Harlequin mice exhibit cognitive impairment, severe loss of Purkinje cells and a compromised bioenergetic status due to the absence of Apoptosis Inducing Factor.

The functional integrity of the central nervous system relies on complex mechanisms in which the mitochondria are crucial actors because of their involvement in a multitude of bioenergetics and biosynthetic pathways. Mitochondrial diseases are among the most prevalent groups of inherited neurological disorders, affecting up to 1 in 5000 adults and despite considerable efforts around the world there is still limited curative treatments. Harlequin mice correspond to a relevant model of recessive X-linked mitochondrial disease due to a proviral insertion in the first intron of the Apoptosis-inducing factor gene, resulting in an almost complete depletion of the corresponding protein.

TRP14 is the rate-limiting enzyme for intracellular cystine reduction and regulates proteome cysteinylation.

It has remained unknown how cells reduce cystine taken up from the extracellular space, which is a required step for further utilization of cysteine in key processes such as protein or glutathione synthesis. Here, we show that the thioredoxin-related protein of 14 kDa (TRP14, encoded by TXNDC17) is the rate-limiting enzyme for intracellular cystine reduction. When TRP14 is genetically knocked out, cysteine synthesis through the transsulfuration pathway becomes the major source of cysteine in human cells, and knockout of both pathways becomes lethal in C.

Neuroglobin overexpression in cerebellar neurons of Harlequin mice improves mitochondrial homeostasis and reduces ataxic behavior.

Neuroglobin, a member of the globin superfamily, is abundant in the brain, retina, and cerebellum of mammals and localizes to mitochondria. The protein exhibits neuroprotective capacities by participating in electron transfer, oxygen supply, and protecting against oxidative stress. Our objective was to determine whether neuroglobin overexpression can be used to treat neurological disorders.

Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice.

Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice.

Analysis of Lipid Peroxidation by UPLC-MS/MS and Retinoprotective Effects of the Natural Polyphenol Pterostilbene.

The loss of redox homeostasis induced by hyperglycemia is an early sign and key factor in the development of diabetic retinopathy. Due to the high level of long-chain polyunsaturated fatty acids, diabetic retina is highly susceptible to lipid peroxidation, source of pathophysiological alterations in diabetic retinopathy. Previous studies have shown that pterostilbene, a natural antioxidant polyphenol, is an effective therapy against diabetic retinopathy development, although its protective effects on lipid peroxidation are not well known.

Early neurotransmission impairment in non-invasive Alzheimer Disease detection.

Alzheimer Disease (AD) is a pathology suffered by millions of people worldwide and it has a great social and economic impact. Previous studies reported a relationship between alterations in different amino acids and derivatives involved in neurotransmission systems and cognitive impairment. Therefore, in this study the neurotransmission impairment associated to early AD has been evaluated.

Impairment of PGC-1 Alpha Up-Regulation Enhances Nitrosative Stress in the Liver during Acute Pancreatitis in Obese Mice.

Acute pancreatitis is an inflammatory process of the pancreatic tissue that often leads to distant organ dysfunction. Although liver injury is uncommon in acute pancreatitis, obesity is a risk factor for the development of hepatic complications. The aim of this work was to evaluate the role of PGC-1α in inflammatory response regulation in the liver and its contribution to the detrimental effect of obesity on the liver during acute pancreatitis.

PGC-1, Inflammation, and Oxidative Stress: An Integrative View in Metabolism.

Peroxisome proliferator-activated receptor- coactivator (PGC)-1 is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1 is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome.

Oxygen Supplementation During Preterm Stabilization and the Relevance of the First 5 min After Birth.

Fetal to neonatal transition entails cardiorespiratory, hemodynamic, and metabolic changes coinciding with the switch from placental to airborne respiration with partial pressures of oxygen of 4-5 kPa raising to 8-9 kPa in few minutes. Preterm infants have immature lung and antioxidant defense system. Very preterm infants (<32 weeks' gestation) frequently require positive pressure ventilation and oxygen to establish lung aeration, a functional residual capacity, and overcome a tendency toward hypoxemia and bradycardia in the first minutes after birth.

Pterostilbene Prevents Early Diabetic Retinopathy Alterations in a Rabbit Experimental Model.

Oxidative stress generated by diabetes plays a key role in the development of diabetic retinopathy (DR), a common diabetic complication. DR remains asymptomatic until it reaches advanced stages, which complicate its treatment. Although it is known that good metabolic control is essential for preventing DR, knowledge of the disease is incomplete and an effective treatment with no side effects is lacking.

Impact of Donor Human Milk in the Preterm Very Low Birth Weight Gut Transcriptome Profile by Use of Exfoliated Intestinal Cells.

Background: Own mother's milk (OMM) is the optimal nutrition for preterm infants. However, pasteurized donor human milk (DHM) is a valid alternative. We explored the differences of the transcriptome in exfoliated epithelial intestinal cells (EEIC) of preterm infants receiving full feed with OMM or DHM.

Oral Monosodium Glutamate Administration Causes Early Onset of Alzheimer's Disease-Like Pathophysiology in APP/PS1 Mice.

Glutamate excitotoxicity has long been related to Alzheimer's disease (AD) pathophysiology, and it has been shown to affect the major AD-related hallmarks, amyloid-β peptide (Aβ) accumulation and tau phosphorylation (p-tau). We investigated whether oral administration of monosodium glutamate (MSG) has effects in a murine model of AD, the double transgenic mice APP/PS1. We found that AD pathogenic factors appear earlier in APP/PS1 when supplemented with MSG, while wildtype mice were essentially not affected.

Blockade of the trans-sulfuration pathway in acute pancreatitis due to nitration of cystathionine β-synthase.

Acute pancreatitis is an inflammatory process of the pancreatic gland that may lead to dysregulation of the trans-sulfuration pathway. The aims of this work were firstly to study the methionine cycle as well as the trans-sulfuration pathway using metabolomic and proteomic approaches identifying the causes of this dysregulation in an experimental model of acute pancreatitis; and secondly to reveal the effects of S-adenosylmethionine administration on these pathways. Acute pancreatitis was induced by cerulein in mice, and a group of animals received S-adenosylmethionine treatment.

Brain oxidative damage in murine models of neonatal hypoxia/ischemia and reoxygenation.

The brain is one of the main organs affected by hypoxia and reoxygenation in the neonatal period and one of the most vulnerable to oxidative stress. Hypoxia/ischemia and reoxygenation leads to impairment of neurogenesis, disruption of cortical migration, mitochondrial damage and neuroinflammation. The extent of the injury depends on the clinical manifestation in the affected regions.

Oxidative Stress in the Newborn Period: Useful Biomarkers in the Clinical Setting.

Aerobic metabolism is highly efficient in providing energy for multicellular organisms. However, even under physiological conditions, an incomplete reduction of oxygen produces reactive oxygen species and, subsequently, oxidative stress. Some of these chemical species are highly reactive free radicals capable of causing functional and structural damage to cell components (protein, lipids, or nucleotides).

Influence of Sex on Gestational Complications, Fetal-to-Neonatal Transition, and Postnatal Adaptation.

Fetal sex is associated with striking differences during development, fetal-to-neonatal transition, and postnatal morbidity and mortality. Male sex fetuses are apparently protected while resulting in a higher secondary sex rate for males than for females. However, during fetal-to-neonatal transition and thereafter in the newborn period, female exhibits a greater degree of maturation that translates into a better capacity to stabilize, less incidence of prematurity and prematurity-associated morbidities, and better long-term outcomes.

7,8-hydroxy-2'-deoxyguanosine/2'-deoxiguanosine ratio determined in hydrolysates of brain DNA by ultrachromatrography coupled to tandem mass spectrometry.

7,8-hydroxy-2'-deoxyguanosine (8-OHdG) is an abundant DNA lesion formed by oxidation of the nucleoside 2'-deoxyguanosine (2-dG) and one of the most studied and accepted oxidative stress biomarkers. 8-OHdG has a strong carcinogenic potential, and prolonged oxidative stress heightens pathological conditions and especially cancer risk. Our aim was to develop, validate and apply a reliable method to assess DNA oxidation in genomic cellular DNA of sensible target organs such as brain.

Oxygen and oxidative stress in the perinatal period.

Fetal life evolves in a hypoxic environment. Changes in the oxygen content in utero caused by conditions such as pre-eclampsia or type I diabetes or by oxygen supplementation to the mother lead to increased free radical production and correlate with perinatal outcomes. In the fetal-to-neonatal transition asphyxia is characterized by intermittent periods of hypoxia ischemia that may evolve to hypoxic ischemic encephalopathy associated with neurocognitive, motor, and neurosensorial impairment.

Oxygen Supplementation to Stabilize Preterm Infants in the Fetal to Neonatal Transition: No Satisfactory Answer.

Fetal life elapses in a relatively low oxygen environment. Immediately after birth with the initiation of breathing, the lung expands and oxygen availability to tissue rises by twofold, generating a physiologic oxidative stress. However, both lung anatomy and function and the antioxidant defense system do not mature until late in gestation, and therefore, very preterm infants often need respiratory support and oxygen supplementation in the delivery room to achieve postnatal stabilization.

Protein-bound tyrosine oxidation, nitration and chlorination by-products assessed by ultraperformance liquid chromatography coupled to tandem mass spectrometry.

Background: Free radicals cause alterations in cellular protein structure and function. Oxidized, nitrated, and chlorinated modifications of aromatic amino acids including phenylalanine and tyrosine are reliable biomarkers of oxidative stress and inflammation in clinical conditions.

Objective: To develop, validate and apply a rapid method for the quantification of known hallmarks of tyrosine oxidation, nitration and chlorination in plasma and tissue proteins providing a snapshot of the oxidative stress and inflammatory status of the organism and of target organs respectively.

Development of a reliable method based on ultra-performance liquid chromatography coupled to tandem mass spectrometry to measure thiol-associated oxidative stress in whole blood samples.

The aminothiols are biological compounds with numerous vital functions. One of the most relevant is their role as antioxidant systems. The reduced to oxidized ratios are extremely useful indicators of oxidative stress and cellular redox status.

Determination of biomarkers of protein oxidation in tissue and plasma.

Oxidative and nitrosative stress cause changes in proteins which can alter their structure and/or function. However, these changes especially in specific amino acid residues have proven to be reliable biomarkers of oxidative stress and inflammation. The aim of this study was to develop and validate a rapid method for the quantification of five selected biomarkers orto-tyrosine (o-tyr), meta-tyrosine (m-tyr), 3NO2-tyrosine (3NO2-tyr), 3I-tyrosine (3I-tyr) and 3Chloro-tyrosine (3Cl-tyr) in liver, brain and plasma, thus providing a snapshot of the oxidative stress status of the organism.

Urinary Lipid Peroxidation Byproducts: Are They Relevant for Predicting Neonatal Morbidity in Preterm Infants?

Preterm infants have an immature antioxidant system; however, they frequently require supplemental oxygen. Oxygen-free radicals cause both pulmonary and systemic inflammation, and they are associated with increased morbidity and mortality. Consequently, screening of metabolite profiles representing the amount of lipid peroxidation is considered of great relevance for the evaluation of in vivo oxidative stress and derived inflammation and damage.

Analysis of lipid peroxidation biomarkers in extremely low gestational age neonate urines by UPLC-MS/MS.

Extremely low gestational age neonates (ELGAN) frequently require the use of oxygen supply in the delivery room leading to systemic inflammation and oxidative stress that are responsible for increased morbidity and mortality. The objective of this study was to establish reference ranges of a set of representative isoprostanes and prostaglandins, which are stable biomarkers of lipid peroxidation often correlated with oxidative stress-related disorders. First, a quantitative ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated.