Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 pathway in a rat model of neonatal HIE

Huang, Juan; Liu, Wei; Doycheva, Desislava; Gamdzyk, Marcin; Lu, WW; Tang, Jiping; Zhang, Junyi

doi:10.1016/j.freeradbiomed.2019.07.001

Cited by 95 publications

(76 citation statements)

References 80 publications

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“…The protective effects of AMPK have been considered in the context of several hormones that might be associated with (systemic) energy depletion or inflammatory stimuli. The "hunger hormone" ghrelin has been considered to be protective in ischemia/reperfusion injury and has been shown to activate AMPK [87,88], probably via CaMKK2 [89]. Also, leptin signaling, which basically acts antagonistic to ghrelin, has been reported to activate AMPK in chronic intermittent hypoxia independently of AMP levels in peripheral tissues like skeletal muscle [13,64,90], whereas it exerts an inhibitory effect on hypothalamic AMPK [91,92].…”

Section: Hormones and Other Mediatorsmentioning

confidence: 99%

Activation of AMPK under Hypoxia: Many Roads Leading to Rome

Dengler

2020

IJMS

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AMP-activated protein kinase (AMPK) is known as a pivotal cellular energy sensor, mediating the adaptation to low energy levels by deactivating anabolic processes and activating catabolic processes in order to restore the cellular ATP supply when the cellular AMP/ATP ratio is increased. Besides this well-known role, it has also been shown to exert protective effects under hypoxia. While an insufficient supply with oxygen might easily deplete cellular energy levels, i.e., ATP concentration, manifold other mechanisms have been suggested and are heavily disputed regarding the activation of AMPK under hypoxia independently from cellular AMP concentrations. However, an activation of AMPK preceding energy depletion could induce a timely adaptation reaction preventing more serious damage. A connection between AMPK and the master regulator of hypoxic adaptation via gene transcription, hypoxia-inducible factor (HIF), has also been taken into account, orchestrating their concerted protective action. This review will summarize the current knowledge on mechanisms of AMPK activation under hypoxia and its interrelationship with HIF.

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Section: Hormones and Other Mediatorsmentioning

confidence: 99%

Activation of AMPK under Hypoxia: Many Roads Leading to Rome

Dengler

2020

IJMS

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“…Instead, enhanced PGC-1α expression may protect neural cells from oxidative stress-mediated cell death [89]. The upregulation of UCP-2 after stroke diminishes the release of ROS and decreases neuronal loss in brain tissue, which suggest novel neuroprotection against ischemic brain injury [219]. Accordingly in animal models of transient focal cerebral ischemia, MnSOD overexpression has a protective effect against oxidative stress-induced neuronal damage [220].…”

mentioning

confidence: 99%

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Rius‐Pérez

Torres-Cuevas

Millán

et al. 2020

Oxidative Medicine and Cellular Longevity

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292

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Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.

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“…In diabetic peripheral neuropathy, overexpression of Sirt1 can increase axonal growth through Sirt1/ PGC-1α/ TFAM axis and improve mitochondrial oxidative metabolism (40). It has also been shown that Sirt1/PGC-1α signaling pathway can further regulate the role of uncoupling protein 2(UCP2) or Forkhead box protein O1(FOXO1) in reducing oxidative stress and neuronal apoptosis (41,42). In our study, decreasing Sirt1 reduced the expression of PGC-1α and increased apoptosis, resulting in intracellular increased MDA and decreased SOD, which are related to cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Sirt1 Regulates Oxidative Stress in Oxygen-Glucose Deprived Hippocampal Neurons

et al. 2020

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Oxidative stress is an important mechanism of neonatal hypoxic-ischemic brain damage. Sirtuin1 (Sirt1) is a deacetylase that depends on NAD + , which has an important role in antioxidant metabolism. Furthermore, peroxisome proliferator-activated receptor γ-co-activator 1α (PGC-1α) is a key regulator of mitochondrial oxidative stress, which is regulated by Sirt1. Here, we investigated the role of Sirt1 in the pathogenesis of brain injuries after modulating its activity in primary cultured hippocampal neurons. Our study shows that the expression of Sirt1 was downregulated after oxygen-glucose deprivation. Activation of Sirt1 with resveratrol improved cell's resistance to oxidative stress, whereas inhibition of Sirt1 with EX527 significantly reduced cell viability after cellular oxidative stress. Our study also shows that activation of Sirt1 with resveratrol exerts its antioxidant effect by regulating the expression of PGC-1α. In contrast, application of EX527 decreased the expression of PGC-1α. In summary, these results confirmed that Sirt1 is a potent protective factor for neurons subjected to oxidative stress, and the protective effect of Sirt1 is attributed to its regulation of PGC-1α.

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Ghrelin attenuates oxidative stress and neuronal apoptosis via GHSR-1α/AMPK/Sirt1/PGC-1α/UCP2 pathway in a rat model of neonatal HIE

Cited by 95 publications

References 80 publications

Activation of AMPK under Hypoxia: Many Roads Leading to Rome

Activation of AMPK under Hypoxia: Many Roads Leading to Rome

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Sirt1 Regulates Oxidative Stress in Oxygen-Glucose Deprived Hippocampal Neurons

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