Antioxidants

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14 pages, 1272 KB

Open AccessArticle

Region-Dependent Responses to Oxygen–Glucose Deprivation and Melatonin in Neonatal Brain Organotypic Slices

by Gorane Beldarrain, Unai Montejo, Marc Chillida, Jon Ander Alart, Antonia Álvarez and Daniel Alonso-Alconada

Antioxidants 2026, 15(1), 13; https://doi.org/10.3390/antiox15010013 - 22 Dec 2025

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Abstract

Hypoxic–ischemic encephalopathy remains a major cause of neonatal mortality and long-term neurological disability. Therapeutic hypothermia is currently the only available treatment in hospitals, but its efficacy is limited, making the search for alternative neuroprotective strategies essential. Melatonin has shown promising results in other [...] Read more.

Hypoxic–ischemic encephalopathy remains a major cause of neonatal mortality and long-term neurological disability. Therapeutic hypothermia is currently the only available treatment in hospitals, but its efficacy is limited, making the search for alternative neuroprotective strategies essential. Melatonin has shown promising results in other models of hypoxia–ischemia, acting as a potent antioxidant and anti-inflammatory molecule. Here, we studied the effects of hypoxia–ischemia and melatonin treatment in two brain regions that are particularly vulnerable to hypoxic–ischemic injury. Neonatal rat organotypic slice cultures from the corticostriatal and hippocampal regions were subjected to oxygen–glucose deprivation and reperfusion (OGDR) and treated with melatonin (50 μM). Cell death (propidium iodide staining), redox state (GSH/GSSG ratio) and the inflammatory profile (Proteome Profiler) were analyzed. OGDR markedly increased cell death in both regions and melatonin treatment significantly reduced it. The GSH/GSSG ratio decreased only in the hippocampus after OGDR, but melatonin treatment elevated this ratio in both regions. In contrast, the inflammatory profile was more pronounced in the corticostriatal region, where the treatment strongly reduced proinflammatory mediators. These findings reveal region-specific mechanisms involved in the response to hypoxic–ischemic damage and support the potential of melatonin as a promising therapy for neonatal brain injury. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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27 pages, 4630 KB

Open AccessArticle

Caffeine Protects Against Hyperoxia-Induced Structural Lung Injury and Restores Alveolar Development in Neonatal Rats

by Stefanie Endesfelder and Christoph Bührer

Antioxidants 2025, 14(12), 1497; https://doi.org/10.3390/antiox14121497 - 12 Dec 2025

Viewed by 395

Abstract

In the developing lung, oxidative stress caused by relative hyperoxia constitutes a central pathogenic mechanism of neonatal lung injury resulting in bronchopulmonary dysplasia (BPD). The immature postnatal lung is highly susceptible to oxidative damage due to incomplete antioxidant defenses and ongoing alveolar and [...] Read more.

In the developing lung, oxidative stress caused by relative hyperoxia constitutes a central pathogenic mechanism of neonatal lung injury resulting in bronchopulmonary dysplasia (BPD). The immature postnatal lung is highly susceptible to oxidative damage due to incomplete antioxidant defenses and ongoing alveolar and vascular maturation. In a postnatal high-oxygen-induced rat model of BPD-associated lung injury, three or five days of exposure to 80% oxygen was found to disrupt developmental signaling pathways, downregulating genes essential for alveolarization and angiogenesis while inducing profibrotic mediators and collagen expression (Sirius Red staining). These changes resulted in simplified alveolar architecture, as quantified by toluidine blue staining and mean linear intercept analysis of normalized volumes of parenchyma, non-parenchyma, airspaces, septa, and edema. Acting as a multifunctional antioxidant with antifibrotic activity, caffeine mitigated structural lung damage and normalized the transcription of angiogenic and fibrotic genes. It counteracted TGF-β/CTGF-driven fibrogenic signaling and promoted recovery of normal lung morphology following hyperoxic injury. Under normoxic conditions, however, caffeine transiently upregulated profibrotic mediators. Overall, caffeine mitigates hyperoxia-induced lung injury and may actively promote physiological lung maturation, warranting future studies to define optimal dosing windows, clarify context-dependent fibrotic signaling, and translate gene-level effects into long-term clinical outcomes. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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16 pages, 2343 KB

Open AccessArticle

The Vasomotor Impact of Cu/ZnSODs Is Higher in Arterial Smooth Muscle of Early Postnatal Rats Compared to Adult Animals

by Anastasia A. Shvetsova, Valentina S. Shateeva, Dmitry S. Semenovich, Rudolf Schubert and Dina K. Gaynullina

Antioxidants 2025, 14(10), 1231; https://doi.org/10.3390/antiox14101231 - 14 Oct 2025

Viewed by 647

Abstract

The mechanisms of vascular tone regulation during early postnatal ontogenesis differ considerably from those in adulthood. We tested the hypothesis that the vasomotor influence of superoxide dismutases is higher in arteries of rats shortly after birth compared to adult animals. Saphenous arteries of [...] Read more.

The mechanisms of vascular tone regulation during early postnatal ontogenesis differ considerably from those in adulthood. We tested the hypothesis that the vasomotor influence of superoxide dismutases is higher in arteries of rats shortly after birth compared to adult animals. Saphenous arteries of 10 to 15 day (“young”) and 3 to 4 month (“adult”) old rats were studied using quantitative PCR, spectrophotometry, Western blotting, and isometric myography. Sod3 mRNA was most abundant in both adult and young saphenous arteries. Total SOD activity, Cu/ZnSODs activity, and SOD3 protein content were higher in young compared to adult arteries. H₂O₂ caused vessel contraction, while elimination of H₂O₂ weakened contractile responses of endothelium-denuded young arteries. The Cu/ZnSOD inhibitor DETC had no influence on contraction of adult arteries, but weakened contraction of endothelium-denuded, but not endothelium-intact arteries of young rats. The latter effect was observed in the presence of the NO-synthase inhibitor L-NNA, but not with the soluble guanylate cyclase inhibitor ODQ. DETC had no effect in the presence of sodium nitroprusside. Thus, Cu/ZnSODs promote contraction of saphenous arteries in the early postnatal period, but not in adult age. This influence of Cu/ZnSODs is counteracted by endothelial NO in early postnatal arteries. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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15 pages, 4308 KB

Open AccessArticle

Prenatal Melatonin Therapy Enhances Postnatal Lung Development in a Mouse Model of Inflammation-Induced Preterm Birth

by So Hee Park, Hee Young Cho, Jin Hyun Jun, Haengseok Song and Ji Yeon Lee

Antioxidants 2025, 14(9), 1094; https://doi.org/10.3390/antiox14091094 - 8 Sep 2025

Viewed by 1027

Abstract

Inflammation-induced preterm birth (PTB) significantly impacts neonatal development, particularly due to fetal lung immaturity. The lungs undergo critical development both in utero and postnatally, and PTB disrupts this process, leading to impaired pulmonary function. Current treatments for promoting lung maturation in preterm infants [...] Read more.

Inflammation-induced preterm birth (PTB) significantly impacts neonatal development, particularly due to fetal lung immaturity. The lungs undergo critical development both in utero and postnatally, and PTB disrupts this process, leading to impaired pulmonary function. Current treatments for promoting lung maturation in preterm infants have limited efficacy and safety. Melatonin, known for its potent antioxidant and anti-inflammatory properties, has shown promise in preventing PTB, but its effects on fetal and postnatal lung maturation remain unclear. This study evaluated the therapeutic efficacy of melatonin in a mouse model of intrauterine inflammation-induced PTB (IPTB). Pregnant mice (Pregnancy Day 17, [PD17]) were assigned to control, lipopolysaccharide (LPS), and LPS + melatonin groups. LPS (25 µg) was injected into the right uterine horn, with melatonin (10 mg/kg) administered intraperitoneally 30 min prior. Uterine tissues were collected at 6 and 24 h post-LPS administration for molecular and histological analyses. PTB occurred in seven out of eleven (63.6%) IPTB mice within 24 h of LPS injection, whereas melatonin significantly reduced this rate to 25% (2/8). In melatonin-treated mice, the downregulation of pro-inflammatory genes in uterine tissues, restoration of placental blood flow, increased lamellar body counts, and prevention of LPS-induced vacuolation in PD18 fetal lungs were observed. Furthermore, melatonin administration enhanced surfactant protein B expression and improved lung structure. In the offspring of IPTB mice that survived, melatonin further suppressed pro-inflammatory markers and promoted lung septal thickening at postnatal day 3. In conclusion, melatonin prevents PTB, mitigates inflammation, and supports fetal lung maturation in IPTB mice, highlighting its therapeutic potential for improving neonatal pulmonary outcomes. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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17 pages, 729 KB

Open AccessArticle

Composition and Antioxidant Status of Vegan Milk—Pilot Study

by Agnieszka Chrustek, Agnieszka Dombrowska-Pali and Dorota Olszewska-Słonina

Antioxidants 2025, 14(5), 505; https://doi.org/10.3390/antiox14050505 - 23 Apr 2025

Viewed by 1173

Abstract

Background: More and more women are following a vegan and vegetarian diet. For some, the use of a vegan diet during lactation is controversial. Purpose: The aim of the study was to comparatively analyze the concentration of selected hormones, micro- and macronutrients, vitamins, [...] Read more.

Background: More and more women are following a vegan and vegetarian diet. For some, the use of a vegan diet during lactation is controversial. Purpose: The aim of the study was to comparatively analyze the concentration of selected hormones, micro- and macronutrients, vitamins, and the basic composition and antioxidant status of the milk of vegan women, compared to the milk of omnivorous women. Methods: The study included 17 breastfeeding vegan women and 27 omnivorous women. The basic composition of human milk was analyzed using the MIRIS HMATM analyzer (Uppsala, Sweden) The levels of hormones and vitamins were determined by the enzyme-linked immunosorbent method. In order to determine the antioxidant activity and micro- and macroelements, spectrophotometric methods were used. Results: The vegan group was characterized by a lower average age, lower BMI, and lower WHR index compared to the control group. The milk of vegan women showed significantly higher cortisol concentrations and lower iron, vitamin B6, and antioxidant status than the milk of omnivorous women. Conclusions: A vegan diet helps maintain a healthy body weight and is more popular among younger women, under 30 years of age. Higher levels of milk cortisol in vegan women may indicate a high level of anxiety and stress experienced by breastfeeding women, which may have negative consequences not only for breastfeeding mothers but also for the development of their children. Lack of appropriate supplementation in women who do not consume meat and animal products may cause a deficiency of micro- and macroelements in breast milk. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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Review

Jump to: Research

15 pages, 426 KB

Open AccessReview

Oxidant Stress, Hyperoxia/Hypoxia and Neonatal Respiratory Disorders

by Ourania Kaltsogianni, Theodore Dassios and Anne Greenough

Antioxidants 2025, 14(12), 1389; https://doi.org/10.3390/antiox14121389 - 21 Nov 2025

Viewed by 795

Abstract

Neonates, especially those born prematurely, have low antioxidant capacity and are highly exposed to oxidant stress during the perinatal period. Oxidant stress damage has been associated with several diseases of prematurity, including respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and pulmonary hypertension. In [...] Read more.

Neonates, especially those born prematurely, have low antioxidant capacity and are highly exposed to oxidant stress during the perinatal period. Oxidant stress damage has been associated with several diseases of prematurity, including respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and pulmonary hypertension. In addition, preterm infants are frequently exposed to hypoxia or hyperoxia, which further increases oxidant stress and morbidity. This narrative review describes the relationship between oxidant stress, hyperoxia/hypoxia, and neonatal respiratory disorders. Preterm infants with respiratory distress syndrome and BPD have higher levels of oxidative stress biomarkers in plasma and in tracheal aspirates and reduced activity of antioxidant enzymes. Early, prolonged, and frequent intermittent hypoxaemic episodes are related to BPD development. Exposure to hyperoxia is linked to longer duration of respiratory support and higher BPD rates. Preclinical data showed that intermittent hypoxia and hyperoxia are associated with pulmonary hypertension (PH) and that hyperoxia can negatively affect the response to pulmonary vasodilators. Antioxidant treatments are not routinely implemented into clinical care due to their modest effect on clinical outcomes, associated complications, and limited clinical data. Optimisation of oxygen delivery and monitoring with closed-loop automated oxygen control systems could potentially reduce oxidant stress in the neonatal environment. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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34 pages, 2161 KB

Open AccessReview

Does the Maternal Gut Microbiome Influence the Outcome of Perinatal Asphyxia?

by Vlad-Petru Morozan, Mara I. Ionescu, Carmen M. D. Zahiu, Ana Maria Catrina, Andreea Racoviță, Ana-Teodora Chirilă, Ioana-Alexandra Dogaru, Cristian Ciotei, Gratiela Gradisteanu Pircalabioru and Ana-Maria Zăgrean

Antioxidants 2025, 14(9), 1134; https://doi.org/10.3390/antiox14091134 - 19 Sep 2025

Viewed by 3022

Abstract

This review explores the maternal gut microbiome’s role in shaping neonatal neurodevelopmental outcomes following perinatal asphyxia (PA), a leading cause of infant mortality and disability with limited therapeutic options beyond hypothermia. We synthesized current evidence on microbiome-mediated neuroprotective mechanisms against hypoxic-ischemic brain injury. [...] Read more.

This review explores the maternal gut microbiome’s role in shaping neonatal neurodevelopmental outcomes following perinatal asphyxia (PA), a leading cause of infant mortality and disability with limited therapeutic options beyond hypothermia. We synthesized current evidence on microbiome-mediated neuroprotective mechanisms against hypoxic-ischemic brain injury. The maternal microbiome influences fetal development through bioactive metabolites (short-chain fatty acids, indole derivatives) that cross the placental barrier, bacterial antigen regulation, and infant microbiome colonization. These pathways activate multiple protective mechanisms: anti-inflammatory signaling via NF-κB suppression and regulatory T cell expansion; antioxidant defenses through Nrf2 activation; neural repair via BDNF upregulation and neurogenesis; and oxytocin system modulation. Animal models demonstrate that maternal dysbiosis from high-fat diet or antibiotics exacerbates PA-induced brain damage, increasing inflammatory markers and hippocampal injury. Conversely, probiotic supplementation, dietary fiber, and specific interventions (omega-3, resveratrol) reduce neuroinflammation and oxidative injury. Human studies link maternal dysbiosis-associated conditions (obesity, gestational diabetes) with adverse pregnancy outcomes, though direct clinical evidence for PA severity remains limited. Understanding the maternal microbiome-fetal brain axis opens therapeutic avenues, including prenatal probiotics, dietary modifications, and targeted metabolite supplementation to prevent or mitigate PA-related neurological sequelae, potentially complementing existing neuroprotective strategies. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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12 pages, 422 KB

Open AccessReview

Inhaled and Systemic Steroids for Bronchopulmonary Dysplasia: Targeting Inflammation and Oxidative Stress

by Francesca Galletta, Alessandra Li Pomi, Sara Manti and Eloisa Gitto

Antioxidants 2025, 14(7), 869; https://doi.org/10.3390/antiox14070869 - 16 Jul 2025

Cited by 1 | Viewed by 2302

Abstract

Bronchopulmonary dysplasia (BPD) remains a significant complication of preterm birth, characterized by impaired alveolar and vascular development, chronic lung inflammation, and long-term respiratory morbidity. Corticosteroids, both systemic and inhaled, have been widely investigated as potential therapeutic agents due to their anti-inflammatory properties and [...] Read more.

Bronchopulmonary dysplasia (BPD) remains a significant complication of preterm birth, characterized by impaired alveolar and vascular development, chronic lung inflammation, and long-term respiratory morbidity. Corticosteroids, both systemic and inhaled, have been widely investigated as potential therapeutic agents due to their anti-inflammatory properties and their emerging role in modulating oxidative stress. This narrative review explores the current evidence regarding the use of inhaled and systemic corticosteroids in the prevention and management of BPD, analyzing their efficacy, safety profiles, and long-term outcomes. While systemic corticosteroids, particularly dexamethasone, have demonstrated benefits in reducing ventilator dependence and lung inflammation, concerns regarding adverse neurodevelopmental effects have limited their routine use. Inhaled steroids have been proposed as a safer alternative, but their role in altering the disease trajectory remains controversial. A better understanding of the optimal timing, dosage, and patient selection is essential to maximize benefits while minimizing risks. Future research should focus on optimizing dosing strategies and identifying subgroups of preterm infants who may derive the greatest benefit from corticosteroid therapy. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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26 pages, 1980 KB

Open AccessReview

The Destructive Cycle in Bronchopulmonary Dysplasia: The Rationale for Systems Pharmacology Therapeutics

by Mia Teng, Tzong-Jin Wu, Kirkwood A. Pritchard, Jr., Billy W. Day, Stephen Naylor and Ru-Jeng Teng

Antioxidants 2025, 14(7), 844; https://doi.org/10.3390/antiox14070844 - 10 Jul 2025

Cited by 1 | Viewed by 1487

Abstract

Bronchopulmonary dysplasia (BPD) remains a significant complication of premature birth and neonatal intensive care. While much is known about the drivers of lung injury, few studies have addressed the interrelationships between oxidative stress, inflammation, and downstream events, such as endoplasmic reticulum (ER) stress. [...] Read more.

Bronchopulmonary dysplasia (BPD) remains a significant complication of premature birth and neonatal intensive care. While much is known about the drivers of lung injury, few studies have addressed the interrelationships between oxidative stress, inflammation, and downstream events, such as endoplasmic reticulum (ER) stress. In this review, we explore the concept of a “destructive cycle” in which these drivers self-amplify to push the lung into a state of maladaptive repair. Animal models, primarily the hyperoxic rat pup model, support a sequential progression from the generation of reactive oxygen species (ROS) and inflammation to endoplasmic reticulum (ER) stress and mitochondrial injury. We highlight how these intersecting pathways offer not just therapeutic targets but also opportunities for interventions that reprogram system-wide responses. Accordingly, we explore the potential of systems pharmacology therapeutics (SPTs) to address the multifactorial nature of BPD. As a prototype SPT, we describe the development of N-acetyl-L-lysyl-L-tyrosyl-L-cysteine amide (KYC), a systems chemico-pharmacology drug (SCPD), which is selectively activated in inflamed tissues and modulates key nodal targets such as high-mobility group box-1 (HMGB1) and Kelch-like ECH-associated protein-1 (Keap1). Collectively, the data suggest that future therapies may require a coordinated, network-level approach to break the destructive cycle and enable proper regeneration rather than partial repair. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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16 pages, 990 KB

Open AccessReview

Impact of E-Cigarettes on Fetal and Neonatal Lung Development: The Influence of Oxidative Stress and Inflammation

by Antonella Gambadauro, Francesca Galletta, Beatrice Andrenacci, Simone Foti Randazzese, Maria Francesca Patria and Sara Manti

Antioxidants 2025, 14(3), 262; https://doi.org/10.3390/antiox14030262 - 25 Feb 2025

Cited by 7 | Viewed by 6410

Abstract

Electronic cigarettes (e-cigs) recently increased their popularity as “safer” alternatives to traditional tobacco smoking, including among pregnant women. However, the effect of e-cig exposure on fetal and neonatal developing lungs remains poorly investigated. In this review, we analysed the impact of e-cig aerosol [...] Read more.

Electronic cigarettes (e-cigs) recently increased their popularity as “safer” alternatives to traditional tobacco smoking, including among pregnant women. However, the effect of e-cig exposure on fetal and neonatal developing lungs remains poorly investigated. In this review, we analysed the impact of e-cig aerosol components (e.g., nicotine, solvents, and flavouring agents) on respiratory system development. We particularly emphasized the role of e-cig-related oxidative stress and inflammation on lung impairment. Nicotine contained in e-cigs can impair lung development at anatomical and molecular levels. Solvents and flavours induce inflammation and oxidative stress and contribute to compromising neonatal lung function. Studies suggest that prenatal e-cig aerosol exposure may increase the risk of future development of respiratory diseases in offspring, such as asthma and chronic obstructive pulmonary disease (COPD). Preventive strategies, such as smoking cessation programs and antioxidant supplementation, may be essential for safeguarding respiratory health. There is an urgent need to explore the safety profile and potential risks of e-cigs, especially considering the limited studies in humans. This review highlights the necessity of regulating e-cig use during pregnancy and promoting awareness of its potential consequences on fetal and neonatal development. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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18 pages, 2872 KB

Open AccessReview

Apnea of Prematurity and Oxidative Stress: Potential Implications

by Lauren Thompson, Joseph W. Werthammer and David Gozal

Antioxidants 2024, 13(11), 1304; https://doi.org/10.3390/antiox13111304 - 27 Oct 2024

Cited by 4 | Viewed by 7424

Abstract

Apnea of prematurity (AOP) occurs in 85% of neonates ≤34 weeks of gestational age. AOP is frequently associated with intermittent hypoxia (IH). This narrative review reports on the putative relationship of AOP with IH and the resulting oxidative stress (OS). Preterm infants are [...] Read more.

Apnea of prematurity (AOP) occurs in 85% of neonates ≤34 weeks of gestational age. AOP is frequently associated with intermittent hypoxia (IH). This narrative review reports on the putative relationship of AOP with IH and the resulting oxidative stress (OS). Preterm infants are susceptible to OS due to an imbalance between oxidant and antioxidant systems with the excessive free radical load leading to serious morbidities that may include retinopathy of prematurity, bronchopulmonary dysplasia, and neurodevelopmental delay. Current therapeutic approaches to minimize the adverse effects of AOP and optimize oxygen delivery include noninvasive ventilation and xanthine inhibitor therapy, but these approaches have only been partially successful in decreasing the incidence of AOP and associated morbidities. Full article

(This article belongs to the Special Issue Oxidative Stress in the Newborn)

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