Iron Metabolism, Oxidative Stress and Cellular Dysfunction

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (20 March 2024) | Viewed by 6954

Special Issue Editors

Centre for Nutraceuticals, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK
Interests: cell biology; iron metabolism; mitochondrial dysfunction; metabolic dysregulation; oxidative stress; alcohol; liver disorders
Centre for Nutraceuticals, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK
Interests: iron metabolism; nutraceuticals; antioxidants; mitochondrial dysfunction; oxidative stress; obesity; satiety; type 2 diabetes; drug delivery; nanoformulations

Special Issue Information

Dear Colleagues,

In this Special Issue, we critically explore and discuss the importance of iron homeostasis and dysregulation.  Iron is an essential mineral fundamental to human life. Although appropriate iron levels are a prerequisite for most cellular and physiological functions, excess iron can be detrimental to the same processes. Excess unbound iron leads to the generation of highly reactive free radicals via Fenton and Haber Weiss chemistry that may promote oxidative stress and consequent cellular dysfunctions. Iron metabolism is therefore regulated by complex integrated homeostatic mechanisms, with any disruption to these fine-tuned processes leading to dysfunction and disease states. The detrimental role of excessive free-iron-mediated oxidative stress in the development of disease states such as type 2 diabetes and neurodegenerative disorders such as Parkinson’s disease has only recently been fully appreciated.  On the other hand, iron deficiency is a still a widespread global disorder, and the first line therapy employing ferrous iron supplementation frequently causes side effects associated with both free-iron-induced oxidative stress and microbiota imbalances.

Understanding the underlying mechanisms will be pivotal to ‘unfolding’ pathogenic pathways, potentially discovering new therapeutic targets and offering insights into novel biomarkers to detect the early onset of a multitude of disorders.

In this Special Issue, we invite researchers to provide original research articles, clinical reports, and review articles that relate to molecular mechanisms and therapeutics or diagnostic strategies focusing on iron metabolism, oxidative stress, and organelle and cellular dysfunction. We welcome studies involving cellular and animal models as well as human participants, and those exploring innovative supplementation or intervention approaches, such as antioxidant delivery systems and novel molecules.

We believe that this Special Issue will significantly enhance our current understanding of iron biology and its role in oxidative stress, cellular dysfunction, and progression to disease states.

Dr. Vinood B. Patel
Prof. Dr. Mohammed Gulrez Zariwala
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • iron
  • mitochondria
  • oxidative stress
  • inflammation
  • metabolism
  • free radicals

Published Papers (5 papers)

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Research

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18 pages, 1868 KiB  
Article
Antioxidant and Antidiabetic Properties of a Thinned-Nectarine-Based Nanoformulation in a Pancreatic β-Cell Line
by Elisabetta Schiano, Ettore Novellino, Marta María Gámez Fernández, Helena Tiekou Lorinczova, Gian Carlo Tenore, Fortuna Iannuzzo, Vinood B. Patel, Satyanarayana Somavarapu and Mohammed Gulrez Zariwala
Antioxidants 2024, 13(1), 63; https://doi.org/10.3390/antiox13010063 - 31 Dec 2023
Viewed by 917
Abstract
Pancreatic β-cells play a crucial role in maintaining glucose homeostasis, although they are susceptible to oxidative damage, which can ultimately impair their functionality. Thinned nectarines (TNs) have gained increasing interest due to their high polyphenol and abscisic acid (ABA) content, both of which [...] Read more.
Pancreatic β-cells play a crucial role in maintaining glucose homeostasis, although they are susceptible to oxidative damage, which can ultimately impair their functionality. Thinned nectarines (TNs) have gained increasing interest due to their high polyphenol and abscisic acid (ABA) content, both of which possess antidiabetic properties. Nevertheless, the efficacy of these bioactive compounds may be compromised by limited stability and bioavailability in vivo. This study aimed to develop nanoformulations (NFs) containing pure ABA or a TN extract (TNE) at an equivalent ABA concentration. Subsequently, the insulinotropic and antioxidant potential of the NFs and their unformulated (free) forms were compared in MIN-6 pancreatic cells exposed to varying glucose (5.5 mM and 20 mM) and iron (100 µM) concentrations. NF-TNE treatment exhibited enhanced antioxidant activity compared to free TNE, while ABA-based groups showed no significant antioxidant activity. Moreover, MIN6 cells incubated with both high glucose and iron levels demonstrated significantly higher insulin AUC levels after treatment with all samples, with NF-TNE displaying the most pronounced effect. In conclusion, these results highlight the additional beneficial potential of TNE due to the synergistic combination of bioactive compounds and demonstrate the significant advantage of using a nanoformulation approach to further increase the benefits of this and similar phytobioactive molecules. Full article
(This article belongs to the Special Issue Iron Metabolism, Oxidative Stress and Cellular Dysfunction)
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20 pages, 12103 KiB  
Article
Dysregulation of Ceramide Metabolism Is Linked to Iron Deposition and Activation of Related Pathways in the Aorta of Atherosclerotic Miniature Pigs
by Zhaowei Cai, Liqun Deng, Yingying Fan, Yujie Ren, Yun Ling, Jue Tu, Yueqin Cai, Xiaoping Xu and Minli Chen
Antioxidants 2024, 13(1), 4; https://doi.org/10.3390/antiox13010004 - 19 Dec 2023
Cited by 1 | Viewed by 847
Abstract
The miniature pig is a suitable animal model for investigating human cardiovascular diseases. Nevertheless, the alterations in lipid metabolism within atherosclerotic plaques of miniature pigs, along with the underlying mechanisms, remain to be comprehensively elucidated. In this study, we aim to examine the [...] Read more.
The miniature pig is a suitable animal model for investigating human cardiovascular diseases. Nevertheless, the alterations in lipid metabolism within atherosclerotic plaques of miniature pigs, along with the underlying mechanisms, remain to be comprehensively elucidated. In this study, we aim to examine the alterations in lipid composition and associated pathways in the abdominal aorta of atherosclerotic pigs induced by a high-fat, high-cholesterol, and high-fructose (HFCF) diet using lipidomics and RNA-Seq methods. The results showed that the content and composition of aortic lipid species, particularly ceramide, hexosyl ceramide, lysophosphatidylcholine, and triglyceride, were significantly altered in HFCF-fed pigs. Meanwhile, the genes governing sphingolipid metabolism, iron ion homeostasis, apoptosis, and the inflammatory response were significantly regulated by the HFCF diet. Furthermore, C16 ceramide could promote iron deposition in RAW264.7 cells, leading to increased intracellular reactive oxygen species (ROS) production, apoptosis, and activation of the toll-like receptor 4 (TLR4)/nuclear Factor-kappa B (NF-қB) inflammatory pathway, which could be mitigated by deferoxamine. Our study demonstrated that dysregulated ceramide metabolism could increase ROS production, apoptosis, and inflammatory pathway activation in macrophages by inducing iron overload, thus playing a vital role in the pathogenesis of atherosclerosis. This discovery could potentially provide a new target for pharmacological therapy of cardiovascular diseases such as atherosclerosis. Full article
(This article belongs to the Special Issue Iron Metabolism, Oxidative Stress and Cellular Dysfunction)
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18 pages, 5288 KiB  
Article
Interaction and Redox Chemistry between Iron, Dopamine, and Alpha-Synuclein C-Terminal Peptides
by Fabio Schifano, Simone Dell’Acqua, Stefania Nicolis, Luigi Casella and Enrico Monzani
Antioxidants 2023, 12(4), 791; https://doi.org/10.3390/antiox12040791 - 24 Mar 2023
Viewed by 1090
Abstract
α-Synuclein (αS), dopamine (DA), and iron have a crucial role in the etiology of Parkinson’s disease. The present study aims to investigate the interplay between these factors by analyzing the DA/iron interaction and how it is affected by the presence of the C-terminal [...] Read more.
α-Synuclein (αS), dopamine (DA), and iron have a crucial role in the etiology of Parkinson’s disease. The present study aims to investigate the interplay between these factors by analyzing the DA/iron interaction and how it is affected by the presence of the C-terminal fragment of αS (Ac-αS119–132) that represents the iron-binding domain. At high DA:Fe molar ratios, the formation of the [FeIII(DA)2] complex prevents the interaction with αS peptides, whereas, at lower DA:Fe molar ratios, the peptide is able to compete with one of the two coordinated DA molecules. This interaction is also confirmed by HPLC-MS analysis of the post-translational modifications of the peptide, where oxidized αS is observed through an inner-sphere mechanism. Moreover, the presence of phosphate groups in Ser129 (Ac-αSpS119–132) and both Ser129 and Tyr125 (Ac-αSpYpS119–132) increases the affinity for iron(III) and decreases the DA oxidation rate, suggesting that this post-translational modification may assume a crucial role for the αS aggregation process. Finally, αS interaction with cellular membranes is another key aspect for αS physiology. Our data show that the presence of a membrane-like environment induced an enhanced peptide effect over both the DA oxidation and the [FeIII(DA)2] complex formation and decomposition. Full article
(This article belongs to the Special Issue Iron Metabolism, Oxidative Stress and Cellular Dysfunction)
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19 pages, 3962 KiB  
Article
Curcumin and N-Acetylcysteine Nanocarriers Alone or Combined with Deferoxamine Target the Mitochondria and Protect against Neurotoxicity and Oxidative Stress in a Co-Culture Model of Parkinson’s Disease
by Leah Mursaleen, Stefanie Ho Yi Chan, Brendon Noble, Satyanarayana Somavarapu and Mohammed Gulrez Zariwala
Antioxidants 2023, 12(1), 130; https://doi.org/10.3390/antiox12010130 - 05 Jan 2023
Cited by 1 | Viewed by 2473
Abstract
As the blood-brain barrier (BBB) prevents most compounds from entering the brain, nanocarrier delivery systems are frequently being explored to potentially enhance the passage of drugs due to their nanometer sizes and functional characteristics. This study aims to investigate whether Pluronic® F68 [...] Read more.
As the blood-brain barrier (BBB) prevents most compounds from entering the brain, nanocarrier delivery systems are frequently being explored to potentially enhance the passage of drugs due to their nanometer sizes and functional characteristics. This study aims to investigate whether Pluronic® F68 (P68) and dequalinium (DQA) nanocarriers can improve the ability of curcumin, n-acetylcysteine (NAC) and/or deferoxamine (DFO), to access the brain, specifically target mitochondria and protect against rotenone by evaluating their effects in a combined Transwell® hCMEC/D3 BBB and SH-SY5Y based cellular Parkinson’s disease (PD) model. P68 + DQA nanoformulations enhanced the mean passage across the BBB model of curcumin, NAC and DFO by 49%, 28% and 49%, respectively (p < 0.01, n = 6). Live cell mitochondrial staining analysis showed consistent co-location of the nanocarriers within the mitochondria. P68 + DQA nanocarriers also increased the ability of curcumin and NAC, alone or combined with DFO, to protect against rotenone induced cytotoxicity and oxidative stress by up to 19% and 14% (p < 0.01, n = 6), as measured by the MTT and mitochondrial hydroxyl radical assays respectively. These results indicate that the P68 + DQA nanocarriers were successful at enhancing the protective effects of curcumin, NAC and/or DFO by increasing the brain penetrance and targeted delivery of the associated bioactives to the mitochondria in this model. This study thus emphasises the potential effectiveness of this nanocarrier strategy in fully utilising the therapeutic benefit of these antioxidants and lays the foundation for further studies in more advanced models of PD. Full article
(This article belongs to the Special Issue Iron Metabolism, Oxidative Stress and Cellular Dysfunction)
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Review

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12 pages, 549 KiB  
Review
Iron, Oxidative Stress, and Metabolic Dysfunction—Associated Steatotic Liver Disease
by Sophie Gensluckner, Bernhard Wernly, Christian Datz and Elmar Aigner
Antioxidants 2024, 13(2), 208; https://doi.org/10.3390/antiox13020208 - 07 Feb 2024
Viewed by 931
Abstract
Excess free iron is a substrate for the formation of reactive oxygen species (ROS), thereby augmenting oxidative stress. Oxidative stress is a well-established cause of organ damage in the liver, the main site of iron storage. Ferroptosis, an iron-dependent mechanism of regulated cell [...] Read more.
Excess free iron is a substrate for the formation of reactive oxygen species (ROS), thereby augmenting oxidative stress. Oxidative stress is a well-established cause of organ damage in the liver, the main site of iron storage. Ferroptosis, an iron-dependent mechanism of regulated cell death, has recently been gaining attention in the development of organ damage and the progression of liver disease. We therefore summarize the main mechanisms of iron metabolism, its close connection to oxidative stress and ferroptosis, and its particular relevance to disease mechanisms in metabolic-dysfunction-associated fatty liver disease and potential targets for therapy from a clinical perspective. Full article
(This article belongs to the Special Issue Iron Metabolism, Oxidative Stress and Cellular Dysfunction)
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