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Mtor and cerebral cortex

Takayoshi Yamauchi, Masaaki Nishiyama, Toshiro Moroishi, Atsuki Kawamura, Keiichi I Nakayama
FBXL5 is the substrate recognition subunit of an SCF-type ubiquitin ligase that serves as a master regulator of iron metabolism in mammalian cells. We previously showed that mice with systemic deficiency of FBXL5 fail to sense intracellular iron levels and die in utero at embryonic day (E) 8.5 as a result of iron overload and subsequent oxidative stress. This early embryonic mortality has thus impeded study of the role of FBXL5 in brain development. We have now generated mice lacking FBXL5 specifically in Nestin-expressing neural stem-progenitor cells (NSPCs) in the brain...
January 9, 2017: Molecular and Cellular Biology
Rosanna Cabré, Mariona Jové, Alba Naudí, Victoria Ayala, Gerard Piñol-Ripoll, Maria P Gil-Villar, Mayelin Dominguez-Gonzalez, Èlia Obis, Rebeca Berdun, Natalia Mota-Martorell, Manuel Portero-Otin, Isidre Ferrer, Reinald Pamplona
Brain neurons offer diverse responses to stresses and detrimental factors during development and aging, and as a result of both neurodegenerative and neuropsychiatric disorders. This multiplicity of responses can be ascribed to the great diversity among neuronal populations. Here we have determined the metabolomic profile of three healthy adult human brain regions-entorhinal cortex, hippocampus, and frontal cortex-using mass spectrometry-based technologies. Our results show the existence of a lessened energy demand, mitochondrial stress, and lower one-carbon metabolism (particularly restricted to the methionine cycle) specifically in frontal cortex...
2016: Frontiers in Molecular Neuroscience
Wen-Chin Huang, Youjun Chen, Damon T Page
Multiple autism risk genes converge on the regulation of mTOR signalling, which is a key effector of neuronal growth and connectivity. We show that mTOR signalling is dysregulated during early postnatal development in the cerebral cortex of germ-line heterozygous Pten mutant mice (Pten(+/-)), which model macrocephaly/autism syndrome. The basolateral amygdala (BLA) receives input from subcortical-projecting neurons in the medial prefrontal cortex (mPFC). Analysis of mPFC to BLA axonal projections reveals that Pten(+/-) mice exhibit increased axonal branching and connectivity, which is accompanied by increased activity in the BLA in response to social stimuli and social behavioural deficits...
November 15, 2016: Nature Communications
Le Fu, Liang Huang, Chunshui Cao, Qin Yin, Jian Liu
Ischemic stroke is one of the most frequent acute cerebrovascular events worldwide. This study evaluated the variability of AMPK and mTOR and their relevance on LC3 and Beclin-1 expression, and further expounded the possible protective mechanism of inhibiting AMPK activity in the cerebral cortex after permanent focal cerebral ischemia injury in mice. Western blot and immunohistochemistry showed that p-AMPK expression was low in the cerebral cortex of the sham group; whereas it was significantly increased at 3h and 6h and peaked at 3h after pMCAO in the cerebral ischemic cortex, and was decreased at 12h and 24h...
November 1, 2016: Brain Research
Qian Zhang, Yonghua Zhao, Youhua Xu, Zhenwei Chen, Naiwei Liu, Chienchih Ke, Bowen Liu, Weikang Wu
BACKGROUND: Studies have indicated that bone marrow stromal cell (BMSC) administration is a promising approach for stroke treatment. For our study, we chose sodium ferulate (SF) and n-butylidenephthalide (BP) combined with BMSC, and observed if the combination treatment possessed more significant effects on angiogenesis and neurogenesis post-stroke. METHODS: We established rat permanent middle cerebral artery occlusion (MCAo) model and evaluated ischemic volumes of MCAo, BMSC, SF + BP, Simvastatin + BMSC and SF + BP + BMSC groups with TTC staining on the 7th day after ischemia...
2016: Journal of Translational Medicine
Yun-Hui Zhang, Jin Zhang, Jian-Nan Song, Xue Xu, Jin-Song Cai, Yang Zhou, Jin-Gui Gao
We investigated roles of PI3K-AKT-mTOR pathway in recovery from general anesthesia. Sprague-Dawley rats divided into five groups: saline+artificial cerebrospinal fluid (ACSF; Group A), ketamine+ACSF (Group B), ketamine+IGF-1 (Group C), ketamine+PI3K inhibitor (Group D), and PI3K/Akt agonists (Group E). Proportion of δ waves on ECoGs was recorded. Rats were tested for duration of loss of righting reflex (LORR), ataxic period and behavior in Morris water maze. mRNA and protein expression of members of PI3K-AKT-mTOR pathway were measured by RT-qPCR and Western blots...
July 5, 2016: Oncotarget
Oak Z Chi, Scott J Mellender, Sylviana Barsoum, Xia Liu, Stacey Damito, Harvey R Weiss
The mammalian target of rapamycin (mTOR) pathway is essential in neuronal survival and repair in cerebral ischemia. Decreases in blood-brain barrier (BBB) disruption are associated with a decrease in neuronal damage in cerebral ischemia. This study was performed to investigate how pre-inhibition of the mTOR pathway with rapamycin would affect BBB disruption and the size of the infarcted cortical area in the early stage of focal cerebral ischemia-reperfusion using quantitative analysis of BBB disruption. Rats were treated with 20mg/kg of rapamycin i...
May 4, 2016: Neuroscience Letters
Yuki Matsushita, Yasunari Sakai, Mitsunori Shimmura, Hiroshi Shigeto, Miki Nishio, Satoshi Akamine, Masafumi Sanefuji, Yoshito Ishizaki, Hiroyuki Torisu, Yusaku Nakabeppu, Akira Suzuki, Hidetoshi Takada, Toshiro Hara
Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons...
2016: Scientific Reports
Erica Barini, Odetta Antico, Yingjun Zhao, Francesco Asta, Valter Tucci, Tiziano Catelani, Roberto Marotta, Huaxi Xu, Laura Gasparini
BACKGROUND: Alzheimer disease (AD) and other tauopathies develop cerebral intracellular inclusions of hyperphosphorylated tau. Epidemiological and experimental evidence suggests a clear link between type 2 diabetes mellitus and AD. In AD animal models, tau pathology is exacerbated by metabolic comorbidities, such as insulin resistance and diabetes. Within this context, anitidiabetic drugs, including the widely-prescribed insulin-sensitizing drug metformin, are currently being investigated for AD therapy...
February 9, 2016: Molecular Neurodegeneration
Jae Seok Lim, Jeong Ho Lee
Focal cortical dysplasia type II (FCDII) is a focal malformation of the developing cerebral cortex and the major cause of intractable epilepsy. However, since the molecular genetic etiology of FCD has remained enigmatic, the effective therapeutic target for this condition has remained poorly understood. Our recent study on FCD utilizing various deep sequencing platforms identified somatic mutations in MTOR (existing as low as 1% allelic frequency) only in the affected brain tissues. We observed that these mutations induced hyperactivation of the mTOR kinase...
February 2016: BMB Reports
Xiao Yang, Changhun Hei, Ping Liu, Yaozu Song, Taylor Thomas, Sylvie Tshimanga, Feng Wang, Jianguo Niu, Tao Sun, P Andy Li
The aims of this study are to clarify the role of mTOR in mediating cerebral ischemic brain damage and the effects of rapamycin on ischemic outcomes. Ten minutes of forebrain ischemia was induced in rats, and their brains were sampled after 3 h, 16 h, and 7 days reperfusion for histology, immunohistochemistry and biochemical analysis. Our data demonstrated that cerebral ischemia resulted in both apoptotic and necrotic neuronal death; cerebral ischemia and reperfusion led to significant increases of mRNA and protein levels of p-mTOR and its downstream p-P70S6K and p-S6; elevation of LC3-II, and release of cytochrome c into the cytoplasm in both the cortex and hippocampus...
2015: International Journal of Biological Sciences
Hong Tan, Chang-Lin Li, Lu Zhang, Zhou-Jing Yang, Xuan Zhao, Ying-Wei Wang
Besides neurotoxic effects, inhaled anesthetics might have other adverse effects on the developing brain. Ribosomal protein S6 (rpS6), the first identified ribosomal protein undergoing phosphorylation, has important physiological functions in regulating protein synthesis, cell proliferation, and glucose homeostasis. To date, the function of sevoflurane on rpS6 phosphorylation is unclear. In our present study, we showed that sevoflurane anesthesia inhibited rpS6 phosphorylation in cerebral cortex and CA1 region of the hippocampus...
2015: International Journal of Clinical and Experimental Medicine
Eun-Bum Kang, Joon-Yong Cho
PURPOSE: Neurofibrillary tangles, one of pathological features of Alzheimer's disease, are produced by the hyperphosphorylation and aggregation of tau protein. This study aimed to investigate the effects of treadmill exercise on PI3K/AKT/mTOR signal transmission, autophagy, and cognitive ability that are involved in the hyperphosphorylation and aggregation of tau protein. METHODS: Experimental animals (NSE/htau23 mice) were divided into non-transgenic control group (Non-Tg-Control; CON; n = 7), transgenic control group (Tg-CON; n = 7), and transgenic exercise group (Tg-Treadmill Exercise; TE; n = 7)...
September 2015: Journal of Exercise Nutrition & Biochemistry
Yao-Wu Liu, Liang Zhang, Yu Li, Ya-Qin Cheng, Xia Zhu, Fan Zhang, Xiao-Xing Yin
Acetylcholinesterase (AChE) is impaired in brain of diabetic animals, which may be one of the reasons for diabetes-associated cognitive decline. However, the mechanism is still unknown. The present study was designed to investigate whether the increased expression of AChE in central neurons under high glucose (HG) condition was due to activation of mammalian target of rapamycin (mTOR) signaling. It was found that more production of reactive oxygen species, and higher levels of phospho-Akt, phospho-mTOR, phospho-p70S6K, and AChE were detected in HT-22 cells in HG group than normal glucose group after culture for 24 h, which were all attenuated by an antioxidant N-acetyl-L-cysteine...
September 2016: Molecular Neurobiology
Zhenya Lu, Furong Liu, Linglin Chen, Huadan Zhang, Yuemin Ding, Jianxiang Liu, Michael Wong, Ling-Hui Zeng
Mammalian target of rapamycin (mTOR) regulates cell growth, cell differentiation and protein synthesis. Rapamycin, an inhibitor of mTOR, has been widely used as an immunosuppressant and anti-cancer drug. Recently, mTOR inhibitors have also been reported to be a potential anti-epileptic drug, which may be effective when used in young patients with genetic epilepsy. Thus, a suitable dose of rapamycin which can maintain the normal function of mTOR and has fewer side effects ideally should be identified. In the present study, we first detected changes in marker proteins of mTOR signaling pathway during development...
2015: PloS One
Youjun Chen, Wen-Chin Huang, Julien Séjourné, Amy E Clipperton-Allen, Damon T Page
UNLABELLED: Abnormal patterns of head and brain growth are a replicated finding in a subset of individuals with autism spectrum disorder (ASD). It is not known whether risk factors associated with ASD and abnormal brain growth (both overgrowth and undergrowth) converge on common biological pathways and cellular mechanisms in the developing brain. Heterozygous mutations in PTEN (PTEN(+/-)), which encodes a negative regulator of the PI3K-Akt-mTOR pathway, are a risk factor for ASD and macrocephaly...
July 15, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Oak Z Chi, Chang-Chih Wu, Xia Liu, Kang H Rah, Estela Jacinto, Harvey R Weiss
Tuberous sclerosis (TSC) is associated with autism spectrum disorders and has been linked to metabolic dysfunction and unrestrained signaling of the mammalian target of rapamycin (mTOR). Inhibition of mTOR by rapamycin can mitigate some of the phenotypic abnormalities associated with TSC and autism, but whether this is due to the mTOR-related function in energy metabolism remains to be elucidated. In young Eker rats, an animal model of TSC and autism, which harbors a germ line heterozygous Tsc2 mutation, we previously reported that cerebral oxygen consumption was pronouncedly elevated...
September 2015: Neuromolecular Medicine
Javier G Villamil-Ortiz, Gloria P Cardona-Gomez
Alzheimer's disease (AD) and cerebral ischemia (CI) are neuropathologies that are characterized by aggregates of tau protein, a hallmark of cognitive disorder and dementia. Protein accumulation can be induced by autophagic failure. Autophagy is a metabolic pathway involved in the homeostatic recycling of cellular components. However, the role of autophagy in those tauopathies remains unclear. In this study, we performed a comparative analysis to identify autophagy related markers in tauopathy generated by AD and CI during short-term, intermediate, and long-term progression using the 3xTg-AD mouse model (aged 6,12, and 18 months) and the global CI 2-VO (2-Vessel Occlusion) rat model (1,15, and 30 days post-ischemia)...
2015: Frontiers in Aging Neuroscience
Dong Liu, Yongqing Zhang, Robert Gharavi, Hee Ra Park, Jaewon Lee, Sana Siddiqui, Richard Telljohann, Matthew R Nassar, Roy G Cutler, Kevin G Becker, Mark P Mattson
Mitochondrial metabolism is highly responsive to nutrient availability and ongoing activity in neuronal circuits. The molecular mechanisms by which brain cells respond to an increase in cellular energy expenditure are largely unknown. Mild mitochondrial uncoupling enhances cellular energy expenditure in mitochondria and can be induced with 2,4-dinitrophenol (DNP), a proton ionophore previously used for weight loss. We found that DNP treatment reduces mitochondrial membrane potential, increases intracellular Ca(2+) levels and reduces oxidative stress in cerebral cortical neurons...
August 2015: Journal of Neurochemistry
Mei Qin, Tianjian Huang, Michael Kader, Leland Krych, Zengyan Xia, Thomas Burlin, Zachary Zeidler, Tingrui Zhao, Carolyn B Smith
BACKGROUND: Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes...
July 2015: International Journal of Neuropsychopharmacology
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