Alzheimer’s disease is a neurological disorder marked by the accumulation of amyloid beta(Aβ)aggregates,resulting from mutations in the amyloid precursor protein.The enzymeβ-secretase,also known asβ-site amyloid p...Alzheimer’s disease is a neurological disorder marked by the accumulation of amyloid beta(Aβ)aggregates,resulting from mutations in the amyloid precursor protein.The enzymeβ-secretase,also known asβ-site amyloid precursor protein cleaving enzyme 1(BACE1),plays a crucial role in generating Aβpeptides.With no targeted therapy available for Alzheimer’s disease,inhibiting BACE1 aspartic protease has emerged as a primary treatment target.Since 1999,compounds demonstrating potential binding to the BACE1 receptor have advanced to human trials.Structural optimization of synthetically derived compounds,coupled with computational approaches,has offered valuable insights for developing highly selective leads with drug-like properties.This review highlights pivotal studies on the design and development of BACE1 inhibitors as anti-Alzheimer’s disease agents.It summarizes computational methods employed in facilitating drug discovery for potential BACE1 inhibitors and provides an update on their clinical status,indicating future directions for novel BACE1 inhibitors.The promising clinical results of Elenbecestat(E-2609)catalyze the development of effective,selective BACE1 inhibitors in the future.展开更多
Background:Oxidative stress and neuroinflammation are key factors in the pathophysiology of Alzheimer's disease(AD).Exercise and Aklil-ol-Malek may reduce AD symptoms.Therefore,the current study investigated the ef...Background:Oxidative stress and neuroinflammation are key factors in the pathophysiology of Alzheimer's disease(AD).Exercise and Aklil-ol-Malek may reduce AD symptoms.Therefore,the current study investigated the effect of weight training and Aklil-ol-Malek consumption on histopathological and inflammatory changes in hippocampal tissue of male AD model rats.Method:We prepared 558-week-old male Wistar rats and transferred them to an animal laboratory.The rats were randomly divided intofive groups:healthy control group,Alzheimer's control group,Alzheimer's group+weight training,Alzheimer's group+Aklil-ol-Malek supplement,and Alzheimer's group+Aklilol-Malek supplement+weight training.AD was induced in the 4 groups.The weight training protocol and Aklil-ol-Malek supplementation were examined as an intervention.The designated groups were administered Aklil-ol-Malek supplements.The anesthetized rats'hippocampi were extracted for further analysis 72 hours after the last session of the protocol.After the induction of AD and supplementation,two-way analysis of variance was used to examine the differences between groups(p<0.05).Results:The results showed a decrease in the expression of CRP and NFE2L2 genes in rats in the Aklil-olMalek and weight training group compared with thefindings in rats in the Alzheimer's group.Changes in the expression of BACE1 were not significant in rats in the weight training with Aklil-ol-Malek group.Conclusion:An intervention receiving exercise and Aklil-ol-Malek extract positively improved health and reduced AD progression.These results were likely to have been caused by the physiological effects of exercise and the antioxidant properties of Aklil-ol-Malek.展开更多
利用溶胶 -凝胶法合成了 Ba Ce1 - x REx O3-δ( RE:稀土 )系列固体电解质 ,结果证明纯 Ba Ce O3 导电性较差 ,RE3+ 的引入 ,取代了晶格中的 Ce4+ ,增加了氧空位 ,大大提高了体系的导电性。文章还研究了掺杂的 Ba Ce O3体系的导电机理 ...利用溶胶 -凝胶法合成了 Ba Ce1 - x REx O3-δ( RE:稀土 )系列固体电解质 ,结果证明纯 Ba Ce O3 导电性较差 ,RE3+ 的引入 ,取代了晶格中的 Ce4+ ,增加了氧空位 ,大大提高了体系的导电性。文章还研究了掺杂的 Ba Ce O3体系的导电机理 ,讨论了不同稀土离子掺杂对电导率的影响 ,以 Ba Ce1 - x REx O3-δ为固体电解质组装了 H2 /O2 燃料电池 ,电池的开路电压接近 1V,短路电流密度超过 10 0 m A/cm2 ,以 Ba Ce0 .8Gd0 .2 O2 .9为 SOFC电解质 ,80 0℃时最大输出功率密度达 30 m W/cm2 。展开更多
目的构建BACE1基因干扰质粒,并研究其在neuro-2a细胞中的表达,为以其为靶点的基因治疗提供稳定转染的质粒。方法选择人、小鼠和大鼠的BACE1基因共有序列为干扰靶点,设计3组连接有GFP的干扰质粒,将构建好的质粒转染neuro-2a细胞,通过Real...目的构建BACE1基因干扰质粒,并研究其在neuro-2a细胞中的表达,为以其为靶点的基因治疗提供稳定转染的质粒。方法选择人、小鼠和大鼠的BACE1基因共有序列为干扰靶点,设计3组连接有GFP的干扰质粒,将构建好的质粒转染neuro-2a细胞,通过Real time RT-PCR及Western-blotting的方法分别在RNA及蛋白质水平上检测BACE1的表达,以分析其干扰的效率。结果经酶切及测序证实,插入的DNA片段序列与设计序列完全一致。与空质粒对照组相比,3个干扰靶点对BACE1基因的表达均有不同程度的抑制作用。其中pYr-1.1-siBACE1在mRNA水平及蛋白质水平干扰效果均最好。结论成功构建了BACE1基因的干扰质粒pYr-1.1-siBACE1,并能有效抑制neuro-2a细胞内源性BACE1基因表达,为靶向BACE1基因的治疗提供了有力的工具。展开更多
文摘Alzheimer’s disease is a neurological disorder marked by the accumulation of amyloid beta(Aβ)aggregates,resulting from mutations in the amyloid precursor protein.The enzymeβ-secretase,also known asβ-site amyloid precursor protein cleaving enzyme 1(BACE1),plays a crucial role in generating Aβpeptides.With no targeted therapy available for Alzheimer’s disease,inhibiting BACE1 aspartic protease has emerged as a primary treatment target.Since 1999,compounds demonstrating potential binding to the BACE1 receptor have advanced to human trials.Structural optimization of synthetically derived compounds,coupled with computational approaches,has offered valuable insights for developing highly selective leads with drug-like properties.This review highlights pivotal studies on the design and development of BACE1 inhibitors as anti-Alzheimer’s disease agents.It summarizes computational methods employed in facilitating drug discovery for potential BACE1 inhibitors and provides an update on their clinical status,indicating future directions for novel BACE1 inhibitors.The promising clinical results of Elenbecestat(E-2609)catalyze the development of effective,selective BACE1 inhibitors in the future.
文摘Background:Oxidative stress and neuroinflammation are key factors in the pathophysiology of Alzheimer's disease(AD).Exercise and Aklil-ol-Malek may reduce AD symptoms.Therefore,the current study investigated the effect of weight training and Aklil-ol-Malek consumption on histopathological and inflammatory changes in hippocampal tissue of male AD model rats.Method:We prepared 558-week-old male Wistar rats and transferred them to an animal laboratory.The rats were randomly divided intofive groups:healthy control group,Alzheimer's control group,Alzheimer's group+weight training,Alzheimer's group+Aklil-ol-Malek supplement,and Alzheimer's group+Aklilol-Malek supplement+weight training.AD was induced in the 4 groups.The weight training protocol and Aklil-ol-Malek supplementation were examined as an intervention.The designated groups were administered Aklil-ol-Malek supplements.The anesthetized rats'hippocampi were extracted for further analysis 72 hours after the last session of the protocol.After the induction of AD and supplementation,two-way analysis of variance was used to examine the differences between groups(p<0.05).Results:The results showed a decrease in the expression of CRP and NFE2L2 genes in rats in the Aklil-olMalek and weight training group compared with thefindings in rats in the Alzheimer's group.Changes in the expression of BACE1 were not significant in rats in the weight training with Aklil-ol-Malek group.Conclusion:An intervention receiving exercise and Aklil-ol-Malek extract positively improved health and reduced AD progression.These results were likely to have been caused by the physiological effects of exercise and the antioxidant properties of Aklil-ol-Malek.
文摘利用溶胶 -凝胶法合成了 Ba Ce1 - x REx O3-δ( RE:稀土 )系列固体电解质 ,结果证明纯 Ba Ce O3 导电性较差 ,RE3+ 的引入 ,取代了晶格中的 Ce4+ ,增加了氧空位 ,大大提高了体系的导电性。文章还研究了掺杂的 Ba Ce O3体系的导电机理 ,讨论了不同稀土离子掺杂对电导率的影响 ,以 Ba Ce1 - x REx O3-δ为固体电解质组装了 H2 /O2 燃料电池 ,电池的开路电压接近 1V,短路电流密度超过 10 0 m A/cm2 ,以 Ba Ce0 .8Gd0 .2 O2 .9为 SOFC电解质 ,80 0℃时最大输出功率密度达 30 m W/cm2 。
文摘目的构建BACE1基因干扰质粒,并研究其在neuro-2a细胞中的表达,为以其为靶点的基因治疗提供稳定转染的质粒。方法选择人、小鼠和大鼠的BACE1基因共有序列为干扰靶点,设计3组连接有GFP的干扰质粒,将构建好的质粒转染neuro-2a细胞,通过Real time RT-PCR及Western-blotting的方法分别在RNA及蛋白质水平上检测BACE1的表达,以分析其干扰的效率。结果经酶切及测序证实,插入的DNA片段序列与设计序列完全一致。与空质粒对照组相比,3个干扰靶点对BACE1基因的表达均有不同程度的抑制作用。其中pYr-1.1-siBACE1在mRNA水平及蛋白质水平干扰效果均最好。结论成功构建了BACE1基因的干扰质粒pYr-1.1-siBACE1,并能有效抑制neuro-2a细胞内源性BACE1基因表达,为靶向BACE1基因的治疗提供了有力的工具。
