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The Janus Face of Oxidative Stress in Normal and Pathological Conditions

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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: 30 June 2026 | Viewed by 13444

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Dr. Marco Fiore

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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
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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

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Keywords

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

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Published Papers (9 papers)

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Research

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17 pages, 3785 KB

Open AccessArticle

Peroxisome Proliferator-Activated Receptor Family of Lipid-Activated Nuclear Receptors Alpha Silencing Promotes Oxidative Stress and Hypertrophic Phenotype in Rat Cardiac Cells

by Marzia Bianchi, Nadia Panera, Sara Petrillo, Nicolò Cicolani, Cristiano De Stefanis, Marco Scarsella, Domenico Ciavardelli, Fiorella Piemonte, Anna Alisi and Anna Pastore

Antioxidants 2025, 14(9), 1059; https://doi.org/10.3390/antiox14091059 - 28 Aug 2025

Viewed by 144

Abstract

The peroxisome proliferator-activated receptor family of lipid-activated nuclear receptors (PPARs) plays a critical role in the regulation of cellular lipid metabolism. In cardiac muscle, PPARα is highly expressed and regulates genes involved in fatty acid oxidation, but its activity is downregulated in hypertrophic hearts; however, the consequences of chronic PPARα deficiency on the cardiac contractile apparatus remain unclear. This study aimed to investigate the PPARα role in hypertrophic phenotype and to evaluate the potential effects of the antioxidant Ebselen (Ebs) treatment on changes associated with PPARα depletion. We thus generated an in vitro model of cardiac hypertrophy by stable silencing of the PPARA gene in H9c2 rat cardiomyoblasts. We observed that PPARα silencing induces a hypertrophic phenotype, characterized by increased NPPB and decreased FBXO32 expression, mitochondrial dysregulation, impaired lipid metabolism, oxidative stress, and ferroptosis-related alterations. Epigenetically, H3K27ac levels increased while H3K27me3 decreased. Moreover, miR-34a, miR-132, and miR-331 were downregulated, implicating a miRNA-mediated mechanism in PPARα-linked cardiac hypertrophy. Treatment with Ebs, a redox-active compound with inhibitory effects on ferroptosis and epigenetics, reversed hypertrophic phenotype and restored miRNA levels. In conclusion, we found that PPARα depletion promotes oxidative stress and hypertrophic phenotype and that Ebs may act as a potential therapeutic agent. 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, 2702 KB

Open AccessArticle

Piperine Induces Apoptosis and Cell Cycle Arrest via Multiple Oxidative Stress Mechanisms and Regulation of PI3K/Akt and MAPK Signaling in Colorectal Cancer Cells

by Wan-Ling Chang, Jyun-Yu Peng, Chain-Lang Hong, Pei-Ching Li, Soi Moi Chye, Fung-Jou Lu, Huei-Yu Lin and Ching-Hsein Chen

Antioxidants 2025, 14(7), 892; https://doi.org/10.3390/antiox14070892 - 21 Jul 2025

Viewed by 760

Abstract

Piperine, a phytochemical alkaloid, exhibits notable anticancer properties in several cancer cell types. In this study, we investigated the mechanisms by which piperine induces cell death and apoptosis in colorectal cancer (CRC) cells, focusing on oxidative stress and key signaling pathways. Using MTT assay, flow cytometry, gene overexpression, and Western blot analysis, we observed that piperine significantly reduced cell viability, triggered G1 phase cell cycle arrest, and promoted apoptosis in DLD-1 cells. In addition, piperine effectively suppressed cell viability and induced apoptosis in other CRC cell lines, including SW480, HT-29, and Caco-2 cells. These effects were associated with increased intracellular reactive oxygen species (ROS) generation, mediated by the regulation of mitochondrial complex III, NADPH oxidase, and xanthine oxidase. Additionally, piperine modulated signaling pathways by inhibiting phosphoinositide 3-kinase (PI3K)/Akt, activating p38 and p-extracellular signal-regulated kinase (ERK). Pretreatment with antimycin A, apocynin, allopurinol, and PD98059, and the overexpression of p-Akt significantly recovered cell viability and reduced apoptosis, confirming the involvement of these pathways. This study is the first to demonstrate piperine induces apoptosis in CRC cells through a multifaceted oxidative stress mechanism and by critically modulating PI3K/Akt and ERK signaling pathways. 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, 6254 KB

Open AccessArticle

CircRNA_1156 Attenuates Neodymium Nitrate-Induced Hepatocyte Ferroptosis by Inhibiting the ACSL4/PKCβII Signaling Pathway

by Ning Wang, Jing Leng, Jing Xu, Kelei Qian, Zhiqing Zheng, Gonghua Tao, Ping Xiao and Xinyu Hong

Antioxidants 2025, 14(6), 700; https://doi.org/10.3390/antiox14060700 - 9 Jun 2025

Viewed by 2865

Abstract

Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has been implicated in the pathogenesis of liver diseases. This study investigates the role of circRNA_1156 in neodymium nitrate (Nd(NO₃)₃)-induced hepatocyte ferroptosis. Our in vitro experiments revealed that exposure to Nd(NO₃)₃ (1.2 µM) significantly reduced the viability of AML12 hepatocytes (p < 0.01), increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA) (p < 0.001), and depleted glutathione (GSH) (p < 0.001). However, overexpression of circRNA_1156 effectively reversed these effects and suppressed the expression of ACSL4 and PKCβII (p < 0.01). In our in vivo experiments, chronic exposure to Nd(NO₃)₃ (7–55 mg/kg for 180 days) induced hepatic iron deposition, mitochondrial damage, and activation of the ACSL4/PKCβII pathway (p < 0.01). These adverse effects were significantly ameliorated by circRNA_1156 overexpression (p < 0.05). Our findings identify circRNA_1156 as a novel inhibitor of Nd(NO₃)₃-induced ferroptosis via downregulation of the ACSL4/PKCβII pathway, providing valuable therapeutic insights for hepatotoxicity caused by rare earth element compounds. Full article

(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)

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16 pages, 1463 KB

Open AccessArticle

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

Cited by 1 | Viewed by 999

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 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 KB

Open AccessArticle

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

Cited by 1 | Viewed by 1794

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 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 KB

Open AccessArticle

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 1649

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 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 k_cat values for R1 and V2 were 34- and 57-fold higher, respectively, than that of the wildtype enzyme, whereas the mutant K_m values were increased approximately 3-fold. A 10-fold increased catalytic efficiency (k_cat/K_m) 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 k_cat. 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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18 pages, 1533 KB

Open AccessReview

The Dual Role of Nanomaterials in Ovarian Cancer and Female Fertility as Anti- and Prooxidants

by Massimo Aloisi, Gianna Rossi and Sandra Cecconi

Antioxidants 2025, 14(9), 1066; https://doi.org/10.3390/antiox14091066 - 29 Aug 2025

Viewed by 170

Abstract

Nanomaterials (NMs) are becoming increasingly important in biomedical applications, especially in reproductive biology and oncology. In this review, we examined the “double face” of NMs as prooxidants and antioxidants in relation to ovarian cancer and female fertility. NMs have been shown to reduce oxidative stress pathways in tumors, enhancing the effectiveness of chemotherapy and serving as carriers for drugs and compounds. They are also considered for their protective effects on female fertility by improving oocyte quality, maturation, and survival under various healthy and adverse conditions. However, certain NMs can induce oxidative stress, mitochondrial dysfunction, and ovarian tissue apoptosis when present in high concentrations or after prolonged exposure. These “double face” effects highlight the complex nature of NMs’ concentration, shape, and biocompatibility. Although NMs show promise in cancer treatment and fertility preservation, a comprehensive assessment of their prooxidant potential is necessary for successful clinical application. Full article

(This article belongs to the Special Issue The Janus Face of Oxidative Stress in Normal and Pathological Conditions)

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28 pages, 1589 KB

Open AccessReview

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

Cited by 1 | Viewed by 1229

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 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 KB

Open AccessReview

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

Cited by 3 | Viewed by 2785

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 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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