OBJECTIVE URB597(KDS-4103)is a potent and selective inhibitor of the enzyme fatty acid amide hydrolase(FAAH)and can ele⁃vate the level of oleoylethanolamide(OEA),a naturally occurring endocannabinoid in the brain.Howe...OBJECTIVE URB597(KDS-4103)is a potent and selective inhibitor of the enzyme fatty acid amide hydrolase(FAAH)and can ele⁃vate the level of oleoylethanolamide(OEA),a naturally occurring endocannabinoid in the brain.However,the effect of URB597 on cerebral isch⁃emic injury in mice remains unclear.METHODS Focal cerebral ischemia was induced by middle cerebral artery occlusion for 30 min followed by reperfusion for 24 h in mice.To observe the dose-dependent effect,URB597(0.04-5.00 mg·kg-1,ip)was administered at the same time of reperfu⁃sion.To determine the time-dependent effect,URB597(1.00 mg·kg-1,ip)was administered as a single dose at 0,1,3 or 5 h after reperfusion.Twenty-four hours after brain ischemia,Beder⁃son scoring test and grip strength test were used to evaluate the neurological function;brain in⁃farct volume was assayed by 2,3,5-triphenyltetra⁃zolium chloride(TTC)staining or diffusion-weighted magnetic resonance imaging(MRI).Laser speckle imaging(LSI)technique was used to assay the regional cerebral blood flow(rCBF);NeuN immunofluorescence staining was used to observe the neuron survival in the penumbra.To further investigate the underlying mechanism,au⁃tophagy flux related proteins(LC3-Ⅱ,P62 and LAMP2)and necroptosis related proteins(pRIPK3 and pMLKL)were detected by Western blotting and immunofluorescence staining.RESULTS Twenty-four hours after brain ischemia,URB597 dose-dependently improved neurological func⁃tion and reduced brain infarct volume.The most effective dose was 1.00 mg·kg-1;the therapeutic time window was within 1 h after ischemic stroke.The protective effect is further confirmed by the results that post-ischemic treatment with URB597(1.00 mg·kg-1)significantly increased neurons survival,promoted autophagy flux and reduced cell necroptosis in cortical penumbra after cerebral I/R.CONCLUSION URB597 dose-and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury.This neu⁃roprotective effect of URB597 may be associated with its restoration of autophagy flux and inhibi⁃tion of neuronal necroptosis in the cortical penumbra.展开更多
目的:吸烟在全世界引起了严重的健康问题,全球约5百万早产儿死于吸烟。此外,吸烟是一种以戒断后反复复吸为特点的慢性复发性疾病。尼古丁是烟草中导致人类成瘾的主要成分,可以使啮齿类动物形成持续的自身给药行为和条件性位置偏爱(CPP)...目的:吸烟在全世界引起了严重的健康问题,全球约5百万早产儿死于吸烟。此外,吸烟是一种以戒断后反复复吸为特点的慢性复发性疾病。尼古丁是烟草中导致人类成瘾的主要成分,可以使啮齿类动物形成持续的自身给药行为和条件性位置偏爱(CPP)。大量数据表明内源性大麻系统在尼古丁成瘾神经机制中有重要的作用。阻断CB1受体减少了尼古丁自身给药,线索诱导的尼古丁渴求的再现,以及尼古丁诱导的CPP。然而,最近的数据提示URB597通过抑制脂肪酸酰胺水解酶(fat acid amide hydrolase,FAAH)增强anandamide的传递,进而减少尼古丁关联行为,如尼古丁自身给药行为的获得和再现,尼古丁诱导大鼠CPP的表达和再现(Scherma et al.,2008)。CB1受体拮抗剂利莫他班对尼古丁自身给药累进比率(progressive ratio,PR),尼古丁点燃诱导的复吸,以及URB597对线索诱导尼古丁渴求再现的作用尚没有研究报道。本研究旨在填补这一空白。方法:大鼠在形成稳定的尼古丁累进自身给药行为后,观察利莫他班急性(0.3-3mg·kg-1,ip)或反复给药(1mg·kg-1,ip)对尼古丁转换点(breaking point)的作用。该测试完成后,所有的大鼠进行消退训练。我们比较了自身给药行为消退后URB597不可逆地选择性抑制FAAH和选择性CB1受体拮抗剂利莫他班两种干预对线索诱导的和尼古丁点燃(0.15mg·kg-1,sc)诱导的尼古丁复吸行为再现的作用。结果:利莫他班(0.3-3mg·kg-1)剂量依赖性的减少了尼古丁的转换点,1mg·kg-1的利莫他班的作用稳定。在尼古丁给药行为消退后,尼古丁点燃和尼古丁相关线索可以再现尼古丁自身给药行为。利莫他班(1mg·kg-1)和URB597(0.3 and 1mg·kg-1)显著减少了这种自身给药行为的再现。结论:本研究结果显示DB1受体的完整性是尼古丁自身给药行为动机所必需的,利莫他班可以稳定的减少这种行为。利莫他班阻断CB1受体或者通过抑制FAAH活性增强anandamide水平都减少了尼古丁渴求行为的再现。URB597的这些作用提示anadamide可能在尼古丁渴求中起抑制性的作用;这个假设还需要进一步研究介导尼古丁渴求的多种内源性大麻物质的功能。既然利莫他班在戒烟和复吸的使用上受精神副作用的限制,我们的结果提示更精确的靶相调节大麻系统可能可以预防戒烟者的复吸。展开更多
Ribosome biogenesis is essential for the cell growth and division. Disruptions in ribosome biogenesis result in developmental defects and a group of diseases, known as ribosomopathies. Here, we report a mutation in ze...Ribosome biogenesis is essential for the cell growth and division. Disruptions in ribosome biogenesis result in developmental defects and a group of diseases, known as ribosomopathies. Here, we report a mutation in zebrafish urb1, which encodes an essential ribosome biogenesis protein. The urb1 cq31 mutant exhibits hypoplastic digestive organs, which is caused by impaired cell proliferation with the differentiation of digestive organ progenitors unaffected. Knockdown of mtor or raptor leads to similar hypoplastic phenotypes and reduced expression of urb1 in the digestive organs. Overexpression of Urb1 results in overgrowth of digestive organs, and can efficiently rescue the hypoplastic liver and pancreas in the mtor and raptor morphants. Reduced syntheses of free ribosomal subunits and impaired assembly of polysomes are observed in the urb1 mutant as well as in the mtor and raptor morphants, which can be rescued by the Urb1 overexpression. These data demonstrate that Urb1 plays an important role in governing ribosome biogenesis and protein synthesis downstream of mammalian/mechanistic target of rapamycin complex 1（mTORC1）, thus regulating the development of digestive organs. Our study indicates the requirement of hyperactive protein synthesis for the digestive organ development.展开更多
为了探讨不同苦荞[Brassica integrifolia（West）O.E.Schulz apud Urb.]品种在不同地点种植下的子粒膳食纤维变异情况和不同品种与基本生态因子的相关性,以7个苦荞品种在全国荞麦主要产区17个不同地点进行栽培试验,测定所得子粒中膳食...为了探讨不同苦荞[Brassica integrifolia（West）O.E.Schulz apud Urb.]品种在不同地点种植下的子粒膳食纤维变异情况和不同品种与基本生态因子的相关性,以7个苦荞品种在全国荞麦主要产区17个不同地点进行栽培试验,测定所得子粒中膳食纤维含量。结果表明,供试7个苦荞品种在17个地点种植下的子粒总膳食纤维（TDF）、不溶性膳食纤维（IDF）、可溶性膳食纤维（SDF）含量变异范围分别为11.68%~24.13%、7.96%~20.05%、1.02%~10.65%。TDF、IDF含量在品种间及地点间的差异均达极显著水平（P〈0.01）;SDF含量在品种间差异达极显著水平（P〈0.01）,在地点间差异不显著（P〉0.05）。Scott-Knott聚类分析显示,以苦荞子粒TDF含量对品种和地点进行分类,可将供试品种分为3类,参试地点分为2类;以IDF含量对品种和地点进行分类,供试品种可分为2类,地点可分为5类;以SDF含量对品种进行分类,供试品种可分为3类。相关性分析表明,苦荞子粒膳食纤维含量与纬度、海拔、生育期均温均无显著相关。展开更多
运用 R/S 方法，对1951～1997年兰州城市气候的温度、水汽压、相对湿度和日照百分率等指标的冬(1月)、夏(7月)及年平均值进行了分析计算，各项指标的Hurst指数 H 均大于0.5，说明它们存在明显的Hurst现象，反映出兰州市过去47年来气候...运用 R/S 方法，对1951～1997年兰州城市气候的温度、水汽压、相对湿度和日照百分率等指标的冬(1月)、夏(7月)及年平均值进行了分析计算，各项指标的Hurst指数 H 均大于0.5，说明它们存在明显的Hurst现象，反映出兰州市过去47年来气候变化存在趋势性成分即持续性的城市化增暖.至于各项指标的Hurst指数在冬、夏及年平均值间有差异，分析证明这是兰州城市化气候效应强度季节不同所造成.展开更多
基金National Natural Science Foundation of China(81603093)and the Open Research Fund of State Key Laboratory of Cellu⁃lar Stress Biology,Xiamen University(SKLC⁃SB2019KF016)。
文摘OBJECTIVE URB597(KDS-4103)is a potent and selective inhibitor of the enzyme fatty acid amide hydrolase(FAAH)and can ele⁃vate the level of oleoylethanolamide(OEA),a naturally occurring endocannabinoid in the brain.However,the effect of URB597 on cerebral isch⁃emic injury in mice remains unclear.METHODS Focal cerebral ischemia was induced by middle cerebral artery occlusion for 30 min followed by reperfusion for 24 h in mice.To observe the dose-dependent effect,URB597(0.04-5.00 mg·kg-1,ip)was administered at the same time of reperfu⁃sion.To determine the time-dependent effect,URB597(1.00 mg·kg-1,ip)was administered as a single dose at 0,1,3 or 5 h after reperfusion.Twenty-four hours after brain ischemia,Beder⁃son scoring test and grip strength test were used to evaluate the neurological function;brain in⁃farct volume was assayed by 2,3,5-triphenyltetra⁃zolium chloride(TTC)staining or diffusion-weighted magnetic resonance imaging(MRI).Laser speckle imaging(LSI)technique was used to assay the regional cerebral blood flow(rCBF);NeuN immunofluorescence staining was used to observe the neuron survival in the penumbra.To further investigate the underlying mechanism,au⁃tophagy flux related proteins(LC3-Ⅱ,P62 and LAMP2)and necroptosis related proteins(pRIPK3 and pMLKL)were detected by Western blotting and immunofluorescence staining.RESULTS Twenty-four hours after brain ischemia,URB597 dose-dependently improved neurological func⁃tion and reduced brain infarct volume.The most effective dose was 1.00 mg·kg-1;the therapeutic time window was within 1 h after ischemic stroke.The protective effect is further confirmed by the results that post-ischemic treatment with URB597(1.00 mg·kg-1)significantly increased neurons survival,promoted autophagy flux and reduced cell necroptosis in cortical penumbra after cerebral I/R.CONCLUSION URB597 dose-and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury.This neu⁃roprotective effect of URB597 may be associated with its restoration of autophagy flux and inhibi⁃tion of neuronal necroptosis in the cortical penumbra.
文摘目的:吸烟在全世界引起了严重的健康问题,全球约5百万早产儿死于吸烟。此外,吸烟是一种以戒断后反复复吸为特点的慢性复发性疾病。尼古丁是烟草中导致人类成瘾的主要成分,可以使啮齿类动物形成持续的自身给药行为和条件性位置偏爱(CPP)。大量数据表明内源性大麻系统在尼古丁成瘾神经机制中有重要的作用。阻断CB1受体减少了尼古丁自身给药,线索诱导的尼古丁渴求的再现,以及尼古丁诱导的CPP。然而,最近的数据提示URB597通过抑制脂肪酸酰胺水解酶(fat acid amide hydrolase,FAAH)增强anandamide的传递,进而减少尼古丁关联行为,如尼古丁自身给药行为的获得和再现,尼古丁诱导大鼠CPP的表达和再现(Scherma et al.,2008)。CB1受体拮抗剂利莫他班对尼古丁自身给药累进比率(progressive ratio,PR),尼古丁点燃诱导的复吸,以及URB597对线索诱导尼古丁渴求再现的作用尚没有研究报道。本研究旨在填补这一空白。方法:大鼠在形成稳定的尼古丁累进自身给药行为后,观察利莫他班急性(0.3-3mg·kg-1,ip)或反复给药(1mg·kg-1,ip)对尼古丁转换点(breaking point)的作用。该测试完成后,所有的大鼠进行消退训练。我们比较了自身给药行为消退后URB597不可逆地选择性抑制FAAH和选择性CB1受体拮抗剂利莫他班两种干预对线索诱导的和尼古丁点燃(0.15mg·kg-1,sc)诱导的尼古丁复吸行为再现的作用。结果:利莫他班(0.3-3mg·kg-1)剂量依赖性的减少了尼古丁的转换点,1mg·kg-1的利莫他班的作用稳定。在尼古丁给药行为消退后,尼古丁点燃和尼古丁相关线索可以再现尼古丁自身给药行为。利莫他班(1mg·kg-1)和URB597(0.3 and 1mg·kg-1)显著减少了这种自身给药行为的再现。结论:本研究结果显示DB1受体的完整性是尼古丁自身给药行为动机所必需的,利莫他班可以稳定的减少这种行为。利莫他班阻断CB1受体或者通过抑制FAAH活性增强anandamide水平都减少了尼古丁渴求行为的再现。URB597的这些作用提示anadamide可能在尼古丁渴求中起抑制性的作用;这个假设还需要进一步研究介导尼古丁渴求的多种内源性大麻物质的功能。既然利莫他班在戒烟和复吸的使用上受精神副作用的限制,我们的结果提示更精确的靶相调节大麻系统可能可以预防戒烟者的复吸。
基金supported by the National Key Basic Research Program of China(2015CB942800)the National Natural Science Foundation of China(Nos.31330051 and 31730060)+2 种基金the 111 Program(B14037)the Natural Science Foundation Project of Chongqing(cstc2014jcyj A10088)the Fundamental Research Funds for the Central Universities(XDJK2015B011)
文摘Ribosome biogenesis is essential for the cell growth and division. Disruptions in ribosome biogenesis result in developmental defects and a group of diseases, known as ribosomopathies. Here, we report a mutation in zebrafish urb1, which encodes an essential ribosome biogenesis protein. The urb1 cq31 mutant exhibits hypoplastic digestive organs, which is caused by impaired cell proliferation with the differentiation of digestive organ progenitors unaffected. Knockdown of mtor or raptor leads to similar hypoplastic phenotypes and reduced expression of urb1 in the digestive organs. Overexpression of Urb1 results in overgrowth of digestive organs, and can efficiently rescue the hypoplastic liver and pancreas in the mtor and raptor morphants. Reduced syntheses of free ribosomal subunits and impaired assembly of polysomes are observed in the urb1 mutant as well as in the mtor and raptor morphants, which can be rescued by the Urb1 overexpression. These data demonstrate that Urb1 plays an important role in governing ribosome biogenesis and protein synthesis downstream of mammalian/mechanistic target of rapamycin complex 1（mTORC1）, thus regulating the development of digestive organs. Our study indicates the requirement of hyperactive protein synthesis for the digestive organ development.
文摘为了探讨不同苦荞[Brassica integrifolia（West）O.E.Schulz apud Urb.]品种在不同地点种植下的子粒膳食纤维变异情况和不同品种与基本生态因子的相关性,以7个苦荞品种在全国荞麦主要产区17个不同地点进行栽培试验,测定所得子粒中膳食纤维含量。结果表明,供试7个苦荞品种在17个地点种植下的子粒总膳食纤维（TDF）、不溶性膳食纤维（IDF）、可溶性膳食纤维（SDF）含量变异范围分别为11.68%~24.13%、7.96%~20.05%、1.02%~10.65%。TDF、IDF含量在品种间及地点间的差异均达极显著水平（P〈0.01）;SDF含量在品种间差异达极显著水平（P〈0.01）,在地点间差异不显著（P〉0.05）。Scott-Knott聚类分析显示,以苦荞子粒TDF含量对品种和地点进行分类,可将供试品种分为3类,参试地点分为2类;以IDF含量对品种和地点进行分类,供试品种可分为2类,地点可分为5类;以SDF含量对品种进行分类,供试品种可分为3类。相关性分析表明,苦荞子粒膳食纤维含量与纬度、海拔、生育期均温均无显著相关。
文摘运用 R/S 方法，对1951～1997年兰州城市气候的温度、水汽压、相对湿度和日照百分率等指标的冬(1月)、夏(7月)及年平均值进行了分析计算，各项指标的Hurst指数 H 均大于0.5，说明它们存在明显的Hurst现象，反映出兰州市过去47年来气候变化存在趋势性成分即持续性的城市化增暖.至于各项指标的Hurst指数在冬、夏及年平均值间有差异，分析证明这是兰州城市化气候效应强度季节不同所造成.
