Glutathione Supplementation Prevents Neonatal Parenteral Nutrition-Induced Short- and Long-Term Epigenetic and Transcriptional Disruptions of Hepatic H2O2 Metabolism in Guinea Pigs.

The parenteral nutrition (PN) received by premature newborns is contaminated with peroxides that induce global DNA hypermethylation via oxidative stress. Exposure to peroxides could be an important factor in the induction of chronic diseases such as those observed in adults who were born preterm. As endogenous H2O2 is a major regulator of glucose-lipid metabolism, our hypothesis was that early exposure to PN induces permanent epigenetic changes in H2O2 metabolism. Three-day-old guinea pigs were fed orally (ON), PN or glutathione-enriched PN (PN+GSSG). GSSG promotes endogenous peroxide detoxification. After 4 days, half the animals were sacrificed, and the other half were fed ON until 16 weeks of age. The liver was harvested. DNA methylation and mRNA levels were determined for the SOD2, GPx1, GCLC, GSase, Nrf2 and Keap1 genes. PN induced GPx1 hypermethylation and decreased GPx1, GCLC and GSase mRNA. These findings were not observed in PN+GSSG. PN+GSSG induced Nrf2 hypomethylation and increased Nrf2 and SOD2 mRNA. These observations were independent of age. In conclusion, in neonatal guinea pigs, PN induces epigenetic changes, affecting the expression of H2O2 metabolism genes. These changes persist for at least 15 weeks after PN. This disruption may signify a permanent reduction in the capacity to detoxify peroxides.

Disturbances of the Lung Glutathione System in Adult Guinea Pigs Following Neonatal Vitamin C or Cysteine Deficiency.

In premature infants receiving parenteral nutrition, oxidative stress is a trigger for the development of bronchopulmonary dysplasia, which is an important factor in the development of adult lung diseases. Neonatal vitamin C and glutathione deficiency is suspected to induce permanent modification of redox metabolism favoring the development of neonatal and adult lung diseases. A total of 64 3-day-old guinea pigs were fed an oral diet that was either complete or deficient in vitamin C (VCD), cysteine (CD) (glutathione-limiting substrate) or both (DD) for 4 days. At 1 week of age, half of the animals were sacrificed while the other started a complete diet until 12 weeks of age. At 1 week, the decrease in lung GSH in all deficient groups was partially explained by the oxidation of liver methionine-adenosyltransferase. mRNA levels of kelch-like ECH-associated protein 1 (Keap1), glutathione-reductase (Gsr) and glutaredoxin-1 (Glrx) were significantly lower only in CD but not in DD. At 12 weeks, glutathione levels were increased in VCD and CD. Keap1, Gsr and Glrx mRNA were increased, while glutathione-reductase and glutaredoxin proteins were lower in CD, favoring a higher glutathionylation status. Both neonatal deficiencies result in a long-term change in glutathione metabolism that could contribute to lung diseases' development.

Parenteral Cysteine Supplementation in Preterm Infants: One Size Does Not Fit All.

Due to their gastrointestinal immaturity or the severity of their pathology, many neonates require parenteral nutrition (PN). An amino acid (AA) solution is an important part of PN. Cysteine is a key AA for protein and taurine synthesis, as well as for glutathione synthesis, which is a cornerstone of antioxidant defenses. As cysteine could be synthesized from methionine, it is considered a nonessential AA. However, many studies suggest that cysteine is a conditionally essential AA in preterm infants due to limitations in their capacity for cysteine synthesis from methionine and the immaturity of their cellular cysteine uptake. This critical review discusses the endogenous synthesis of cysteine, its main biological functions and whether cysteine is a conditionally essential AA. The clinical evidence evaluating the effectiveness of the current methods of cysteine supplementation, between 1967 and 2023, is then reviewed. The current understanding of cysteine metabolism is applied to explain why these methods were not proven effective. To respond to the urgent need for changing the current methods of parenteral cysteine supplementation, glutathione addition to PN is presented as an innovative alternative with promising results in an animal model. At the end of this review, future directions for research in this field are proposed.

Dose-Response Effects of Glutathione Supplement in Parenteral Nutrition on Pulmonary Oxidative Stress and Alveolarization in Newborn Guinea Pig.

In premature infants, glutathione deficiency impairs the capacity to detoxify the peroxides resulting from O2 metabolism and those contaminating the parenteral nutrition (PN) leading to increased oxidative stress, which is a major contributor to bronchopulmonary dysplasia (BPD) development. In animals, the supplementation of PN with glutathione prevented the induction of pulmonary oxidative stress and hypoalveolarization (characteristic of BPD). Hypothesis: the dose of glutathione that corrects the plasma glutathione deficiency is sufficient to prevent oxidative stress and preserve pulmonary integrity. Three-day-old guinea pigs received a PN, supplemented or not with GSSG (up to 1300 µg/kg/d), the stable form of glutathione in PN. Animals with no handling other than being orally fed constituted the control group. After 4 days, lungs were removed to determine the GSH, GSSG, redox potential and the alveolarization index. Total plasma glutathione was quantified. The effective dose to improve pulmonary GSH and prevent the loss of alveoli was 330 µg/kg/d. A 750 µg/kg/d dose corrected the low-plasma glutathione, high-pulmonary GSSG and oxidized redox potential. Therefore, the results suggest that, in a clinical setting, the dose that improves low-plasma glutathione could be effective in preventing BPD development.

Stability of glutathione added as a supplement to parenteral nutrition.

BACKGROUND: Most very premature newborns (<32 weeks of gestation) receive parenteral nutrition (PN) that is inherently contaminated with peroxides. Oxidative stress induced by PN is associated with bronchopulmonary dysplasia, a main pathological complication in these infants who have weak antioxidant capacity to detoxify peroxides because of their glutathione deficiency. In animals, glutathione supplementation of PN prevented oxidative stress and alveolar loss (the main characteristic of bronchopulmonary dysplasia). Of its two forms-oxidized glutathione (GSSG) and reduced glutathione (GSH)-GSSG was used because of its better stability. However, a 30% loss of GSSG in PN is observed. The potentially high therapeutic benefits of GSSG supplementation on the health of very premature infants make the study of its stability highly important. METHODS: GSSG was incubated in combination with the following components of PN: dextrose, multivitamins, Primene, and Travasol, and with cysteine, cystine, and peroxides, for 24 h. Total glutathione in these solutions was measured 0-24 h after the addition of GSSG. RESULTS: The combination of cysteine and multivitamins caused the maximum loss of glutathione. The stability of GSSG was not affected by multivitamins. The cysteine was responsible for ∼20% of the loss of GSSG; in the presence of multivitamins, the loss reached >70%. Removing the cysteine prevented the degradation of glutathione. CONCLUSION: GSSG reacts with cysteine to form cysteine-glutathione mixed disulfide, another suitable glutathione substrate for preterm neonates. The study confirms that GSSG added to PN can potentially provide a precursor to de novo synthesis of glutathione in vivo.

CARDEA study protocol: investigating early markers of cardiovascular disease and their association with lifestyle habits, inflammation and oxidative stress in adolescence using a cross-sectional comparison of adolescents with type 1 diabetes and healthy controls.

INTRODUCTION: Little is known regarding associations between potentially modifiable lifestyle habits and early markers of cardiovascular disease (CVD) in pediatric type 1 diabetes (T1D), hindering early prevention efforts. Specific objectives are: (1) compare established risk factors (dyslipidemia, hypertension) with novel early markers for CVD (cardiac phenotype, aortic distensibility, endothelial function) in adolescents with T1D and healthy age-matched and sex-matched controls; (2) examine associations between these novel early markers with: (i) lifestyle habits; (ii) adipokines and measures of inflammation; and (iii) markers of oxidative stress among adolescents with T1D and controls, and determine group differences in these associations; (3) explore, across both groups, associations between CVD markers and residential neighbourhood features. METHODS AND ANALYSES: Using a cross-sectional design, we will compare 100 participants aged 14-18 years with T1D to 100 healthy controls. Measures include: anthropometrics; stage of sexual maturity (Tanner stages); physical activity (7-day accelerometry); sleep and sedentary behaviour (self-report and accelerometry); fitness (peak oxygen consumption); and dietary intake (three non-consecutive 24- hour dietary recalls). Repeated measures of blood pressure will be obtained. Lipid profiles will be determined after a 12- hour fast. Cardiac structure/function: non-contrast cardiac magnetic resonance imaging (CMR) images will evaluate volume, mass, systolic and diastolic function and myocardial fibrosis. Aortic distensibility will be determined by pulse wave velocity with elasticity and resistance studies at the central aorta. Endothelial function will be determined by flow-mediated dilation. Inflammatory markers include plasma leptin, adiponectin, tumour necrosis factor alpha (TNF-α), type I and type II TNF-α soluble receptors and interleukin-6 concentrations. Measures of endogenous antioxidants include manganese superoxide dismutase, glutathione peroxidase and glutathione in blood. Neighbourhood features include built and social environment indicators and air quality. ETHICS AND DISSEMINATION: This study was approved by the Sainte-Justine Hospital Research Ethics Board. Written informed assent and consent will be obtained from participants and their parents. TRIAL REGISTRATION NUMBER: NCT04304729.

Neonatal Vitamin C and Cysteine Deficiencies Program Adult Hepatic Glutathione and Specific Activities of Glucokinase, Phosphofructokinase, and Acetyl-CoA Carboxylase in Guinea Pigs' Livers.

Premature neonates are submitted to an early-life oxidative stress from parenteral nutrition, which is vitamin C (VC) deficient and induces low endogenous levels of glutathione. The oxidative stress caused by these deficiencies may permanently affect liver glycolysis and lipogenesis. This study evaluates the short- and long-term effects of neonatal VC and cysteine deficient diets on redox and energy metabolism. Three-day-old Hartley guinea pigs from both sexes were given a regular or a deficient diet (VC, cysteine, or both) until week 1 of life. Half of the animals were sacrificed at this age, while the other half ate a complete diet until 12 weeks. Liver glutathione and the activity and protein levels of glucokinase, phosphofructokinase, and acetyl-CoA-carboxylase were measured. Statistics: factorial ANOVA (5% threshold). At 1 week, all deficient diets decreased glutathione and the protein levels of glucokinase and phosphofructokinase, while cysteine deficiency decreased acetyl-CoA-carboxylase levels. A similar enzyme level was observed in control animals at 12 weeks. At this age, VC deficiency decreased glutathione, while cysteine increased it. Acetyl-CoA-carboxylase protein levels were increased, which decreased its specific activity. Early-life VC and cysteine deficiencies induce neonatal oxidative stress and an adult-like metabolism, while predisposing to increased lipogenic rates during adulthood.

Neonatal parenteral nutrition affects the metabolic flow of glucose in newborn and adult male Hartley guinea pigs' liver.

Extremely premature birth is associated with a permanent disruption of energy metabolism. The underlying mechanisms are poorly understood. The oxidative stress induced by parenteral nutrition (PN) during the first week of life is suspected to reprogram energy metabolism in the liver. Full-term male Hartley guinea pigs (to isolate PN from prematurity) receiving PN enriched or not with glutathione (to isolate PN effects from PN-induced oxidative stress effects) or an Oral Nutrition (ON) during the first week of life were used. At 1 week (neonatal) and 16 weeks (adult), measurements of liver glutathione (GSH and GSSG) and activities of three key enzymes of energy metabolism (glucokinase (GCK), phosphofructokinase (PFK), and acetyl-CoA carboxylase (ACC)) were performed. Differences between groups were reported if p ≤ 0.05 (Analysis of Variance). At 1 week, compared to ON, PN induced higher GSSG (oxidative stress), higher GCK activity, and lower PFK and ACC activity, the glutathione supplement prevented all PN effects. At 16 weeks, early PN induced lower GSSG (reductive stress) and lower GCK activity, which was prevented by added glutathione, and higher ACC activity independent of glutathione supplement. ACC was negatively associated (r2 = 0.33) with GSSG. Increased nicotinamide adenine dinucleotide phosphate levels confirmed the glucose-6-phosphate accumulation at 1 week, whereas our protocol failed to document lipid accumulation at 16 weeks. In adult male guinea pigs, neonatal exposure to PN affected glutathione metabolism leading to reductive stress (lower GSSG) and an altered metabolic flow of glucose. Partial prevention with glutathione supplementation suggests that, in addition to peroxides, other factors of PN are involved.

Relationship between redox potential of glutathione and DNA methylation level in liver of newborn guinea pigs.

The metabolism of DNA methylation is reported to be sensitive to oxidant molecules or oxidative stress. Hypothesis: early-life oxidative stress characterized by the redox potential of glutathione influences the DNA methylation level. The in vivo study aimed at the impact of modulating redox potential of glutathione on DNA methylation. Newborn guinea pigs received different nutritive modalities for 4 days: oral nutrition, parenteral nutrition including lipid emulsion Intralipid (PN-IL) or SMOFLipid (PN-SF), protected or not from ambient light. Livers were collected for biochemical determinations. Redox potential (p < 0.001) and DNA methylation (p < 0.01) were higher in PN-infused animals and even higher in PN-SF. Their positive correlation was significant (r2 = 0.51; p < 0.001). Methylation activity was higher in PN groups (p < 0.01). Protein levels of DNA methyltransferase (DNMT)-1 were lower in PN groups (p < 0.01) while those of both DNMT3a isoforms were increased (p < 0.01) and significantly correlated with redox potential (r2 > 0.42; p < 0.001). The ratio of SAM (substrate) to SAH (inhibitor) was positively correlated with the redox potential (r2 = 0.36; p < 0.001). In conclusion, early in life, the redox potential value strongly influences the DNA methylation metabolism, resulting in an increase of DNA methylation as a function of increased oxidative stress. These results support the notion that early-life oxidative stress can reprogram the metabolism epigenetically. This study emphasizes once again the importance of improving the quality of parenteral nutrition solutions administered early in life, especially to newborn infants. Abbreviation of Title: Parenteral nutrition and DNA methylation.

Extracellular microparticles exacerbate oxidative damage to retinal pigment epithelial cells.

Oxidative stress-induced retinal pigment epithelial cell (RPE) dysfunction is a primary contributing factor to early dry age-related macular degeneration (AMD). Oxidative injury to the retina may promote extracellular vesicles (EVs) released from RPE. In this study, we investigated the effects of oxidative-induced RPE cell-derived microparticles (RMPs) on RPE cell functions. The oxidative stress induced more RMPs released from RPE cells in vitro and in vivo, and significant more RMPs were released from aged RPE cells than that from younger RPE cells. RMPs were taken up by RPE cells in a time-dependent manner; however, blockage of CD36 attenuated the uptake process. Furthermore, the decrease of RPE cell viability by RMPs treatment was associated with an increased expression of cyclin-dependent kinase inhibitors p15 and p21. RMPs enhanced senescence and interrupted phagocytic activity of RPE cells as well. The present study demonstrated that RMPs produce a strong effect of inducing RPE cell degeneration. This finding further supports the postulate that RMPs exacerbate oxidative stress damage to RPE cells, which may uncover a potentially relevant process in the genesis of dry AMD.

Increased Incidence but Lack of Association Between Cardiovascular Risk Factors in Adults Born Preterm.

Preterm birth incurs an increased risk of early cardiovascular events and death. In the general population, cardiovascular risk factors cluster in the context of inflammation and oxidative stress. Whether this also occurs in young adults born preterm is unknown. We analyzed 101 healthy young adults (ages 18-29) born preterm (≤29 weeks of gestation) and 105 full-term controls, predominantly (90%) white. They underwent a comprehensive clinical and biological evaluation, including measurement of blood pressure, lung function (spirometry), glucose metabolism (fasting glucose, glycated hemoglobin, and oral glucose tolerance test), as well as biomarkers of inflammation and oxidative stress. Individuals born preterm were at higher risk than those born full-term of stage ≥1 hypertension (adjusted odds ratio, 2.91 [95% CI, 1.51-5.75]), glucose intolerance (adjusted odds ratio, 2.22 [95% CI, 1.13-4.48]), and airflow limitation (adjusted odds ratio, 3.47 [95% CI, 1.76-7.12]). Hypertension was strongly associated with adiposity and with glucose intolerance in participants born full-term but not in those born preterm. We did not find any group difference in levels of biomarkers of inflammation and oxidative stress. In individuals born preterm, inflammation, and oxidative stress were not related to hypertension or glucose intolerance but were associated with adiposity. In those born preterm, cardiovascular risk factors were not related to each other suggesting different pathophysiological pathways leading to the development of cardiovascular risk following preterm birth. Clinicians should consider screening for these abnormalities irrespectively of other risk factors in this at-risk population. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03261609.

Glutathione Supplementation of Parenteral Nutrition Prevents Oxidative Stress and Sustains Protein Synthesis in Guinea Pig Model.

Peroxides contaminating parenteral nutrition (PN) limit the use of methionine as a precursor of cysteine. Thus, PN causes a cysteine deficiency, characterized by low levels of glutathione, the main molecule used in peroxide detoxification, and limited growth in individuals receiving long-term PN compared to the average population. We hypothesize that glutathione supplementation in PN can be used as a pro-cysteine that improves glutathione levels and protein synthesis and reduces oxidative stress caused by PN. One-month-old guinea pigs (7-8 per group) were used to compare glutathione-enriched to a non-enriched PN, animals on enteral nutrition were used as a reference. PN: Dextrose, amino acids (Primene), lipid emulsion (Intralipid), multivitamins, electrolytes; five-day infusion. Glutathione (GSH, GSSG, redox potential) and the incorporation of radioactive leucine into the protein fraction (protein synthesis index) were measured in the blood, lungs, liver, and gastrocnemius muscle. Data were analysed by ANOVA; p < 0.05 was considered significant. The addition of glutathione to PN prevented the PN-induced oxidative stress in the lungs and muscles and supported protein synthesis in liver and muscles. The results potentially support the recommendation to add glutathione to the PN and demonstrate that glutathione could act as a biologically available cysteine precursor.

A Short-Term High-Fat Diet Alters Glutathione Levels and IL-6 Gene Expression in Oxidative Skeletal Muscles of Young Rats.

Obesity and ensuing disorders are increasingly prevalent worldwide. High-fat diets (HFD) and diet-induced obesity have been shown to induce oxidative stress and inflammation while altering metabolic homeostasis in many organs, including the skeletal muscle. We previously observed that 14 days of HFD impairs contractile functions of the soleus (SOL) oxidative skeletal muscle. However, the mechanisms underlying these effects are not clarified. In order to determine the effects of a short-term HFD on skeletal muscle glutathione metabolism, young male Wistar rats (100-125 g) were fed HFD or a regular chow diet (RCD) for 14 days. Reduced (GSH) and disulfide (GSSG) glutathione levels were measured in the SOL. The expression of genes involved in the regulation of glutathione metabolism, oxidative stress, antioxidant defense and inflammation were measured by RNA-Seq. We observed a significant 25% decrease of GSH levels in the SOL muscle. Levels of GSSG and the GSH:GSSG ratio were similar in both groups. Further, we observed a 4.5 fold increase in the expression of pro-inflammatory cytokine interleukin 6 (IL-6) but not of other cytokines or markers of inflammation and oxidative stress. We hereby demonstrate that a short-term HFD significantly lowers SOL muscle GSH levels. This effect could be mediated through the increased expression of IL-6. Further, the skeletal muscle antioxidant defense could be impaired under cellular stress. We surmise that these early alterations could contribute to HFD-induced insulin resistance observed in longer protocols.

Parenteral nutrition and oxidant stress in the newborn: A narrative review.

There is strong evidence that oxidant molecules from various sources contaminate solutions of parenteral nutrition following interactions between the mixture of nutrients and some of the environmental conditions encountered in clinical practice. The continuous infusion of these organic and nonorganic peroxides provided us with a unique opportunity to study in cells, in vascular and animal models, the mechanisms involved in the deleterious reactions of oxidation in premature infants. Potential clinical impacts of peroxides infused with TPN include: a redox imbalance, vasoactive responses, thrombosis of intravenous catheters, TPN-related hepatobiliary complications, bronchopulmonary dysplasia and mortality. This is a narrative review of published data.

Impact of SMOFLipid on Pulmonary Alveolar Development in Newborn Guinea Pigs.

BACKGROUND: Parenteral nutrition (PN) is associated with bronchopulmonary dysplasia in premature infants. In animals, PN leads to alveolar loss following stimulation of apoptosis by oxidative stress (oxidized redox potential). Peroxides and aldehydes generated in PN can induce hypo-alveolarization. The implication of peroxides, which is reduced by light protection, is demonstrated. The implication of aldehydes from omega-6 fatty acids oxidation is expected. The hypothesis is that composition and light exposure of PN influences bronchopulmonary dysplasia development. Since SMOFLipid (SMOF) contains a lower amount of omega-6 fatty acids than Intralipid (IL), the aim was to compare, the impacts of PN compounded with SMOF or IL, photo-protected or not, on alveolar development. MATERIALS AND METHODS: Three-day-old Guinea pigs received PN, photo-protected or not, made with SMOF or IL through a jugular vein catheter. After 4 days, lungs were sampled for determinations of redox potential of glutathione, apoptosis (caspase-3, caspase-8, and caspase-9) and alveolarization index (histology: number of intercepts/mm). RESULTS: Compared with IL, SMOF induces a greater oxidation of redox potential (-200 ± 1 versus [vs] -205 ± 1 mV), apoptosis (caspase-3: 0.27 ± 0.04 vs 0.16 ± 0.02; caspase-9: 0.47 ± 0.03 vs 0.30 ± 0.03), and a lower alveolarization index (27.2 ± 0.8 vs 30.0 ± 0.9). Photo-protection prevented activation of caspase-9 and was statistically without effect on redox potential, caspase-3, and alveolarization index. CONCLUSION: In our model, SMOF is pro-oxidant and induces hypo-alveolarization following exaggerated apoptosis. These results highlight the need for further studies before introducing SMOFLipid in standard neonatal care.

Sex-Specificity of Oxidative Stress in Newborns Leading to a Personalized Antioxidant Nutritive Strategy.

Oxidative stress is a critical process that triggers several diseases observed in premature infants. Growing recognition of the detriment of oxidative stress in newborns warrants the use of an antioxidant strategy that is likely to be nutritional in order to restore redox homeostasis. It appears essential to have a personalized approach that will take into account the age of gestation at birth and the sex of the infant. However, the link between sex and oxidative stress remains unclear. The aim of this study was to find a common denominator explaining the discrepancy between studies related to sex-specific effects of oxidative stress. Results highlight a specificity of sex in the levels of oxidative stress markers linked to the metabolism of glutathione, as measured in the intracellular compartments. Levels of all sex-dependent oxidative stress markers are greater and markers associated to a better antioxidant defense are lower in boys compared to girls during the neonatal period. This sex-specific discrepancy is likely to be related to estrogen metabolism, which is more active in baby-girls and promotes the activation of glutathione metabolism. CONCLUSION: our observations suggest that nutritive antioxidant strategies need to target glutathione metabolism and, therefore, should be personalized considering, among others, the sex specificity.

Adult Consequences of Extremely Preterm Birth: Cardiovascular and Metabolic Diseases Risk Factors, Mechanisms, and Prevention Avenues.

Extremely preterm babies are exposed to various sources of injury during critical stages of development. The extremely preterm infant faces premature transition to ex utero physiology and undergoes adaptive mechanisms that may be deleterious in the long term because of permanent alterations in organ structure and function. Perinatal events can also directly cause structural injury. These disturbances induce morphologic and functional changes in their organ systems that might heighten their risks for later adult chronic diseases. This review examines the pathophysiology of programming of long-term health and diseases after preterm birth and associated perinatal risk factors.

Shielding Parenteral Nutrition From Light Improves Survival Rate in Premature Infants.

BACKGROUND: Intravenous nutrition preparations that are not photoprotected generate oxidants, which are deleterious for cell survival. The question remains: are these observations of clinical relevance in individuals receiving parenteral nutrition (PN), especially in those who exhibit immature antioxidant defenses such as premature infants? OBJECTIVE: To review clinical trials reporting the effect of light-exposed vs light-protected PN to determine whether photoprotection reduces neonatal mortality in preterm infants. DATA SOURCE: Electronic databases, abstracts in relevant journals, and references in manuscripts between 1980 and 2014. SELECTION CRITERIA: Newborn, premature infants, PN, photoprotection, shielding from light, randomization, mortality, death. METHODS: Consensus for inclusion reached by 2 reviewers; meta-analysis of trials and observational studies reporting mortality at 36 weeks' gestational age or hospital discharge. RESULTS: Four trials meeting selection criteria, which involved a total of 800 newborn premature infants, were included. Across trials, gestational age (mean ± SD) ranged from 26 ± 1 to 31 ± 2 weeks, birth weight from 775 ± 161 to 1588 ± 366 g, and mortality from 5%-32%. Mortality in the light-protected group was half of that in the light-exposed group (95% confidence interval, 0.32-0.87) and twice as high in males compared with females (χ2, P = .01). CONCLUSION: Shielding PN from light has vital repercussions that call for action to provide photoprotected delivery systems and infusion sets in premature infants. Further studies should be extended to the increasing number of children and adults receiving long-term home PN to evaluate the effects of light protection on severe complications that impede their quality of life.

Ascorbylperoxide Contaminating Parenteral Nutrition Is Associated With Bronchopulmonary Dysplasia or Death in Extremely Preterm Infants.

BACKGROUND: Ascorbylperoxide (AscOOH) is a hydrogen peroxide-dependent by-product of ascorbic acid that contaminates parenteral nutrition. In a guinea pig model, it caused oxidized redox potential, increased apoptosis, and decreased alveolarization. AscOOH detoxification is carried out by glutathione peroxidase (GPX). We hypothesize that extremely preterm infants have limited capacity for AscOOH detoxification. Our objective was to determine if there is an association between an early level of urinary AscOOH and later development of bronchopulmonary dysplasia (BPD) or death. MATERIALS AND METHODS: This prospective cohort study included 51 infants at <29 weeks of gestation. Baseline clinical characteristics and clinical outcomes data were collected. Urine samples were collected on days 3, 5, and 7 of life for urinary AscOOH. Blood samples on day 7 were collected for total plasma glutathione, GPX, and glutathione reductase. χ2, Student's t test, Spearman correlation ( r), linear regression (adjusted r2), and repeated-measure analysis of variance were used as appropriate. P < .05 was considered significant. RESULTS: Urinary AscOOH increased over time ( P = .001) and was higher in infants who later developed BPD or died ( P = .037). Compared with adults and full-term infants, total plasma glutathione concentration was low (median, 1.02 µmol/L; 25th-75th percentiles, 0.49-1.76 µmol/L), whereas GPX and glutathione reductase activities were sufficient (3.98 ± 1.25 and 0.36 ± 0.01 nmol/min/mg of protein, respectively). CONCLUSION: Extremely preterm infants have low glutathione levels, which limit their capacity to detoxify AscOOH. Higher first-week urinary AscOOH levels are associated with an increased incidence of BPD or death.

Impact of glutathione supplementation of parenteral nutrition on hepatic methionine adenosyltransferase activity.

BACKGROUND: The oxidation of the methionine adenosyltransferase (MAT) by the combined impact of peroxides contaminating parenteral nutrition (PN) and oxidized redox potential of glutathione is suspected to explain its inhibition observed in animals. A modification of MAT activity is suspected to be at origin of the PN-associated liver disease as observed in newborns. We hypothesized that the correction of redox potential of glutathione by adding glutathione in PN protects the MAT activity. AIM: To investigate whether the addition of glutathione to PN can reverse the inhibition of MAT observed in animal on PN. METHODS: Three days old guinea pigs received through a jugular vein catheter 2 series of solutions. First with methionine supplement, (1) Sham (no infusion); (2) PN: amino acids, dextrose, lipids and vitamins; (3) PN-GSSG: PN+10µM GSSG. Second without methionine, (4) D: dextrose; (5) D+180µM ascorbylperoxide; (6) D+350µM H2O2. Four days later, liver was sampled for determination of redox potential of glutathione and MAT activity in the presence or absence of 1mM DTT. Data were compared by ANOVA, p<0.05. RESULTS: MAT activity was 45±4% lower in animal infused with PN and 23±7% with peroxides generated in PN. The inhibition by peroxides was associated with oxidized redox potential and was reversible by DTT. Correction of redox potential (PN+GSSG) or DTT was without effect on the inhibition of MAT by PN. The slope of the linear relation between MAT activity and redox potential was two fold lower in animal infused with PN than in others groups. CONCLUSION: The present study suggests that prevention of peroxide generation in PN and/or correction of the redox potential by adding glutathione in PN are not sufficient, at least in newborn guinea pigs, to restore normal MAT activity.