Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroblastoma is a malignant pediatric tumor with poor survival. The phosphatidylinositol 3'-kinase/AKT pathway is a crucial regulator of cellular processes including apoptosis. Thioredoxin 1, an inhibitor of tumor-suppressor phosphatase and tensin homolog, is overexpressed in many tumors. The objective of this study was to explore phosphatidylinositol 3'-kinase/AKT pathway activation and regulation by thioredoxin 1 to identify potential therapeutic targets. Immunohistochemical analysis was done on tissue microarrays from tumor samples of 101 patients, using antibodies against phosphatidylinositol 3'-kinase, AKT, activated AKT, phosphatase and tensin homolog, phosphorylated phosphatase and tensin homolog, thioredoxin 1, epidermal growth factor receptor, vascular endothelial growth factor and receptors (vascular endothelial growth factor 1 and vascular endothelial growth receptor 2), platelet-derived growth factor receptors, insulin-like growth factor 1 receptor, neurotrophic tyrosine kinase receptor type 2, phosphorylated 70-kd S6 protein kinase, 4E-binding protein 1, and phosphorylated mammalian target of rapamycin. Using 3 neuroblastoma cell lines, we investigated cell viability with AKT-specific inhibitors (LY294002, RAD001) and thioredoxin 1 alone or in combination. We found activated AKT and AKT expressed in 97% and 98%, respectively, of neuroblastomas, despite a high expression of phosphatase and tensin homolog correlated with thioredoxin 1. AKT expression was greater in metastatic than primary tumors. Insulin-like growth factor 1 receptor, tyrosine kinase receptor type 2, vascular endothelial growth receptor 1, and downstream phosphorylated 70-kd S6 protein kinase were correlated with activated AKT. LY294002 and RAD001 significantly reduced AKT activity and cell viability and induced a G(1) cell cycle arrest. Thioredoxin 1 decreased cytotoxicity of AKT inhibitors and doxorubicin, up-regulated AKT activation, and induced cell growth. Thus, vascular endothelial growth receptor 1, tyrosine kinase receptor type 2, insulin-like growth factor 1 receptor, and thioredoxin 1 emerged as preferentially committed to phosphatidylinositol 3'-kinase/AKT pathway activation as observed in neuroblastoma. Thioredoxin 1 is a potential target for therapeutic intervention.
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PMID:Activation of the phosphatidylinositol 3'-kinase/AKT pathway in neuroblastoma and its regulation by thioredoxin 1. 2164 Oct 13

The metabolic benefits of lixisenatide as an anti-diabetic agent are recognized but potential extra-pancreatic effects of this glucagon-like peptide-1 (GLP-1) mimetic in the brain are less well known. This study examines actions within the hippocampus following chronic 40-day peripheral administration of lixisenatide to high-fat fed mice with established obesity, insulin resistance and impaired cognition. Lixisenatide (50 nmol/kg bw, twice-daily) resulted in marked improvements in glycemic status, insulin secretion and insulin sensitivity. Examination of pancreatic tissue revealed decreased islet area, increased islet number, and increased insulin content, with no evidence of pancreatic inflammation. Lixisenatide improved recognition memory during a novel object recognition task and this was associated with up-regulation of hippocampal expression of neurotrophic tyrosine kinase receptor type 2 (NTRK2) and mammalian target of rapamycin (mTOR) genes involved in modulating synaptic plasticity and long-term potentiation. Lixisenatide also enhanced progenitor cell proliferation and increased the number of immature neurons in the hippocampal dentate gyrus. These data indicate that lixisenatide is not only a new efficacious drug for treatment of diabetes but it also exerts favorable neuroprotective effects, reversing memory impairment in obesity-diabetes. Further clinical studies are necessary to fully assess potential beneficial actions of lixisenatide in the hippocampus and cognition in man.
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PMID:Lixisenatide improves recognition memory and exerts neuroprotective actions in high-fat fed mice. 2519 84

It has been previously demonstrated that compromise of glucose-dependent insulinotropic polypeptide receptor (GIPR) action and chronic consumption of a high-fat diet can independently impair memory and learning ability, however, the underlying pathology remain to be elucidated. The present study investigated the effects of GIPR knockout (KO), alone and in combination with a high-fat diet, on aspects of cognitive function and hippocampal gene expression in mice. In object recognition tests, normal mice exhibited effective memory, preferring to investigate the novel over the familiar object. However, wild-type (WT) mice fed a high-fat diet and GIPR KO mice fed a standard or high-fat diet demonstrated no such discrimination, suggesting the impairment of memory function. This decline in cognitive function was associated with marked changes in the expression levels of hippocampal genes involved in memory and learning. The chronic consumption of a high-fat diet decreased the hippocampal gene expression levels of mammalian target of rapamycin (mTOR), neurotrophic tyrosine kinase receptor type 2 (NTRK2) and synaptophysin. Notably, the GIPR KO mice fed a high-fat diet exhibited no reduction in the hippocampal expression of synaptophysin expression, however, the GIPR KO mice fed a standard rodent maintenance diet exhibited reduced hippocampal expression of mTOR compared with the WT controls. These data highlighted the importance of intact GIPR signalling and dietary composition in modulating memory and learning, and hippocampal pathways involved in the maintenance of synaptic plasticity, including mTOR and NTRK2, appear to be key in this regard.
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PMID:Effects of glucose-dependent insulinotropic polypeptide receptor knockout and a high-fat diet on cognitive function and hippocampal gene expression in mice. 2617 13