Metformin may reduce food intake and body weight, but the anorexigenic effects of metformin are still poorly understood. In this study, Sprague-Dawley rats were administered a single intracere- broventricular dose of ...Metformin may reduce food intake and body weight, but the anorexigenic effects of metformin are still poorly understood. In this study, Sprague-Dawley rats were administered a single intracere- broventricular dose of metformin and compound C, in a broader attempt to investigate the regula- tory effects of metformin on food intake and to explore the possible mechanism. Results showed that central administration of metformin significantly reduced food intake and body weight gain, par- ticularly after 4 hours. A reduction of neuropeptide Y expression and induction of AMP-activated protein kinase phosphorylation in the hypothalamus were also observed 4 hours after metformin administration, which could be reversed by compound C, a commonly-used antagonist of AMP-activated protein kinase. Furthermore, metformin also improved lipid metabolism by reducing plasma low-density lipoprotein. Our findings suggest that under normal physiological conditions, central regulation of appetite by metformin is related to a decrease in neuropeptide Y gene expres- sion, and that the activation of AMP-activated protein kinase may simply be a response to the anorexigenic effect of metformin.展开更多
The present study analyzed the influence of 3-[3-(3-florophenyl-2-propyn-l-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-l-methylpyridine oxalate (EUK1001), a novel xanomeline derivative of the M1/M4 rece...The present study analyzed the influence of 3-[3-(3-florophenyl-2-propyn-l-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-l-methylpyridine oxalate (EUK1001), a novel xanomeline derivative of the M1/M4 receptor agonist, on hippocampal neurogenesis in adult C57BL6 mice. Results showed that 15-day EUK1001 treatment via intraperitoneal injection promoted neural cell proliferation in the dentate gyrus, although cell differentiation did not change. The majority of bromodeoxyuridine-positive cells co-expressed the immature neuronal marker doublecortin. In addition, the level of neurogenesis in the subventricular zone was not altered. Brain-derived neurotrophic factor mRNA expression was up-regulated following EUK1001 treatment, but no change was observed in expression of camp-responsive element binding protein 1, paired box gene 6, vascular endothelial growth factor alpha, neurogenic differentiation factor 1, and wingless-related mouse mammary tumor virus integration site 3A mRNA. These experimental findings indicated that EUK1001 enhanced proliferation and survival of hippocampal cells, possibly by increasing brain-derived neurotrophic factor expression.展开更多
In addition to senile plaques and cerebral amyloid angiopathy,the hyperphosphorylation of tau protein and formation of intraneuronal neurofibrillary tangles(NFTs)represents another neuropathological hallmark in AD bra...In addition to senile plaques and cerebral amyloid angiopathy,the hyperphosphorylation of tau protein and formation of intraneuronal neurofibrillary tangles(NFTs)represents another neuropathological hallmark in AD brain.Tau is a microtubule-associated protein and localizes predominantly in the axons of neurons with the primary function in maintaining microtubules stability.When the balance between tau phosphorylation and dephosphorylation is changed in favor of the former,tau is hyperphosphorylated and the level of the free tau fractions elevated.The hyperphosphorylation of tau protein and formation of NFTs represent a characteristic neuropathological feature in AD brain.We have discussed the role of Aβin AD in our previous review,this review focused on the recent advances in tau-mediated AD pathology,mainly including tau hyperphosphorylation,propagation of tau pathology and the relationship between tau and Aβ.展开更多
Alzheimer’s disease(AD)is a common neurodegenerative disease characterized clinically by progressive deterioration of memory,and pathologically by histopathological changes including extracellular deposits of amyloid...Alzheimer’s disease(AD)is a common neurodegenerative disease characterized clinically by progressive deterioration of memory,and pathologically by histopathological changes including extracellular deposits of amyloid-beta(A-beta)peptides forming senile plaques(SP)and the intracellular neurofibrillary tangles(NFT)of hyperphosphorylated tau in the brain.This review focused on the new developments of amyloid cascade hypothesis with details on the production,metabolism and clearance of A-beta,and the key roles of some important A-beta-related genes in the pathological processes of AD.The most recent research advances in genetics,neuropathology and pathogenesis of the disease were also discussed.展开更多
基金supported by grants from the National Natural Science Foundation of China,No.31171019 and No.31200820the Opening Project of Shanghai Key Laboratory of Brain Functional Genomics and Key Laboratory of Brain Functional Genomics(East China Normal University)of the Ministry of Education
文摘Metformin may reduce food intake and body weight, but the anorexigenic effects of metformin are still poorly understood. In this study, Sprague-Dawley rats were administered a single intracere- broventricular dose of metformin and compound C, in a broader attempt to investigate the regula- tory effects of metformin on food intake and to explore the possible mechanism. Results showed that central administration of metformin significantly reduced food intake and body weight gain, par- ticularly after 4 hours. A reduction of neuropeptide Y expression and induction of AMP-activated protein kinase phosphorylation in the hypothalamus were also observed 4 hours after metformin administration, which could be reversed by compound C, a commonly-used antagonist of AMP-activated protein kinase. Furthermore, metformin also improved lipid metabolism by reducing plasma low-density lipoprotein. Our findings suggest that under normal physiological conditions, central regulation of appetite by metformin is related to a decrease in neuropeptide Y gene expres- sion, and that the activation of AMP-activated protein kinase may simply be a response to the anorexigenic effect of metformin.
基金supported by the National Natural Science Foundation of China, No. 31000574the Fundamental Research Fund for the Central Universities, No.78210042
文摘The present study analyzed the influence of 3-[3-(3-florophenyl-2-propyn-l-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-l-methylpyridine oxalate (EUK1001), a novel xanomeline derivative of the M1/M4 receptor agonist, on hippocampal neurogenesis in adult C57BL6 mice. Results showed that 15-day EUK1001 treatment via intraperitoneal injection promoted neural cell proliferation in the dentate gyrus, although cell differentiation did not change. The majority of bromodeoxyuridine-positive cells co-expressed the immature neuronal marker doublecortin. In addition, the level of neurogenesis in the subventricular zone was not altered. Brain-derived neurotrophic factor mRNA expression was up-regulated following EUK1001 treatment, but no change was observed in expression of camp-responsive element binding protein 1, paired box gene 6, vascular endothelial growth factor alpha, neurogenic differentiation factor 1, and wingless-related mouse mammary tumor virus integration site 3A mRNA. These experimental findings indicated that EUK1001 enhanced proliferation and survival of hippocampal cells, possibly by increasing brain-derived neurotrophic factor expression.
基金This work was supported by the grants from the National Natural Science Foundation of China(No.31171019,No.81173108,No.31000574 and No.31200820)the Opening Projects of Shanghai Key Laboratory of Brain Functional Genomics and Key Laboratory of Brain Functional Genomics(East China Normal University),Ministry of Education。
文摘In addition to senile plaques and cerebral amyloid angiopathy,the hyperphosphorylation of tau protein and formation of intraneuronal neurofibrillary tangles(NFTs)represents another neuropathological hallmark in AD brain.Tau is a microtubule-associated protein and localizes predominantly in the axons of neurons with the primary function in maintaining microtubules stability.When the balance between tau phosphorylation and dephosphorylation is changed in favor of the former,tau is hyperphosphorylated and the level of the free tau fractions elevated.The hyperphosphorylation of tau protein and formation of NFTs represent a characteristic neuropathological feature in AD brain.We have discussed the role of Aβin AD in our previous review,this review focused on the recent advances in tau-mediated AD pathology,mainly including tau hyperphosphorylation,propagation of tau pathology and the relationship between tau and Aβ.
基金This work was supported by the grants from the National Natural Science Foundation of China(No.31171019,No.81173108 and No.31000574)the Opening Projects of Shanghai Key Laboratory of Brain Functional Genomics and Key Laboratory of Brain Functional Genomics(East China Normal University),Ministry of Education.
文摘Alzheimer’s disease(AD)is a common neurodegenerative disease characterized clinically by progressive deterioration of memory,and pathologically by histopathological changes including extracellular deposits of amyloid-beta(A-beta)peptides forming senile plaques(SP)and the intracellular neurofibrillary tangles(NFT)of hyperphosphorylated tau in the brain.This review focused on the new developments of amyloid cascade hypothesis with details on the production,metabolism and clearance of A-beta,and the key roles of some important A-beta-related genes in the pathological processes of AD.The most recent research advances in genetics,neuropathology and pathogenesis of the disease were also discussed.