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
Intravenous anesthetics are known to cause amnesia, but the underlying molecular mechanisms remain elusive. To identify a possible molecular mechanism, we recently turned our attention to a key intracellular signaling...Intravenous anesthetics are known to cause amnesia, but the underlying molecular mechanisms remain elusive. To identify a possible molecular mechanism, we recently turned our attention to a key intracellular signaling pathway organized by a family of mitogen-activated protein kinases （MAPKs）. As a prominent synapse-to-nucleus superhighway, MAPKs couple surface glutamate receptors to nuclear transcriptional events essential for the development and/or maintenance of different forms of synaptic plasticity （long-term potentiation and long-term depression） and memory formation. To define the role of MAPK-dependent transcription in the amnesic property of anesthetics, we conducted a series of studies to examine the effect of a prototype intravenous anesthetic propofol on the MAPK response to N-methyl-D-aspartate receptor （NMDAR） stimulation in hippocampal neurons. Our results suggest that propofol possesses the ability to inhibit NMDAR-mediated activation of a classic subclass of MAPKs, extracellular signal-regulated protein kinase 1/2 （ERK1/2）. Concurrent inhibition of transcriptional activity also occurs as a result of inhibited responses of ERK1/2 to NMDA. These findings provide first evidence for an inhibitory modulation of the NMDAR-MAPK pathway by an intravenous anesthetic and introduce a new avenue to elucidate a transcription-dependent mechanism processing the amnesic effect of anesthetics.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
NFAT5 plays a critical role in maintaining the renal functions. Its dis-regulation in the kidney leads to or is associated with certain renal diseases or disorders, most notably the urinary concentration defect. Hyper...NFAT5 plays a critical role in maintaining the renal functions. Its dis-regulation in the kidney leads to or is associated with certain renal diseases or disorders, most notably the urinary concentration defect. Hypertonicity, which the kidney medulla is normally exposed to,activates NFAT5 through phosphorylation of a signaling molecule or NFAT5 itself. Hypotonicity inhibits NFAT5 through a similar mechanism. More than a dozen of protein and lipid kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. Hypertonicity activates NFAT5 by increasing its nuclear localization and transactivating activity in the early phase and protein abundance in the late phase. The known mechanism for inhibition of NFAT5 by hypotonicity is a decrease of nuclear NFAT5. The present article reviews the effect of each kinase on NFAT5 nuclear localization, transactivation and protein abundance, and the relationship among these kinases, if known. Cyclosporine A and tacrolimus suppress immune reactions by inhibiting the phosphatase calcineurin-dependent activation of NFAT1. It is hoped that this review would stimulate the interest to seek explanations from the NFAT5 regulatory pathways for certain clinical presentations and to explore novel therapeutic approaches based on the pathways. On the basic science front, this review raises two interesting questions. The first one is how these kinases can specifcally signal to NFAT5 in the context of hypertonicity or hypotonicity, because they also regulate other cellular activities and even opposite activities in some cases. The second one is why these many kinases, some of which might have redundant functions, are needed to regulate NFAT5 activity. This review reiterates the concept of signaling through cooperation. Cells need these kinases working in a coordinated way to provide the signaling specificity that is lacking in the individual one. Redundancy in regulation of NFAT5 is a critical strategy for cells to maintain robustness against hypertonic or hypotonic stress.展开更多
Lysophosphatidic acid （LPA） is a pleiotropic lipid med-iator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fbroblast-like syno-viocytes （FLS） from patients with rheumatoid ar...Lysophosphatidic acid （LPA） is a pleiotropic lipid med-iator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fbroblast-like syno-viocytes （FLS） from patients with rheumatoid arthritis. LPA activates several proteins within the mitogen acti-vated protein （MAP） kinase signaling network, including extracellular signal-regulated kinases （ERK） 1/2 and p38 MAP kinase （MAPK）. Upon docking to mitogen and stress-activated kinases （MSKs）, ERK1/2 and p38 MAPK phosphorylate serine and threonine residues within its C-terminal domain and cause autophosphorylation of MSKs. Activated MSKs can then directly phosphorylate cAMP response element-binding protein （CREB） at Ser133 in FLS. Phosphorylation of CREB by MSKs is essential for the production of pro-inflammatory and anti-infammatory cytokines. However, other downstream effectors of MSK1/2 such as nuclear factor-kappa B, histone H3, and high mobility group nucleosome binding domain 1 may also regulate gene expression in immune cells involved in disease pathogenesis. MSKs are master regulators of cell function that integrate signals induced by growth factors, proinflammatory cytokines, and cellular stresses, as well as those induced by LPA.展开更多
Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS...Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS-,nNOS-and nNOS-2.Monomer of nNOS is inactive,and dimer is the active form.Dimerization requires tetrahydrobiopterin （BH 4）,heme and L-arginine binding.Regulation of nNOS expression relies largely on cAMP response element-binding protein （CREB） activity,and nNOS activity is regulated by heat shock protein 90 （HSP90）/HSP70,calmodulin （CaM）,phosphorylation and dephosphorylation at Ser847 and Ser1412,and the protein inhibitor of nNOS （PIN）.There are primarily 9 nNOS-interacting proteins,including post-synaptic density protein 95 （PSD95）,clathrin assembly lymphoid leukemia （CALM）,calcium/calmodulindependent protein kinase II alpha （CAMKIIA）,Disks large homolog 4 （DLG4）,DLG2,6-phosphofructokinase,muscle type （PFK-M）,carboxy-terminal PDZ ligand of nNOS （CAPON） protein,syntrophin and dynein light chain （LC）.Among them,PSD95,CAPON and PFK-M are important nNOS adapter proteins in neurons.The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death.nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states,and negatively regulates neurogenesis under physiological and pathological conditions.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.
文摘Intravenous anesthetics are known to cause amnesia, but the underlying molecular mechanisms remain elusive. To identify a possible molecular mechanism, we recently turned our attention to a key intracellular signaling pathway organized by a family of mitogen-activated protein kinases （MAPKs）. As a prominent synapse-to-nucleus superhighway, MAPKs couple surface glutamate receptors to nuclear transcriptional events essential for the development and/or maintenance of different forms of synaptic plasticity （long-term potentiation and long-term depression） and memory formation. To define the role of MAPK-dependent transcription in the amnesic property of anesthetics, we conducted a series of studies to examine the effect of a prototype intravenous anesthetic propofol on the MAPK response to N-methyl-D-aspartate receptor （NMDAR） stimulation in hippocampal neurons. Our results suggest that propofol possesses the ability to inhibit NMDAR-mediated activation of a classic subclass of MAPKs, extracellular signal-regulated protein kinase 1/2 （ERK1/2）. Concurrent inhibition of transcriptional activity also occurs as a result of inhibited responses of ERK1/2 to NMDA. These findings provide first evidence for an inhibitory modulation of the NMDAR-MAPK pathway by an intravenous anesthetic and introduce a new avenue to elucidate a transcription-dependent mechanism processing the amnesic effect of anesthetics.
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.
文摘NFAT5 plays a critical role in maintaining the renal functions. Its dis-regulation in the kidney leads to or is associated with certain renal diseases or disorders, most notably the urinary concentration defect. Hypertonicity, which the kidney medulla is normally exposed to,activates NFAT5 through phosphorylation of a signaling molecule or NFAT5 itself. Hypotonicity inhibits NFAT5 through a similar mechanism. More than a dozen of protein and lipid kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. Hypertonicity activates NFAT5 by increasing its nuclear localization and transactivating activity in the early phase and protein abundance in the late phase. The known mechanism for inhibition of NFAT5 by hypotonicity is a decrease of nuclear NFAT5. The present article reviews the effect of each kinase on NFAT5 nuclear localization, transactivation and protein abundance, and the relationship among these kinases, if known. Cyclosporine A and tacrolimus suppress immune reactions by inhibiting the phosphatase calcineurin-dependent activation of NFAT1. It is hoped that this review would stimulate the interest to seek explanations from the NFAT5 regulatory pathways for certain clinical presentations and to explore novel therapeutic approaches based on the pathways. On the basic science front, this review raises two interesting questions. The first one is how these kinases can specifcally signal to NFAT5 in the context of hypertonicity or hypotonicity, because they also regulate other cellular activities and even opposite activities in some cases. The second one is why these many kinases, some of which might have redundant functions, are needed to regulate NFAT5 activity. This review reiterates the concept of signaling through cooperation. Cells need these kinases working in a coordinated way to provide the signaling specificity that is lacking in the individual one. Redundancy in regulation of NFAT5 is a critical strategy for cells to maintain robustness against hypertonic or hypotonic stress.
基金Supported by A research grant from the Arthritis Society of CanadaNo.RG10/011(to Bourgoin SG)
文摘Lysophosphatidic acid （LPA） is a pleiotropic lipid med-iator that promotes motility, survival, and the synthesis of chemokines/cytokines in human fbroblast-like syno-viocytes （FLS） from patients with rheumatoid arthritis. LPA activates several proteins within the mitogen acti-vated protein （MAP） kinase signaling network, including extracellular signal-regulated kinases （ERK） 1/2 and p38 MAP kinase （MAPK）. Upon docking to mitogen and stress-activated kinases （MSKs）, ERK1/2 and p38 MAPK phosphorylate serine and threonine residues within its C-terminal domain and cause autophosphorylation of MSKs. Activated MSKs can then directly phosphorylate cAMP response element-binding protein （CREB） at Ser133 in FLS. Phosphorylation of CREB by MSKs is essential for the production of pro-inflammatory and anti-infammatory cytokines. However, other downstream effectors of MSK1/2 such as nuclear factor-kappa B, histone H3, and high mobility group nucleosome binding domain 1 may also regulate gene expression in immune cells involved in disease pathogenesis. MSKs are master regulators of cell function that integrate signals induced by growth factors, proinflammatory cytokines, and cellular stresses, as well as those induced by LPA.
基金supported by the National Natural Science Foundation of China(No. 30971021,81030023 and 30901550)
文摘Neuronal nitric oxide synthase （nNOS） is mainly expressed in neurons,to some extent in astrocytes and neuronal stem cells.The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS,including nNOS-,nNOS-,nNOS-,nNOS-and nNOS-2.Monomer of nNOS is inactive,and dimer is the active form.Dimerization requires tetrahydrobiopterin （BH 4）,heme and L-arginine binding.Regulation of nNOS expression relies largely on cAMP response element-binding protein （CREB） activity,and nNOS activity is regulated by heat shock protein 90 （HSP90）/HSP70,calmodulin （CaM）,phosphorylation and dephosphorylation at Ser847 and Ser1412,and the protein inhibitor of nNOS （PIN）.There are primarily 9 nNOS-interacting proteins,including post-synaptic density protein 95 （PSD95）,clathrin assembly lymphoid leukemia （CALM）,calcium/calmodulindependent protein kinase II alpha （CAMKIIA）,Disks large homolog 4 （DLG4）,DLG2,6-phosphofructokinase,muscle type （PFK-M）,carboxy-terminal PDZ ligand of nNOS （CAPON） protein,syntrophin and dynein light chain （LC）.Among them,PSD95,CAPON and PFK-M are important nNOS adapter proteins in neurons.The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death.nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states,and negatively regulates neurogenesis under physiological and pathological conditions.
