Metabolomics, Oxidative, and Nitrosative Stress in the Perinatal Period

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 (30 April 2022) | Viewed by 24337

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Special Issue Editors

Neonatal Research Group, Health Research Institute La Fe, 46026 Valencia, Spain
Interests: metabolomics; biomarkers; liquid chromatography–mass spectrometry (LC–MS); vibrational spectroscopy; newborn
Special Issues, Collections and Topics in MDPI journals
Division of Neonatology, University and Polytechnic Hospital La Fe, Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain
Interests: oxygen; oxidative stress; nitrosative stress; biomarkers; redox biology; perinatal medicine

Special Issue Information

Dear Colleagues,

The perinatal period is extremely sensitive to external stimuli, and events that may disturb the equilibrium within the mother–infant dyad might have a substantial short- and long-term impact on the infant’s health and development. Namely, oxidative stress has been shown to be of key importance in the pathophysiology of several diseases coined by Professor OD Saugstad as the “Oxygen radical diseases of Neonatology” (1), affecting term as well as preterm infants. In recent years, and with the advent of powerful high resolution and high throughput analytical methods, researchers have started to successfully develop and implement novel approaches in this context. New insights gained in such studies have great potential to be translated into novel diagnostic approaches, as well as the development of alternative preventive and treatment strategies. In view of this, research focusing on the study of the physiology of the newborn as well as the assessment of diseases occurring in the perinatal period are in the spotlight of this Special Issue with the aim of providing a forum for this specific field of application. Specifically, this Special Issue encourages submissions focused on clinical studies, animal and in vitro models involving the use of metabolomic,s and the assessment of oxidative and nitrosative stress in situations of health and disease of the newborn. In addition, submission related to the development of customized analysis approaches addressing the particular challenges of studying the newborn, e.g., limited number of accessible samples, are also welcome.

(1) Saugstad OD. Oxygen radical disease in neonatology. Semin Neonatol. 1998; 3:229.238.

Dr. Julia Kuligowski
Prof. Dr. Máximo Vento
Guest Editors

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Keywords

  • Metabolomic analysis of newborn biospecimens
  • Biomarkers of oxidative and nitrosative stress
  • Monitoring of changes in the perinatal period
  • Study of diseases of the newborn

Published Papers (10 papers)

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Editorial

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3 pages, 202 KiB  
Editorial
Metabolomics, Oxidative, and Nitrosative Stress in the Perinatal Period
by Julia Kuligowski and Máximo Vento
Antioxidants 2022, 11(7), 1357; https://doi.org/10.3390/antiox11071357 - 12 Jul 2022
Viewed by 1085
Abstract
The perinatal period is extremely sensitive to external stimuli, and events that may disturb the equilibrium within the mother–infant dyad might have a substantial short- and long-term impact on the infant’s health and development [...] Full article

Research

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13 pages, 3045 KiB  
Article
The Mechanism of the Neuroprotective Effect of Kynurenic Acid in the Experimental Model of Neonatal Hypoxia–Ischemia: The Link to Oxidative Stress
by Ewelina Bratek-Gerej, Apolonia Ziembowicz, Jakub Godlewski and Elzbieta Salinska
Antioxidants 2021, 10(11), 1775; https://doi.org/10.3390/antiox10111775 - 05 Nov 2021
Cited by 5 | Viewed by 1437
Abstract
The over-activation of NMDA receptors and oxidative stress are important components of neonatal hypoxia–ischemia (HI). Kynurenic acid (KYNA) acts as an NMDA receptor antagonist and is known as a reactive oxygen species (ROS) scavenger, which makes it a potential therapeutic compound. This study [...] Read more.
The over-activation of NMDA receptors and oxidative stress are important components of neonatal hypoxia–ischemia (HI). Kynurenic acid (KYNA) acts as an NMDA receptor antagonist and is known as a reactive oxygen species (ROS) scavenger, which makes it a potential therapeutic compound. This study aimed to establish the neuroprotective and antioxidant potential of KYNA in an experimental model of HI. HI on seven-day-old rats was used as an experimental model. The animals were injected i.p. with different doses of KYNA 1 h or 6 h after HI. The neuroprotective effect of KYNA was determined by the measurement of brain damage and elements of oxidative stress (ROS and glutathione (GSH) level, SOD, GPx, and catalase activity). KYNA applied 1 h after HI significantly reduced weight loss of the ischemic hemisphere, and prevented neuronal loss in the hippocampus and cortex. KYNA significantly reduced HI-increased ROS, GSH level, and antioxidant enzyme activity. Only the highest used concentration of KYNA showed neuroprotection when applied 6 h after HI. The presented results indicate induction of neuroprotection at the ROS formation stage. However, based on the presented data, it is not possible to pinpoint whether NMDA receptor inhibition or the scavenging abilities are the dominant KYNA-mediated neuroprotective mechanisms. Full article
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11 pages, 1653 KiB  
Article
Effects of Hypothermia and Allopurinol on Oxidative Status in a Rat Model of Hypoxic Ischemic Encephalopathy
by Cristina Durán Fernández-Feijóo, Javier Rodríguez-Fanjul, Miriam Lopez-Abat, Stephanie Hadley, Mónica Cavia-Saiz, Pilar Muñiz, Juan Arnaez, José Ramón Fernández-Lorenzo and Marta Camprubí Camprubí
Antioxidants 2021, 10(10), 1523; https://doi.org/10.3390/antiox10101523 - 25 Sep 2021
Cited by 4 | Viewed by 1967
Abstract
Hypoxic ischemic encephalopathy (HIE) is one of the main causes of morbidity and mortality during the neonatal period, despite treatment with hypothermia. There is evidence that oxidative damage plays an important role in the pathophysiology of hypoxic-ischemic (HI) brain injury. Our aim was [...] Read more.
Hypoxic ischemic encephalopathy (HIE) is one of the main causes of morbidity and mortality during the neonatal period, despite treatment with hypothermia. There is evidence that oxidative damage plays an important role in the pathophysiology of hypoxic-ischemic (HI) brain injury. Our aim was to investigate whether postnatal allopurinol administration in combination with hypothermia would reduce oxidative stress (OS) biomarkers in an animal model of HIE. Postnatal 10-day rat pups underwent unilateral HI of moderate severity. Pups were randomized into: Sham operated, hypoxic-ischemic (HI), HI + allopurinol (HIA), HI + hypothermia (HIH), and HI + hypothermia + allopurinol (HIHA). Biomarkers of OS and antioxidants were evaluated: GSH/GSSG ratio and carbonyl groups were tested in plasma. Total antioxidant capacity (TAC) was analyzed in plasma and cerebrospinal fluid, and 8-iso-prostaglandin F2α was measured in brain tissue. Plasma 2,2′–azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS) levels were preserved in those groups that received allopurinol and dual therapy. In cerebrospinal fluid, only the HIA group presented normal ferric reducing ability of plasma (FRAP) levels. Protein oxidation and lipid peroxidation were significantly reduced in all groups treated with hypothermia and allopurinol, thus enhancing neuroprotection in HIE. Full article
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14 pages, 1718 KiB  
Article
A Reductive Metabolic Switch Protects Infants with Transposition of Great Arteries Undergoing Atrial Septostomy against Oxidative Stress
by José David Piñeiro-Ramos, Otto Rahkonen, Virpi Korpioja, Guillermo Quintás, Jaana Pihkala, Olli Pitkänen-Argillander, Paula Rautiainen, Sture Andersson, Julia Kuligowski and Máximo Vento
Antioxidants 2021, 10(10), 1502; https://doi.org/10.3390/antiox10101502 - 22 Sep 2021
Cited by 2 | Viewed by 1949
Abstract
Transposition of the great arteries (TGA) is one of the most common cyanotic congenital heart diseases requiring neonatal surgical intervention. Parallel circulations that result in impaired cerebral oxygen delivery already in utero may lead to brain damage and long-term neurodevelopmental delay. Balloon atrial [...] Read more.
Transposition of the great arteries (TGA) is one of the most common cyanotic congenital heart diseases requiring neonatal surgical intervention. Parallel circulations that result in impaired cerebral oxygen delivery already in utero may lead to brain damage and long-term neurodevelopmental delay. Balloon atrial septostomy (BAS) is often employed to mix deoxygenated and oxygenated blood at the atrial level. However, BAS causes a sudden increase in arterial blood oxygenation and oxidative stress. We studied changes in oxygen saturation as well as metabolic profiles of plasma samples from nine newborn infants suffering from TGA before and until 48 h after undergoing BAS. The plasma metabolome clearly changed over time and alterations of four metabolic pathways, including the pentose phosphate pathway, were linked to changes in the cerebral tissue oxygen extraction. In contrast, no changes in levels of lipid peroxidation biomarkers over time were observed. These observations suggest that metabolic adaptations buffer the free radical burst triggered by re-oxygenation, thereby avoiding structural damage at the macromolecular level. This study enhances our understanding of the complex response of infants with TGA to changes in oxygenation induced by BAS. Full article
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21 pages, 2182 KiB  
Article
NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes
by Dorothea D Jenkins, Hunter G Moss, Truman R Brown, Milad Yazdani, Sudhin Thayyil, Paolo Montaldo, Maximo Vento, Julia Kuligowski, Carol Wagner, Bruce W Hollis and Donald B Wiest
Antioxidants 2021, 10(9), 1344; https://doi.org/10.3390/antiox10091344 - 25 Aug 2021
Cited by 5 | Viewed by 3632
Abstract
N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) [...] Read more.
N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years. Full article
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17 pages, 3449 KiB  
Article
NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats
by Lauren E. Adams, Hunter G. Moss, Danielle W. Lowe, Truman Brown, Donald B. Wiest, Bruce W. Hollis, Inderjit Singh and Dorothea D. Jenkins
Antioxidants 2021, 10(3), 489; https://doi.org/10.3390/antiox10030489 - 20 Mar 2021
Cited by 6 | Viewed by 2746
Abstract
Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately [...] Read more.
Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O2), followed by hypothermia alone or with N-acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)2D3, 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection. Full article
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Review

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13 pages, 319 KiB  
Review
Supplemental Oxygen in the Newborn: Historical Perspective and Current Trends
by Maxwell Mathias, Jill Chang, Marta Perez and Ola Saugstad
Antioxidants 2021, 10(12), 1879; https://doi.org/10.3390/antiox10121879 - 25 Nov 2021
Cited by 16 | Viewed by 2829
Abstract
Oxygen is the final electron acceptor in aerobic respiration, and a lack of oxygen can result in bioenergetic failure and cell death. Thus, administration of supplemental concentrations of oxygen to overcome barriers to tissue oxygen delivery (e.g., heart failure, lung disease, ischemia), can [...] Read more.
Oxygen is the final electron acceptor in aerobic respiration, and a lack of oxygen can result in bioenergetic failure and cell death. Thus, administration of supplemental concentrations of oxygen to overcome barriers to tissue oxygen delivery (e.g., heart failure, lung disease, ischemia), can rescue dying cells where cellular oxygen content is low. However, the balance of oxygen delivery and oxygen consumption relies on tightly controlled oxygen gradients and compartmentalized redox potential. While therapeutic oxygen delivery can be life-saving, it can disrupt growth and development, impair bioenergetic function, and induce inflammation. Newborns, and premature newborns especially, have features that confer particular susceptibility to hyperoxic injury due to oxidative stress. In this review, we will describe the unique features of newborn redox physiology and antioxidant defenses, the history of therapeutic oxygen use in this population and its role in disease, and clinical trends in the use of therapeutic oxygen and mitigation of neonatal oxidative injury. Full article
11 pages, 500 KiB  
Review
Metabolomics to Diagnose Oxidative Stress in Perinatal Asphyxia: Towards a Non-Invasive Approach
by Anne Lee Solevåg, Svetlana N. Zykova, Per Medbøe Thorsby and Georg M. Schmölzer
Antioxidants 2021, 10(11), 1753; https://doi.org/10.3390/antiox10111753 - 02 Nov 2021
Cited by 4 | Viewed by 1943
Abstract
There is a need for feasible and non-invasive diagnostics in perinatal asphyxia. Metabolomics is the study of small molecular weight products of cellular metabolism that may, directly and indirectly, reflect the level of oxidative stress. Saliva analysis is a novel approach that has [...] Read more.
There is a need for feasible and non-invasive diagnostics in perinatal asphyxia. Metabolomics is the study of small molecular weight products of cellular metabolism that may, directly and indirectly, reflect the level of oxidative stress. Saliva analysis is a novel approach that has a yet unexplored potential in metabolomics in perinatal asphyxia. The aim of this review was to give an overview of metabolomics studies of oxidative stress in perinatal asphyxia, particularly searching for studies analyzing non-invasively collected biofluids including saliva. We searched the databases PubMed/Medline and included 11 original human and 4 animal studies. In perinatal asphyxia, whole blood, plasma, and urine are the most frequently used biofluids used for metabolomics analyses. Although changes in oxidative stress-related salivary metabolites have been reported in adults, the utility of this approach in perinatal asphyxia has not yet been explored. Human and animal studies indicate that, in addition to antioxidant enzymes, succinate and hypoxanthine, as well acylcarnitines may have discriminatory diagnostic and prognostic properties in perinatal asphyxia. Researchers may utilize the accumulating evidence of discriminatory metabolic patterns in perinatal asphyxia to develop bedside methods to measure oxidative stress metabolites in perinatal asphyxia. Although only supported by indirect evidence, saliva might be a candidate biofluid for such point-of-care diagnostics. Full article
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13 pages, 745 KiB  
Review
The Effect of Pasteurization on the Antioxidant Properties of Human Milk: A Literature Review
by Hannah G. Juncker, Eliza J. M. Ruhé, George L. Burchell, Chris H. P. van den Akker, Aniko Korosi, Johannes B. van Goudoever and Britt J. van Keulen
Antioxidants 2021, 10(11), 1737; https://doi.org/10.3390/antiox10111737 - 29 Oct 2021
Cited by 7 | Viewed by 2401
Abstract
High rates of oxidative stress are common in preterm born infants and have short- and long-term consequences. The antioxidant properties of human milk limits the consequences of excessive oxidative damage. However, as the mother’s own milk it is not always available, donor milk [...] Read more.
High rates of oxidative stress are common in preterm born infants and have short- and long-term consequences. The antioxidant properties of human milk limits the consequences of excessive oxidative damage. However, as the mother’s own milk it is not always available, donor milk may be provided as the best alternative. Donor milk needs to be pasteurized before use to ensure safety. Although pasteurization is necessary for safety reasons, it may affect the activity and concentration of several biological factors, including antioxidants. This literature review describes the effect of different pasteurization methods on antioxidant properties of human milk and aims to provide evidence to guide donor milk banks in choosing the best pasteurization method from an antioxidant perspective. The current literature suggests that Holder pasteurization reduces the antioxidant properties of human milk. Alternative pasteurization methods seem promising as less reduction is observed in several studies. Full article
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Other

14 pages, 1299 KiB  
Systematic Review
Male Disadvantage in Oxidative Stress-Associated Complications of Prematurity: A Systematic Review, Meta-Analysis and Meta-Regression
by Elke van Westering-Kroon, Maurice J Huizing, Eduardo Villamor-Martínez and Eduardo Villamor
Antioxidants 2021, 10(9), 1490; https://doi.org/10.3390/antiox10091490 - 18 Sep 2021
Cited by 21 | Viewed by 2526
Abstract
A widely accepted concept is that boys are more susceptible than girls to oxidative stress-related complications of prematurity, including bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and periventricular leukomalacia (PVL). We aimed to quantify the effect size [...] Read more.
A widely accepted concept is that boys are more susceptible than girls to oxidative stress-related complications of prematurity, including bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and periventricular leukomalacia (PVL). We aimed to quantify the effect size of this male disadvantage by performing a systematic review and meta-analysis of cohort studies exploring the association between sex and complications of prematurity. Risk ratios (RRs) and 95% CIs were calculated by a random-effects model. Of 1365 potentially relevant studies, 41 met the inclusion criteria (625,680 infants). Male sex was associated with decreased risk of hypertensive disorders of pregnancy, fetal distress, and C-section, but increased risk of low Apgar score, intubation at birth, respiratory distress, surfactant use, pneumothorax, postnatal steroids, late onset sepsis, any NEC, NEC > stage 1 (RR 1.12, CI 1.06–1.18), any IVH, severe IVH (RR 1.28, CI 1.22–1.34), severe IVH or PVL, any BPD, moderate/severe BPD (RR 1.23, CI 1.18–1.27), severe ROP (RR 1.14, CI 1.07–1.22), and mortality (RR 1.23, CI 1.16–1.30). In conclusion, preterm boys have higher clinical instability and greater need for invasive interventions than preterm girls. This leads to a male disadvantage in mortality and short-term complications of prematurity. Full article
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