Hepcidin Protects Neuron from Hemin-Mediated Injury by Reducing Iron

Zhou, Yu‐Fu; Zhang, Chao; Yang, Guang; Qian, Zhong Ming; Zhang, Meng-Wan; Ma, Juan; Zhang, Fa‐Li; Ke, Ya

doi:10.3389/fphys.2017.00332

Cited by 33 publications

(31 citation statements)

References 55 publications

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“…This occurs because during brain inflammation, cytokines, and hepcidin have agonistic effects in suppressing cellular iron efflux ( Urrutia et al, 2013 ; Xiong et al, 2016 ; Zhao Y. et al, 2018 ). In addition, inflammatory signaling overrides the blocking effect of hepcidin on cellular iron uptake which creates an ideal environment that promotes brain iron overload by both, inflammatory signals and hepcidin ( Urrutia et al, 2013 ; Du et al, 2015 ; Gong et al, 2016 ; Xiong et al, 2016 ; Zhou et al, 2017 ; Zhao Y. et al, 2018 ).…”

Section: Role Of Systemic Hepcidin In Brain Homeostasismentioning

confidence: 99%

“…Furthermore, iron dysregulation has been proposed as a pathogenic factor in neurodegenerative diseases as well ( Ward et al, 2014 ). Recent research suggests that brain iron dysmetabolism can be tackled via hepcidin manipulation, since local hepcidin production in the brain has been shown to affect cellular iron transport ( Urrutia et al, 2013 ; Du et al, 2015 ; Gong et al, 2016 ; Xiong et al, 2016 ; Zhou et al, 2017 ). But, it seems that the presence or absence of inflammation dictates the deleterious vs. beneficial effects of hepcidin in the brain.…”

Section: Introductionmentioning

confidence: 99%

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The Dual Role of Hepcidin in Brain Iron Load and Inflammation

Vela

2018

Front. Neurosci.

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Hepcidin is the major regulator of systemic iron metabolism, while the role of this peptide in the brain has just recently been elucidated. Studies suggest a dual role of hepcidin in neuronal iron load and inflammation. This is important since neuronal iron load and inflammation are pathophysiological processes frequently associated with neurodegeneration. Furthermore, manipulation of hepcidin activity has recently been used to recover neuronal damage due to brain inflammation in animal models and cultured cells. Therefore, understanding the mechanistic insights of hepcidin action in the brain is important to uncover its role in treating neuronal damage in neurodegenerative diseases.

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Section: Role Of Systemic Hepcidin In Brain Homeostasismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Dual Role of Hepcidin in Brain Iron Load and Inflammation

Vela

2018

Front. Neurosci.

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“…NIPAM-hemin did not decrease cell viability, even though hemin is known to be toxic to several cell types. 16,17 One of the causes of hemin-induced cytotoxicity is the hydrophobicity of the heme group, which interacts with lipids and leads to peroxidation. 16 NIPAM is soluble and binds to the non-soluble hemin to form a soluble copolymer.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of a hemin-containing copolymer as a novel immunostimulator that induces IFN-gamma production

Hoshi¹,

Yamazaki²,

Yoshikawa³

et al. 2018

IJN

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BackgroundHemozoin, a chemical analog of a malarial pigment, is a crystal composed of heme dimers that can act as a potent Th1-type adjuvant, which strongly induces antibody production. However, the clinical applications of malarial hemozoin have limitations due to biosafety concerns and difficulties in the manufacturing process. Based on the premise that an analog of the heme polymer might display immunostimulatory effects, a hemin-containing polymer was developed as a novel immunostimulator.Materials and methodsTo synthesize the copolymer containing hemin and N-isopropylacrylamide (NIPAM), this study employed a conventional radical polymerization method using 2,2′-azodiisobutyronitrile as the radical initiator; the synthesized copolymer was designated as NIPAM-hemin.ResultsNIPAM-hemin was soluble and showed no cytotoxicity in vitro. The NIPAM-hemin copolymer induced the production of interferon (IFN)-γ and interleukin (IL)-6 from peripheral blood mononuclear cells, although hemin and the NIPAM monomer individually did not induce the production of any cytokines. The production of IFN-γ induced by NIPAM-hemin was independent of toll-like receptor 9 and the NLRP3 inflammasome pathway.ConclusionGiven that NIPAM-hemin induced IL-6 and IFN-γ production in immune cells without any cytotoxic effects, NIPAM-hemin has potential therapeutic applications as a Th1-type adjuvant.

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“…In addition to iron release protein Fpn1, hepcidin was also found to significantly inhibit the expression of iron uptake proteins TfR1 and DMT1 in cultured microvascular endothelial cells, neurons, and astrocytes . The inhibitory effect of hepcidin on iron uptake proteins was also observed in iron‐depleted astrocytes, indicating that the inhibition effect of iron uptake proteins by hepcidin is a direct rather than an indirect effect by the increased cellular iron induced by the hepcidin‐induced reduction in Fpn1.…”

Section: Hepcidin and The Treatment Of Neurodegenerative Disordersmentioning

confidence: 93%

Hepcidin and its therapeutic potential in neurodegenerative disorders

Qian

2019

Medicinal Research Reviews

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Abnormally high brain iron, resulting from the disrupted expression or function of proteins involved in iron metabolism in the brain, is an initial cause of neuronal death in neuroferritinopathy and aceruloplasminemia, and also plays a causative role in at least some of the other neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich's ataxia. As such, iron is believed to be a novel target for pharmacological intervention in these disorders. Reducing iron toward normal levels or hampering the increases in iron associated with age in the brain is a promising therapeutic strategy for all iron‐related neurodegenerative disorders. Hepcidin is a crucial regulator of iron homeostasis in the brain. Recent studies have suggested that upregulating brain hepcidin levels can significantly reduce brain iron content through the regulation of iron transport protein expression in the blood‐brain barrier and in neurons and astrocytes. In this review, we focus on the discussion of the therapeutic potential of hepcidin in iron‐associated neurodegenerative diseases and also provide a systematic overview of recent research progress on how misregulated brain iron metabolism is involved in the development of multiple neurodegenerative disorders.

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Hepcidin Protects Neuron from Hemin-Mediated Injury by Reducing Iron

Cited by 33 publications

References 55 publications

The Dual Role of Hepcidin in Brain Iron Load and Inflammation

The Dual Role of Hepcidin in Brain Iron Load and Inflammation

Synthesis of a hemin-containing copolymer as a novel immunostimulator that induces IFN-gamma production

Hepcidin and its therapeutic potential in neurodegenerative disorders

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