TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-po...TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-pore domain potassium channels is the last big family of channels being discovered, therefore it is not surprising that most of the information we know about TREK channels predominantly comes from the study of heterologously expressed channels. Notw让hstanding, in this review we pay special attention to the limited amount of information available on native TREK-like channels and real neurons in relation to neuroprotection. Mainly we focus on the role of free fatty acids, lysophospholipids and other neuroprotective agents like riluzole in the modulation of TREK channels, emphasizing on how important this modulation may be for the development of new therapies against neuropathic pain, depression, schizophrenia, epilepsy, ischemia and cardiac complications.展开更多
OBJECTIVE To find that the extracellular cap of a K2P channel can act as a new allosteric site and may serve as a direct drug target.METHODS Molecular biology and cell transfection,electrophysiology,molecular docking,...OBJECTIVE To find that the extracellular cap of a K2P channel can act as a new allosteric site and may serve as a direct drug target.METHODS Molecular biology and cell transfection,electrophysiology,molecular docking,molecular dynamics simulations,virtual screening for TREK1,and depressive-related behavior tests.RESULTS Extracellular domain of TREK1 channel existed a dynamic cavity in the extracellular domain by the method of computations,mutagenesis and electrophysiology.Molecular dynamics simulations suggested that ligand-induced allosteric conformational transitions lead to blockage of the ion conductive pathway.Using virtual screening approach,we identified other inhibitors targeting the extracellular allosteric ligand-binding site of these channels.Overall,our results suggested that the allosteric site at the extracellular cap of the K2P channels might be a promising drug target for these membrane proteins.The TREK1 inhibitor TKDC had significantly faster onset than that of fluoxetine in chronic administration trials,and the study confirms that TREK1 was an important target for the development of rapid antidepressants.CONCLUSION The study is a significant step forward for understanding the function of TREK and for identifying specific inhibitors,which should be of interest to others in the field.展开更多
LI BINGBING, 10, gets up at 6：30 every morning, washes, dresses and has breakfast. Then her grandmother takes her to school 2 km away. Li is a third-grade learner at the Central Primary School in Liucun Village of Xi...LI BINGBING, 10, gets up at 6：30 every morning, washes, dresses and has breakfast. Then her grandmother takes her to school 2 km away. Li is a third-grade learner at the Central Primary School in Liucun Village of Xingtai City in north Chinas Hebei Province. The school is a merger of eight schools in nearby villages catering for children from grade one to six.展开更多
Areas at high-altitude,annually attract millions of tourists,skiers,trekkers,and climbers.If not adequately prepared and not considering certain ascent rules,a considerable proportion of those people will suffer from ...Areas at high-altitude,annually attract millions of tourists,skiers,trekkers,and climbers.If not adequately prepared and not considering certain ascent rules,a considerable proportion of those people will suffer from acute mountain sickness(AMS)or even from life-threatening high-altitude cerebral(HACE)or/and pulmonary edema(HAPE).Reduced inspired oxygen partial pressure with gain in altitude and consequently reduced oxygen availability is primarily responsible for getting sick in this setting.Appropriate acclimatization by slowly raising the hypoxic stimulus(e.g.,slow ascent to high altitude)and/or repeated exposures to altitude or artificial,nor-mobaric hypoxia will largely prevent those illnesses.Understanding physiological mechanisms of acclimatization and pathophysiological mechanisms of high-altitude diseases,knowledge of symptoms and signs,treatment and prevention strategies will largely contribute to the risk reduction and increased safety,success and enjoyment at high altitude.Thus,this review is intended to provide a sound basis for both physicians counseling high-altitude visitors and high-altitude visitors themselves.展开更多
The disruption of epithelial barrier integrity is an important factor in the pathogenesis of various immune disorders. However, the restitution of the compromised barrier functions is difficult. This study investigate...The disruption of epithelial barrier integrity is an important factor in the pathogenesis of various immune disorders. However, the restitution of the compromised barrier functions is difficult. This study investigates the regulation of TWIK-related potassium channel-1 （Trek1） in the restitution of intestinal epithelial barrier functions. The human colon epithelial cell line T84 was cultured in monolayers and used to observe epithelial barrier functions in vitro. An intestinal allergy mouse model was created. Cytokine levels were determined by enzyme-linked immunosorbent assay and western blotting. The results showed that Trek1 deficiency induced T84 monolayer barrier disruption. Allergic responses markedly suppressed the expression of Trek1 in the intestinal epithelia via activating the mitogen-activated protein kinase pathways and increasing the expression of histone deacetylase-1. The inhibition of histone deacetylase-1 by sodium butyrate or the administration of a butyrate-producing probiotic （Clostridium butyricum） restored the intestinal epithelial barrier functions and markedly enhanced the effect of antigen-specific immunotherapy. The data suggest that Trek1 is required for the maintenance of intestinal epithelial barrier integrity. Allergic responses induce an insufficiency of Trek1 expression in the intestinal epithelia. Trek1 expression facilitates the restoration of intestinal epithelial barrier functions in an allergic environment.展开更多
With the support of the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Yang Huaiyu(阳怀宇)from the East China Normal University and Prof.Li Yang(李扬)from Shangha...With the support of the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Yang Huaiyu(阳怀宇)from the East China Normal University and Prof.Li Yang(李扬)from Shanghai Institute of Materia Medica,Chinese Academy of Sciences展开更多
On August 8, 1998, Wu Qi and Yu Yan arrived at Beijing, the destination of a journey that had taken them more than three years. In travelling across 28 provinces, autonomous regions and municipalities, by foot, bus an...On August 8, 1998, Wu Qi and Yu Yan arrived at Beijing, the destination of a journey that had taken them more than three years. In travelling across 28 provinces, autonomous regions and municipalities, by foot, bus and train, these two young women from Guangzhou had covered a distance of 120,000 kJlometers, the first continuous cross-country journey accomplished by women. On the eve of International Women’s Day (March 8th) of 1995, Wu Qi and Yu Yan quit their jobs and started out on their展开更多
基金supported by grants to JAL from the Spanish Government:Secretaría de Estado de Investigación,Desarrollo e Innovación(MINECO,BFU2014-58999-P),Galician Government:Consellería de Cultura,Educación e Ordenación Universitaria,Xunta de Galicia(GPC2015/022)European Regional Development Fund(FP7-316265-BIOCAPS)supported with Fondo Europeo de Desarrollo Regional Funds
文摘TWIK-related potassium channels (TREK) belong to a subfamily of the two-pore domain potassium channels family with three members, TREK1, TREK2 and TWIK-related arachidonic acid-activated potassium channels. The two-pore domain potassium channels is the last big family of channels being discovered, therefore it is not surprising that most of the information we know about TREK channels predominantly comes from the study of heterologously expressed channels. Notw让hstanding, in this review we pay special attention to the limited amount of information available on native TREK-like channels and real neurons in relation to neuroprotection. Mainly we focus on the role of free fatty acids, lysophospholipids and other neuroprotective agents like riluzole in the modulation of TREK channels, emphasizing on how important this modulation may be for the development of new therapies against neuropathic pain, depression, schizophrenia, epilepsy, ischemia and cardiac complications.
基金National Natural Science Foundation of China(3120077181030065+5 种基金8127405531371066013117101101)Ministry of Science and Technology(2013CB91060101)National Science Technology Major Project of China (2012ZX09301-001-062014ZX09102001-005).
文摘OBJECTIVE To find that the extracellular cap of a K2P channel can act as a new allosteric site and may serve as a direct drug target.METHODS Molecular biology and cell transfection,electrophysiology,molecular docking,molecular dynamics simulations,virtual screening for TREK1,and depressive-related behavior tests.RESULTS Extracellular domain of TREK1 channel existed a dynamic cavity in the extracellular domain by the method of computations,mutagenesis and electrophysiology.Molecular dynamics simulations suggested that ligand-induced allosteric conformational transitions lead to blockage of the ion conductive pathway.Using virtual screening approach,we identified other inhibitors targeting the extracellular allosteric ligand-binding site of these channels.Overall,our results suggested that the allosteric site at the extracellular cap of the K2P channels might be a promising drug target for these membrane proteins.The TREK1 inhibitor TKDC had significantly faster onset than that of fluoxetine in chronic administration trials,and the study confirms that TREK1 was an important target for the development of rapid antidepressants.CONCLUSION The study is a significant step forward for understanding the function of TREK and for identifying specific inhibitors,which should be of interest to others in the field.
文摘LI BINGBING, 10, gets up at 6：30 every morning, washes, dresses and has breakfast. Then her grandmother takes her to school 2 km away. Li is a third-grade learner at the Central Primary School in Liucun Village of Xingtai City in north Chinas Hebei Province. The school is a merger of eight schools in nearby villages catering for children from grade one to six.
文摘Areas at high-altitude,annually attract millions of tourists,skiers,trekkers,and climbers.If not adequately prepared and not considering certain ascent rules,a considerable proportion of those people will suffer from acute mountain sickness(AMS)or even from life-threatening high-altitude cerebral(HACE)or/and pulmonary edema(HAPE).Reduced inspired oxygen partial pressure with gain in altitude and consequently reduced oxygen availability is primarily responsible for getting sick in this setting.Appropriate acclimatization by slowly raising the hypoxic stimulus(e.g.,slow ascent to high altitude)and/or repeated exposures to altitude or artificial,nor-mobaric hypoxia will largely prevent those illnesses.Understanding physiological mechanisms of acclimatization and pathophysiological mechanisms of high-altitude diseases,knowledge of symptoms and signs,treatment and prevention strategies will largely contribute to the risk reduction and increased safety,success and enjoyment at high altitude.Thus,this review is intended to provide a sound basis for both physicians counseling high-altitude visitors and high-altitude visitors themselves.
文摘The disruption of epithelial barrier integrity is an important factor in the pathogenesis of various immune disorders. However, the restitution of the compromised barrier functions is difficult. This study investigates the regulation of TWIK-related potassium channel-1 （Trek1） in the restitution of intestinal epithelial barrier functions. The human colon epithelial cell line T84 was cultured in monolayers and used to observe epithelial barrier functions in vitro. An intestinal allergy mouse model was created. Cytokine levels were determined by enzyme-linked immunosorbent assay and western blotting. The results showed that Trek1 deficiency induced T84 monolayer barrier disruption. Allergic responses markedly suppressed the expression of Trek1 in the intestinal epithelia via activating the mitogen-activated protein kinase pathways and increasing the expression of histone deacetylase-1. The inhibition of histone deacetylase-1 by sodium butyrate or the administration of a butyrate-producing probiotic （Clostridium butyricum） restored the intestinal epithelial barrier functions and markedly enhanced the effect of antigen-specific immunotherapy. The data suggest that Trek1 is required for the maintenance of intestinal epithelial barrier integrity. Allergic responses induce an insufficiency of Trek1 expression in the intestinal epithelia. Trek1 expression facilitates the restoration of intestinal epithelial barrier functions in an allergic environment.
文摘With the support of the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Yang Huaiyu(阳怀宇)from the East China Normal University and Prof.Li Yang(李扬)from Shanghai Institute of Materia Medica,Chinese Academy of Sciences
文摘On August 8, 1998, Wu Qi and Yu Yan arrived at Beijing, the destination of a journey that had taken them more than three years. In travelling across 28 provinces, autonomous regions and municipalities, by foot, bus and train, these two young women from Guangzhou had covered a distance of 120,000 kJlometers, the first continuous cross-country journey accomplished by women. On the eve of International Women’s Day (March 8th) of 1995, Wu Qi and Yu Yan quit their jobs and started out on their
