correlation with the senile plaques load process in 4-, 8-, 16-month-old APP/PS1 transgenic mice. Moreover, senile plaques load was detected in vivo as early as 4 months of age that even at the very beginning of plaques developed in APP/PS1 transgenic mice. Taken together, this novel peptide-based probe achieved dynamic monitoring senile plaques in APP/PS1 transgenic mice and have been ready to use in drug development in AD mouse model.展开更多
Sulfuretin is a flavonoid that protects cell from damage induced by reactive oxygen species and inflammation.In this study,we investigated the role of sulfuretin in the processing of amyloid precursor protein(APP),in ...Sulfuretin is a flavonoid that protects cell from damage induced by reactive oxygen species and inflammation.In this study,we investigated the role of sulfuretin in the processing of amyloid precursor protein(APP),in association with the two catalytic enzymes the a-secretase a disintegrin and metalloproteinase(ADAM10),and the beta-site APP cleaving enzyme 1(BACE1)that play important roles in the generation of β amyloid protein(Aβ)in Alzheimer’s disease(AD).We found that sulfuretin increased the levels of the immature but not the mature form of ADAM10 protein.The enhanced ADAM10 transcription by sulfuretin was mediated by the nucleotides444 to300 in the promoter region,and was attenuated by silencing or mutation of transcription factor retinoid X receptor(RXR)and by GW6471,a specific inhibitor of peroxisome proliferator-activated receptor α(PPAR-α).We further found that sulfuretin preferentially increased protein levels of the immature form of APP(im-APP)but significantly reduced those of BACE1,sAPPβ and β-CTF,whereas Ab1-42 levels were slightly increased.Finally,the effect of sulfuretin on BACE1 and im-APP was selectively attenuated by the translation inhibitor cycloheximide and by lysosomal inhibitor chloroquine,respectively.Taken together,(1)RXR/PPAR-α signaling was involved in sulfuretin-mediated ADAM10 transcription.(2)Alteration of Aβ protein level by sulfuretin was not consistent with that of ADAM10 and BACE1 protein levels,but was consistent with the elevated level of im-APP protein,suggesting that im-APP,an isoform mainly localized to trans-Golgi network,plays an important role in Ab generation.展开更多
Alzheimer’s disease(AD)is characterized by senile plaques(SP)composed of b-amyloid protein(Ab)and neurofibrillary tangles(NFTs)composed of intracellular hyperphosphorylated tau.Recently,nuclear receptor subfamily 4 g...Alzheimer’s disease(AD)is characterized by senile plaques(SP)composed of b-amyloid protein(Ab)and neurofibrillary tangles(NFTs)composed of intracellular hyperphosphorylated tau.Recently,nuclear receptor subfamily 4 group A member 1(NR4A1)was implicated in synaptic plasticity,long-term memory formation,suggesting that it may play a role in the pathophysiology of AD.Here,we showed that the expression of NR4A1 was significantly increased in the hippocampus of APP/PS1 transgenic mice.In addition,NR4A1 overexpression in HT22 cells up-regulated APP and BACE1 levels,down-regulated ADAM10 expression,and promoted amyloidogenesis as indicated by decreased a-CTF levels and elevated b-CTF levels.Furthermore,a raised level of phospho-tau(p-tau,S396)was accompanied by p-GSK3b(S9)expression reducing,but total tau,p-tau(S262 and T231),CDK5 and ERK remained unchanged in NR4A1-overexpressing cells.Collectively,our results suggest that NR4A1 promotes the amyloidogenic processing of APP by regulating ADAM10 and BACE1 expression in HT22 cells;as well as NR4A1 accelerates tau hyperphosphorylation by GSK3b signal.Therefore,NR4A1 may play an important role in the pathogenesis of AD.展开更多
Vps34(vacuolar protein-sorting 34)plays important role in autophagy and endosomal trafficking.These processes are closely associated protein ubiquitination and degradation.We have hypothesized that Vps34 ubiquitinatio...Vps34(vacuolar protein-sorting 34)plays important role in autophagy and endosomal trafficking.These processes are closely associated protein ubiquitination and degradation.We have hypothesized that Vps34 ubiquitination status would also control its degradation.Here,we report that our results did not support this assumption.In cells transiently transfected with ubiquitin(UB)constructs contained different lysine residues(Ks),Vps34 ubiquitination could occur regardless of the presence of any Ks in UB.However,Vps34 protein levels were not significantly altered in cells transiently transfected with these UB mutants.We further found that Vps34 protein was altered by pharmacological manipulation of E2/E3 activity;yet this effect was not significantly affected by UB overexpression.In vivo experiments revealed that in APP/PS1 mice,an animal model of Alzheimer’s disease(AD),although ubiquitination of Vps34 was significantly reduced,Vps34 protein levels remained unchanged.Vps34 indeed was subjected to proteasomal or lysosomal degradation,as prolonged treatment of proteasomal inhibitor MG132 or lysosomal inhibitor chloroquine elevated Vps34 protein levels.We conclude that unlike most of other proteins,Vps34 ubiquitination is not closely associated with its degradation.展开更多
The existence of adult stem cells was first described in tissues with high proliferation rates,such as the hematopoietic system and the intestine.Since then,stem cells have been found in almost all adult tissues,inclu...The existence of adult stem cells was first described in tissues with high proliferation rates,such as the hematopoietic system and the intestine.Since then,stem cells have been found in almost all adult tissues,including the nervous system.Adult neurogenesis is supported by multipotent neural stem cells(NSCs),which maintain some of the cellular and molecular characteristics of their embryonic counterparts.Because of their suggestive appeal as therapeutic agents and their presumed relevance for cognition in health and disease,adult neurogenesis is attracting considerable attention from neuroscientists.展开更多
Multiple sclerosis(MS),a leading cause of non-traumatic disability in young adults,is a chronic inflammatory demyelinating disease of the central nervous system(CNS)associated with aberrant autoimmune responses.It has...Multiple sclerosis(MS),a leading cause of non-traumatic disability in young adults,is a chronic inflammatory demyelinating disease of the central nervous system(CNS)associated with aberrant autoimmune responses.It has long been thought that therapeutic development should be centered on immunomodulatory agents.However,none of the agents tested could prevent chronic progressive disease and disability.On the other hand,direct repair of injured myelin might represent an alternative strategy for treating MS.This may be achieved by either promoting the inherent repair mechanism of neurons or by recruiting cells derived from oligodendrocyte progenitor cells(OPCs),which are unfortunately silent in MS.The latter approach was recently demonstrated by Najm et al at Case Western Reserve University and Northwestern University.1 They demonstrated that miconazole and clobetasol,screened from a library of bioactive smallmolecules onmouse pluripotent epiblast stem cell-derived OPCs,2e4 promoted precocious myelination,significantly increased the number of new oligodendrocytes and enhanced remyelination.Strikingly,both smallmolecules reversed the disease severity in mouse models of MS.展开更多
文摘Patients presenting with recurrence of anginal symptoms after saphenous vein bypass surgery pose an increasingly frequent challenge.In general,approximately 40%to 50%of saphenous vein graft(SVG)will become diseased or occluded within the first ten years after surgery.[1]Because adverse clinical outcomes,such as high restenosis rates and distal embolization,have been reported,percutaneous coronary intervention(PCI)for SVG is not recommended as a first-line strategy.[2]Distal embolization occurs in 2%–17%of patients despite advances in therapy,including the utilization of embolic protection device(EPD),which may lead to increased mortality at both short follow-up and midterm follow-up.[3]However,these patients often associated with inappropriate anatomic characteristics of native vessel intervention including calcification,tortuosity,abundant plaque burden,and complex chronic total occlusion(CTO)lesions.Moreover,repeat coronary bypass surgery is an option but is technically more demanding and is associated with a higher mortality.Therefore,it can sometimes result in SVG stenosis being the only intervention option.This is why the recanalization of SVG lesions,especially totally occluded lesions,remains one of the most challenging procedures in interventional cardiology.
基金Financial support provided by the Fundamental Research Funds for the Central Universities of China(N2225022)is gratefully acknowledged.
文摘The velocity distribution of sinter and gas in vertical cooling furnace(VCF)has an important influence on gas-solid heat transfer.Based on the slot model of single hopper in the VCF of Meishan Iron and Steel Co.,Ltd.,the velocity and particle size distribution of sinter and the velocity and pressure distribution of gas were studied using a computational fluid dynamics-discrete element method model to obtain the gas-solid flow rule in the VCF.The results showed that the velocity of sinter near the wall and the edge of vent cowl was lower than that in the rest of the same plane.Therefore,the rectangular section of the vertical cooling furnace can be divided into a quasi-static zone,a plug flow zone and a convergent flow zone according to the flow velocity of the sinter.The average particle size and the void fraction of sinter bed were distributed in"W"and"V"shape along the width direction,respectively.The distribution of gas velocity in the furnace cavity was uneven,and the high-velocity area gradually changed from the center to the edge of the furnace cavity with the rise of gas.Reducing the ratio of edge to center gas flow from 2.7∶1 to 0.7∶1 could improve the gas velocity,but could not change the gas velocity distribution.The gas velocity distribution was more affected by the average particle size distribution of the sinter bed.It was suggested that measures need be taken to adjust it to improve the gas velocity distribution in the VCF.
基金This work was supported by National Natural Science Foundation of China(NSFC)grants(numbers 81171197&81220108010)Bureau of Health of Chongqing Medical Research Grant(number 2011-1-018)to G-J.C.
文摘Alzheimer’s disease(AD)remains the most common neurodegenerative disease characterized by b-amyloid protein(Ab)deposition and memory loss.Studies have shown that mitochondrial dysfunction plays a crucial role in AD,which involves oxidative stress-induced respiratory chain dysfunction,loss of mitochondrial biogenesis,defects of mitochondrial dynamics and mtDNA mutations.Thus mitochondria might serve as drug therapy target for AD.In this article,we first briefly discussed mitochondrial theory in the development of AD,and then we summarized recent advances of mitochondrial abnormalities in AD pathology and introduced a series of drugs and techniques targeting mitochondria.We think that maintaining mitochondrial function may provide a new way of thinking in the treatment of AD.
基金supported by the National Key Research and Development Program of China (2016YFC1305900)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB02030001)the National Natural Science Foundation of China (91132304, 91432305)
文摘In vivo monitoring neuropathological changes in Alzheimer's disease(AD) animal model is critical for drug development. Here, by integrating blood-brain barrier penetrable peptide, we have developed a peptide probe which based on angiopep-2. Angiopep-based probe exhibited high binding affinity to Ab aggregates and labeled senile plaques in vivo. Remarkably, the in vivo near-infrared imaging data revealed that fluorescence signals of this probe were nearly 3-fold higher in the brains of 16-monthold APP/PS1 transgenic mice compared to C57 mice and exhibited linear correlation with the senile plaques load process in 4-, 8-, 16-month-old APP/PS1 transgenic mice. Moreover, senile plaques load was detected in vivo as early as 4 months of age that even at the very beginning of plaques developed in APP/PS1 transgenic mice. Taken together, this novel peptide-based probe achieved dynamic monitoring senile plaques in APP/PS1 transgenic mice and have been ready to use in drug development in AD mouse model.
基金This work was supported by National Key R&D Program of China(2018YFC1314700)to L-J Jinby NSFC(81971030)+3 种基金Chongqing Science and Technology Commission grant(cstc2018jcyjAX0067)to G-J.Chenby The strategic science&technology cooperation Project of North Sichuan Medical College and Nanchong Municipal Government(18SXHZ0184)Scientific Research Development Project of North Sichuan Medical College(CBY17-A-ZD03)Sichuan Provincial Health and Family Planning Commission(18PJ335)to Li-Tian Hu.
文摘Sulfuretin is a flavonoid that protects cell from damage induced by reactive oxygen species and inflammation.In this study,we investigated the role of sulfuretin in the processing of amyloid precursor protein(APP),in association with the two catalytic enzymes the a-secretase a disintegrin and metalloproteinase(ADAM10),and the beta-site APP cleaving enzyme 1(BACE1)that play important roles in the generation of β amyloid protein(Aβ)in Alzheimer’s disease(AD).We found that sulfuretin increased the levels of the immature but not the mature form of ADAM10 protein.The enhanced ADAM10 transcription by sulfuretin was mediated by the nucleotides444 to300 in the promoter region,and was attenuated by silencing or mutation of transcription factor retinoid X receptor(RXR)and by GW6471,a specific inhibitor of peroxisome proliferator-activated receptor α(PPAR-α).We further found that sulfuretin preferentially increased protein levels of the immature form of APP(im-APP)but significantly reduced those of BACE1,sAPPβ and β-CTF,whereas Ab1-42 levels were slightly increased.Finally,the effect of sulfuretin on BACE1 and im-APP was selectively attenuated by the translation inhibitor cycloheximide and by lysosomal inhibitor chloroquine,respectively.Taken together,(1)RXR/PPAR-α signaling was involved in sulfuretin-mediated ADAM10 transcription.(2)Alteration of Aβ protein level by sulfuretin was not consistent with that of ADAM10 and BACE1 protein levels,but was consistent with the elevated level of im-APP protein,suggesting that im-APP,an isoform mainly localized to trans-Golgi network,plays an important role in Ab generation.
基金This study was supported by the National Natural Science Foundation of China(grant numbers:31500821).
文摘Alzheimer’s disease(AD)is characterized by senile plaques(SP)composed of b-amyloid protein(Ab)and neurofibrillary tangles(NFTs)composed of intracellular hyperphosphorylated tau.Recently,nuclear receptor subfamily 4 group A member 1(NR4A1)was implicated in synaptic plasticity,long-term memory formation,suggesting that it may play a role in the pathophysiology of AD.Here,we showed that the expression of NR4A1 was significantly increased in the hippocampus of APP/PS1 transgenic mice.In addition,NR4A1 overexpression in HT22 cells up-regulated APP and BACE1 levels,down-regulated ADAM10 expression,and promoted amyloidogenesis as indicated by decreased a-CTF levels and elevated b-CTF levels.Furthermore,a raised level of phospho-tau(p-tau,S396)was accompanied by p-GSK3b(S9)expression reducing,but total tau,p-tau(S262 and T231),CDK5 and ERK remained unchanged in NR4A1-overexpressing cells.Collectively,our results suggest that NR4A1 promotes the amyloidogenic processing of APP by regulating ADAM10 and BACE1 expression in HT22 cells;as well as NR4A1 accelerates tau hyperphosphorylation by GSK3b signal.Therefore,NR4A1 may play an important role in the pathogenesis of AD.
基金This work was supported by The National Natural Science Foudantion of China grant(81220108010).
文摘Vps34(vacuolar protein-sorting 34)plays important role in autophagy and endosomal trafficking.These processes are closely associated protein ubiquitination and degradation.We have hypothesized that Vps34 ubiquitination status would also control its degradation.Here,we report that our results did not support this assumption.In cells transiently transfected with ubiquitin(UB)constructs contained different lysine residues(Ks),Vps34 ubiquitination could occur regardless of the presence of any Ks in UB.However,Vps34 protein levels were not significantly altered in cells transiently transfected with these UB mutants.We further found that Vps34 protein was altered by pharmacological manipulation of E2/E3 activity;yet this effect was not significantly affected by UB overexpression.In vivo experiments revealed that in APP/PS1 mice,an animal model of Alzheimer’s disease(AD),although ubiquitination of Vps34 was significantly reduced,Vps34 protein levels remained unchanged.Vps34 indeed was subjected to proteasomal or lysosomal degradation,as prolonged treatment of proteasomal inhibitor MG132 or lysosomal inhibitor chloroquine elevated Vps34 protein levels.We conclude that unlike most of other proteins,Vps34 ubiquitination is not closely associated with its degradation.
基金This work was supported by NSFC grants(81220108010 and 81171197)to GC and a NIH grant(HL096800)to FS.
文摘The existence of adult stem cells was first described in tissues with high proliferation rates,such as the hematopoietic system and the intestine.Since then,stem cells have been found in almost all adult tissues,including the nervous system.Adult neurogenesis is supported by multipotent neural stem cells(NSCs),which maintain some of the cellular and molecular characteristics of their embryonic counterparts.Because of their suggestive appeal as therapeutic agents and their presumed relevance for cognition in health and disease,adult neurogenesis is attracting considerable attention from neuroscientists.
基金This work was supported by NSFC grants(81220108010 and 81171197)to GC and NIH grant HL096800 to FS.
文摘Multiple sclerosis(MS),a leading cause of non-traumatic disability in young adults,is a chronic inflammatory demyelinating disease of the central nervous system(CNS)associated with aberrant autoimmune responses.It has long been thought that therapeutic development should be centered on immunomodulatory agents.However,none of the agents tested could prevent chronic progressive disease and disability.On the other hand,direct repair of injured myelin might represent an alternative strategy for treating MS.This may be achieved by either promoting the inherent repair mechanism of neurons or by recruiting cells derived from oligodendrocyte progenitor cells(OPCs),which are unfortunately silent in MS.The latter approach was recently demonstrated by Najm et al at Case Western Reserve University and Northwestern University.1 They demonstrated that miconazole and clobetasol,screened from a library of bioactive smallmolecules onmouse pluripotent epiblast stem cell-derived OPCs,2e4 promoted precocious myelination,significantly increased the number of new oligodendrocytes and enhanced remyelination.Strikingly,both smallmolecules reversed the disease severity in mouse models of MS.