OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHOD...OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHODS ELISA assay was performed in both HEK293-APPswe and CHO-APP cells to demonstrate the efficacy of DDPU in reducing Ab level.SH-SY5 Y,primary neurons and astrocyte cellswereused to study the regulation of DDPU against the signaling pathways involved in Aβ/ER-stress pathology.APP/PS1 transgenic mice wereusedto study the regulation of DDPU against ADL and cognitive deficits.APP/PS1 transgenic mice were randomly placed into three groups(n=10):The two 6-month transgenic groups were administrated with 30 mg·kg^(-1) DDPU or vehicle and the 6-month non-transgenic group was administrated with vehicle for 100 days by intraperitonealinjec.tion.After 100-day administration,nest construction assay and Morris water maze(MWM) assay were applied to evaluate the daily living activities and cognitive abilities of the mice with continuous DDPU treatment.Upon completion of behavior assays,mice were euthanized,and the brains were removed and bisected in mid-sagittal plane.The right hemispheres were frozen and stored at-80°C,and the left hemispheres were fixed in 4% paraformaldehyde.RESULTS DDPU effectively improved learning and memory impairments in APP/PS1 transgenic mice,and the underlying mechanisms have been inten.sively investigated.DDPU reduced Ab production by inhibiting the PERK/eIF2 a signaling-mediated BACE1 translation,while promoted Ab clearance as a PI3K inhibitor thus negatively regulating PI3K/AKT/mTOR signaling in promotion of autophagy.Moreover,DDPU also exhibited neuroprotective effect by attenuating ER stress.Therefore,all findings have clearly demonstrated the crosstalk between Ab and ER stress,and confirmed that targeting ER stress should be a potential target for innovative anti-AD drug development,while highlighted the potential of DDPU in the treatment of AD.展开更多
To increase launching frequency and decrease drag force of underwater projectiles,a serial multiprojectiles structure based on the principle of supercavitation is proposed in this paper.The drag reduction and supercav...To increase launching frequency and decrease drag force of underwater projectiles,a serial multiprojectiles structure based on the principle of supercavitation is proposed in this paper.The drag reduction and supercavitation characteristics of the underwater serial multi-projectiles are studied with computational fluid dynamics(CFD)and machine learning.Firstly,the numerical simulation model for the underwater supercavitating projectile is established and verified by experimental data.Then the evolution of the supercavitation for the serial multi-projectiles is described.In addition,the effects of different cavitation numbers and different distances between projectiles are investigated to demonstrate the supercavitation and drag reduction performance.Finally,the artificial neural network(ANN)model is established to predict the evolution of drag coefficient based on the data obtained by CFD,and the results predicted by ANN are in good agreement with the data obtained by CFD.The finding provides a useful guidance for the research of drag reduction characteristics of underwater serial projectiles.展开更多
基金supported by National Natural Science Foundation of China(81220108025,81473141) NSFC-TRF collaboration projects(81561148011,DBG5980001)+3 种基金 Drug Innovation Project of SIMM(CASIMM0120154035) Personalized Medicine-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of Chinese Academy of Sciences (XDA12040303) the Project Funded by the Priority Aca-demic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medi-cine17KJA350002) National Natural Science Foundation for Young Scientists of China (81703806)
文摘OBJECTIVE To explore the potential effect and mechanisms of protopanaxadiol deriva.tive 1-(3,4-dimethoxyphenethyl)-3-(3-dehydroxyl-20(s)-protopa-naxadiol-3 b-yl)-urea(DDPU) in the treatment of Alzheimer disease.METHODS ELISA assay was performed in both HEK293-APPswe and CHO-APP cells to demonstrate the efficacy of DDPU in reducing Ab level.SH-SY5 Y,primary neurons and astrocyte cellswereused to study the regulation of DDPU against the signaling pathways involved in Aβ/ER-stress pathology.APP/PS1 transgenic mice wereusedto study the regulation of DDPU against ADL and cognitive deficits.APP/PS1 transgenic mice were randomly placed into three groups(n=10):The two 6-month transgenic groups were administrated with 30 mg·kg^(-1) DDPU or vehicle and the 6-month non-transgenic group was administrated with vehicle for 100 days by intraperitonealinjec.tion.After 100-day administration,nest construction assay and Morris water maze(MWM) assay were applied to evaluate the daily living activities and cognitive abilities of the mice with continuous DDPU treatment.Upon completion of behavior assays,mice were euthanized,and the brains were removed and bisected in mid-sagittal plane.The right hemispheres were frozen and stored at-80°C,and the left hemispheres were fixed in 4% paraformaldehyde.RESULTS DDPU effectively improved learning and memory impairments in APP/PS1 transgenic mice,and the underlying mechanisms have been inten.sively investigated.DDPU reduced Ab production by inhibiting the PERK/eIF2 a signaling-mediated BACE1 translation,while promoted Ab clearance as a PI3K inhibitor thus negatively regulating PI3K/AKT/mTOR signaling in promotion of autophagy.Moreover,DDPU also exhibited neuroprotective effect by attenuating ER stress.Therefore,all findings have clearly demonstrated the crosstalk between Ab and ER stress,and confirmed that targeting ER stress should be a potential target for innovative anti-AD drug development,while highlighted the potential of DDPU in the treatment of AD.
基金supported by the National Natural Science Foun-dation of China(Grant No.11972194,12072160).
文摘To increase launching frequency and decrease drag force of underwater projectiles,a serial multiprojectiles structure based on the principle of supercavitation is proposed in this paper.The drag reduction and supercavitation characteristics of the underwater serial multi-projectiles are studied with computational fluid dynamics(CFD)and machine learning.Firstly,the numerical simulation model for the underwater supercavitating projectile is established and verified by experimental data.Then the evolution of the supercavitation for the serial multi-projectiles is described.In addition,the effects of different cavitation numbers and different distances between projectiles are investigated to demonstrate the supercavitation and drag reduction performance.Finally,the artificial neural network(ANN)model is established to predict the evolution of drag coefficient based on the data obtained by CFD,and the results predicted by ANN are in good agreement with the data obtained by CFD.The finding provides a useful guidance for the research of drag reduction characteristics of underwater serial projectiles.
