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Antioxidants
Special Issues
Redox Homeostasis and Diseases Related to Iron Metabolism
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Redox Homeostasis and Diseases Related to Iron Metabolism

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 (31 July 2022) | Viewed by 22841

Special Issue Editors

Dr. Sérgio Paulo Bydlowski

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Guest Editor
Lipids, Oxidation, and Cell Biology Group, Laboratory of Immunology (LIM19), Heart Institute (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
Interests: oxysterol; cell proliferation; cell death; lipid oxidation; antioxidants; cancer; atherosclerosis; stem cell biology; regenerative medicine
Special Issues, Collections and Topics in MDPI journals
Dr. José Carlos Toledo Junior

E-Mail Website
Guest Editor
Department of Chemistry, Faculty of Philosophy, Science and Letters of Ribeirão Preto (FFCLRP), University of São Paulo, Ribeirão Preto- SP, Brazil
Interests: labile iron pool, reactive species, nitric oxide, superoxide, peroxinitrite, redox signaling
Dr. Débora Levy

E-Mail Website
Guest Editor
Lipids, Oxidation, and Cell Biology Group, Laboratory of Immunology (LIM19), Heart Institute (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo/SP, Brazil
Interests: oxysterol; cell proliferation; cell death; lipid oxidation; antioxidants; cancer; stem cell biology; regenerative medicine

Special Issue Information

Dear Colleagues,

IRON: Iron is a redox active metal that is essential for life, carrying out distinct fundamental physiological functions at the cell and systemic levels. Dysregulation of the balance between iron influx and efflux can lead to iron accumulation or insufficiency. Lack of iron can have consequences for cell metabolism, including proliferation and viability. Iron excess and accumulation occurs under several circumstances, including release of iron contained in dying cells and dysregulation of iron homeostasis. Although iron is closely related to redox homeostasis, excess redox active ferrous iron can react with hydrogen peroxide to generate highly toxic hydroxyl or lipid radicals. Thus, iron levels need to be tightly regulated.

ROS: Higher life forms are dependent on molecular oxygen and iron for a variety of processes. Endogenous reactive oxygen species (ROS), such as peroxides, superoxide, hydroxyl radical, singlet oxygen and alpha-oxygen, are constantly produced in cell membranes, mitochondria, peroxisomes, and are, therefore, products of normal cell metabolism. Some of them may even be involved in the so-called redox homeostasis processes, which may include hormone synthesis, signaling pathways, cell proliferation and differentiation, and transcriptional regulation. However, cells are also stressed by ROS. The damaging effects of ROS excess can be neutralized by a large number of different enzymatic antioxidants such as superoxide dismutases, glutathione peroxidases, and peroxiredoxins. Therefore, healthy cells balance the formation and elimination of ROS, maintaining redox homeostasis.

OXIDATIVE STRESS: Several endogenous and exogenous factors (smoking, environmental pollution, heavy metals, among others) challenge the redox balance and hemostasis. Loss of physiological equilibrium between antioxidant and pro-oxidant stimuli is called oxidative stress, leading to increased generation of ROS and reactive nitrogen species (RNS). ROS-mediated oxidative damage includes lipid peroxidation, DNA modification, and the secretion of inflammatory cytokines. Oxidative stress plays a major role in both the physiology and pathophysiology of various diseases, such as atherosclerosis and cardiovascular diseases, neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Down syndrome, and Huntington disease), autoimmune and metabolic disorders (obesity and diabetes) but also inflammation, cancer, or even healthy aging.

CELL DEATH: Oxidative stress injuries can result in apoptotic, autophagic or necrosis types of cell death. In 2012, a novel form of iron-mediated lipid damage and cell death called ferroptosis was described. Ferroptosis is a regulated form of non-apoptotic cell death, which occurs when iron-mediated free radicals trigger lipid peroxidation in the absence of sufficient antioxidant defense. This results in the generation of increasing amounts of damaging lipid radicals.

We invite you to submit your original research articles or comprehensive reviews to this Special Issue, “Redox Homeostasis and Diseases related to Iron Metabolism”. This Special Issue will help to highlight the most recent advances on all aspects of iron metabolism and redox biology in physiological as well as pathological conditions, including mechanisms that regulate cellular iron uptake, intracellular storage and release, regulation and dysregulation of homeostasis, cellular mechanisms of ROS production, signaling pathways, cell death (including ferroptosis), and any aspect related to iron and ROS-mediated-diseases (inflammation, cancer, neurodegenerative diseases, metabolic disorders, autoimmunity).

We look forward to receiving your contributions.

Dr. Sérgio Paulo Bydlowski
Dr. José Carlos Toledo Junior
Dr. Débora Levy
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

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

  • oxidative stress
  • iron metabolism
  • antioxidant
  • redox homeostasis
  • ROS
  • ferroptosis
  • cell death

Published Papers (7 papers)

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Research

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18 pages, 4303 KiB  
Article
Ryanodine Receptor Mediated Calcium Release Contributes to Ferroptosis Induced in Primary Hippocampal Neurons by GPX4 Inhibition
by Silvia Gleitze, Omar A. Ramírez, Ignacio Vega-Vásquez, Jing Yan, Pedro Lobos, Hilmar Bading, Marco T. Núñez, Andrea Paula-Lima and Cecilia Hidalgo
Antioxidants 2023, 12(3), 705; https://doi.org/10.3390/antiox12030705 - 13 Mar 2023
Cited by 4 | Viewed by 2276
Abstract
Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. [...] Read more.
Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. Scant information is available on GPX4-induced ferroptosis in hippocampal neurons. Moreover, the role of calcium (Ca2+) signaling in ferroptosis remains elusive. Here, we report that RSL3, a selective inhibitor of GPX4, caused dendritic damage, lipid peroxidation, and induced cell death in rat primary hippocampal neurons. Previous incubation with the ferroptosis inhibitors deferoxamine or ferrostatin-1 reduced these effects. Likewise, preincubation with micromolar concentrations of ryanodine, which prevent Ca2+ release mediated by Ryanodine Receptor (RyR) channels, partially protected against RSL3-induced cell death. Incubation with RSL3 for 24 h suppressed the cytoplasmic Ca2+ concentration increase induced by the RyR agonist caffeine or by the SERCA inhibitor thapsigargin and reduced hippocampal RyR2 protein content. The present results add to the current understanding of ferroptosis-induced neuronal cell death in the hippocampus and provide new information both on the role of RyR-mediated Ca2+ signals on this process and on the effects of GPX4 inhibition on endoplasmic reticulum calcium content. Full article
(This article belongs to the Special Issue Redox Homeostasis and Diseases Related to Iron Metabolism)
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15 pages, 3117 KiB  
Article
GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis
by Wenchao Xu, Taotao Sun, Jiaxin Wang, Tao Wang, Shaogang Wang, Jihong Liu and Hao Li
Antioxidants 2022, 11(10), 1896; https://doi.org/10.3390/antiox11101896 - 25 Sep 2022
Cited by 10 | Viewed by 2887
Abstract
Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a [...] Read more.
Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 106 infectious units), and DMED + high-dose group (2 × 106 infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED. Full article
(This article belongs to the Special Issue Redox Homeostasis and Diseases Related to Iron Metabolism)
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17 pages, 5426 KiB  
Article
Targeting NRF2 Sensitizes Esophageal Adenocarcinoma Cells to Cisplatin through Induction of Ferroptosis and Apoptosis
by Farah Ballout, Heng Lu, Zheng Chen, Tianling Hu, Lei Chen, Mary Kay Washington, Wael El-Rifai and Dunfa Peng
Antioxidants 2022, 11(10), 1859; https://doi.org/10.3390/antiox11101859 - 21 Sep 2022
Cited by 10 | Viewed by 2484
Abstract
Esophageal adenocarcinoma (EAC), the predominant type of esophageal cancer in the United States, develops through Barrett’s esophagus (BE)-dysplasia-carcinoma cascade. Gastroesophageal reflux disease, where acidic bile salts refluxate into the esophagus, is the main risk factor for the development of BE and its progression [...] Read more.
Esophageal adenocarcinoma (EAC), the predominant type of esophageal cancer in the United States, develops through Barrett’s esophagus (BE)-dysplasia-carcinoma cascade. Gastroesophageal reflux disease, where acidic bile salts refluxate into the esophagus, is the main risk factor for the development of BE and its progression to EAC. The NFE2-related factor 2 (NRF2) is the master cellular antioxidant regulator. We detected high NRF2 protein levels in the EAC cell lines and primary tissues. Knockdown of NRF2 significantly enhanced acidic bile salt-induced oxidative stress, DNA damage, and inhibited EAC cell growth. Brusatol, an NRF2 inhibitor, significantly inhibited NRF2 transcriptional activity and downregulated the NRF2 target genes. We discovered that in addition to inducing apoptosis, Brusatol alone or in combination with cisplatin (CDDP) induced significant lipid peroxidation and ferroptosis, as evidenced by reduced xCT and GPX4 expression, two known ferroptosis markers. The combination of Brusatol and CDDP significantly inhibited EAC tumor xenograft growth in vivo and confirmed the in vitro data showing ferroptosis as an important mechanism in the tumors treated with Brusatol or Brusatol and CDDP combination. Our data support the role of NRF2 in protecting against stress-induced apoptosis and ferroptosis in EACs. Targeting NRF2 in combination with platinum therapy can be an effective strategy for eliminating cancer cells in EAC. Full article
(This article belongs to the Special Issue Redox Homeostasis and Diseases Related to Iron Metabolism)
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18 pages, 3775 KiB  
Article
Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models
by Giuseppe Carota, Alfio Distefano, Mariarita Spampinato, Cesarina Giallongo, Giuseppe Broggi, Lucia Longhitano, Giuseppe A. Palumbo, Rosalba Parenti, Rosario Caltabiano, Sebastiano Giallongo, Michelino Di Rosa, Riccardo Polosa, Vincenzo Bramanti, Nunzio Vicario, Giovanni Li Volti and Daniele Tibullo
Antioxidants 2022, 11(8), 1596; https://doi.org/10.3390/antiox11081596 - 18 Aug 2022
Cited by 10 | Viewed by 2706 | Correction
Abstract
Hemoglobin and iron overload is considered the major contributor to intracerebral hemorrhage (ICH)-induced brain injury. Accumulation of iron in the brain leads to microglia activation, inflammation and cell loss. Current available treatments for iron overload-mediated disorders are characterized by severe adverse effects, making [...] Read more.
Hemoglobin and iron overload is considered the major contributor to intracerebral hemorrhage (ICH)-induced brain injury. Accumulation of iron in the brain leads to microglia activation, inflammation and cell loss. Current available treatments for iron overload-mediated disorders are characterized by severe adverse effects, making such conditions an unmet clinical need. We assessed the potential of α-lipoic acid (ALA) as an iron chelator, antioxidant and anti-inflammatory agent in both in vitro and in vivo models of iron overload. ALA was found to revert iron-overload-induced toxicity in HMC3 microglia cell line, preventing cell apoptosis, reactive oxygen species generation and reducing glutathione depletion. Furthermore, ALA regulated gene expression of iron-related markers and inflammatory cytokines, such as IL-6, IL-1β and TNF. Iron toxicity also affects mitochondria fitness and biogenesis, impairments which were prevented by ALA pre-treatment in vitro. Immunocytochemistry assay showed that, although iron treatment caused inflammatory activation of microglia, ALA treatment resulted in increased ARG1 expression, suggesting it promoted an anti-inflammatory phenotype. We also assessed the effects of ALA in an in vivo zebrafish model of iron overload, showing that ALA treatment was able to reduce iron accumulation in the brain and reduced iron-mediated oxidative stress and inflammation. Our data support ALA as a novel approach for iron-overload-induced brain damage. Full article
(This article belongs to the Special Issue Redox Homeostasis and Diseases Related to Iron Metabolism)
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11 pages, 1802 KiB  
Article
Dietary Iron Restriction Improves Muscle Function, Dyslipidemia, and Decreased Muscle Oxidative Stress in Streptozotocin-Induced Diabetic Rats
by Manuel Alejandro Vargas-Vargas, Alfredo Saavedra-Molina, Mariana Gómez-Barroso, Donovan Peña-Montes, Christian Cortés-Rojo, Huerta Miguel, Xochitl Trujillo and Rocío Montoya-Pérez
Antioxidants 2022, 11(4), 731; https://doi.org/10.3390/antiox11040731 - 7 Apr 2022
Cited by 1 | Viewed by 1676
Abstract
Diabetes mellitus is a chronic degenerative disease characterized by hyperglycemia and oxidative stress. Iron catalyzes free radical overproduction. High iron concentrations have previously been reported to promote an increase in oxidative stress; however, the effect of iron restriction in diabetes has not yet [...] Read more.
Diabetes mellitus is a chronic degenerative disease characterized by hyperglycemia and oxidative stress. Iron catalyzes free radical overproduction. High iron concentrations have previously been reported to promote an increase in oxidative stress; however, the effect of iron restriction in diabetes has not yet been explored, so we tested to see if iron restriction in diabetic rats reduces oxidative damage and improved muscle function. Wistar rats were assigned to 4 groups: Control; Diabetic; Diabetic rats with a high iron diet, and Diabetic with dietary iron restriction. After 8 weeks the rats were sacrificed, the muscles were extracted to prepare homogenates, and serum was obtained for biochemical measurements. Low iron diabetic rats showed an increase in the development of muscle strength in both muscles. Dietary iron restriction decreased triglyceride concentrations compared to the untreated diabetic rats and the levels of extremely low-density lipoproteins. Aggravation of lipid peroxidation was observed in the diabetic group with a high iron diet, while these levels remained low with iron restriction. Iron restriction improved muscle strength development and reduced fatigue times; this was related to better lipid profile control and decreased oxidant stress markers. Full article
(This article belongs to the Special Issue Redox Homeostasis and Diseases Related to Iron Metabolism)
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Review

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25 pages, 1104 KiB  
Review
Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury
by Yihang Pan, Xueke Wang, Xiwang Liu, Lihua Shen, Qixing Chen and Qiang Shu
Antioxidants 2022, 11(11), 2196; https://doi.org/10.3390/antiox11112196 - 6 Nov 2022
Cited by 31 | Viewed by 5609
Abstract
Ischemia-reperfusion (I/R) injury is a major challenge in perioperative medicine that contributes to pathological damage in various conditions, including ischemic stroke, myocardial infarction, acute lung injury, liver transplantation, acute kidney injury and hemorrhagic shock. I/R damage is often irreversible, and current treatments for [...] Read more.
Ischemia-reperfusion (I/R) injury is a major challenge in perioperative medicine that contributes to pathological damage in various conditions, including ischemic stroke, myocardial infarction, acute lung injury, liver transplantation, acute kidney injury and hemorrhagic shock. I/R damage is often irreversible, and current treatments for I/R injury are limited. Ferroptosis, a type of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, has been implicated in multiple diseases, including I/R injury. Emerging evidence suggests that ferroptosis can serve as a therapeutic target to alleviate I/R injury, and pharmacological strategies targeting ferroptosis have been developed in I/R models. Here, we systematically summarize recent advances in research on ferroptosis in I/R injury and provide a comprehensive analysis of ferroptosis-regulated genes investigated in the context of I/R, as well as the therapeutic applications of ferroptosis regulators, to provide insights into developing therapeutic strategies for this devastating disease. Full article
(This article belongs to the Special Issue Redox Homeostasis and Diseases Related to Iron Metabolism)
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20 pages, 1523 KiB  
Review
Ferroptosis and Its Multifaceted Role in Cancer: Mechanisms and Therapeutic Approach
by Heshu Chen, Chenyu Wang, Zemin Liu, Xinmiao He, Wenjie Tang, Liuqin He, Yanzhong Feng, Di Liu, Yulong Yin and Tiejun Li
Antioxidants 2022, 11(8), 1504; https://doi.org/10.3390/antiox11081504 - 31 Jul 2022
Cited by 24 | Viewed by 4209
Abstract
Ferroptosis, a new type of non-apoptotic cell death modality, is different from other modes of cell death and has been primarily found in tumor cells. Previous studies have reported that ferroptosis can be triggered by specific modulators (e.g., drugs, nutrients, and iron chelators), [...] Read more.
Ferroptosis, a new type of non-apoptotic cell death modality, is different from other modes of cell death and has been primarily found in tumor cells. Previous studies have reported that ferroptosis can be triggered by specific modulators (e.g., drugs, nutrients, and iron chelators), leading to increased intracellular lipid reactive oxygen species (ROS) accumulation and iron overload. Recent reports have shown that ferroptosis at the cellular and organism levels can prevent an inflammatory storm and cancer development. Emerging evidence suggests potential mechanisms (e.g., system Xc-, glutathione peroxidase 4 (GPX4), lipid peroxidation, glutathione (GSH), and iron chelators) are involved in ferroptosis, which may mediate biological processes such as oxidative stress and iron overload to treat cancer. To date, there are at least three pathways that mediate ferroptosis in cancer cells: system Xc-/GSH/GPX4, FSP1/CoQ10/NAD(P)H, and ATG5/ATG7/NCOA4. Here, we summarize recent advances in the occurrence and development of ferroptosis in the context of cancer, the associations between ferroptosis and various modulators, and the potential mechanisms and therapeutic strategies targeting ferroptosis for the treatment of cancer. Full article
(This article belongs to the Special Issue Redox Homeostasis and Diseases Related to Iron Metabolism)
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