Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular me...Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.展开更多
Until recently, the synaptic transmission and excitatory amino acid transporters activation of neurons are very well discussed in the previous studies and are considered to be the two distinct features of Synapse. It ...Until recently, the synaptic transmission and excitatory amino acid transporters activation of neurons are very well discussed in the previous studies and are considered to be the two distinct features of Synapse. It is also found that a large number of interactions take place in the domain of ionic exchanges and protein interactions in synapses. It is evolutionary to have destined to release of Neurotransmitters to conduct an impulse to the other consecutive neurons, which forms the most important characteristic of synapse. From the popular perspective, it has been identified that detailed theoretical closer correlation of data produced through various studies about synapse can unravel many mysteries related to functions of synapse. Hence, this research paper tries to concentrate on a selected group of prominent characteristics and properties of synapse and also highlights some noteworthy discoveries, emphasizing the influential capabilities of them in the thought process and improving the knowledge of the field. It also highlights the expressive properties and forms of synapse brought out through the evidences available in sparse to dense data in a correlational way.展开更多
The brain is a complex network system that has the capacity to support emotion, thought, action, learning and memory, and is characterized by constant activity, constant structural remodeling, and constant attempt to ...The brain is a complex network system that has the capacity to support emotion, thought, action, learning and memory, and is characterized by constant activity, constant structural remodeling, and constant attempt to compensate for this remodeling. The basic insight that emerges from complex network organization is that substantively different networks can share common key organizational principles. Moreover, the interdependence of network organization and behavior has been successfully demonstrated for several specific tasks. From this viewpoint, increasing experimental/clinical observations suggest that mental disorders are neural network disorders. On one hand, single psychiatric disorders arise from multiple, multifactorial molecular and cellular structural/functional alterations spreading throughout local/global circuits leading to multifaceted and heterogeneous clinical symptoms. On the other hand, various mental diseases may share functional deficits across the same neural circuit as reflected in the overlap of symptoms throughout clinical diagnoses. An integrated framework including experimental measures and clinical observations will be necessary to formulate a coherent and comprehensive understanding of how neural connectivity mediates and constraints the phenotypic expression of psychiatric disorders.展开更多
The study of the neuron has always been a fundamental aspect when it came to studying mental illnesses such as autism and depression. The protein protocadherin-9 (PCDH9) is an important transmembrane protein in the de...The study of the neuron has always been a fundamental aspect when it came to studying mental illnesses such as autism and depression. The protein protocadherin-9 (PCDH9) is an important transmembrane protein in the development of the neuron synapse. Hence, research on its protein interactome is key to understanding its functionality and specific properties. A newly discovered biotin ligase, TurboID, is a proximity labeler that is designed to be able to label and observe transmembrane proteins, something that previous methods struggled with. The TurboID method is verified in HEK293T cells and primary cultured mouse cortical neurons. Results have proven the validity of the TurboID method in observing PCDH9-interacting proteins.展开更多
The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling network...The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions.Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders.Supporting this notion,efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation,maturation,synaptogenesis and synaptic function.Fasciculation and elongation protein zeta-1,a Kinesin-1 adapter,has emerged as a key central player involved in many of these processes.Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment.Furthermore,it acts downstream of guidance cue pathways to regulate axo-dendritic development.Significantly,perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system.Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders.Moreover,altered phosphorylation of the protein contributes to neurodegenerative disorders.Together,these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.展开更多
Background： Despite its high prevalence, morbidity, and mortality, sepsis-associated encephalopathy （SAE） is still poorly understood. The aim of this prospective and observational study was to investigate the clini...Background： Despite its high prevalence, morbidity, and mortality, sepsis-associated encephalopathy （SAE） is still poorly understood. The aim of this prospective and observational study was to investigate the clinical significance of calcium-binding protein A8 （S 100AS） in serum and tumor necrosis factor receptor-associated factor 6 （TRAF6） in peripheral blood mononuclear cells （PBMCs） in diagnosing SAE and predicting its prognosis. Methods： Data of septic patients were collected within 24 h after Intensive Care Unit admission fi-om July 2014 to March 2015. Healthy medical personnel served as the control group. SAE was defined as cerebral dysfhnction in the presence of sepsis that fulfilled the exclusion criteria. The biochemical indicators, Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation score II, TRAF6 in PBMC, serum S 100A8, S 10013, and neuron-specific enolase were evaluated in SAE patients afresh. TRAF6 and S 100A8 were also measured in the control group. Results： Of the 57 enrolled patients, 29 were diagnosed with SAE. The S 100A8 and TRAF6 concentrations in SAE patients were both significantly higher than that in no-encephalopathy （NE） patients, and higher in NE than that in controls （3.74 ± 3.13 vs. 1.08 ± 0.75 vs. 0.37 ± 0.14 ng/ml, P 〈 0.01 ; 3.18 ± 1.55 vs. 1.02 ± 0.63 vs. 0.47 ± 0.10, P 〈 0.01）. S 100A8 levels of 1.93 ng/ml were diagnostic of SAE with 92.90% specificity and 69.00% sensitivity in the receiver operating characteristic （ROC） curve, and the area under the curve was 0.86 （95% confidence interval [CI]： 0.76-0.95）. TRAF6-relative levels of 1.44 were diagnostic of SAE with 85.70% specificity and 86.20% sensitivity, and the area under the curve was 0.94 （95% CI： 0.88-0.99）. In addition, S 100A8 levels of 2.41 ng/ml predicted 28-day mortality of SAE with 90.00% specificity and 73.70% sensitivity in the ROC curve, and the area under the curve was 0.88. TRAF6 relative levels of 2.94 predicted 28-day mortality of SAE with 80.00% specificity and 68.40% sensitivity, and the area under the curve was 0.77. Compared with TRAF6, the specificity of serum S 100A8 in diagnosing SAE and predicting mortality was higher, although the sensitivity was low. In contrast, the TRAF6 had higher sensitivity for diagnosis. Conclusions： Peripheral blood levels of S 100A8 and TRAF6 in SAE patients were elevated and might be related to the severity of SAE and predict the outcome of SAE. The efficacy and specificity of S 100A8 for SAE diagnosis were superior, despite its weak sensitivity. S100A8 might be a better biomarker for diagnosis of SAE and predicting prognosis.展开更多
Background:Tumor necrosis factor receptor-associated protein 1(TRAP1)plays a protective effect in hypoxic cardiomyocytes,but the precise mechanisms are not well clarified.The study is aimed to identify the mechanism o...Background:Tumor necrosis factor receptor-associated protein 1(TRAP1)plays a protective effect in hypoxic cardiomyocytes,but the precise mechanisms are not well clarified.The study is aimed to identify the mechanism of TRAP1 on hypoxic damage in cardiomyocytes.Methods:In this study,the effects of TRAP1 and cytochrome c oxidase subunit Ⅱ(COXⅡ)on apoptosis in hypoxia-induced cardiomyocytes were explored using overexpression and knockdown methods separately.Results:Hypoxia induced cardiomyocyte apoptosis,and TRAP1 overexpression notably inhibited apoptosis induced by hypoxia.Conversely,TRAP1 silencing promoted apoptosis in hypoxic cardiomyocytes.Further investigation revealed that the proapoptotic effects caused by the silencing of TRAP1 were prevented by COXⅡ overexpression,whereas COXⅡ knockdown reduced the antiapoptotic function induced by TRAP1 overexpression.Additionally,changes in the release of cytochrome c from mitochondria into the cytosol and the caspase-3 activity in the cytoplasm,as well as reactive oxygen species production,were found to be correlated with the changes in apoptosis.Conclusions:The current study uncovered that TRAP1 regulates hypoxia-induced cardiomyocyte apoptosis through a mitochondria-dependent apoptotic pathway mediated by COXⅡ,in which reactive oxygen species presents as an important component.展开更多
Chemical synapses are asymmetric intercellular junc. tions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temp...Chemical synapses are asymmetric intercellular junc. tions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules （CAMs） at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion chan- nels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer＇s disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.展开更多
基金supported by the National Natural Science Foundation of China, No. 81771140 (to YDZ)the Natural Science Foundation of Jiangsu Province of China, No. BK20201117 (to YDZ)Jiangsu “Six One Project” for Distinguished Medical Scholars of China, No. LGY2020013 (to TJ)
文摘Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.
文摘Until recently, the synaptic transmission and excitatory amino acid transporters activation of neurons are very well discussed in the previous studies and are considered to be the two distinct features of Synapse. It is also found that a large number of interactions take place in the domain of ionic exchanges and protein interactions in synapses. It is evolutionary to have destined to release of Neurotransmitters to conduct an impulse to the other consecutive neurons, which forms the most important characteristic of synapse. From the popular perspective, it has been identified that detailed theoretical closer correlation of data produced through various studies about synapse can unravel many mysteries related to functions of synapse. Hence, this research paper tries to concentrate on a selected group of prominent characteristics and properties of synapse and also highlights some noteworthy discoveries, emphasizing the influential capabilities of them in the thought process and improving the knowledge of the field. It also highlights the expressive properties and forms of synapse brought out through the evidences available in sparse to dense data in a correlational way.
文摘The brain is a complex network system that has the capacity to support emotion, thought, action, learning and memory, and is characterized by constant activity, constant structural remodeling, and constant attempt to compensate for this remodeling. The basic insight that emerges from complex network organization is that substantively different networks can share common key organizational principles. Moreover, the interdependence of network organization and behavior has been successfully demonstrated for several specific tasks. From this viewpoint, increasing experimental/clinical observations suggest that mental disorders are neural network disorders. On one hand, single psychiatric disorders arise from multiple, multifactorial molecular and cellular structural/functional alterations spreading throughout local/global circuits leading to multifaceted and heterogeneous clinical symptoms. On the other hand, various mental diseases may share functional deficits across the same neural circuit as reflected in the overlap of symptoms throughout clinical diagnoses. An integrated framework including experimental measures and clinical observations will be necessary to formulate a coherent and comprehensive understanding of how neural connectivity mediates and constraints the phenotypic expression of psychiatric disorders.
文摘The study of the neuron has always been a fundamental aspect when it came to studying mental illnesses such as autism and depression. The protein protocadherin-9 (PCDH9) is an important transmembrane protein in the development of the neuron synapse. Hence, research on its protein interactome is key to understanding its functionality and specific properties. A newly discovered biotin ligase, TurboID, is a proximity labeler that is designed to be able to label and observe transmembrane proteins, something that previous methods struggled with. The TurboID method is verified in HEK293T cells and primary cultured mouse cortical neurons. Results have proven the validity of the TurboID method in observing PCDH9-interacting proteins.
基金the Singapore Ministry of Education(T1-2015 Apr-03)the National University of SingaporeInstitute for Health Innovation and Technology to JJEC.
文摘The human brain contains an estimated 100 billion neurons that must be systematically organized into functional neural circuits for it to function properly.These circuits range from short-range local signaling networks between neighboring neurons to long-range networks formed between various brain regions.Compelling converging evidence indicates that alterations in neural circuits arising from abnormalities during early neuronal development or neurodegeneration contribute significantly to the etiology of neurological disorders.Supporting this notion,efforts to identify genetic causes of these disorders have uncovered an over-representation of genes encoding proteins involved in the processes of neuronal differentiation,maturation,synaptogenesis and synaptic function.Fasciculation and elongation protein zeta-1,a Kinesin-1 adapter,has emerged as a key central player involved in many of these processes.Fasciculation and elongation protein zeta-1-dependent transport of synaptic cargoes and mitochondria is essential for neuronal development and synapse establishment.Furthermore,it acts downstream of guidance cue pathways to regulate axo-dendritic development.Significantly,perturbing its function causes abnormalities in neuronal development and synapse formation both in the brain as well as the peripheral nervous system.Mutations and deletions of the fasciculation and elongation protein zeta-1 gene are linked to neurodevelopmental disorders.Moreover,altered phosphorylation of the protein contributes to neurodegenerative disorders.Together,these findings strongly implicate the importance of fasciculation and elongation protein zeta-1 in the establishment of neuronal circuits and its maintenance.
文摘Background： Despite its high prevalence, morbidity, and mortality, sepsis-associated encephalopathy （SAE） is still poorly understood. The aim of this prospective and observational study was to investigate the clinical significance of calcium-binding protein A8 （S 100AS） in serum and tumor necrosis factor receptor-associated factor 6 （TRAF6） in peripheral blood mononuclear cells （PBMCs） in diagnosing SAE and predicting its prognosis. Methods： Data of septic patients were collected within 24 h after Intensive Care Unit admission fi-om July 2014 to March 2015. Healthy medical personnel served as the control group. SAE was defined as cerebral dysfhnction in the presence of sepsis that fulfilled the exclusion criteria. The biochemical indicators, Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation score II, TRAF6 in PBMC, serum S 100A8, S 10013, and neuron-specific enolase were evaluated in SAE patients afresh. TRAF6 and S 100A8 were also measured in the control group. Results： Of the 57 enrolled patients, 29 were diagnosed with SAE. The S 100A8 and TRAF6 concentrations in SAE patients were both significantly higher than that in no-encephalopathy （NE） patients, and higher in NE than that in controls （3.74 ± 3.13 vs. 1.08 ± 0.75 vs. 0.37 ± 0.14 ng/ml, P 〈 0.01 ; 3.18 ± 1.55 vs. 1.02 ± 0.63 vs. 0.47 ± 0.10, P 〈 0.01）. S 100A8 levels of 1.93 ng/ml were diagnostic of SAE with 92.90% specificity and 69.00% sensitivity in the receiver operating characteristic （ROC） curve, and the area under the curve was 0.86 （95% confidence interval [CI]： 0.76-0.95）. TRAF6-relative levels of 1.44 were diagnostic of SAE with 85.70% specificity and 86.20% sensitivity, and the area under the curve was 0.94 （95% CI： 0.88-0.99）. In addition, S 100A8 levels of 2.41 ng/ml predicted 28-day mortality of SAE with 90.00% specificity and 73.70% sensitivity in the ROC curve, and the area under the curve was 0.88. TRAF6 relative levels of 2.94 predicted 28-day mortality of SAE with 80.00% specificity and 68.40% sensitivity, and the area under the curve was 0.77. Compared with TRAF6, the specificity of serum S 100A8 in diagnosing SAE and predicting mortality was higher, although the sensitivity was low. In contrast, the TRAF6 had higher sensitivity for diagnosis. Conclusions： Peripheral blood levels of S 100A8 and TRAF6 in SAE patients were elevated and might be related to the severity of SAE and predict the outcome of SAE. The efficacy and specificity of S 100A8 for SAE diagnosis were superior, despite its weak sensitivity. S100A8 might be a better biomarker for diagnosis of SAE and predicting prognosis.
基金supported by the National Natural Science Foundation of China(NSFC)(Grant No:81101426,81571898).
文摘Background:Tumor necrosis factor receptor-associated protein 1(TRAP1)plays a protective effect in hypoxic cardiomyocytes,but the precise mechanisms are not well clarified.The study is aimed to identify the mechanism of TRAP1 on hypoxic damage in cardiomyocytes.Methods:In this study,the effects of TRAP1 and cytochrome c oxidase subunit Ⅱ(COXⅡ)on apoptosis in hypoxia-induced cardiomyocytes were explored using overexpression and knockdown methods separately.Results:Hypoxia induced cardiomyocyte apoptosis,and TRAP1 overexpression notably inhibited apoptosis induced by hypoxia.Conversely,TRAP1 silencing promoted apoptosis in hypoxic cardiomyocytes.Further investigation revealed that the proapoptotic effects caused by the silencing of TRAP1 were prevented by COXⅡ overexpression,whereas COXⅡ knockdown reduced the antiapoptotic function induced by TRAP1 overexpression.Additionally,changes in the release of cytochrome c from mitochondria into the cytosol and the caspase-3 activity in the cytoplasm,as well as reactive oxygen species production,were found to be correlated with the changes in apoptosis.Conclusions:The current study uncovered that TRAP1 regulates hypoxia-induced cardiomyocyte apoptosis through a mitochondria-dependent apoptotic pathway mediated by COXⅡ,in which reactive oxygen species presents as an important component.
文摘Chemical synapses are asymmetric intercellular junc. tions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules （CAMs） at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion chan- nels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer＇s disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.
