Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice

Guo, Chuangxin; Hao, Lijuan; Yang, Zhaohui; Chai, Rui; Zhang, Shuai; Gu, Yu; Gao, Huiling; Zhong, Manli; Wang, Tao; Li, Jiayi; Wang, Zhan-You

doi:10.1016/j.expneurol.2016.03.016

Cited by 72 publications

(61 citation statements)

References 69 publications

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“…One recent report found that the inhibition of ERK1/2 signaling blocked c-Fos activation54. Guo C et al 50. found that desferrioxamine-mediated up-regulation of HIF-1α occurred via the activation of the ERK signaling pathway in SH-SY5Y cells.…”

Section: Discussionmentioning

confidence: 98%

“…Multiple studies demonstrated that the activity of C/EBP β, c-Fos and HIF-1αis also regulated by posttranslational modification caused by phosphorylation by different kinases, such as MAPK, cdc2, PKA and PKC1617484950. Previous studies targeted the effects of ERK1/2 pathways on GPR91-dependent VEGF expression in the retinas of streptozotocin-induced diabetic rats7.…”

Section: Discussionmentioning

confidence: 99%

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Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Gao

et al. 2017

Sci Rep

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Hypoxia is the most important factor in the pathogenesis of diabetic retinopathy (DR). Our previous studies demonstrated that G protein-coupled receptor 91(GPR91) participated in the regulation of vascular endothelial growth factor (VEGF) secretion in DR. The present study induced OIR model in newborn rats using exposure to alternating 24-hour episodes of 50% and 12% oxygen for 14 days. Treatment with GPR91 shRNA attenuated the retinal avascular area, abnormal neovascularization and pericyte loss. Western blot and qRT-PCR demonstrated that CoCl2 exposure promoted VEGF expression and secretion, activated the ERK1/2 signaling pathways and upregulated C/EBP and AP-1. Knockdown of GPR91 inhibited ERK1/2 activity. GPR91 siRNA transduction and the ERK1/2 inhibitor U0126 inhibited the increases in C/EBP β, C/EBP δ, c-Fos and HIF-1α. Luciferase reporter assays and a chromatin immunoprecipitation (ChIP) assay demonstrated that C/EBP β and c-Fos bound the functional transcriptional factor binding site in the region of the VEGF promoter, but not C/EBP δ. Knockdown of C/EBP β and c-Fos using RNAi reduced VEGF expression. Our data suggest that activation of the GPR91-ERK1/2-C/EBP β (c-Fos, HIF-1α) signaling pathway plays a tonic role in regulating VEGF transcription in rat retinal ganglion cells.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Gao

et al. 2017

Sci Rep

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“…Interestingly, deferoxamine, an iron chelator, has also been shown to up-regulate HIF-1α (Guo et al, 2016). We observed a clear induction of HIF-1α level by D-607 in PC12 cells from concentration of drug as low as 100 nM to a higher concentration of 5 μM (Fig.…”

Section: Discussionmentioning

confidence: 99%

A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo

et al. 2017

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Here, we report the characterization of a novel hybrid D2/D3 agonist and iron (II) specific chelator, D-607, as a multi-target-directed ligand against Parkinson's disease (PD). In our previously published report, we showed that D-607 is a potent agonist of dopamine (DA) D2/D3 receptors, exhibits efficacy in a reserpinized PD animal model and preferentially chelates to iron (II). As further evidence of its potential as a neuroprotective agent in PD, the present study reveals D-607 to be protective in neuronal PC12 cells against 6-OHDA toxicity. In an in vivo Drosophila melanogaster model expressing a disease-causing variant of α-synuclein (α-Syn) protein in fly eyes, the compound was found to significantly suppress toxicity compared to controls, concomitant with reduced levels of aggregated α-Syn. Furthermore, D-607 was able to rescue DAergic neurons from MPTP toxicity in mice, a well-known PD neurotoxicity model, following both sub-chronic and chronic MPTP administration. Mechanistic studies indicated that possible protection of mitochondria, up-regulation of hypoxia-inducible factor, reduction in formation of α-Syn aggregates and antioxidant activity may underlie the observed neuroprotection effects. These observations strongly suggest that D-607 has potential as a promising multifunctional lead molecule for viable symptomatic and disease-modifying therapy for PD.

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“…Moreover, the expression of A53T mutant h α-syn aggravates Fe 2+ mediated toxicity which results in an increased oxidative stress and DNA damage (Chew et al, 2011). Interestingly, intranasal treatment with desferrioxamine (DFO), a chelator widely used in clinical settings for the treatment of iron overload, down-regulated the expression of both α-syn and divalent metal transporter 1(DMT1; Guo et al, 2016). …”

Section: Role Of Metals In Synucleinopathiesmentioning

confidence: 99%

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

Toni¹,

Massimino

Mario

et al. 2017

Front. Neurosci.

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Metal ions are key elements in organisms' life acting like cofactors of many enzymes but they can also be potentially dangerous for the cell participating in redox reactions that lead to the formation of reactive oxygen species (ROS). Any factor inducing or limiting a metal dyshomeostasis, ROS production and cell injury may contribute to the onset of neurodegenerative diseases or play a neuroprotective action. Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative disorders affecting the central nervous system (CNS) of human and other mammalian species. The causative agent of TSEs is believed to be the scrapie prion protein PrPSc, the β sheet-rich pathogenic isoform produced by the conformational conversion of the α-helix-rich physiological isoform PrPC. The peculiarity of PrPSc is its ability to self-propagate in exponential fashion in cells and its tendency to precipitate in insoluble and protease-resistance amyloid aggregates leading to neuronal cell death. The expression “prion-like diseases” refers to a group of neurodegenerative diseases that share some neuropathological features with prion diseases such as the involvement of proteins (α-synuclein, amyloid β, and tau) able to precipitate producing amyloid deposits following conformational change. High social impact diseases such as Alzheimer's and Parkinson's belong to prion-like diseases. Accumulating evidence suggests that the exposure to environmental metals is a risk factor for the development of prion and prion-like diseases and that metal ions can directly bind to prion and prion-like proteins affecting the amount of amyloid aggregates. The diet, source of metal ions but also of natural antioxidant and chelating agents such as polyphenols, is an aspect to take into account in addressing the issue of neurodegeneration. Epidemiological data suggest that the Mediterranean diet, based on the abundant consumption of fresh vegetables and on low intake of meat, could play a preventive or delaying role in prion and prion-like neurodegenerative diseases. In this review, metal role in the onset of prion and prion-like diseases is dealt with from a nutritional, cellular, and molecular point of view.

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Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice

Cited by 72 publications

References 69 publications

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

Transcription factors regulate GPR91-mediated expression of VEGF in hypoxia-induced retinopathy

A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

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