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Selenium inhibits ferroptosis in hyperglycemic cerebral ischemia/reperfusion injury by stimulating the Hippo pathway.

ABSTRACT: Hyperglycemia can exacerbate cerebral ischemia/reperfusion (I/R) injury, and the mechanism involves oxidative stress, apoptosis, autophagy and mitochondrial function. Our previous research showed that selenium (Se) could alleviate this injury. The aim of this study was to examine how selenium alleviates hyperglycemia-mediated exacerbation of cerebral I/R injury by regulating ferroptosis. Middle cerebral artery occlusion (MCAO) and reperfusion models were established in rats under hyperglycemic conditions. An in vitro model of hyperglycemic cerebral I/R injury was created with oxygen-glucose deprivation and reoxygenation (OGD/R) and high glucose was employed. The results showed that hyperglycemia exacerbated cerebral I/R injury, and sodium selenite pretreatment decreased infarct volume, edema and neuronal damage in the cortical penumbra. Moreover, sodium selenite pretreatment increased the survival rate of HT22 cells under OGD/R and high glucose conditions. Pretreatment with sodium selenite reduced the hyperglycemia mediated enhancement of ferroptosis. Furthermore, we observed that pretreatment with sodium selenite increased YAP and TAZ levels in the cytoplasm while decreasing YAP and TAZ levels in the nucleus. The Hippo pathway inhibitor XMU-MP-1 eliminated the inhibitory effect of sodium selenite on ferroptosis. The findings suggest that pretreatment with sodium selenite can regulate ferroptosis by activating the Hippo pathway, and minimize hyperglycemia-mediated exacerbation of cerebral I/R injury.

SUBMITTER: Li L

PROVIDER: S-EPMC10490962 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Selenium inhibits ferroptosis in hyperglycemic cerebral ischemia/reperfusion injury by stimulating the Hippo pathway.

Li Lu L Wang Meng M Ma Yan-Mei YM Yang Lan L Zhang Deng-Hai DH Guo Feng-Ying FY Jing Li L Zhang Jian-Zhong JZ

PloS one 20230908 9

Hyperglycemia can exacerbate cerebral ischemia/reperfusion (I/R) injury, and the mechanism involves oxidative stress, apoptosis, autophagy and mitochondrial function. Our previous research showed that selenium (Se) could alleviate this injury. The aim of this study was to examine how selenium alleviates hyperglycemia-mediated exacerbation of cerebral I/R injury by regulating ferroptosis. Middle cerebral artery occlusion (MCAO) and reperfusion models were established in rats under hyperglycemic c ...[more]

PMID: 37682882

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Project description:ObjectiveIschemic stroke is a leading cause of death and disability in individuals worldwide. Cerebral ischemia-reperfusion injury (CIRI) typically results in severe secondary injury and complications following reperfusion therapy. Microglia play critical roles in the inflammatory reaction of CIRI. However, less attention has been given to microglial death in this process. Our study aims to explore microglial death in CIRI and the effects and mechanism of minocycline treatment on microglia.MethodsA middle cerebral artery occlusion (MCAO) model was applied to induce CIRI in rats. At 0 h, 24 h and 48 h post-operation, rats were intraperitoneally injected with 45 mg/kg minocycline. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, assessment of activated microglia and examination of mitochondrial structure were conducted and checked at 72 h after reperfusion. Additionally, an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) model was established. BV-2 cells were treated with various pharmacological inhibitors of cell death or minocycline. Cell viability, lipid peroxidation, mitochondrial structure and function, and labile Fe2+ and ferroptosis-associated gene/protein levels were measured. Hemin was used for further validation after transcriptome analysis.ResultsIn the MCAO and OGD/R models, ferroptosis was identified as a major form of microglial death. Minocycline inhibited microglia ferroptosis by reducing HO-1 expression. In addition, minocycline improved mitochondrial membrane potential, mitochondrial structures and microglial survival in vivo. Minocycline also decreased labile Fe2+ levels, lipid peroxidation, and expression of ferritin heavy chain (FTH) and it improved mitochondrial structure and function in vitro. Upregulation of HO-1 counteracted the protective effect of minocycline.ConclusionFerroptosis is a major form of microglial death in CIRI. The protective mechanism of minocycline in CIRI partially hinges on its ability to effectively ameliorate microglia ferroptosis by downregulating HO-1 expression. Consequently, targeting microglia ferroptosis is a promising treatment for CIRI.

Project description:BackgroundEmerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function.MethodsWe performed circRNA sequencing to explore circRNAs differentially expressed after myocardial I/R. We used quantitative polymerase chain reactions to determine the circRNA expression in different tissues and detect the circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down was applied to explore proteins interacting with circRNA.ResultsHere, we identified a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in cardiomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase (NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expression, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 (Fth1), a ferroptosis suppressor, which resulted in the inhibition of cardiomyocyte ferroptosis.ConclusionsOur finding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis participates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic heart diseases.

Project description:Macrophages play a critical role in the development of acute ischemic stroke (AIS). Cerebral ischemia-reperfusion injury (CIRI) is a pivotal pathological process that exacerbates AIS, with exosomes act as crucial mediators. However, the effects and mechanisms of action of macrophage-derived exosomes on CIRI remain unclear. This study demonstrated that macrophage-derived exosomes induce endothelial ferroptosis and barrier disruption during CIRI. Through proteomic sequencing and the reanalysis of transcriptomic and single-cell sequencing data, thrombospondin-1 (THBS1) was identified as a key exosomal molecule. Elevated THBS1 was observed in exosomes and monocytes from the peripheral blood of patients with AIS in oxygen-glucose deprivation/reoxygenation (OGD/R)-stimulated THP-1 and RAW264.7, in their secreted exosomes, and in macrophages within the brains of transient middle cerebral artery occlusion (tMCAO) mice. Additionally, THBS1 expression in exosomes was positively correlated with vascular barrier injury biomarkers, including MMP-9 and S100B. Modulation of THBS1 in macrophage-derived exosomes affected exosome-induced ferroptosis in endothelial cells. The mechanism by which THBS1 binds directly to OTUD5 and promotes GPX4 ubiquitination was elucidated using RNA interference, adeno-associated virus transfection, and endothelial-specific Gpx4 knockout mice. High-throughput screening of small-molecule compounds targeting THBS1 was performed. Molecular docking, molecular dynamics simulations, and cellular thermal shift assays further confirmed that salvianolic acid B (SAB) has a potent binding affinity for THBS1. SAB treatment inhibited the interaction between THBS1 and OTUD5, leading to reduced GPX4 ubiquitination. Further research revealed that SAB treatment enhanced the cerebral protective effects of THBS1 inhibition. In conclusion, this study explored the role of exosome-mediated signaling between macrophages and cerebral vascular endothelial cells in CIRI, highlighting the THBS1-OTUD5-GPX4 axis as a driver of endothelial ferroptosis and brain injury. Targeting this signaling axis represents a potential therapeutic strategy for treating CIRI.

Project description:BackgroundDual antiplatelet therapy with aspirin and clopidogrel (ASA + CPG) during the first 21 days has been shown to reduce the risk of major ischemic events in patients with transient ischemic attack (TIA) or minor stroke. However, the mechanisms underlying combination treatment with ASA + CPG in experimental ischemic stroke has not been fully elucidated.MethodsMinor cerebral ischemia was induced in mice by transient distal middle cerebral artery occlusion (tdMCAO). Two doses of ASA + CPG (12 and 24 mg/kg/day) or vehicle were administered by gavage daily. Neurological behaviors were assessed using the modified Garcia scores, Rotarod test, Y maze, and open field test. Platelet function was assessed in vitro by flow cytometry and in vivo by bleeding and clotting time. The neutrophil ratio and the levels of inflammatory cytokines were measured by flow cytometry and the Meso Scale Discovery (MSD) electrochemilunimescence, respectively.ResultsSensorimotor function was partially recovered with ASA + CPG treatment after ischemia. Anxiety levels and cognitive functions showed improvement in the ASA + CPG group at 12 mg/kg/day after 21 days. Both tail bleeding time and flow cytometry showed significantly decreased platelet function after ASA + CPG treatment. Notably, ASA + CPG at 12 mg/kg/day prolonged clotting time at 28 days after injury. Furthermore, the ratio of neutrophils, an indicator of inflammation, was reduced with 12 mg/kg/day ASA + CPG treatment in the bone marrow (BM) at 21 days and in the peripheral blood (PB) at 21 and 28 days after tdMCAO. Both doses of ASA + CPG decreased pro-inflammatory cytokine interleukin (IL)-6 expression 21 days after stroke. Taken together, these results demonstrated that combination treatment with ASA + CPG improved long-term neurological function after stroke and may inhibit platelet-neutrophil interaction by decreasing the concentration of pro-inflammatory cytokine, IL-6.ConclusionsThese findings indicate a neuroprotective effect of combination treatment with ASA + CPG for a duration of 21 days in an experimental acute minor stroke model. These findings provide further evidence that dual antiplatelet therapy may be a viable neuroprotective treatment to decrease the recurrence of stroke.

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Selenium inhibits ferroptosis in hyperglycemic cerebral ischemia/reperfusion injury by stimulating the Hippo pathway.

Publications

Selenium inhibits ferroptosis in hyperglycemic cerebral ischemia/reperfusion injury by stimulating the Hippo pathway.

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