The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries.At 60 days after modeling,escape latency and swi...The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries.At 60 days after modeling,escape latency and swimming path length during hidden-platform acquisition training in Morris water maze significantly increased in the model group.In addition,the number of accurate crossings over the original platform significantly decreased,hippocampal CA1 synaptophysin and growth-associated protein 43 expression significantly decreased,cAMP response element-binding protein expression remained unchanged,and phosphorylated cAMP response element-binding protein expression significantly decreased.Results suggested that abnormal expression of hippocampal synaptic structural protein and cAMP response element-binding protein phosphorylation played a role in cognitive impairment following chronic cerebral hypoperfusion.展开更多
The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs ...The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.展开更多
Objective： To investigate the effect and molecular mechanism of Tiantai No.1 （天泰1号）, a compound Chinese herbal preparation, for the prevention and reduction of neurotoxicity induced by betaamyloid peptides （Ab...Objective： To investigate the effect and molecular mechanism of Tiantai No.1 （天泰1号）, a compound Chinese herbal preparation, for the prevention and reduction of neurotoxicity induced by betaamyloid peptides （Abeta） in vitro and its effects on nuclear factor-κB （NF-κB） and cAMP responsive element-binding protein （CREB） pathways using the gene transfection technique. Methods： B104 neuronal cells were used to examine the effects of Tiantai No.1 on lowering the neurotoxicity induced by Abeta. The cells were pre-treated with Tiantai No.1 at doses of 50, 100,150, or 200μg/mL respectively for 3 days and co-treated with Tiantai No.1 and beta-amyloid peptidel-40 （Aβ 1-40, 10 μmol/L） for 48 h or post-treated with Tiantai No.1 for 48 h after the cells were exposed to beta-amyloid peptides25-35 （Aβ 25-35） for 8 h. In gene transfection assays, cells were treated with Tiantai No.1 at 50 μg/mL and 150μg/mL for 5 days or co-treated with Tiantai No.1 and A 13 1-40 （5 μmo/L） for 3 days after electroporation for the evaluation of NF- κB and CREB expression. Results： Pre-treating and co-treating B104 neuronal cells with Tiantai No.1 lowered the neurotoxicity induced by Abeta, and post-treating with Tiantai No.1 reduced or blocked B104 neuronal apoptotic death induced by Abeta （P〈0.05, P〈0.01）. With a dose-dependent relationship, the same treatments increased the expression of NF-κB or CREB in B104 neuronal cells （P〈0.05, P〈0.01）. Meanwhile, Tiantai No.1 reduced Aβ-40 induced inhibition on NF-κB expression （P〈0.01）. Conclusions： Tiantai No.1 can protect neurons against the neurotoxicity induced by Abeta. The neuroprotective mechanisms may be associated with the activation of NF-κB and cAMP cellular signal pathways.展开更多
Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippoca...Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice.To investigate the effects of entacapone,a modulator of dopamine,on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus,60 mice(7 weeks old)were randomly divided into a vehicle-treated group and the groups treated with 10,50,or 200 mg/kg entacapone.The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition.Immunohistochemical staining results revealed that after entacapone treatment,the numbers of Ki67-positive proliferating cells,doublecortin-positive immature neurons,and phosphorylated cAMP response element-binding protein(pCREB)-positive cells were significantly increased.Western blot analysis results revealed that treatment with tyrosine kinase receptor B(TrkB)receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor(BDNF).Entacapone treatment antagonized the effects of TrkB receptor antagonist.These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway.This study was approved by the Institutional Animal Care and Use Committee of Seoul National University(approval No.SNU-130730-1)on February 24,2014.展开更多
Metal ions play critical roles in the interaction between deoxyribonucleic acid(DNA) and protein.The experimental research has demonstrated that the Mg^2+ ion can affect the binding between transcription factor and DN...Metal ions play critical roles in the interaction between deoxyribonucleic acid(DNA) and protein.The experimental research has demonstrated that the Mg^2+ ion can affect the binding between transcription factor and DNA.In our work,by full-atom molecular dynamic simulation, the effects of the Mg^2+ ion on the cyclic adenosine monophosphate(cAMP)response element binding protein(CREB)/cAMP response elements(CRE) complex are investigated.It is illustrated that the number of hydrogen bonds formed at the interface between protein and DNA is significantly increased when the Mg^2+ ion is added.Hence, an obvious change in the structure of the DNA is observed.Then the DNA base groove and base pair parameters are analyzed.We find that, due to the introduction of the Mg2+ ion, the DNA base major groove becomes narrower.A potential mechanism for this observation is proposed.It is confirmed that the Mg^2+ ion can enhance the stability of the DNA–protein complex.展开更多
Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by ...Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit.The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment.Methods MK-801 was used to induce SZ in rats.Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats.The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment,respectively.Results The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats.Interestingly,among the upstream kinases of CREB,merely ERK1/2 was downregulated,while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats.The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133,and induced synaptic dysfunction in primary hippocampal neurons.Conversely,the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment.Conclusion These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment.The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.展开更多
基金supported by the National Natural Science Foundation of China,No.30973782the National Natural Science Foundation for the Youth,No.81001693+1 种基金the Natural Science Foundation of Beijing,No.7102014,7122018the Science and Technology Foundation for Chinese Medicine in Beijing,No.JJ2008-042
文摘The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries.At 60 days after modeling,escape latency and swimming path length during hidden-platform acquisition training in Morris water maze significantly increased in the model group.In addition,the number of accurate crossings over the original platform significantly decreased,hippocampal CA1 synaptophysin and growth-associated protein 43 expression significantly decreased,cAMP response element-binding protein expression remained unchanged,and phosphorylated cAMP response element-binding protein expression significantly decreased.Results suggested that abnormal expression of hippocampal synaptic structural protein and cAMP response element-binding protein phosphorylation played a role in cognitive impairment following chronic cerebral hypoperfusion.
基金supported by the National Natural Science Foundation of China,No.81202620the Domestic Visiting Scholar Program for Young Talent Teachers in University of Shandong Province
文摘The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.
文摘Objective： To investigate the effect and molecular mechanism of Tiantai No.1 （天泰1号）, a compound Chinese herbal preparation, for the prevention and reduction of neurotoxicity induced by betaamyloid peptides （Abeta） in vitro and its effects on nuclear factor-κB （NF-κB） and cAMP responsive element-binding protein （CREB） pathways using the gene transfection technique. Methods： B104 neuronal cells were used to examine the effects of Tiantai No.1 on lowering the neurotoxicity induced by Abeta. The cells were pre-treated with Tiantai No.1 at doses of 50, 100,150, or 200μg/mL respectively for 3 days and co-treated with Tiantai No.1 and beta-amyloid peptidel-40 （Aβ 1-40, 10 μmol/L） for 48 h or post-treated with Tiantai No.1 for 48 h after the cells were exposed to beta-amyloid peptides25-35 （Aβ 25-35） for 8 h. In gene transfection assays, cells were treated with Tiantai No.1 at 50 μg/mL and 150μg/mL for 5 days or co-treated with Tiantai No.1 and A 13 1-40 （5 μmo/L） for 3 days after electroporation for the evaluation of NF- κB and CREB expression. Results： Pre-treating and co-treating B104 neuronal cells with Tiantai No.1 lowered the neurotoxicity induced by Abeta, and post-treating with Tiantai No.1 reduced or blocked B104 neuronal apoptotic death induced by Abeta （P〈0.05, P〈0.01）. With a dose-dependent relationship, the same treatments increased the expression of NF-κB or CREB in B104 neuronal cells （P〈0.05, P〈0.01）. Meanwhile, Tiantai No.1 reduced Aβ-40 induced inhibition on NF-κB expression （P〈0.01）. Conclusions： Tiantai No.1 can protect neurons against the neurotoxicity induced by Abeta. The neuroprotective mechanisms may be associated with the activation of NF-κB and cAMP cellular signal pathways.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea Government(MSIP)(NRF-2016R1A2B4009156)the Promising-Pioneering Researcher Program through Seoul National University(SNU)in 2015 and by the Research Institute for Veterinary Science,Seoul National University.
文摘Entacapone,a catechol-O-methyltransferase inhibitor,can strengthen the therapeutic effects of levodopa on the treatment of Parkinson’s disease.However,few studies are reported on whether entacapone can affect hippocampal neurogenesis in mice.To investigate the effects of entacapone,a modulator of dopamine,on proliferating cells and immature neurons in the mouse hippocampal dentate gyrus,60 mice(7 weeks old)were randomly divided into a vehicle-treated group and the groups treated with 10,50,or 200 mg/kg entacapone.The results showed that 50 and 200 mg/kg entacapone increased the exploration time for novel object recognition.Immunohistochemical staining results revealed that after entacapone treatment,the numbers of Ki67-positive proliferating cells,doublecortin-positive immature neurons,and phosphorylated cAMP response element-binding protein(pCREB)-positive cells were significantly increased.Western blot analysis results revealed that treatment with tyrosine kinase receptor B(TrkB)receptor antagonist significantly decreased the exploration time for novel object recognition and inhibited the expression of phosphorylated TrkB and brain-derived neurotrophic factor(BDNF).Entacapone treatment antagonized the effects of TrkB receptor antagonist.These results suggest that entacapone treatment promoted hippocampal neurogenesis and improved memory function through activating the BDNF-TrkB-pCREB pathway.This study was approved by the Institutional Animal Care and Use Committee of Seoul National University(approval No.SNU-130730-1)on February 24,2014.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11705064,11675060,and 91730301)the Fundamental Research Funds for the Central Universities,China(Grant Nos.2662016QD005 and 26622018JC017)the Huazhong Agricultural University Scientific and Technological Self-Innovation Foundation Program,China(Grant No.2015RC021)
文摘Metal ions play critical roles in the interaction between deoxyribonucleic acid(DNA) and protein.The experimental research has demonstrated that the Mg^2+ ion can affect the binding between transcription factor and DNA.In our work,by full-atom molecular dynamic simulation, the effects of the Mg^2+ ion on the cyclic adenosine monophosphate(cAMP)response element binding protein(CREB)/cAMP response elements(CRE) complex are investigated.It is illustrated that the number of hydrogen bonds formed at the interface between protein and DNA is significantly increased when the Mg^2+ ion is added.Hence, an obvious change in the structure of the DNA is observed.Then the DNA base groove and base pair parameters are analyzed.We find that, due to the introduction of the Mg2+ ion, the DNA base major groove becomes narrower.A potential mechanism for this observation is proposed.It is confirmed that the Mg^2+ ion can enhance the stability of the DNA–protein complex.
基金supported in part by grants from National Natural Science Foundation of China(No.31929002,No.82201326 No.82071440 and No.92049107)Science,Technology and Innovation Commission of Shenzhen Municipality(No.JCYJ20210324141405014)+1 种基金Guangdong Basic and Applied Basic Research Foundation(No.2020B1515120017)the Academic Frontier Youth Team Project to Xiao-chuan WANG from Huazhong University of Science and Technology.
文摘Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit.The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment.Methods MK-801 was used to induce SZ in rats.Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats.The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment,respectively.Results The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats.Interestingly,among the upstream kinases of CREB,merely ERK1/2 was downregulated,while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats.The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133,and induced synaptic dysfunction in primary hippocampal neurons.Conversely,the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment.Conclusion These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment.The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.
