mTOR partly mediates insulin resistance by phosphorylation of insulin receptor substrate-1 on serine307 residues after burn

Xin-Long, Chen; Xia, Zhaofan; Ben, Daofeng; Wei, Duo

doi:10.1016/j.burns.2010.04.005

Cited by 14 publications

(12 citation statements)

References 40 publications

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“…It has been proposed that mTOR activity impacts neutrophil recruitment, RONS production and TLR signaling . mTOR can act downstream of the insulin receptor, making it a target of hyperinsulinemia observed in burn patients . Furthermore, processes downstream of mTOR activation, such as oxidative burst and protein translation, are enhanced by hyperglycemia …”

Section: Resultsmentioning

confidence: 99%

“…To this end, in addition to immune dysfunction, burn patients also experience severe metabolic dysregulation, characterized by elevated basal metabolic rate and a paradoxical comingling of hyperglycemia and hyperinsulinemia. [17][18][19][20][21] Similarly, several animal studies have demonstrated altered metabolism in animal models of burn injury, including insulin resistance and hyperglycemia. [21][22][23] The relationship between metabolism and immunity has been focus of much recent research activity.…”

Section: Burn Injury Generates Numerous Inflammatory Stimuli Includingmentioning

confidence: 99%

“…With that said, it is appreciated that the mTOR axis acts as a molecular switch to regulate inflammatory and metabolic functions. To this end, in addition to immune dysfunction, burn patients also experience severe metabolic dysregulation, characterized by elevated basal metabolic rate and a paradoxical comingling of hyperglycemia and hyperinsulinemia . Similarly, several animal studies have demonstrated altered metabolism in animal models of burn injury, including insulin resistance and hyperglycemia .…”

Section: Introductionmentioning

confidence: 99%

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Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury

Dunn

Kartchner

Gast

et al. 2018

Journal of Leukocyte Biology

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Bacterial pneumonia is a leading cause of death late after burn injury due to the severe immune dysfunction that follows this traumatic injury. The Mechanistic/Mammalian Target of Rapamycin (mTOR) pathway drives many effector functions of innate immune cells required for bacterial clearance. Studies have demonstrated alterations in multiple cellular processes in patients and animal models following burn injury in which mTOR is a central component. Goals of this study were to (1) investigate the importance of mTOR signaling in antimicrobial activity by neutrophils and (2) therapeutically target mTOR to promote normalization of the immune response. We utilized a murine model of 20% total body surface area burn and the mTOR-specific inhibitor rapamycin. Burn injury led to innate immune hyperresponsiveness in the lung including recruitment of neutrophils with greater ex vivo oxidative activity compared with neutrophils from sham-injured mice. Elevated oxidative function correlated with improved clearance of Pseudomonas aeruginosa, despite down-regulated expression of the bacterial-sensing TLR molecules. Rapamycin administration reversed the burn injury-induced lung innate immune hyperresponsiveness and inhibited enhanced bacterial clearance in burn mice compared with untreated burn mice, resulting in significantly higher mortality. Neutrophil ex vivo oxidative burst was decreased by rapamycin treatment. These data indicate that (1) neutrophil function within the lung is more important than recruitment for bacterial clearance following burn injury and (2) mTOR inhibition significantly impacts innate immune hyperresponsiveness, including neutrophil effector function, allowing normalization of the immune response late after burn injury.

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Section: Resultsmentioning

confidence: 99%

Section: Burn Injury Generates Numerous Inflammatory Stimuli Includingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury

Dunn

Kartchner

Gast

et al. 2018

Journal of Leukocyte Biology

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“…It is clarified that the mTOR signaling pathway is activated by inhibiting the activity of insulin/IGF-1 signaling key components, including insulin receptor, insulin receptor substrate 1 (IRS-1), and IGF-1R 156,159–161. Furthermore, mTOR can induce insulin resistance by phosphorylation of IRS-1 on serine307 residues 162. Clearly, the insulin/IGF-1/mTOR signaling pathway is a negative cycle loop that regulates a variety of pathophysiological features.…”

Section: The Activation Of Mtor: a Trigger For Aβ Generation And Failmentioning

confidence: 99%

Activation of mTOR: a culprit of Alzheimer’s disease?

Cai¹,

Chen²,

He³

et al. 2015

NDT

123

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Alzheimer’s disease (AD) is characterized by cognitive impairment in clinical presentation, and by β-amyloid (Aβ) production and the hyper-phosphorylation of tau in basic research. More highlights demonstrate that the activation of the mammalian target of rapamycin (mTOR) enhances Aβ generation and deposition by modulating amyloid precursor protein (APP) metabolism and upregulating β- and γ-secretases. mTOR, an inhibitor of autophagy, decreases Aβ clearance by scissoring autophagy function. mTOR regulates Aβ generation or Aβ clearance by regulating several key signaling pathways, including phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt), glycogen synthase kinase 3 [GSK-3], AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1). The activation of mTOR is also a contributor to aberrant hyperphosphorylated tau. Rapamycin, the inhibitor of mTOR, may mitigate cognitive impairment and inhibit the pathologies associated with amyloid plaques and neurofibrillary tangles by promoting autophagy. Furthermore, the upstream and downstream components of mTOR signaling are involved in the pathogenesis and progression of AD. Hence, inhibiting the activation of mTOR may be an important therapeutic target for AD.

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“…The gerosuppressants metformin, calorie restriction and GLP-I agonists (via hydrogen sulphide (Selley et al, 2014)) might suppress hyperactive and aberrant mTOR signalling (Shaw, 2009;Potter et al, 2010, O'Callaghan andRoopra, 2014;Dogan et al, 2011; responsible for the epileptogenic late-long term potentiation (L-LTP), which plays a role in progression of seizures to intractable epilepsy, via reduction in ROS production. mTOR partly mediates insulin resistance (Xin-Long et al, 2011), upregulates proteins such as AMPARs responsible for drug addiction/relapse (Dayas et al, 2012;Neasta et al, 2010) and is a biomarker and central pathway to disorders such as obesity, epilepsy and aging (Perl, 2015). AMPK activators via attenuating microglial activation (Matsushita et al, 2013) and other inhibitors of Mtor such as l-cysteine may prevent drug tolerance and reinstatement.The AMPK pathway which is activated by metformin, cannabinoids and valproate may also protect the brain from seizure-induced cell death by upregulating the Bcl 2 -modifying facor (Bmf) which prevents neuronal death in status epilepticus (Moran et al, 2013).…”

Section: Type 2 Diabetes Mellitus Drug Addiction Bipolar Disorder Amentioning

confidence: 99%

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

Oriaifo¹

2015

J. Med. Med. Sci

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The prevalence of diabetes and co-morbid diseases, especially in developing countries, may have already exceeded estimates. Accumulating reports indicate considerable underpinnings in the mechanisms of the aetiopathogenesis of metabolic syndrome, bipolar disorder, epilepsy and, recently, substance addiction. Continuing evidence incriminates dysfunction in genetic, mitochondrial and inflammatory cascade mechanisms as contributory factors to the dysregulation of neurotrophic, serotonergic, dopaminergic, adrenergic, glutamatergic, GABAergic and autophagic pathways. There may also be co-incident dysregulation of the global anti-oxidant network, the endogenous digitalis system, the vasopressin signalling and the hypothalamo-pituitary-adrenal axis. Nuclear factor-kappa B (NF-kappa B) signaling and reactive oxygen species lead to activation of the mammalian target of rapamycin complex I (mTORCI) and this process may be central to the aetiopathogenesis of drug addiction, obesity, foetal programming, diabetes mellitus, epilepsy and bipolar disorder. Antiglycaemics such as cannabinoid CB2 agonists, metformin, artesunate and valproate; insulin-mimetics such as glucagon-like peptide-I (GLP-I) and its analogues; phytomedicines from garlic and curcumin are now shown to exhibit neuroprotective effects. These agents which may down-regulate inflammatory cytokines, upregulate endothelial nitric oxide (eNOS) and peroxisome proliferator-activated receptor alpha (PPAR-α) signalling, attenuate mitochondrial dysfunction, enhance the actions of glucagon-like peptide-I (GLP-I), inhibit mTOR, NF-kappa B, interleukin-I β and glycogen synthase kinase-3 β stand to be of benefit in these illnesses which demonstrate considerable overlay in their aetopathogenic mechanisms. Underpinnings and bidirectional relationships between the metabolic syndrome and mental health disorders may pave way for common new fronts to drug development in translational cardiovascular psychiatry and neurology.

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mTOR partly mediates insulin resistance by phosphorylation of insulin receptor substrate-1 on serine307 residues after burn

Cited by 14 publications

References 40 publications

Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury

Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury

Activation of mTOR: a culprit of Alzheimer’s disease?

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

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mTOR partly mediates insulin resistance by phosphorylation of insulin receptor substrate-1 on serine307 residues after burn

Cited by 14 publications

References 40 publications

Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury

Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury

Activation of mTOR: a culprit of Alzheimer&rsquo;s disease?

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

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Product

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Activation of mTOR: a culprit of Alzheimer’s disease?