Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative mechanisms of injury are involved in many neurodegenerative diseases such as stroke, ischemia-reperfusion injury and multiple sclerosis. G protein-coupled receptor kinase 2 (GRK2) plays a key role in G protein-coupled receptor (GPCR) signaling modulation, and its expression levels are decreased after brain hypoxia/ischemia and reperfusion as well as in several inflammatory conditions. We report here that hydrogen peroxide downregulates GRK2 expression in C6 rat glioma cells. The hydrogen peroxide-induced decrease in GRK2 is prevented by a calpain protease inhibitor, but does not involve increased GRK2 degradation or changes in GRK2 mRNA level. Instead we show that hydrogen peroxide treatment impairs GRK2 translation in a process that requires Cdk1 activation and involves the mTOR pathway. This novel mechanism for the control of GRK2 expression in glial cells upon oxidative stress challenge may contribute to the modulation of GPCR signaling in different pathological conditions.
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PMID:Hydrogen peroxide impairs GRK2 translation via a calpain-dependent and cdk1-mediated pathway. 1696 27

The mammalian target of rapamycin (mTOR) is a protein tyrosine kinase that regulates cell proliferation and survival via its effects on transcription, translation and autophagy. The activity of mTOR is controlled by a number of nutrient and energy sensing pathways, inhibiting cell proliferation under conditions of deprivation. In addition, mTOR has been associated with the inhibition of apoptosis and the clearance of toxic protein aggregates. Many neurodegenerative diseases are characterized by neuronal death via apoptosis, and it is possible that modulation of mTOR activity may offer some protection against their effects. In particular, diseases involving oxygen and nutrient deprivation, such as stroke, or diseases characterized by aggregate formation, such as Alzheimer's and Huntington's disease, could gain substantial benefit by either inhibiting or enhancing mTOR activity. In addition, inhibition of mTOR in cancerous tissue decreases cell proliferation and increases apoptosis, and is an effective therapy for brain tumors. In this article, the effects of mTOR and their potential usefulness for the treatment of neurological disease are examined.
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PMID:The mTOR pathway as a potential target for the development of therapies against neurological disease. 1808 36

Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target of rapamycin (mTOR) binding region yields immunophilin ligands, WYE-592 and ILS-920, with potent neurotrophic activities in cortical neuronal cultures, efficacy in a rodent model for ischemic stroke, and significantly reduced immunosuppressive activity. Surprisingly, both compounds showed higher binding selectivity for FKBP52 versus FKBP12, in contrast to previously reported immunophilin ligands. Affinity purification revealed two key binding proteins, the immunophilin FKBP52 and the beta1-subunit of L-type voltage-dependent Ca(2+) channels (CACNB1). Electrophysiological analysis indicated that both compounds can inhibit L-type Ca(2+) channels in rat hippocampal neurons and F-11 dorsal root ganglia (DRG)/neuroblastoma cells. We propose that these immunophilin ligands can protect neurons from Ca(2+)-induced cell death by modulating Ca(2+) channels and promote neurite outgrowth via FKBP52 binding.
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PMID:Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. 1816 40

Obesity and age are important risk factors for cardiovascular disease. However, the signaling mechanism linking obesity with age-related vascular senescence is unknown. Here we show that mice fed a high-fat diet show increased vascular senescence and vascular dysfunction compared to mice fed standard chow and are more prone to peripheral and cerebral ischemia. All of these changes involve long-term activation of the protein kinase Akt. In contrast, mice with diet-induced obesity that lack Akt1 are resistant to vascular senescence. Rapamycin treatment of diet-induced obese mice or of transgenic mice with long-term activation of endothelial Akt inhibits activation of mammalian target of rapamycin (mTOR)-rictor complex 2 and Akt, prevents vascular senescence without altering body weight, and reduces the severity of limb necrosis and ischemic stroke. These findings indicate that long-term activation of Akt-mTOR signaling links diet-induced obesity with vascular senescence and cardiovascular disease.
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PMID:Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR. 1929 29

We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content ( approximately 400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.
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PMID:Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation. 1939 13

Reduction in or dysfunction of glutamate transporter 1 (GLT1) is linked to several neuronal disorders such as stroke, Alzheimer's disease, and amyotrophic lateral sclerosis. However, the detailed mechanism underlying GLT1 regulation has not been fully elucidated. In the present study, we first demonstrated the effects of mammalian target of rapamycin (mTOR) signaling on GLT1 regulation. We prepared astrocytes cultured in astrocyte-defined medium (ADM), which contains several growth factors including epidermal growth factor (EGF) and insulin. The levels of phosphorylated Akt (Ser473) and mTOR (Ser2448) increased, and GLT1 levels were increased in ADM-cultured astrocytes. Treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor or an Akt inhibitor suppressed the phosphorylation of Akt (Ser473) and mTOR (Ser2448) as well as decreased ADM-induced GLT1 upregulation. Treatment with the mTOR inhibitor rapamycin decreased GLT1 protein and mRNA levels. In contrast, rapamycin did not affect Akt (Ser473) phosphorylation. Our results suggest that mTOR is a downstream target of the PI3K/Akt pathway regulating GLT1 expression.
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PMID:PI3K/Akt/mTOR signaling regulates glutamate transporter 1 in astrocytes. 2015 9

Cystatin C (CysC) expression in the brain is elevated in human patients with epilepsy, in animal models of neurodegenerative conditions, and in response to injury, but whether up-regulated CysC expression is a manifestation of neurodegeneration or a cellular repair response is not understood. This study demonstrates that human CysC is neuroprotective in cultures exposed to cytotoxic challenges, including nutritional-deprivation, colchicine, staurosporine, and oxidative stress. While CysC is a cysteine protease inhibitor, cathepsin B inhibition was not required for the neuroprotective action of CysC. Cells responded to CysC by inducing fully functional autophagy via the mTOR pathway, leading to enhanced proteolytic clearance of autophagy substrates by lysosomes. Neuroprotective effects of CysC were prevented by inhibiting autophagy with beclin 1 siRNA or 3-methyladenine. Our findings show that CysC plays a protective role under conditions of neuronal challenge by inducing autophagy via mTOR inhibition and are consistent with CysC being neuroprotective in neurodegenerative diseases. Thus, modulation of CysC expression has therapeutic implications for stroke, Alzheimer's disease, and other neurodegenerative disorders.
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PMID:Induction of autophagy by cystatin C: a mechanism that protects murine primary cortical neurons and neuronal cell lines. 2035 8

Stroke-prone spontaneously hypertensive rats (SHRSP) demonstrate impaired endothelium-dependent relaxation and often develop brain injuries. We investigated whether the regulatory mechanism for endothelial NOS (eNOS) phosphorylation and activation is altered in the cerebral cortex of SHRSP at a younger age. Western blot analysis revealed a low ratio of phosphor-eNOS (Ser1177) to total eNOS in SHRSP at 10 weeks of age. In addition, urinary nitric oxide metabolites (ie, nitrate and nitrite) were decreased compared with normal control WKY rats. Likewise, Akt phosphorylation (especially Ser473) was significantly reduced, with no changes in total Akt. Furthermore, the amount of the phosphatidylinositol 3-kinase (PI3K) was upstream of Akt was diminished, although attenuation of the PI3K/Akt pathway was not an effect of mTOR, another downstream target of Akt. Our findings indicate that abnormalities of the PI3K/Akt pathway in the cerebral cortex are involved in the impaired eNOS phosphorylation and activation in SHRSP.
J Stroke Cerebrovasc Dis
PMID:Phosphorylated endothelial NOS Ser1177 via the PI3K/Akt pathway is depressed in the brain of stroke-prone spontaneously hypertensive rat. 2081 49

The mammalian target of rapamycin (mTOR) and its associated cell signaling pathways have garnered significant attention for their roles in cell biology and oncology. Interestingly, the explosion of information in this field has linked mTOR to neurological diseases with promising initial studies. mTOR, a 289 kDa serine/threonine protein kinase, plays an important role in cell growth and proliferation and is activated through phosphorylation in response to growth factors, mitogens, and hormones. Growth factors, amino acids, cellular nutrients, and oxygen deficiency can down-regulate mTOR activity. The function of mTOR signaling is mediated primarily through two mTOR complexes: mTORC1 and mTORC2. mTORC1 initiates cap-dependent protein translation, a rate-limiting step of protein synthesis, through the phosphorylation of the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K). In contrast, mTORC2 regulates development of the cytoskeleton and also controls cell survival. Although closely tied to tumorigenesis, mTOR and the downstream signaling pathways are significantly involved in the central nervous system (CNS) with synaptic plasticity, memory retention, neuroendocrine regulation associated with food intake and puberty, and modulation of neuronal repair following injury. The signaling pathways of mTOR also are believed to be a significant component in a number of neurological diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, tuberous sclerosis, neurofibromatosis, fragile X syndrome, epilepsy, traumatic brain injury, and ischemic stroke. Here we describe the role of mTOR in the CNS and illustrate the potential for new strategies directed against neurological disorders.
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PMID:Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. 2130 46

The acronym mTOR defines a family of serine-threonine protein kinase called mammalian target of rapamycin. The major role of these kinases in the cell is to merge extracellular instructions with information about cellular metabolic resources and to control the rate of anabolic and catabolic processes accordingly. In mammalian cells mTOR is present in two distinct heteromeric protein complexes commonly referred to as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), involved in the control of a wide variety of cellular processes. It has been recently reported that compounds acting modulating mTOR activity, beside mediating the well recognized processes exploited in the anticancer and immunosuppressant effects, are provided with neuroprotective properties. In fact, mTOR is involved in the mechanism of PI3K/Akt-induced upregulation of glutamate transporter 1, GLT1, that is linked to several neuronal disorders such as stroke, Alzheimer's disease, and amyotrophic lateral sclerosis. Furthermore, in adult brain mTOR is crucial for numerous physiological processes such as synaptic plasticity, learning, memory, and brain control of food uptake. Moreover, the activation of mTOR pathway is involved in neuronal development, dendrite development and spine morphogenesis.
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PMID:Neuroprotective, immunosuppressant and antineoplastic properties of mTOR inhibitors: current and emerging therapeutic options. 2164 48


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