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Our aim was to evaluate whether administration of additional cysteine is safe and stimulates glutathione synthesis in preterm infants in early life.
We conducted a prospective, randomized, clinical trial with infants with birth weights of <1500 g (N = 20). The infants were assigned randomly to receive either a standard dose (45 mg/kg per day) or a...
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Early discontinuation of total parenteral nutrition (TPN) at 100 ml/kg/day of enteral feeds, compared with 140 ml/kg/day, led to significant delay in time to regain the birth weight in very low birth weight infants (birth weight < 1500 g, VLBW). Our aim was to compare the growth of infants in relation with timing of TPN discontinuation up to 2 year...
Background:
Few studies in the literature have analyzed the long-term neurodevelopmental outcomes of the administration of a multicomponent versus a soybean-based lipid emulsion (LE) in preterm infants receiving parenteral nutrition (PN). A recent randomized controlled trial conducted in our unit provided evidence of better growth in head circumfe...
Background
Recent studies suggest that postnatal weight gain can play an important role in the development of retinopathy of prematurity (ROP).
Aim
To analyze the low weight gain (WG) from birth to 6 weeks of life to predict the development of severe retinopathy of prematurity (ROP) among very low birth weight preterm babies (VLBW).
Methods
A prosp...
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Citations
... Of the six studies included in the Cochrane review, two studies were already identified in the four included studies [61,62], three studies included in the Cochrane review were excluded from our review as they were in abstract format only [68][69][70] and the last study was added to our results [60]. When searching the references of all the retained papers, one study was identified as eligible and was added to our review [71]. All the included studies are described in chronological order of their publication in Table 2 [60][61][62]64,65,71]. ...
... When searching the references of all the retained papers, one study was identified as eligible and was added to our review [71]. All the included studies are described in chronological order of their publication in Table 2 [60][61][62]64,65,71]. Quasi-randomized trial: ...
... According to recent advances in our understanding of cysteine/GSH metabolism, these results were expected. In infants less than 32 weeks on exclusive PN as in Ahola et al. and te Braake et al. [60,71], the effectiveness of parenteral supplementation of cysteine is compromised by the immature cellular uptake of cysteine [22]. In addition, for Ahola et al.'s study [60], intravenous NAC was suspected to be poorly deacetylated in preterm infants. ...
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.
... For instance, one-electron oxidation of cysteine by reactive oxygen species generates thiyl radicals, whereas two-electron oxidation between cysteine by reactive oxygen species produces sulfenic acid [59,60], which leads to loss of a cysteine possessing protein functions [61]. Although the infusion of high doses of cysteine in TPN to preterm infants is considered safe, it was reported to not increase the amount of plasma glutathione or cystine levels [62], and it increased nitrogen retention in tissues [63]. The other sulfur amino acid, methionine, produces two diastereomer structures-methionine-S-sulfoxide and methionine-R-sulfoxide-during its oxidation, because it contains a prochiral center [64]. ...
Neonates with preterm, gastrointestinal dysfunction and very low birth weights are often intolerant to oral feeding. In such infants, the provision of nutrients via parenteral nutrition (PN) becomes necessary for short-term survival, as well as long-term health. However, the elemental nutrients in PN can be a major source of oxidants due to interactions between nutrients, imbalances of anti- and pro-oxidants, and environmental conditions. Moreover, neonates fed PN are at greater risk of oxidative stress, not only from dietary sources, but also because of immature antioxidant defences. Various interventions can lower the oxidant load in PN, including the supplementation of PN with antioxidant vitamins, glutathione, additional arginine and additional cysteine; reduced levels of pro-oxidant nutrients such as iron; protection from light and oxygen; and proper storage temperature. This narrative review of published data provides insight to oxidant molecules generated in PN, nutrient sources of oxidants, and measures to minimize oxidant levels.
... Pulmonary stores of glutathione, responsible for NAPQI detoxification, are limited. [199][200][201][202][203][204][205][206][207] Interestingly, it has recently been demonstrated that maternal treatment with N-acetylcysteine significantly decreases the incidence of BPD, even in the absence of APAP exposure. 208 These data are not dissimilar from other interventions to enhance nutritional/antioxidant status shown to improve the respiratory health of offspring. ...
... In order to assess the impact of these modifications on the antioxidant defenses, CAT, SOD, and GPx activity, lipid peroxidation products (TBARS), TAP, serum vitamin levels, and urinary peroxides have been measured in preterm infants [49,168,169]. In particular, for cysteine enrichment, total GSH and GSH synthesis rates were measured, but no significant changes were observed [173]. ...
Oxidative stress (OS) plays a key role in the pathophysiology of preterm infants. Accurate assessment of OS remains an analytical challenge that has been partially addressed during the last few decades. A plethora of approaches have been developed to assess preterm biofluids to demonstrate a link postnatally with preterm OS, giving rise to a set of widely employed biomarkers. However, the vast number of different analytic methods and lack of standardization hampers reliable comparison of OS-related biomarkers. In this chapter, we discuss approaches for the study of OS in prematurity with respect to methodologic considerations, the metabolic source of different biomarkers and their role in clinical studies.
... A number of studies have explored the benefits of cysteine, cystine or the precursor N-acetyl-cysteine on a range of short outcomes, but whilst there is some evidence of improved nitrogen retention, more important benefits have not been demonstrated. 9,81 Taurine is the most abundant free amino acid in human milk and has important roles in hepatic function (e.g. bile acid conjugation), skeletal muscle function, and in neuro-development (especially auditory and visual development). ...
Proteins are key structural components of all human cells and are also involved in key physiologic processes through their roles as enzymes, hormones and transport proteins. Protein requirements are substantially higher in preterm infants than those born at term, yet inadequate protein intakes are a common problem on many neonatal units. Very preterm infants (VPT, <32 weeks) commonly receive parenteral amino acid solutions which are typically commenced on admission, and increased over the next few days. Several recent studies have explored differing parenteral amino acid intakes in the first few days, and recommendations have recently been updated. Parenteral nutrition intakes are decreased as enteral feeds are tolerated, but human milk alone will not meet protein needs in most VPT and supplementation or fortification will be required. This review paper considers basic protein and amino acid physiology in the newborn period, and the evidence base for current recommendations.
... Cysteine is required for the synthesis of GSH and taurine, which are essential compounds for host defense against oxidative stress [27]. However, in a previous study, cysteine administration did not accelerate the GSH synthesis rate and its concentration in preterm infants in the early life [46], possibly because cysteine undergoes rapid spontaneous oxidation at neutral pH to form cystine and hydrogen peroxide, and the production of large amounts of hydrogen peroxide at certain extracellular and intracellular sites has negative consequences [47]. Thus, there seems to be a particular need for the nutritional and functional role of methionine in the intestinal development of IUGR infants. ...
Purpose:
The present study investigated whether dietary methionine supplementation might protect against intrauterine growth retardation (IUGR)-induced damage in the intestine of piglets.
Methods:
Thirty normal birth weight (NBW) female piglets and sixty same-sex IUGR piglets were weaned at 21 days of postnatal age and fed the control diet (4.0 g methionine per kg of feed, NBW-CON, and IUGR-CON groups) or the methionine-supplemented diet (5.2 g methionine per kg of feed, IUGR-MET group) for 28 days (n = 6).
Results:
Piglets in the IUGR-CON group showed decreased average daily feed intake and average daily gain and an increased feed conversion ratio than those in the NBW-CON group. Compared with NBW-CON piglets, IUGR-CON piglets had decreased villus height (VH) and villus height-to-crypt depth ratio in both the jejunum and ileum. In addition, in comparison with the NBW-CON piglets, IUGR increased the concentration of malondialdehyde (MDA) and the index of apoptosis, while it decreased the concentrations of methionine and reduced glutathione (GSH), the ratio of reduced glutathione/oxidized glutathione (GSH/GSSG), and the protein expression of occludin (OCLN) in both the jejunum and ileum. Dietary methionine supplementation decreased the MDA and protein carbonyl concentrations and the apoptotic index, while it increased the VH level, methionine and GSH concentrations, GSH/GSSG ratio, and the OCLN protein expression in the jejunum of IUGR-MET piglets.
Conclusions:
Methionine may have beneficial effects in improving intestinal integrity and oxidative status in IUGR weanling piglets.
... Whether cysteine is essential for the PN-fed preterm infants is unclear: (1) the activity of cystathionase, a key enzyme for cysteine synthesis, is low in fetal liver; (2) methionine is less well converted to cysteine when methionine is provided by NP than enterally [72]; (3) premature infants experience major oxidative stress and GSH deficiency; and (4) due to poor stability, little cysteine is included in PN mixtures. However, cysteine supplementation of PN failed to correct GSH deficiency [73]. Cysteine deficiency may in fact occur prior to birth, since it is observed in the blood of mothers delivering preterm infants [55]. ...
Due to transient gut immaturity, most very preterm infants receive parenteral nutrition (PN) in the first few weeks of life. Yet providing enough protein and energy to sustain optimal growth in such infants remains a challenge. Extrauterine growth restriction is frequently observed in very preterm infants at the time of discharge from hospital, and has been found to be associated with later impaired neurodevelopment. A few recent randomized trials suggest that intensified PN can improve early growth; whether or not such early PN improves long-term neurological outcome is still unclear. Several other questions regarding what is optimal PN for very preterm infants remain unanswered. Amino acid mixtures designed for infants contain large amounts of branched-chain amino acids and taurine, but there is no consensus on the need for some nonessential amino acids such as glutamine, arginine, and cysteine. Whether excess growth in the first few weeks of life, at a time when very preterm infants receive PN, has an imprinting effect, increasing the risk of metabolic or vascular disease at adulthood continues to be debated. Even though uncertainty remains regarding the long-term effect of early PN, it appears reasonable to propose intensified initial PN. The aim of the current position paper is to review the evidence supporting such a strategy with regards to the early phase of nutrition, which is mainly covered by parenteral nutrition. More randomized trials are, however, needed to further support this type of approach and to demonstrate that this strategy improves short- and long-term outcome.
... Cysteine starvation has been demonstrated to induce apoptosis, since cysteine availability is a rate-limiting factor in GSH de novo synthesis [44]. However, in a previous study, cysteine administration does not accelerate GSH synthesis rate and its concentration in preterm infants in early life [45], possibly because cysteine undergoes rapid spontaneous oxidation at neutral pH to form cystine and hydrogen peroxide, and the production of large amounts of hydrogen peroxide at certain extracellular and intracellular sites would have negative consequences [46]. Therefore, it has drawn attention to the development of pharmacologically useful cysteine prodrugs [47]. ...
PurposeThe objective of the present study was to test the hypothesis that N-acetylcysteine (NAC) may play beneficial roles against intrauterine growth retardation (IUGR)-induced hepatic damage in suckling piglets. Methods
Fourteen IUGR and seven normal birth weight (NBW) neonatal male piglets were selected. Piglets were weaned at 7 days of postnatal age and fed the control formula milk (NBW-CON and IUGR-CON groups) or the control formula milk supplemented with 1.2 g/kg NAC (IUGR-NAC group) for 14 days (n = 7). The plasma and liver samples were analyzed for the parameters related to hepatic damage, redox status, apoptosis, and autophagy. ResultsCompared with the NBW-CON group, IUGR-CON group exhibited increased activities of plasma aminotransferases, increased numbers of apoptotic hepatocytes, as well as higher concentrations of protein carbonyl, malondialdehyde (MDA), microtubule-associated protein 1 light chain 3 beta, and phospholipid-conjugated form (MAP1LC3B-II), along with a decrease in the content of reduced glutathione (GSH). NAC treatment increased GSH content and GSH-to-oxidized GSH ratio in the liver of IUGR-NAC group, most likely owing to the improved activities of γ-glutamine-cysteine ligase, γ-glutamine-cysteine synthetase, and glutathione reductase. The hepatic protein carbonyl and MDA contents were decreased in the IUGR-NAC group compared with the IUGR-CON group. In addition, NAC-treated piglets had an increased content of B cell lymphoma/leukemia 2 protein, whereas a decreased expression level of MAP1LC3B-II in the liver. ConclusionsNAC may have beneficial effects in improving GSH synthesis and cellular homeostasis in the liver of IUGR suckling piglets.
... The availability of cysteine is thought to be the rate limiting substrate for the synthesis of GSH [6] [7] [8] [9], though this has been questioned as well by investigators [10] [11]. Several previous studies in children with protein energy malnutrition (PEM) and human immunodeficiency virus (HIV) have demonstrated low RBC GSH concentrations that are responsive to acetylcysteine supplementation [7] [12]. ...
... 21 The lower dose of cysteine, used in study 1, approximates a dose that has been found to increase glutathione synthesis in preterm infants. 28 Higher doses do not appear to further enhance glutathione production. The last Cochrane review found no significant effect of cysteine supplementation on growth or clinical outcomes and insufficient evidence with which to evaluate the risks due to metabolic acidosis associated with cysteine supplementation. ...
