mTOR (Mammalian Target of Rapamycin): Hitting the Bull’s Eye for Enhancing Neurogenesis After Cerebral Ischemia?

Gao, Jiale; Yao, Mingjiang; Chang, Dennis Hsu-Tung; Liu, Jianxun

doi:10.1161/strokeaha.122.040376

Cited by 15 publications

(11 citation statements)

References 98 publications

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“…While studies on ischemic stroke outcomes are lacking, increased TNFSF14 predicts major adverse cardiovascular events in patients with stable coronary artery disease [ 30 ], which is directionally concordant to what we observe here. 4EBP1 is a eukaryotic initiation factor 4E (eIF4E)-binding protein, which plays a key role in translational regulation driven by the mTOR (mammalian target of rapamycin) signaling pathway [ 31 ] (Fig. 3 ).…”

Section: Discussionmentioning

confidence: 99%

“…3 ). The stimulation of mTOR signaling after ischemic brain injury has several functions of plausible relevance for neural repair, such as promoting neural stem cell/progenitor cell proliferation and differentiation, enhancing angiogenesis and synaptic plasticity [ 31 ] and targeting this pathway has been proposed as a promising therapeutic strategy for stroke [ 32 ]. CCL25 [alias TECK] is a chemokine that together with its receptor (CCR9) is involved in the regulation of immune cell migration and activation and plays a role in the development of T-cells.…”

Section: Discussionmentioning

confidence: 99%

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Proteomic profiling identifies novel inflammation-related plasma proteins associated with ischemic stroke outcome

Angerfors,

Brännmark,

Lagging

et al. 2023

J Neuroinflammation

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Background The inflammatory response to cerebral ischemia is complex; however, most clinical studies of stroke outcome focus on a few selected proteins. We, therefore, aimed to profile a broad range of inflammation-related proteins to: identify proteins associated with ischemic stroke outcome that are independent of established clinical predictors; identify proteins subsets for outcome prediction; and perform sex and etiological subtype stratified analyses. Methods Acute-phase plasma levels of 65 inflammation-related proteins were measured in 534 ischemic stroke cases. Logistic regression was used to estimate associations to unfavorable 3-month functional outcome (modified Rankin Scale score > 2) and LASSO regressions to identify proteins with independent effects. Results Twenty proteins were associated with outcome in univariable models after correction for multiple testing (FDR < 0.05), and for 5 the association was independent of clinical variables, including stroke severity (TNFSF14 [LIGHT], OSM, SIRT2, STAMBP, and 4E-BP1). LASSO identified 9 proteins that could best separate favorable and unfavorable outcome with a predicted diagnostic accuracy (AUC) of 0.81; three associated with favorable (CCL25, TRAIL [TNFSF10], and Flt3L) and 6 with unfavorable outcome (CSF-1, EN-RAGE [S100A12], HGF, IL-6, OSM, and TNFSF14). Finally, we identified sex- and etiologic subtype-specific associations with the best discriminative ability achieved for cardioembolic, followed by cryptogenic stroke. Conclusions We identified candidate blood-based protein biomarkers for post-stroke functional outcome involved in, e.g., NLRP3 inflammasome regulation and signaling pathways, such as TNF, JAK/STAT, MAPK, and NF-κB. These proteins warrant further study for stroke outcome prediction as well as investigations into the putative causal role for stroke outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proteomic profiling identifies novel inflammation-related plasma proteins associated with ischemic stroke outcome

Angerfors,

Brännmark,

Lagging

et al. 2023

J Neuroinflammation

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“…The mechanistic target of rapamycin (mTOR) is a 289-kDa serine/threonine protein kinase that is encoded by a single gene FRAP1 [6,81,87,212,[246][247][248][249]. mTOR also is known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 [222].…”

Section: A Central Role For the Mechanistic Target Of Rapamycin (Mtor...mentioning

confidence: 99%

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System

Maiese

2023

Biomolecules

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It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer’s disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

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“…MS and demyelinating disease can be significantly impacted by the mechanistic target of rapamycin (mTOR) pathways (Figure 1). mTOR is a 289-kDa serine/threonine protein kinase that is encoded by a single gene, FRAP1 [13,46,71,73,98,124,243,244,393] (Table 1). mTOR is also known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 [22,98,229].…”

Section: The Mechanistic Target Of Rapamycin and Multiple Sclerosismentioning

confidence: 99%

Cognitive Impairment in Multiple Sclerosis

Maiese

2023

Bioengineering

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Almost three million individuals suffer from multiple sclerosis (MS) throughout the world, a demyelinating disease in the nervous system with increased prevalence over the last five decades, and is now being recognized as one significant etiology of cognitive loss and dementia. Presently, disease modifying therapies can limit the rate of relapse and potentially reduce brain volume loss in patients with MS, but unfortunately cannot prevent disease progression or the onset of cognitive disability. Innovative strategies are therefore required to address areas of inflammation, immune cell activation, and cell survival that involve novel pathways of programmed cell death, mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and associated pathways with the apolipoprotein E (APOE-ε4) gene and severe acute respiratory syndrome coronavirus (SARS-CoV-2). These pathways are intertwined at multiple levels and can involve metabolic oversight with cellular metabolism dependent upon nicotinamide adenine dinucleotide (NAD+). Insight into the mechanisms of these pathways can provide new avenues of discovery for the therapeutic treatment of dementia and loss in cognition that occurs during MS.

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mTOR (Mammalian Target of Rapamycin): Hitting the Bull’s Eye for Enhancing Neurogenesis After Cerebral Ischemia?

Cited by 15 publications

References 98 publications

Proteomic profiling identifies novel inflammation-related plasma proteins associated with ischemic stroke outcome

Proteomic profiling identifies novel inflammation-related plasma proteins associated with ischemic stroke outcome

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System

Cognitive Impairment in Multiple Sclerosis

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