Large-scale epidemiological studies have found that hyperhomocysteinemia is a powerful, independent risk factor for Alzheimer＇s disease. Trillium tschonoskii maxim is a traditional Chinese medicine that is used to pr...Large-scale epidemiological studies have found that hyperhomocysteinemia is a powerful, independent risk factor for Alzheimer＇s disease. Trillium tschonoskii maxim is a traditional Chinese medicine that is used to promote memory. However, scientific understanding of its mechanism of action is limited. This report studied the potential neuroprotective effects of Trillium tschonoskii maxim extract against homocysteine-induced cognitive deficits. Rats were intravenously injected with homocysteine（400 μg/kg） for 14 days to induce a model of Alzheimer＇s disease. These rats were then intragastrically treated with Trillium tschonoskii maxim extract（0.125 or 0.25 g/kg） for 7 consecutive days. Open field test and Morris water maze test were conducted to measure spontaneous activity and learning and memory abilities. Western blot assay was used to detect the levels of Tau protein and other factors involved in Tau phosphorylation in the hippocampus. Immunohistochemical staining was used to examine Tau protein in the hippocampus. Golgi staining was applied to measure hippocampal dendritic spines. Our results demonstrated that homocysteine produced learning and memory deficits and increased levels of Tau phosphorylation, and diminished the activity of catalytic protein phosphatase 2A. The total number of hippocampal dendritic spines was also decreased. Trillium tschonoskii maxim extract treatment reversed the homocysteine-induced changes. The above results suggest that Trillium tschonoskii maxim extract can lessen homocysteine-induced abnormal Tau phosphorylation and improve cognitive deterioration such as that present in Alzheimer＇s disease.展开更多
Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup ...Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup C and 6,706-bp genomic DNA(g DNA) deletion, were identified in three families with focal epilepsy by linkage analysis, whole exome sequencing(WES) and Sanger sequencing. NPRL3 protein is a component of the GATOR1 complex, a major inhibitor of m TOR signaling. These mutations led to truncation of the NPRL3 protein and hampered the binding between NPRL3 and DEPDC5, which is another component of the GATOR1 complex. Consequently, the mutant proteins enhanced m TOR signaling in cultured cells, possibly due to impaired inhibition of m TORC1 by GATOR1. Knockdown of nprl3 in Drosophila resulted in epilepsy-like behavior and abnormal synaptic development. Taken together, these findings expand the genotypic spectrum of NPRL3-associated focal epilepsy and provide further insight into how NPRL3 mutations lead to epilepsy.展开更多
基金supported in part by grants from the National Natural Science Foundation of China,No.81260172,81660223the Opening Foundation of Hubei Key Laboratory of Biological Resource Protection and Utilization of China,No.PKLHB1318+2 种基金the Science and Technology Innovation Team Project of Hubei University for Nationalities of China,No.MY2011T005the Doctoral Fund of Hubei University for Nationalities of China,No.MY2012B015the Natural Science Foundation of Hubei Province of China,No.2017CFB451
文摘Large-scale epidemiological studies have found that hyperhomocysteinemia is a powerful, independent risk factor for Alzheimer＇s disease. Trillium tschonoskii maxim is a traditional Chinese medicine that is used to promote memory. However, scientific understanding of its mechanism of action is limited. This report studied the potential neuroprotective effects of Trillium tschonoskii maxim extract against homocysteine-induced cognitive deficits. Rats were intravenously injected with homocysteine（400 μg/kg） for 14 days to induce a model of Alzheimer＇s disease. These rats were then intragastrically treated with Trillium tschonoskii maxim extract（0.125 or 0.25 g/kg） for 7 consecutive days. Open field test and Morris water maze test were conducted to measure spontaneous activity and learning and memory abilities. Western blot assay was used to detect the levels of Tau protein and other factors involved in Tau phosphorylation in the hippocampus. Immunohistochemical staining was used to examine Tau protein in the hippocampus. Golgi staining was applied to measure hippocampal dendritic spines. Our results demonstrated that homocysteine produced learning and memory deficits and increased levels of Tau phosphorylation, and diminished the activity of catalytic protein phosphatase 2A. The total number of hippocampal dendritic spines was also decreased. Trillium tschonoskii maxim extract treatment reversed the homocysteine-induced changes. The above results suggest that Trillium tschonoskii maxim extract can lessen homocysteine-induced abnormal Tau phosphorylation and improve cognitive deterioration such as that present in Alzheimer＇s disease.
基金supported by the National Natural Science Foundation of China (32270663, 31871262, U20A20355,32022035)Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the Ministry of Science and Technology of China STI2030-Major Projects (2021ZD0203202)。
文摘Focal epilepsy accounts for 60% of all forms of epilepsy, but the pathogenic mechanism is not well understood. In this study,three novel mutations in NPRL3(nitrogen permease regulator-like 3), c.937_945del, c.1514dup C and 6,706-bp genomic DNA(g DNA) deletion, were identified in three families with focal epilepsy by linkage analysis, whole exome sequencing(WES) and Sanger sequencing. NPRL3 protein is a component of the GATOR1 complex, a major inhibitor of m TOR signaling. These mutations led to truncation of the NPRL3 protein and hampered the binding between NPRL3 and DEPDC5, which is another component of the GATOR1 complex. Consequently, the mutant proteins enhanced m TOR signaling in cultured cells, possibly due to impaired inhibition of m TORC1 by GATOR1. Knockdown of nprl3 in Drosophila resulted in epilepsy-like behavior and abnormal synaptic development. Taken together, these findings expand the genotypic spectrum of NPRL3-associated focal epilepsy and provide further insight into how NPRL3 mutations lead to epilepsy.
