The role of transferrins and iron-related proteins in brain iron transport: applications to neurological diseases

Campos-Escamilla, Camila

doi:10.1016/bs.apcsb.2020.09.002

Cited by 16 publications

(11 citation statements)

References 88 publications

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“…However, iron is an oxidant, and excessive deposition can also cause severe damage to the cell. Excessive free iron causes oxidative nitrification stress, inflammation, and excitatory toxicity, resulting in cell damage and neurodegeneration [ 9 ]. The consequences of metabolic disorders of iron ions may be the main cause of PD.…”

Section: Introductionmentioning

confidence: 99%

Sorting Nexin 5 Plays an Important Role in Promoting Ferroptosis in Parkinson’s Disease

Huang

Han

et al. 2022

Oxidative Medicine and Cellular Longevity

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Parkinson’s disease (PD) is a common neurodegenerative disease in the elderly, which is related to brain iron metabolism disorders. Ferroptosis is a newly discovered iron-dependent programmed cell death mode, which has been considered an essential mechanism of PD pathogenesis in recent years. However, its underlying mechanisms have not been fully understood. In the present study, the PD rat model and PD cell model were induced by 6-hydroyxdopamine (6-OHDA). The results showed that the expression of Sorting Nexin 5 (SNX5) and the level of ferroptosis will increase after treatment with 6-OHDA. Consistent with these results, ferroptosis inducer erastin synergistically reduced the expression of glutathione peroxidase 4 (GPX4) and increased the expression of SNX5 in the PD cell model, while ferroptosis inhibitor ferrostatin-1 (Fer-1) inhibited the decrease of GPX4 and the increase of SNX5 in the PD cell model. Knockdown of SNX5 in PC-12 cells could reduce intracellular lipid peroxidation and accumulation of Fe2+ and significantly inhibit the occurrence of ferroptosis. In conclusion, the present study suggested that SNX5 promotes ferroptosis in the PD model, thus providing new insights and potential for research on the pharmacological targets of PD.

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Section: Introductionmentioning

confidence: 99%

Sorting Nexin 5 Plays an Important Role in Promoting Ferroptosis in Parkinson’s Disease

Huang

Han

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Cells acquire iron from Tf [ 4 ], which binds iron with a high affinity to form a unique chelated form of iron. Transferrin receptors (TfRs) are involved in the uptake of Tf-bound iron from the plasma into cerebral endothelial cells; among these receptors, TfR1 is essential for cellular iron uptake and is widely distributed in neurons [ 5 , 6 ]. Fn is the main iron storage protein, which is composed of two subunit types, the H- and L-chains [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Roots of Astragalus propinquus Schischkin Regulate Transmembrane Iron Transport and Ferroptosis to Improve Cerebral Ischemia-Reperfusion Injury

Chen

Bao

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. The dried roots of the Astragalus propinquus Schischkin (RAP) plant, as a traditional Chinese medicine, has been widely used to treat stroke, cerebral ischemia, qi deficiency, and hypertension. Buyang Huanwu decoction is traditionally used to treat stroke in China for more than 200 years and has a significant effect on cerebral ischemia, and RAP is monarch medicine of Buyang Huanwu decoction. Therefore, this study was designed to observe the regulatory effect of RAP on transmembrane iron transporters and ferroptosis-related factors in cerebral ischemia-reperfusion injury (CIRI) in rats. Methods. Middle cerebral artery occlusion (MCAO) was used to block blood flow in the blood supply area of the middle cerebral artery in seventy male SD rats to induce focal CIRI to establish a rat model of CIRI. RAP was administered to explore the regulatory effect of RAP on iron transmembrane transport under the condition of CIRI. The infarct size was measured using 2,3,5-triphenyl-tetrazolium chloride (TTC) staining, the pathological structure of brain tissue was observed by HE staining, and neuronal injury was evaluated by Nissl staining after treatment. Then, changes in the iron transporters ferritin (Fn), ferritin heavy chain (FHC), ferritin light chain (FLC), transferrin (Tf), transferrin receptor (TfR), divalent metal transporter 1 (DMT1), L-type calcium channel (LTCC), transient receptor potential canonical 6 (TRPC6), and ferroportin 1 (FPN1) were observed by immunohistochemistry staining (IHC) and Western blotting. The expression of key factors of ferroptosis, including the membrane sodium-dependent cystine/glutamate antiporter System Xc− (System Xc−) light chain subunit (XCT) and heavy chain subunit (SLC3A2), glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2), heme oxygenase-1 (HO-1), and iron-responsive element-binding protein 2 (IREB2) in the brain tissues of rats was assessed by Western blotting. RAP decreased the infarct size and neuronal injury after CIRI in rats. Similarly, RAP treatment regulated the expression of iron transporters. As such, RAP was able to reduce the expression of Fn, FHC, FLC, Tf, TfR, DMT1, and TRPC6 and increase the expression of FPN1 through a Tf/TfR-independent pathway after CIRI in rats. Conclusion. RAP stimulation inhibited ferroptosis by regulating the expression of the key ferroptosis factors XCT, SLC3A2, GPX4, NRF2, HO-1, and IREB2. In conclusion, RAP regulates transmembrane iron transport and ferroptosis to improve CIRI.

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“…When ICAS occurs, cerebral cells of the corresponding blood supply region, including vascular endothelial cells, can become ischemic and hypoxic, which in turn leads to the destruction of blood-brain barrier. Endothelial cells are key regulators of iron transport, and blood-brain barrier is an important structure for regulating iron transport and metabolism in the brain ( 9 , 10 ). When both structures are damaged, iron circulation homeostasis is altered and excessive iron deposits in the brain.…”

Section: Introductionmentioning

confidence: 99%

Iron Deposition in Gray Matter Nuclei of Patients With Intracranial Artery Stenosis: A Quantitative Susceptibility Mapping Study

Mao¹,

Dou²,

Wang³

et al. 2022

Front. Neurol.

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Purpose: This study aimed to use quantitative susceptibility mapping (QSM) to systematically investigate the changes of iron content in gray matter (GM) nuclei in patients with long-term anterior circulation artery stenosis (ACAS) and posterior circulation artery stenosis (PCAS).Methods: Twenty-five ACAS patients, 25 PCAS patients, and 25 age- and sex-matched healthy controls underwent QSM examination. Patients were scored using the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) to assess the degree of neural function deficiency. On QSM images, iron related susceptibility of GM nuclei, including bilateral caudate nucleus, putamen (PU), globus pallidus (GP), thalamus (TH), substantia nigra (SN), red nucleus, and dentate nucleus (DN), were assessed. Susceptibility was compared between bilateral GM nuclei in healthy controls, ACAS patients, and PCAS patients. Partial correlation analysis, with age as a covariate, was separately performed to assess the relationships of susceptibility with NIHSS and mRS scores.Results: There were no significant differences between the susceptibilities for left and right hemispheres in all seven GM nucleus subregions for healthy controls, ACAS patients, and PCAS patients. Compared with healthy controls, mean susceptibility of bilateral PU, GP, and SN in ACAS patients and of bilateral PU, GP, SN, and DN in PCAS patients were significantly increased (all P < 0.05). In addition, mean susceptibility of bilateral TH and SN in PCAS patients was significantly higher than in ACAS patients (both P < 0.05). With partial correlation analysis, mean susceptibility at bilateral PU of ACAS patients was significantly correlated with mRS score (r = 0.415, P < 0.05), and at bilateral PU in PCAS patients was correlated with NIHSS score (r = 0.424, P < 0.05).Conclusion: Our findings indicated that abnormal iron metabolism may present in different subregions of GM nuclei after long-term ACAS and PCAS. In addition, iron content of PU in patients with ACAS and PCAS was correlated with neurological deficit scores. Therefore, iron quantification measured by QSM susceptibility may provide a new insight to understand the pathological mechanism of ischemic stroke caused by ACAS and PCAS.

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The role of transferrins and iron-related proteins in brain iron transport: applications to neurological diseases

Cited by 16 publications

References 88 publications

Sorting Nexin 5 Plays an Important Role in Promoting Ferroptosis in Parkinson’s Disease

Sorting Nexin 5 Plays an Important Role in Promoting Ferroptosis in Parkinson’s Disease

Roots of Astragalus propinquus Schischkin Regulate Transmembrane Iron Transport and Ferroptosis to Improve Cerebral Ischemia-Reperfusion Injury

Iron Deposition in Gray Matter Nuclei of Patients With Intracranial Artery Stenosis: A Quantitative Susceptibility Mapping Study

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