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Article ; Online: Striking a NRF2: The Rusty and Rancid Vulnerabilities Toward Ferroptosis in Alzheimer's Disease.

Lane, Darius J R / Alves, Francesca / Ayton, Scott J / Bush, Ashley I

2023 Volume 39, Issue 1-3, Page(s) 141–161

Abstract: Significance: ...

Abstract	Significance:
MeSH term(s)	Humans ; Ferroptosis ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Alzheimer Disease ; NF-E2-Related Factor 2/metabolism ; Cell Death/genetics ; Lipid Peroxidation/genetics ; Iron/metabolism
Chemical Substances	Phospholipid Hydroperoxide Glutathione Peroxidase (EC 1.11.1.12) ; NF-E2-Related Factor 2 ; Iron (E1UOL152H7)
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2023.0318
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Article ; Online: Ferroptosis and NRF2: an emerging battlefield in the neurodegeneration of Alzheimer's disease.

Lane, Darius J R / Metselaar, Billie / Greenough, Mark / Bush, Ashley I / Ayton, Scott J

Essays in biochemistry

2021 Volume 65, Issue 7, Page(s) 925–940

Abstract: Ferroptosis is an iron- and lipid peroxidation-dependent cell death modality and emerging evidence indicates that ferroptosis has great explanatory potential for neuronal loss and associated CNS dysfunction in a range of neurodegenerative diseases (e.g., ...

Abstract	Ferroptosis is an iron- and lipid peroxidation-dependent cell death modality and emerging evidence indicates that ferroptosis has great explanatory potential for neuronal loss and associated CNS dysfunction in a range of neurodegenerative diseases (e.g., Alzheimer's, Parkinson's and Huntington's diseases, Motor neuron disease, Friedreich ataxia (FRDA)). Ferroptotic death results from lethal levels of phospholipid hydroperoxides that are generated by iron-dependent peroxidation of polyunsaturated fatty acids (PUFAs), such as arachidonic and adrenic acids, which are conjugated to specific phospholipids (e.g., phosphatidylethanolamines (PEs)). The major cellular protector against ferroptosis is glutathione peroxidase 4 (GPX4), a membrane-associated selenoenzyme that reduces deleterious phospholipid hydroperoxides to their corresponding benign phospholipid alcohols in a glutathione-dependent manner. Other complementary protective systems have also been identified that act to bolster cellular defences against ferroptosis. Many pharmacological modulators of the ferroptosis pathway have been identified, targeting proteins involved in iron homoeostasis and autophagy; the production and detoxification of lipid peroxides, and cyst(e)ine/glutathione metabolism. While a growing number of cell signalling pathways converge to regulate the ferroptosis cascade, an emerging understanding of ferroptosis regulation suggests that the ferroptotic 'tone' of cells can be set by the transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), which transcriptionally controls many key components of the ferroptosis pathway. In this review, we provide a critical overview of the relationship between ferroptosis and NRF2 signalling. With a focus on the role of ferroptosis in Alzheimer's disease (AD), we discuss how therapeutic modulation of the NRF2 pathway is a viable strategy to explore in the treatment of ferroptosis-driven neurodegeneration.
MeSH term(s)	Alzheimer Disease/metabolism ; Ferroptosis ; Humans ; Lipid Peroxidation ; Lipid Peroxides ; NF-E2-Related Factor 2/metabolism
Chemical Substances	Lipid Peroxides ; NF-E2-Related Factor 2
Language	English
Publishing date	2021-10-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1744-1358 ; 0071-1365
ISSN (online)	1744-1358
ISSN	0071-1365
DOI	10.1042/EBC20210017
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Article ; Online: Iron and Alzheimer's Disease: An Update on Emerging Mechanisms.

Lane, Darius J R / Ayton, Scott / Bush, Ashley I

Journal of Alzheimer's disease : JAD

2018 Volume 64, Issue s1, Page(s) S379–S395

Abstract: Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron's biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. ... ...

Abstract	Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron's biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This "Janus-faced" nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer's disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves "ferroptosis", a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD.
MeSH term(s)	Alzheimer Disease/metabolism ; Animals ; Humans ; Iron/metabolism
Chemical Substances	Iron (E1UOL152H7)
Language	English
Publishing date	2018-06-04
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-179944
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Article ; Online: Neuropathological Mechanisms of β-N-Methylamino-L-Alanine (BMAA) with a Focus on Iron Overload and Ferroptosis.

Kazemi Shariat Panahi, Hamed / Dehhaghi, Mona / Heng, Benjamin / Lane, Darius J R / Bush, Ashley I / Guillemin, Gilles J / Tan, Vanessa X

Neurotoxicity research

2022 Volume 40, Issue 2, Page(s) 614–635

Abstract: The incidence of neurodegenerative diseases and cyanobacterial blooms is concomitantly increasing worldwide. The cyanotoxin β-N-methylamino-L-alanine (BMAA) is produced by most of the Cyanobacteria spp. This cyanotoxin is described as a potential ... ...

Abstract	The incidence of neurodegenerative diseases and cyanobacterial blooms is concomitantly increasing worldwide. The cyanotoxin β-N-methylamino-L-alanine (BMAA) is produced by most of the Cyanobacteria spp. This cyanotoxin is described as a potential environmental etiology factor for some sporadic neurodegenerative diseases. Climate change and eutrophication significantly increase the frequency and intensity of cyanobacterial bloom in water bodies. This review evaluates different neuropathological mechanisms of BMAA at molecular and cellular levels and compares the related studies to provide some useful recommendations. Additionally, the structure and properties of BMAA as well as its microbial origin, especially by gut bacteria, are also briefly covered. Unlike previous reviews, we hypothesize the possible neurotoxic mechanism of BMAA through iron overload. We also discuss the involvement of BMAA in excitotoxicity, TAR DNA-binding protein 43 (TDP-43) translocation and accumulation, tauopathy, and other protein misincorporation and misfolding.
MeSH term(s)	Amino Acids, Diamino/metabolism ; Amino Acids, Diamino/toxicity ; Cyanobacteria/chemistry ; Cyanobacteria Toxins ; Ferroptosis ; Humans ; Iron Overload ; Neurodegenerative Diseases/chemically induced ; Neurotoxins/toxicity
Chemical Substances	Amino Acids, Diamino ; Cyanobacteria Toxins ; Neurotoxins ; beta-N-methylamino-L-alanine (108SA6URTV)
Language	English
Publishing date	2022-01-13
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2036826-4
ISSN	1476-3524 ; 1029-8428
ISSN (online)	1476-3524
ISSN	1029-8428
DOI	10.1007/s12640-021-00455-6
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Zs.A 5749: Show issues

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Article ; Online: Receptor-Independent Anti-Ferroptotic Activity of TrkB Modulators.

Jakaria, Md / Belaidi, Abdel A / Southon, Adam / Dent, Krista A / Lane, Darius J R / Bush, Ashley I / Ayton, Scott

International journal of molecular sciences

2022 Volume 23, Issue 24

Abstract: Dysregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling is implicated in several neurodegenerative diseases, including Alzheimer's disease. A failure of neurotrophic support may participate in ... ...

Abstract	Dysregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling is implicated in several neurodegenerative diseases, including Alzheimer's disease. A failure of neurotrophic support may participate in neurodegenerative mechanisms, such as ferroptosis, which has likewise been implicated in this disease class. The current study investigated whether modulators of TrkB signalling affect ferroptosis. Cell viability, C11 BODIPY, and cell-free oxidation assays were used to observe the impact of TrkB modulators, and an immunoblot assay was used to detect TrkB expression. TrkB modulators such as agonist BDNF, antagonist ANA-12, and inhibitor K252a did not affect RSL3-induced ferroptosis sensitivity in primary cortical neurons expressing detectable TrkB receptors. Several other modulators of the TrkB receptor, including agonist 7,8-DHF, activator phenelzine sulphate, and inhibitor GNF-5837, conferred protection against a range of ferroptosis inducers in several immortalised neuronal and non-neuronal cell lines, such as N27 and HT-1080 cells. We found these immortalised cell lines lack detectable TrkB receptor expression, so the anti-ferroptotic activity of these TrkB modulators was most likely due to their inherent radical-trapping antioxidant properties, which should be considered when interpreting their experimental findings. These modulators or their variants could be potential anti-ferroptotic therapeutics for various diseases.
Language	English
Publishing date	2022-12-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232416205
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Article: Integrin αvβ3 Is a Master Regulator of Resistance to TKI-Induced Ferroptosis in HER2-Positive Breast Cancer.

Nagpal, Aadya / Needham, Kristen / Lane, Darius J R / Ayton, Scott / Redvers, Richard P / John, Melissa / Selistre-de-Araujo, Heloisa S / Denoyer, Delphine / Pouliot, Normand

Cancers

2023 Volume 15, Issue 4

Abstract: Human epidermal growth factor receptor-2 (HER2)-targeting therapies provide clinical benefits for patients with HER2-positive breast cancer. However, the resistance to monotherapies invariably develops and leads to disease relapse and treatment failure. ... ...

Abstract	Human epidermal growth factor receptor-2 (HER2)-targeting therapies provide clinical benefits for patients with HER2-positive breast cancer. However, the resistance to monotherapies invariably develops and leads to disease relapse and treatment failure. Previous studies have demonstrated a link between the potency of HER2-targeting tyrosine kinase inhibitors (TKIs) and their ability to induce an iron-dependent form of cell death called ferroptosis. The aim of this study was to understand the mechanisms of resistance to TKI-induced ferroptosis and identify novel approaches to overcome treatment resistance. We used mouse and human HER2-positive models of acquired TKI resistance to demonstrate an intimate link between the resistance to TKIs and to ferroptosis and present the first evidence that the cell adhesion receptor αvβ3 integrin is a critical mediator of resistance to TKI-induced ferroptosis. Our findings indicate that αvβ3 integrin-mediated resistance is associated with the re-wiring of the iron/antioxidant metabolism and persistent activation of AKT signalling. Moreover, using gene manipulation approaches and pharmacological inhibitors, we show that this "αvβ3 integrin addiction" can be targeted to reverse TKI resistance. Collectively, these findings provide critical insights into new therapeutic strategies to improve the treatment of advanced HER2-positive breast cancer patients.
Language	English
Publishing date	2023-02-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15041216
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Article ; Online: Perturbed iron biology in the prefrontal cortex of people with schizophrenia.

Lotan, Amit / Luza, Sandra / Opazo, Carlos M / Ayton, Scott / Lane, Darius J R / Mancuso, Serafino / Pereira, Avril / Sundram, Suresh / Weickert, Cynthia Shannon / Bousman, Chad / Pantelis, Christos / Everall, Ian P / Bush, Ashley I

Molecular psychiatry

2023 Volume 28, Issue 5, Page(s) 2058–2070

Abstract: Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, ... ...

Abstract	Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.
MeSH term(s)	Young Adult ; Humans ; Adult ; Schizophrenia ; Iron ; Prefrontal Cortex ; Ferritins ; Biology
Chemical Substances	Iron (E1UOL152H7) ; Ferritins (9007-73-2)
Language	English
Publishing date	2023-02-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-023-01979-3
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Zs.A 4812: Show issues

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Article ; Online: Mega-dose sodium ascorbate: a pilot, single-dose, physiological effect, double-blind, randomized, controlled trial.

Yanase, Fumitaka / Spano, Sofia / Maeda, Akinori / Chaba, Anis / Naorungroj, Thummaporn / Ow, Connie Pei Chen / Lankadeva, Yugeesh R / May, Clive N / Betrie, Ashenafi H / Lane, Darius J R / Eastwood, Glenn M / Plummer, Mark P / Bellomo, Rinaldo

Critical care (London, England)

2023 Volume 27, Issue 1, Page(s) 371

Abstract: Background: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown.: Methods: We conducted a pilot, single-dose, double-blind, randomized ... ...

Abstract	Background: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown. Methods: We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score. Results: We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes. Conclusion: In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.
MeSH term(s)	Humans ; Shock, Septic/complications ; Ascorbic Acid/pharmacology ; Ascorbic Acid/therapeutic use ; Australia ; Sepsis/complications ; Double-Blind Method ; Vasoconstrictor Agents/therapeutic use
Chemical Substances	Ascorbic Acid (PQ6CK8PD0R) ; Vasoconstrictor Agents
Language	English
Publishing date	2023-10-12
Publishing country	England
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	2041406-7
ISSN	1466-609X ; 1364-8535
ISSN (online)	1466-609X
ISSN	1364-8535
DOI	10.1186/s13054-023-04644-x
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Article ; Online: A rapid and specific microplate assay for the determination of intra- and extracellular ascorbate in cultured cells.

Lane, Darius J R / Lawen, Alfons

Journal of visualized experiments : JoVE

2014 , Issue 86

Abstract: Vitamin C (ascorbate) plays numerous important roles in cellular metabolism, many of which have only come to light in recent years. For instance, within the brain, ascorbate acts in a neuroprotective and neuromodulatory manner that involves ascorbate ... ...

Abstract	Vitamin C (ascorbate) plays numerous important roles in cellular metabolism, many of which have only come to light in recent years. For instance, within the brain, ascorbate acts in a neuroprotective and neuromodulatory manner that involves ascorbate cycling between neurons and vicinal astrocytes--a relationship that appears to be crucial for brain ascorbate homeostasis. Additionally, emerging evidence strongly suggests that ascorbate has a greatly expanded role in regulating cellular and systemic iron metabolism than is classically recognized. The increasing recognition of the integral role of ascorbate in normal and deregulated cellular and organismal physiology demands a range of medium-throughput and high-sensitivity analytic techniques that can be executed without the need for highly expensive specialist equipment. Here we provide explicit instructions for a medium-throughput, specific and relatively inexpensive microplate assay for the determination of both intra- and extracellular ascorbate in cell culture.
MeSH term(s)	Ascorbic Acid/analysis ; Ascorbic Acid/metabolism ; Astrocytes/chemistry ; Astrocytes/cytology ; Astrocytes/metabolism ; Cell Culture Techniques/methods ; Colorimetry/instrumentation ; Colorimetry/methods ; Extracellular Fluid/chemistry ; Extracellular Fluid/metabolism ; Humans ; K562 Cells ; Sensitivity and Specificity
Chemical Substances	Ascorbic Acid (PQ6CK8PD0R)
Language	English
Publishing date	2014-04-11
Publishing country	United States
Document type	Journal Article ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/51322
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Article ; Online: Renal arterial infusion of tempol prevents medullary hypoperfusion, hypoxia, and acute kidney injury in ovine Gram-negative sepsis.

Betrie, Ashenafi H / Ma, Shuai / Ow, Connie P C / Peiris, Rachel M / Evans, Roger G / Ayton, Scott / Lane, Darius J R / Southon, Adam / Bailey, Simon R / Bellomo, Rinaldo / May, Clive N / Lankadeva, Yugeesh R

Acta physiologica (Oxford, England)

2023 Volume 239, Issue 1, Page(s) e14025

Abstract: Aim: Renal medullary hypoperfusion and hypoxia precede acute kidney injury (AKI) in ovine sepsis. Oxidative/nitrosative stress, inflammation, and impaired nitric oxide generation may contribute to such pathophysiology. We tested whether the antioxidant ... ...

Abstract	Aim: Renal medullary hypoperfusion and hypoxia precede acute kidney injury (AKI) in ovine sepsis. Oxidative/nitrosative stress, inflammation, and impaired nitric oxide generation may contribute to such pathophysiology. We tested whether the antioxidant and anti-inflammatory drug, tempol, may modify these responses. Methods: Following unilateral nephrectomy, we inserted renal arterial catheters and laser-Doppler/oxygen-sensing probes in the renal cortex and medulla. Noanesthetized sheep were administered intravenous (IV) Escherichia coli and, at sepsis onset, IV tempol (IVT; 30 mg kg Results: Septic sheep receiving vehicle developed renal medullary hypoperfusion (76 ± 16% decrease in perfusion), hypoxia (70 ± 13% decrease in oxygenation), and AKI (87 ± 8% decrease in creatinine clearance) with similar changes during IVT. However, RAT preserved medullary perfusion (1072 ± 307 to 1005 ± 271 units), oxygenation (46 ± 8 to 43 ± 6 mmHg), and creatinine clearance (61 ± 10 to 66 ± 20 mL min Conclusions: In ovine Gram-negative sepsis, renal arterial infusion of tempol prevented renal medullary hypoperfusion and hypoxia and AKI and decreased TNF-α expression and uncoupling of eNOS. However, it did not affect markers of oxidative/nitrosative stress, which were significantly decreased by Gram-negative sepsis.
MeSH term(s)	Animals ; Sheep ; Tumor Necrosis Factor-alpha ; Creatinine ; Renal Circulation/physiology ; Kidney/metabolism ; Acute Kidney Injury/metabolism ; Hypoxia/metabolism ; Sepsis/metabolism ; Escherichia coli
Chemical Substances	tempol (U78ZX2F65X) ; Tumor Necrosis Factor-alpha ; Creatinine (AYI8EX34EU)
Language	English
Publishing date	2023-08-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2218636-0
ISSN	1748-1716 ; 1748-1708
ISSN (online)	1748-1716
ISSN	1748-1708
DOI	10.1111/apha.14025
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