Iron Pathophysiology in Stroke

Almutairi, Mohammed; Xu, Grace; Shi, Honglian

doi:10.1007/978-981-13-9589-5_6

Cited by 15 publications

(9 citation statements)

References 123 publications

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“…By using PEG-SOD and a SOD inhibitor, we demonstrated for the first time that changes in FeRhoNox-1 fluorescence provide a useful measure of reoxygenation-induced superoxide generation in brain microvascular endothelial cells. Release of labile iron is closely associated with reactive oxygen species generation, and iron accumulation occurs in stroke [ 63 ], traumatic brain injury [ 64 ] and neurodegenerative disorders [ 65 , 66 ]. Furthermore, mitochondria exposed to superoxide anions release iron from iron-sulphur clusters, such that increased free radical generation will result in increased free iron [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Nrf2-regulated redox signaling in brain endothelial cells adapted to physiological oxygen levels: Consequences for sulforaphane mediated protection against hypoxia-reoxygenation

et al. 2020

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Ischemic stroke is associated with a surge in reactive oxygen species generation during reperfusion. The narrow therapeutic window for the delivery of intravenous thrombolysis and endovascular thrombectomy limits therapeutic options for patients. Thus, understanding the mechanisms regulating neurovascular redox defenses are key for improved clinical translation. Our previous studies in a rodent model of ischemic stroke established that activation of Nrf2 defense enzymes by pretreatment with sulforaphane (SFN) affords protection against neurovascular and neurological deficits. We here further investigate SFN mediated protection in mouse brain microvascular endothelial cells (bEnd.3) adapted long-term (5 days) to hyperoxic (18 kPa) and normoxic (5 kPa) O 2 levels. Using an O 2 -sensitive phosphorescent nanoparticle probe, we measured an intracellular O 2 level of 3.4 ± 0.1 kPa in bEnd 3 cells cultured under 5 kPa O 2 . Induction of HO-1 and GCLM by SFN (2.5 μM) was significantly attenuated in cells adapted to 5 kPa O 2 , despite nuclear accumulation of Nrf2. To simulate ischemic stroke, bEnd.3 cells were adapted to 18 or 5 kPa O 2 and subjected to hypoxia (1 kPa O 2 , 1 h) and reoxygenation. In cells adapted to 18 kPa O 2 , reoxygenation induced free radical generation was abrogated by PEG-SOD and significantly attenuated by pretreatment with SFN (2.5 μM). Silencing Nrf2 transcription abrogated HO-1 and NQO1 induction and led to a significant increase in reoxygenation induced free radical generation. Notably, reoxygenation induced oxidative stress, assayed using the luminescence probe L-012 and fluorescence probes MitoSOX™ Red and FeRhoNox™-1, was diminished in cells cultured under 5 kPa O 2 , indicating an altered redox phenotype in brain microvascular cells adapted to physiological normoxia. As redox and other intracellular signaling pathways are critically affected by O 2 , the development of antioxidant therapies targeting the Keap1-Nrf2 defense pathway in treatment of ischemia-reperfusion injury in stroke, coronary and renal disease will require in vitro studies conducted under well-defined O 2 levels.

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Section: Discussionmentioning

confidence: 99%

Nrf2-regulated redox signaling in brain endothelial cells adapted to physiological oxygen levels: Consequences for sulforaphane mediated protection against hypoxia-reoxygenation

et al. 2020

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“…Defined as cell death triggered by generation of excessive lipid reactive oxygen species (ROS) dependent on iron, ferroptosis is different from other classical modes of programmed cell death. 5 Iron accumulation was previously observed in stroke patients, 6 while iron inhibitors and chelators such as ferrostatin-1 and deferoxamine presented significant protective benefits against focal cerebral ischemia-reperfusion injury in mice. 7 As a class of non-coding RNAs with a length of larger than 200 nucleotides, long non-coding RNAs (lncRNAs) are involved in many critical physiological and pathophysiological processes, such as cell differentiation, cell proliferation, immunity, inflammation and apoptosis, through modulating their target genes.…”

Section: Introductionmentioning

confidence: 94%

Long noncoding RNA Meg3 mediates ferroptosis induced by oxygen and glucose deprivation combined with hyperglycemia in rat brain microvascular endothelial cells, through modulating the p53/GPX4 axis

et al. 2021

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Individuals with diabetes are exposed to a higher risk of perioperative stroke than non-diabetics mainly due to persistent hyperglycemia. LncRNA Meg3 has been considered as an important mediator in regulating ischemic stroke. However, the functional and regulatory roles of Meg3 in diabetic brain ischemic injury remain unclear. In this study, rat brain microvascular endothelial cells (RBMVECs) were exposed to 6 h of oxygen and glucose deprivation (OGD), and subsequent reperfusion via incubating cells with glucose of various high concentrations for 24 h to imitate in vitro diabetic brain ischemic injury. It was shown that the marker events of ferroptosis and increased Meg3 expression occurred after the injury induced by OGD combined with hyperglycemia. However, all ferroptotic events were reversed with the treatment of Meg3-siRNA. Moreover, in this in vitro model, p53 was also characterized as a downstream target of Meg3. Furthermore, p53 knockdown protected RBMVECs against OGD + hyperglycemic reperfusion-induced ferroptosis, while the overexpression of p53 exerted opposite effects, implying that p53 served as a positive regulator of ferroptosis. Additionally, the overexpression or knockdown of p53 significantly modulated GPX4 expression in RBMVECs exposed to the injury induced by OGD combined with hyperglycemic treatment. Furthermore, GPX4 expression was suppressed again after the reintroduction of p53 into cells silenced by Meg3. Finally, chromatin immunoprecipitation assay uncovered that p53 was bound to GPX4 promoter. Altogether, these data revealed that, by modulating GPX4 transcription and expression, the Meg3-p53 signaling pathway mediated the ferroptosis of RBMVECs upon injury induced by OGD combined with hyperglycemic reperfusion.

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“…This contradictory phenomenon indicates that there must be another undiscovered mechanism regulating TF. Apart from that, Hepcidin, a cysteine-rich polypeptide encoded by the human HAMP gene and secreted by the liver ( Reichert et al, 2017 ), also has been identified as an important regulator of iron homeostasis recently ( Almutairi et al, 2019 ). Hepcidin can bind to the iron efflux protein FPN1, thereby inhibiting its activity and promoting its degradation, finally suppressing the iron excretion ( Gulec et al, 2014 ) and causing iron overload and oxidative stress damage in both ischemic and hemorrhagic stroke ( Słomka et al, 2015 ; Tan et al, 2016 ; Xiong et al, 2016 ).…”

Section: The Possible Regulatory Mechanism Of Ferroptosis In Strokementioning

confidence: 99%

Ferroptosis and Its Multifaceted Roles in Cerebral Stroke

Zhang

Lü

Tai

et al. 2021

Front. Cell. Neurosci.

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Ferroptosis is a unique regulated cell death defined by the intracellular iron overload and distinct biological features compared with other well-known programmed cell death. Ferroptosis can be triggered by many causes including decreased expression of glutathione (GSH), inhibition of the function of glutathione-dependent peroxidase 4 (GPX4), and system xc–, all of which finally lead to the over-accumulation of lipid peroxides in the cell. Ferroptosis has been reported to play an important role in the pathophysiological process of various cancers. In recent years, much evidence also proved that ferroptosis is involved in the progress of cerebral stroke. In this review, we summarized the characteristics of ferroptosis and the potential relationship between ferroptosis and ischemic and hemorrhagic stroke, to provide new targets and ideas for the therapy of stroke.

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Iron Pathophysiology in Stroke

Cited by 15 publications

References 123 publications

Nrf2-regulated redox signaling in brain endothelial cells adapted to physiological oxygen levels: Consequences for sulforaphane mediated protection against hypoxia-reoxygenation

Nrf2-regulated redox signaling in brain endothelial cells adapted to physiological oxygen levels: Consequences for sulforaphane mediated protection against hypoxia-reoxygenation

Long noncoding RNA Meg3 mediates ferroptosis induced by oxygen and glucose deprivation combined with hyperglycemia in rat brain microvascular endothelial cells, through modulating the p53/GPX4 axis

Ferroptosis and Its Multifaceted Roles in Cerebral Stroke

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