OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with wh...OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with white matter damage,and optogenetics and skin stroking were exerted to activate glutamater⁃gic neurons in the somatosensory cortex in a clas⁃sical mouse model of ischemia vascular dementia.RESULTS White matter damage was correlated with disrupted cortical structure from MRI results.In a mouse model,activating glutamatergic neu⁃rons in the somatosensory cortex promotes prolif⁃eration of OPCs and remyelination to rescue cog⁃nitive impairment after chronic cerebral hypoper⁃fusion.Such therapeutic action was limited to stimulation with moderate intensity at the upper layers of the cortex,but was achieved over a wide time window after ischemia.Mechanistically,enhanced glutamatergic neuron-OPC functional synaptic connections are required for protection from activation of cortical glutamatergic neurons.Finally,skin stroking activation of the somatosen⁃sory cortex,an easier approach for clinical trans⁃lation,promoted OPC proliferation and remyelin⁃ation as well as cognitive recovery after cerebral hypoperfusion.CONCLUSION Activation of gluta⁃matergic neurons in the somatosensory cortex may serve as novel approaches for treating isch⁃emic vascular dementia through precise modula⁃tion of glutamatergic neuron-OPC circuits.展开更多
OBJECTIVE To systematically review the clinical efficacy and safety on TCHMs that are used for vascular dementia(VaD).METHODS To identify studies for systematical review,electronic searches were performed through seve...OBJECTIVE To systematically review the clinical efficacy and safety on TCHMs that are used for vascular dementia(VaD).METHODS To identify studies for systematical review,electronic searches were performed through several databases-ALOIS,CNKI,CBM,Weipu,Wanfang,etc.Only randomized control trials(RCTs)or controlled clinical trials(CCTs)were included.Patients were diagnosed with VaD by diagnostic criteria(DSM,NINDS-AIREN,ICD or HIS)as well as imaging technique(CT,MRI or functional imaging,etc).Eligible TCHMs must be recognized in the Chinese Pharmacopeia or the National Essential Drug List of the People′s Republic of China.Included studies were appraised using the Cochrane Collaboration risk-of-bias criteria.Efficacy and safety outcomes were evaluated by meta-analysis.Efficacy outcomes include cognition,daily function,global performance and behaviour;safety was assessed by the number of adverse events and number of subjects experiencing adverse events.Assessment of heterogeneity,subgroup analysis and sensitivity analysis were also performed.RESULTS A total of 46 trials on 29TCHMs(3522patients)were included.45 studies were RCTs and 1was CCT.In these 45 RCTs,only 2were appraised as adequately randomised.5of 46 trials were appraised as having low risk of bias in blinding.Sample sizes were generally small ranging from 26 to 216with a median of 68.All trials were conducted in China from 1997 to 2013.All 46 studies assessed cognition using one or a combination of the following scales:MMSE(n=40 studies;3096 patients),HDS(n=22;1664 patients),ADAS-Cog(n=4;241 patients),CDT(n=1;60patients)and CCSE(n=1;26patients).Half of the studies assessed daily function using either the ADL(n=22;1743 patients)or IADL(n=2;203patients).Only 6studies measured behaviour using the FAQ(n=3;226 subjects),BBS(n=1;48patients),NPI(n=1;100subjects)or Neurological Deficits Function Scale(n=1;91patients).30 studies measured global performance.31 of 46 studies made conclusions regarding the safety of the TCHMs.Despite the problems of methodology and reporting,we can identify three TCHMs-NaoXinTong,Shenfu and Tongxinluo as having relatively stronger evidence of efficacy.There is weak evidence for the safety of TCHMs for VaD.CONCLUSION There is weak evidence for the efficacy and safety of TCHMs for VaD because of the poor methodology,short duration of follow-up and inadequate reporting.However the agents appear to be relatively free of severe short-term AEs,hence we encourage further better designed and reported trials.展开更多
OBJECTIVE To explore the mechanisms of the volatiles of Wendan granule for the treatment of senile dementia,network pharmacology method integrating absorption,distribution,metab.olism,and excretion(ADME) screening,tar...OBJECTIVE To explore the mechanisms of the volatiles of Wendan granule for the treatment of senile dementia,network pharmacology method integrating absorption,distribution,metab.olism,and excretion(ADME) screening,target fishing,network constructing,pathway analyzing,and correlated diseases prediction was applied.METHODS Twelve small molecular compounds of WDG were selected as the objects from 74 volatiles with the relative abundances above 2%,and their ADME parameters were collected from Traditional Chinese Medicine Systems Pharmacology platform(TCMSP),and then the corresponding targets,genes,pathways and diseases were predicted according to the data provided by TCMSP,DrugBank,Uniport and the Database for Annotation,Visualization and Integrated Discovery(DAVID).The related pathways and correlation analysis were explored by the Kyoto Encyclo.pedia and Genomes(KEGG) database.Finally,the networks of compound-target,target-pathway and pathway-disease of WDG were constructed by Cytoscape software.RESULTS Twelve compounds interacted with 49 targets,of which top three targets were Gamma-aminobutyric acid receptor subunit alpha-1(GABRA1),Prostaglandin G/H synthase 2(PGHS-2) and Sodium-dependent noradrenaline transporter.Interestingly,these targets were highly associated with depression,insomnia and Alzheimer′s disease that mainly corresponded to mental and emotional illnesses.CONCLUSION The integrated network pharmacology method provides precise probe to illuminate the molecular mechanisms of volatiles of WDG for relieving senile dementia related syndromes,which will also facilitate the application of traditional Chinese medicine in modern medicine,as well as follow-up studies such as upgrading the quality stan.dard of clinical medicine and novel drug development.展开更多
目的研究血管性痴呆(vascular dementia,VaD)小鼠模型海马神经元的死亡机制,探讨海马神经元程序性坏死与VaD小鼠学习记忆受损之间的关系。方法慢性脑低灌注血管性痴呆小鼠模型采用双侧血管阻断法(bilateral occlusion of the common car...目的研究血管性痴呆(vascular dementia,VaD)小鼠模型海马神经元的死亡机制,探讨海马神经元程序性坏死与VaD小鼠学习记忆受损之间的关系。方法慢性脑低灌注血管性痴呆小鼠模型采用双侧血管阻断法(bilateral occlusion of the common carotid arteries,2VO)构建。用Morris水迷宫检测小鼠模型学习记忆能力。用实时荧光定量PCR(qPCR)法检测动物模型海马区神经元RIPK1、RIPK3和MLKL mRNA的表达。免疫印迹法检测RIPK1、RIPK3、pRIPK3和MLKL蛋白的表达,并与小鼠模型学习记忆能力进行相关性分析。免疫荧光双标记法检测RIPK1、RIPK3和MLKL的共定位情况。结果qPCR检测发现,与假手术组相比,VaD组小鼠模型海马区神经元RIPK1、RIPK3和MLKL的mRNA表达显著增高。免疫印迹结果显示VaD组小鼠模型海马区神经元RIPK1、pRIPK3、和MLKL的蛋白表达水平明显增高。免疫荧光双标记显示在小鼠模型海马区,RIPK1、RIPK3与MLKL共表达定位显著增强。进一步研究发现,程序性坏死标志物RIPK1、RIPK3和MLKL的表达与小鼠模型目标象限停留时间及穿越平台次数呈负相关关系。结论在VaD小鼠模型中,海马神经元的丢失及其学习记忆功能障碍的发生发展,可能是通过激活RIPK1/RIPK3/MLKL信号通路,进而引起海马神经元程序性坏死所致。展开更多
文摘OBJECTIVE Chronic cerebral hy⁃poperfusion can lead to progressive demyelin⁃ation and ischemic vascular dementia,yet there are no effective treatments.METHODS Magnetic resonance imaging was employed in patients with white matter damage,and optogenetics and skin stroking were exerted to activate glutamater⁃gic neurons in the somatosensory cortex in a clas⁃sical mouse model of ischemia vascular dementia.RESULTS White matter damage was correlated with disrupted cortical structure from MRI results.In a mouse model,activating glutamatergic neu⁃rons in the somatosensory cortex promotes prolif⁃eration of OPCs and remyelination to rescue cog⁃nitive impairment after chronic cerebral hypoper⁃fusion.Such therapeutic action was limited to stimulation with moderate intensity at the upper layers of the cortex,but was achieved over a wide time window after ischemia.Mechanistically,enhanced glutamatergic neuron-OPC functional synaptic connections are required for protection from activation of cortical glutamatergic neurons.Finally,skin stroking activation of the somatosen⁃sory cortex,an easier approach for clinical trans⁃lation,promoted OPC proliferation and remyelin⁃ation as well as cognitive recovery after cerebral hypoperfusion.CONCLUSION Activation of gluta⁃matergic neurons in the somatosensory cortex may serve as novel approaches for treating isch⁃emic vascular dementia through precise modula⁃tion of glutamatergic neuron-OPC circuits.
文摘OBJECTIVE To systematically review the clinical efficacy and safety on TCHMs that are used for vascular dementia(VaD).METHODS To identify studies for systematical review,electronic searches were performed through several databases-ALOIS,CNKI,CBM,Weipu,Wanfang,etc.Only randomized control trials(RCTs)or controlled clinical trials(CCTs)were included.Patients were diagnosed with VaD by diagnostic criteria(DSM,NINDS-AIREN,ICD or HIS)as well as imaging technique(CT,MRI or functional imaging,etc).Eligible TCHMs must be recognized in the Chinese Pharmacopeia or the National Essential Drug List of the People′s Republic of China.Included studies were appraised using the Cochrane Collaboration risk-of-bias criteria.Efficacy and safety outcomes were evaluated by meta-analysis.Efficacy outcomes include cognition,daily function,global performance and behaviour;safety was assessed by the number of adverse events and number of subjects experiencing adverse events.Assessment of heterogeneity,subgroup analysis and sensitivity analysis were also performed.RESULTS A total of 46 trials on 29TCHMs(3522patients)were included.45 studies were RCTs and 1was CCT.In these 45 RCTs,only 2were appraised as adequately randomised.5of 46 trials were appraised as having low risk of bias in blinding.Sample sizes were generally small ranging from 26 to 216with a median of 68.All trials were conducted in China from 1997 to 2013.All 46 studies assessed cognition using one or a combination of the following scales:MMSE(n=40 studies;3096 patients),HDS(n=22;1664 patients),ADAS-Cog(n=4;241 patients),CDT(n=1;60patients)and CCSE(n=1;26patients).Half of the studies assessed daily function using either the ADL(n=22;1743 patients)or IADL(n=2;203patients).Only 6studies measured behaviour using the FAQ(n=3;226 subjects),BBS(n=1;48patients),NPI(n=1;100subjects)or Neurological Deficits Function Scale(n=1;91patients).30 studies measured global performance.31 of 46 studies made conclusions regarding the safety of the TCHMs.Despite the problems of methodology and reporting,we can identify three TCHMs-NaoXinTong,Shenfu and Tongxinluo as having relatively stronger evidence of efficacy.There is weak evidence for the safety of TCHMs for VaD.CONCLUSION There is weak evidence for the efficacy and safety of TCHMs for VaD because of the poor methodology,short duration of follow-up and inadequate reporting.However the agents appear to be relatively free of severe short-term AEs,hence we encourage further better designed and reported trials.
基金supported by Natural science foundation of Hubei(2015CFB321) Key Project of National Natural Science Foundation of China(81130064)
文摘OBJECTIVE To explore the mechanisms of the volatiles of Wendan granule for the treatment of senile dementia,network pharmacology method integrating absorption,distribution,metab.olism,and excretion(ADME) screening,target fishing,network constructing,pathway analyzing,and correlated diseases prediction was applied.METHODS Twelve small molecular compounds of WDG were selected as the objects from 74 volatiles with the relative abundances above 2%,and their ADME parameters were collected from Traditional Chinese Medicine Systems Pharmacology platform(TCMSP),and then the corresponding targets,genes,pathways and diseases were predicted according to the data provided by TCMSP,DrugBank,Uniport and the Database for Annotation,Visualization and Integrated Discovery(DAVID).The related pathways and correlation analysis were explored by the Kyoto Encyclo.pedia and Genomes(KEGG) database.Finally,the networks of compound-target,target-pathway and pathway-disease of WDG were constructed by Cytoscape software.RESULTS Twelve compounds interacted with 49 targets,of which top three targets were Gamma-aminobutyric acid receptor subunit alpha-1(GABRA1),Prostaglandin G/H synthase 2(PGHS-2) and Sodium-dependent noradrenaline transporter.Interestingly,these targets were highly associated with depression,insomnia and Alzheimer′s disease that mainly corresponded to mental and emotional illnesses.CONCLUSION The integrated network pharmacology method provides precise probe to illuminate the molecular mechanisms of volatiles of WDG for relieving senile dementia related syndromes,which will also facilitate the application of traditional Chinese medicine in modern medicine,as well as follow-up studies such as upgrading the quality stan.dard of clinical medicine and novel drug development.
文摘目的研究血管性痴呆(vascular dementia,VaD)小鼠模型海马神经元的死亡机制,探讨海马神经元程序性坏死与VaD小鼠学习记忆受损之间的关系。方法慢性脑低灌注血管性痴呆小鼠模型采用双侧血管阻断法(bilateral occlusion of the common carotid arteries,2VO)构建。用Morris水迷宫检测小鼠模型学习记忆能力。用实时荧光定量PCR(qPCR)法检测动物模型海马区神经元RIPK1、RIPK3和MLKL mRNA的表达。免疫印迹法检测RIPK1、RIPK3、pRIPK3和MLKL蛋白的表达,并与小鼠模型学习记忆能力进行相关性分析。免疫荧光双标记法检测RIPK1、RIPK3和MLKL的共定位情况。结果qPCR检测发现,与假手术组相比,VaD组小鼠模型海马区神经元RIPK1、RIPK3和MLKL的mRNA表达显著增高。免疫印迹结果显示VaD组小鼠模型海马区神经元RIPK1、pRIPK3、和MLKL的蛋白表达水平明显增高。免疫荧光双标记显示在小鼠模型海马区,RIPK1、RIPK3与MLKL共表达定位显著增强。进一步研究发现,程序性坏死标志物RIPK1、RIPK3和MLKL的表达与小鼠模型目标象限停留时间及穿越平台次数呈负相关关系。结论在VaD小鼠模型中,海马神经元的丢失及其学习记忆功能障碍的发生发展,可能是通过激活RIPK1/RIPK3/MLKL信号通路,进而引起海马神经元程序性坏死所致。
