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Antioxidants
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The Janus Face of Oxidative Stress in Normal and Pathological...
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The Janus Face of Oxidative Stress in Normal and Pathological Conditions

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: 20 August 2025 | Viewed by 5421

Special Issue Editor

Dr. Marco Fiore

E-Mail Website
Guest Editor
Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, Rome, Italy
Interests: neurobiology; endocrinology; neurotrophins; oxidative stress; cancer; toxicology; addiction; antioxidants; polyphenols; alcohol use disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue entitled "The Janus Face of Oxidative Stress in Normal and Pathological Conditions" purposes to delve into the dualistic environment of oxidative stress, a phenomenon that plays a crucial role in both the conservation of cellular homeostasis and the evolution of various diseases. This collection of articles will discover the subtle balance between the beneficial and detrimental outcomes of reactive oxygen/nitrogen species (ROS/RNS), highlighting how these molecules, while indispensable for standard physiological functions such as signaling and immune response, can also drive pathological activities when their regulation is altered. By combining cutting-edge research and comprehensive reviews, this issue pursues to provide a greater understanding of the mechanisms underlying oxidative stress and disclose potential therapeutic approaches for moderating its harmful impacts in disorders such as cancer, addiction, immune-endocrine conditions, neurodegenerative diseases, and cardiovascular disorders. Through this double perspective, this Special Issue emphasizes the importance of context in oxidative stress research, highlighting that the same molecular events can lead to vastly different consequences depending on the cellular and systemic setting.

We welcome original research (clinical and preclinical data) and review articles relating to this hot topic.

Dr. Marco Fiore
Guest Editor

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

  • ethanol
  • toxicity
  • abuse
  • addiction
  • binge drinking
  • oxidative stress
  • psychoactive drug
  • cancer
  • recreational drug
  • FASD

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Published Papers (5 papers)

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Research

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16 pages, 1463 KiB  
Article
Trimethylamine N-Oxide (TMAO) Acts as Inhibitor of Endothelial Nitric Oxide Synthase (eNOS) and Hampers NO Production and Acetylcholine-Mediated Vasorelaxation in Rat Aortas
by Alma Martelli, Federico Abate, Michele Roggia, Giada Benedetti, Eugenio Caradonna, Vincenzo Calderone, Gian Carlo Tenore, Sandro Cosconati, Ettore Novellino and Mariano Stornaiuolo
Antioxidants 2025, 14(5), 517; https://doi.org/10.3390/antiox14050517 - 25 Apr 2025
Viewed by 270
Abstract
Trimethylamine N-oxide (TMAO) is an endogenous osmolyte produced by enzymatic reactions starting in the human gut, where microbiota release trimethylamine (TMA) from foods, and ending in the liver, where TMA is oxidized to TMAO by flavin-containing monooxygenase 3 (FMO3). While physiological concentrations of [...] Read more.
Trimethylamine N-oxide (TMAO) is an endogenous osmolyte produced by enzymatic reactions starting in the human gut, where microbiota release trimethylamine (TMA) from foods, and ending in the liver, where TMA is oxidized to TMAO by flavin-containing monooxygenase 3 (FMO3). While physiological concentrations of TMAO help proteins preserve their folding, high levels of this metabolite are harmful and promote oxidative stress, inflammation, and atherosclerosis. In humans, elevated levels of circulating TMAO predispose individuals to cardiovascular diseases and chronic kidney disease and increase mortality risk, especially in the elderly. How TMAO exerts its negative effects has been only partially elucidated. In hypertensive rats, the eNOS substrate L-arginine and Taurisolo®, a nutraceutical endowed with TMAO-reducing activity, act synergistically to reduce arterial blood pressure. Here, we investigate the molecular mechanisms underpinning this synergism and prove that TMAO, the target of Taurisolo®, acts as direct inhibitor of endothelial nitric oxide synthase (eNOS) and competes with L-arginine at its catalytic site, ultimately inhibiting NO production and acetylcholine (Ach)-induced relaxation in murine aortas. Full article
(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)
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21 pages, 4110 KiB  
Article
Succinate Regulates Endothelial Mitochondrial Function and Barrier Integrity
by Reham Atallah, Juergen Gindlhuber, Wolfgang Platzer, Rishi Rajesh and Akos Heinemann
Antioxidants 2024, 13(12), 1579; https://doi.org/10.3390/antiox13121579 - 21 Dec 2024
Viewed by 1309
Abstract
Endothelial dysfunction is a hallmark of several pathological conditions, including cancer, cardiovascular disease and inflammatory disorders. In these conditions, perturbed TCA cycle and subsequent succinate accumulation have been reported. The role of succinate as a regulator of immunological responses and inflammation is increasingly [...] Read more.
Endothelial dysfunction is a hallmark of several pathological conditions, including cancer, cardiovascular disease and inflammatory disorders. In these conditions, perturbed TCA cycle and subsequent succinate accumulation have been reported. The role of succinate as a regulator of immunological responses and inflammation is increasingly being recognized. Nevertheless, how endothelial cell function and phenotype are altered by elevated intracellular succinate has not been addressed yet. Thus, we employed numerous in vitro functional assays using primary HUVECs and diethyl succinate (DES), a cell membrane-permeable succinate analogue. An MTS assay 1 h post stimulation with DES suggested reduced metabolic activity in HUVECs. Concurrently, elevated production of ROS, including mitochondrial superoxide, and a reduction in mitochondrial membrane potential were observed. These findings were corroborated by Seahorse mito-stress testing, which revealed that DES acutely lowered the OCR, maximal respiration and ATP production. Given the link between mitochondrial stress and apoptosis, we examined important survival signalling pathways. DES transiently reduced ERK1/2 phosphorylation, a response that was followed by a skewed pro-apoptotic shift in the BAX to BCL2L1 gene expression ratio, which coincided with upregulating VEGF gene expression. This indicated an induction of mixed pro-apoptotic and pro-survival signals in the cell. However, the BAX/BCL-XL protein ratio was unchanged, suggesting that the cells did not commit themselves to apoptosis. An MTS assay, caspase 3/7 activity assay and annexin V/propidium iodide staining confirmed this finding. By contrast, stimulation with DES induced acute endothelial barrier permeability, forming intercellular gaps, altering cell size and associated actin filaments without affecting cell count. Notably, during overnight DES exposure gradual recovery of the endothelial barrier and cell sprouting was observed, alongside mitochondrial membrane potential restoration, albeit with sustained ROS production. COX-2 inhibition and EP4 receptor blockade hindered barrier restoration, implicating a role of COX-2/PGE2/EP4 signalling in this process. Interestingly, ascorbic acid pre-treatment prevented DES-induced acute barrier disruption independently from ROS modulation. In conclusion, succinate acts as a significant regulator of endothelial mitochondrial function and barrier integrity, a response that is counterbalanced by upregulated VEGF and prostaglandin production by the endothelial cells. Full article
(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)
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18 pages, 2401 KiB  
Article
Mutations Selectively Evolving Peroxidase Activity Among Alternative Catalytic Functions of Human Glutathione Transferase P1-1
by Aram Ismail and Bengt Mannervik
Antioxidants 2024, 13(11), 1347; https://doi.org/10.3390/antiox13111347 - 2 Nov 2024
Viewed by 1258
Abstract
Glutathione transferases are detoxication enzymes with broad catalytic diversity, and small alterations to the protein’s primary structure can have considerable effects on the enzyme’s substrate selectivity profile. We demonstrate that two point mutations in glutathione transferase P1-1 suffice to generate 20-fold enhanced non-selenium-dependent [...] Read more.
Glutathione transferases are detoxication enzymes with broad catalytic diversity, and small alterations to the protein’s primary structure can have considerable effects on the enzyme’s substrate selectivity profile. We demonstrate that two point mutations in glutathione transferase P1-1 suffice to generate 20-fold enhanced non-selenium-dependent peroxidase activity indicating a facile evolutionary trajectory. Designed mutant libraries of the enzyme were screened for catalytic activities with alternative substrates representing four divergent chemistries. The chemical reactions comprised aromatic substitution, Michael addition, thiocarbamoylation, and hydroperoxide reduction. Two mutants, R1 (Y109H) and an R1-based mutant V2 (Q40M-E41Q-A46S-Y109H-V200L), were discovered with 16.3- and 30-foldincreased peroxidase activity with cumene hydroperoxide (CuOOH) compared to the wildtype enzyme, respectively. The basis of the improved peroxidase activity of the mutant V2 was elucidated by constructing double-point mutants. The mutants V501 (Q40M-Y109H) and V503 (E41Q-Y109H) were found to have 20- and 21-fold improvements in peroxidase activity relative to the wildtype enzyme, respectively. The steady-state kinetic profiles of mutants R1 and V2 in the reduction of CuOOH were compared to the wildtype parameters. The kcat values for R1 and V2 were 34- and 57-fold higher, respectively, than that of the wildtype enzyme, whereas the mutant Km values were increased approximately 3-fold. A 10-fold increased catalytic efficiency (kcat/Km) in CuOOH reduction is accomplished by the Tyr109His point mutation in R1. The 23-fold increase of the efficiency obtained in V2 was caused by adding further mutations primarily enhancing kcat. In all mutants with elevated peroxidase activity, His109 played a pivotal role. Full article
(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)
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Review

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28 pages, 1589 KiB  
Review
The Janus Face of Oxidative Stress and Hydrogen Sulfide: Insights into Neurodegenerative Disease Pathogenesis
by Constantin Munteanu, Anca Irina Galaction, Gelu Onose, Marius Turnea and Mariana Rotariu
Antioxidants 2025, 14(3), 360; https://doi.org/10.3390/antiox14030360 - 19 Mar 2025
Viewed by 646
Abstract
Oxidative stress plays an essential role in neurodegenerative pathophysiology, acting as both a critical signaling mediator and a driver of neuronal damage. Hydrogen sulfide (H2S), a versatile gasotransmitter, exhibits a similarly “Janus-faced” nature, acting as a potent antioxidant and cytoprotective molecule [...] Read more.
Oxidative stress plays an essential role in neurodegenerative pathophysiology, acting as both a critical signaling mediator and a driver of neuronal damage. Hydrogen sulfide (H2S), a versatile gasotransmitter, exhibits a similarly “Janus-faced” nature, acting as a potent antioxidant and cytoprotective molecule at physiological concentrations, but becoming detrimental when dysregulated. This review explores the dual roles of oxidative stress and H2S in normal cellular physiology and pathophysiology, focusing on neurodegenerative disease progression. We highlight potential therapeutic opportunities for targeting redox and sulfur-based signaling systems in neurodegenerative diseases by elucidating the intricate balance between these opposing forces. Full article
(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)
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41 pages, 3706 KiB  
Review
The Dual Role of Oxidative Stress in Atherosclerosis and Coronary Artery Disease: Pathological Mechanisms and Diagnostic Potential
by Marcin Myszko, Jerzy Bychowski, Elżbieta Skrzydlewska and Wojciech Łuczaj
Antioxidants 2025, 14(3), 275; https://doi.org/10.3390/antiox14030275 - 26 Feb 2025
Viewed by 1116
Abstract
Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and coronary artery disease (CAD), with both beneficial and detrimental effects on cardiovascular health. On one hand, the excessive production of reactive oxygen species (ROS) contributes to endothelial dysfunction, inflammation, and vascular [...] Read more.
Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and coronary artery disease (CAD), with both beneficial and detrimental effects on cardiovascular health. On one hand, the excessive production of reactive oxygen species (ROS) contributes to endothelial dysfunction, inflammation, and vascular remodeling, which are central to the development and progression of CAD. These pathological effects drive key processes such as atherosclerosis, plaque formation, and thrombosis. On the other hand, moderate levels of oxidative stress can have beneficial effects on cardiovascular health. These include regulating vascular tone by promoting blood vessel dilation, supporting endothelial function through nitric oxide production, and enhancing the immune response to prevent infections. Additionally, oxidative stress can stimulate cellular adaptation to stress, promote cell survival, and encourage angiogenesis, which helps form new blood vessels to improve blood flow. Oxidative stress also holds promise as a source of biomarkers that could aid in the diagnosis, prognosis, and monitoring of CAD. Specific oxidative markers, such as malondialdehyde (MDA), isoprostanes (isoP), ischemia-modified albumin, and antioxidant enzyme activity, have been identified as potential indicators of disease severity and therapeutic response. This review explores the dual nature of oxidative stress in atherosclerosis and CAD, examining its mechanisms in disease pathogenesis as well as its emerging role in clinical diagnostics and targeted therapies. The future directions for research aimed at harnessing the diagnostic and therapeutic potential of oxidative stress biomarkers are also discussed. Understanding the balance between the detrimental and beneficial effects of oxidative stress could lead to innovative approaches in the prevention and management of CAD. Full article
(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)
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