Oxygen in the neonatal period: Oxidative stress, oxygen load and epigenetic changes

Preterm infants frequently require positive pressure ventilation and oxygen supplementation in the first minutes after birth. It has been shown that the amount of oxygen provided during stabilization, the oxygen load, if excessive may cause hyperoxia, and oxidative damage to DNA. Epidemiologic studies have associated supplementation with pure oxygen in the first minutes after birth with childhood cancer. Recent studies have shown that the amount of oxygen supplemented to preterm infants after birth modifies the epigenome. Of note, the degree of DNA hyper-or hypomethylation correlates with the oxygen load provided upon stabilization. If these epigenetic modifications would persist, oxygen su…

A common SNP in the UNG gene decreases ovarian cancer risk in BRCA2 mutation carriers

Single nucleotide polymorphisms (SNPs) in DNA glycosylase genes involved in the base excision repair (BER) pathway can modify breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We previously found that SNP rs34259 in the uracil-DNA glycosylase gene (UNG) might decrease ovarian cancer risk in BRCA2 mutation carriers. In the present study, we validated this finding in a larger series of familial breast and ovarian cancer patients to gain insights into how this UNG variant exerts its protective effect. We found that rs34259 is associated with significant UNG downregulation and with lower levels of DNA damage at telomeres. In addition, we found that this SNP is associated with…

Irisin: A new potential hormonal target for the treatment of obesity and type 2 diabetes

Oxidative Stress and Inflammation in COVID-19-Associated Sepsis: The Potential Role of Anti-Oxidant Therapy in Avoiding Disease Progression

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak emerged, countless efforts are being made worldwide to understand the molecular mechanisms underlying the coronavirus disease 2019 (COVID-19) in an attempt to identify the specific clinical characteristics of critically ill COVID-19 patients involved in its pathogenesis and provide therapeutic alternatives to minimize COVID-19 severity. Recently, COVID-19 has been closely related to sepsis, which suggests that most deceases in intensive care units (ICU) may be a direct consequence of SARS-CoV-2 infection-induced sepsis. Understanding oxidative stress and the molecular inflammation mechanisms contributing to COVI…

Role of glutathione in the regulation of epigenetic mechanisms in disease

Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence. Histone H3, one of the basic proteins in the nucleosomes that make up chromatin, is S-glutathionylated in mammalian cells and tissues, making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a physiological antioxidant and second messenger in cells, a new post-translational modifier of the histone code that alters the structure of the nucleosome. However, the role of GSH in the epigenetic mechanisms likely goes beyond a mere structural function. Evidence supports the hypothesis that there is a link between GSH metabolism and the control of epigenetic mechanisms…

Epigenetic IVD Tests for Personalized Precision Medicine in Cancer

Epigenetic alterations play a key role in the initiation and progression of cancer. Therefore, it is possible to use epigenetic marks as biomarkers for predictive and precision medicine in cancer. Precision medicine is poised to impact clinical practice, patients, and healthcare systems. The objective of this review is to provide an overview of the epigenetic testing landscape in cancer by examining commercially available epigenetic-based in vitro diagnostic tests for colon, breast, cervical, glioblastoma, lung cancers, and for cancers of unknown origin. We compile current commercial epigenetic tests based on epigenetic biomarkers (i.e., DNA methylation, miRNAs, and histones) that can actua…

Efficient DNA Cleavage Induced by Copper(II) Complexes of Hydrolysis Derivatives of 2,4,6‐Tri(2‐pyridyl)‐1,3,5‐triazine in the Presence of Reducing Agents

The reaction of 2,4,6-tri(pyridyl)-1,3,5-triazine (ptz) and copper(II) salts in dmf/water (1:1) results in the hydrolysis of ptz and formation of the anions bis(2-pyridylcarbonyl)amide (ptO2–) and bis(2-pyridylamine)amide (ptN2–), which are found in the complexes [Cu(ptN2)(OAc)]·3H2O (1), [Cu(ptO2)(OAc)(H2O)]·H2O (2), [Cu(ptN2)(for)]·3H2O (3) (for = formate), [Cu(ptO2)(for)(H2O)] (4), [Cu(ptO2)(benz)]·H2O (5) (benz = benzoate), and [Cu(ptO2)F(H2O)]2·3H2O (6). This report includes the chemical and spectroscopic characterization of all these complexes along with the crystal structures of 4–6. The coordination spheres of CuII in 4 and 5 are best described as distorted tetragonal square pyramid…

Extracellular histones disarrange vasoactive mediators reléase through COX-NOS interaction in human endothelial cells

Abstract Extracellular histones are mediators of inflammation, tissue injury and organ dysfunction. Interactions between circulating histones and vascular endothelial cells are key events in histone‐mediated pathologies. Our aim was to investigate the implication of extracellular histones in the production of the major vasoactive compounds released by human endothelial cells (HUVECs), prostanoids and nitric oxide (NO). HUVEC exposed to increasing concentrations of histones (0.001 to 100 μg/ml) for 4 hrs induced prostacyclin (PGI2) production in a dose‐dependent manner and decreased thromboxane A2 (TXA2) release at 100 μg/ml. Extracellular histones raised cyclooxygenase‐2 (COX‐2) and prostac…

Lafora disease fibroblasts exemplify the molecular interdependence between thioredoxin 1 and the proteasome in mammalian cells

13 páginas, 8 figuras (que no aparecen en este documento, se pueden consultar en: http://www.sciencedirect.com/science/article/pii/S0891584913003274#ec0005)

Biological Activity of Flavonoids Copper Complexes

Three flavonoid copper(II) complexes Cu2(quercetin)(CH3COO)3(CH3OH) (1), Cu(anthrarufin)(CH3COO)·1/2H2O (2) and Cu(naringin)(OCH3)(CH3OH)2 (3) have been synthesized and characterized by elemental analysis, IR, electronic absorption and EPR (X-band) spectroscopy. The complexes have a strong protective action over the Δsod1 mutant of S. cerevisiae against reactive oxygen radicals generated by an external source of free radicals (H2O2 or the superoxide-generating, menadione). On the other hand, the complexes cleave DNA efficiently even in the absence of reducing agents. The main reactive oxygen species responsible for the DNA strand cleavage have been determined using radical scavengers. A pro…

Maintenance of glutathione levels and its importance in epigenetic regulation.

Glutathione (GSH) is present in almost all cell types playing an important function in organisms. It is the main antioxidant in many cell types and it also regulates the function of proteins, including transcription factors (reviewed in Pallardo et al., 2009; Markovic et al., 2010; Garcia-Gimenez et al., 2013a). Over recent years, growing evidence has suggested a link between GSH metabolism and the control of epigenetic mechanisms. Epigenetics is defined as the mitotically/meiotically heritable changes in gene expression that are not due to changes in the primary DNA sequence. This link between GSH and epigenetics occurs at different levels. Hence, GSH can affect DNA and histone methylation…

Differential expression of PGC-1α and metabolic sensors suggest age-dependent induction of mitochondrial biogenesis in Friedreich ataxia fibroblasts.

11 pages, 6 figures. PMID:21687738[PubMed] PMCID: PMC3110204

Implementing Precision Medicine in Human Frailty through Epigenetic Biomarkers

The main epigenetic features in aging are: reduced bulk levels of core histones, altered pattern of histone post-translational modifications, changes in the pattern of DNA methylation, replacement of canonical histones with histone variants, and altered expression of non-coding RNA. The identification of epigenetic mechanisms may contribute to the early detection of age-associated subclinical changes or deficits at the molecular and/or cellular level, to predict the development of frailty, or even more interestingly, to improve health trajectories in older adults. Frailty reflects a state of increased vulnerability to stressors as a result of decreased physiologic reserves, and even dysregu…

Oxidative post‐translational modifications in histones

Epigenetic regulation is attracting much attention because it explains many of the effects that the external environment induces in organisms. Changes in the cellular redox status and even more specifically in its nuclear redox compartment is one of these examples. Redox changes can induce modulation of the epigenetic regulation in cells. Here we present a few cases where reactive oxygen or nitrogen species induces epigenetic marks in histones. Posttranslational modification of these proteins like histone nitrosylation, carbonylation, or glutathionylation together with other mechanisms not reviewed here are the cornerstones of redox-related epigenetic regulation. We currently face a new fie…

Cellular Responses in Human Dental Pulp Stem Cells Treated with Three Endodontic Materials

Human dental pulp stem cells (HDPSCs) are of special relevance in future regenerative dental therapies. Characterizing cytotoxicity and genotoxicity produced by endodontic materials is required to evaluate the potential for regeneration of injured tissues in future strategies combining regenerative and root canal therapies. This study explores the cytotoxicity and genotoxicity mediated by oxidative stress of three endodontic materials that are widely used on HDPSCs: a mineral trioxide aggregate (MTA-Angelus white), an epoxy resin sealant (AH-Plus cement), and an MTA-based cement sealer (MTA-Fillapex). Cell viability and cell death rate were assessed by flow cytometry. Oxidative stress was m…

Increased oxidative stress and impaired antioxidant response in Lafora disease.

15 páginas, 10 figuras

Oxidative Stress and Rare Diseases: From Molecular Crossroads to Therapeutic Avenues.

Writing an editorial about rare diseases can become a messy subject from the biological perspective [...]

Circular RNAs in Sepsis: Biogenesis, Function, and Clinical Significance

Sepsis is a life-threatening condition that occurs when the body responds to an infection that damages it is own tissues. The major problem in sepsis is rapid, vital status deterioration in patients, which can progress to septic shock with multiple organ failure if not properly treated. As there are no specific treatments, early diagnosis is mandatory to reduce high mortality. Despite more than 170 different biomarkers being postulated, early sepsis diagnosis and prognosis remain a challenge for clinicians. Recent findings propose that circular RNAs (circRNAs) may play a prominent role in regulating the patients’ immune system against different pathogens, including bacteria and viruses. Mou…

Role of p16INK4a and BMI-1 in oxidative stress-induced premature senescence in human dental pulp stem cells

Human dental pulp stem cells (hDPSCs) are a source for cell therapy. Before implantation, an in vitro expansion step is necessary, with the inconvenience that hDPSCs undergo senescence following a certain number of passages, loosing their stemness properties. Long-term in vitro culture of hDPSCs at 21% (ambient oxygen tension) compared with 3–6% oxygen tension (physiological oxygen tension) caused an oxidative stress-related premature senescence, as evidenced by increased β-galactosidase activity and increased lysil oxidase expression, which is mediated by p16INK4a pathway. Furthermore, hDPSCs cultured at 21% oxygen tension underwent a downregulation of OCT4, SOX2, KLF4 and c-MYC factors, w…

Oxidative stress and antioxidant response in fibroblasts from Werner and Atypical Werner Syndromes

Werner Syndrome (WS, ICD-10 E34.8, ORPHA902) and Atypical Werner Syndrome (AWS, ICD-10 E34.8, ORPHA79474) are very rare inherited syndromes characterized by premature aging. While approximately 90% of WS individuals have any of a range of mutations in theWRN gene, there exists a clinical subgroup in which the mutation occurs in the LMNA/C gene in heterozygosity. Although both syndromes exhibit an age-related pleiotropic phenotype, AWS manifests the onset of the disease during childhood, while major symptoms in WS appear between the ages of 20 and 30. To study the molecular mechanisms of progeroid diseases provides a useful insight into the normal aging process. Main changes found were the d…

Epigenetic biomarkers for human sepsis and septic shock: insights from immunosuppression

Sepsis is a life-threatening condition that occurs when the body responds to an infection damaging its own tissues. Sepsis survivors sometimes suffer from immunosuppression increasing the risk of death. To our best knowledge, there is no ‘gold standard’ for defining immunosuppression except for a composite clinical end point. As the immune system is exposed to epigenetic changes during and after sepsis, research that focuses on identifying new biomarkers to detect septic patients with immunoparalysis could offer new epigenetic-based strategies to predict short- and long-term pathological events related to this life-threatening state. This review describes the most relevant epigenetic mecha…

Small RNA-seq analysis of circulating miRNAs to identify phenotypic variability in Friedreich's ataxia patients.

AbstractFriedreich’s ataxia (FRDA; OMIM 229300), an autosomal recessive neurodegenerative mitochondrial disease, is the most prevalent hereditary ataxia. In addition, FRDA patients have shown additional non-neurological features such as scoliosis, diabetes, and cardiac complications. Hypertrophic cardiomyopathy, which is found in two thirds of patients at the time of diagnosis, is the primary cause of death in these patients. Here, we used small RNA-seq of microRNAs (miRNAs) purified from plasma samples of FRDA patients and controls. Furthermore, we present the rationale, experimental methodology, and analytical procedures for dataset analysis. This dataset will facilitate the identificatio…

Decreased cell proliferation and higher oxidative stress in fibroblasts from Down Syndrome fetuses. Preliminary study

Abstract Down Syndrome is the most common chromosomal disease and is also known for its decreased incidence of solid tumors and its progeroid phenotype. Cellular and systemic oxidative stress has been considered as one of the Down Syndrome phenotype causes. We correlated, in a preliminary study, the fibroblast proliferation rate and different cell proliferation key regulators, like Rcan1 and the telomere length from Down Syndrome fetuses, with their oxidative stress profile and the Ribonucleic acid and protein expression of the main antioxidant enzymes together with their activity. Increased oxidized glutathione/glutathione ratio and high peroxide production were found in our cell model. Th…

Circulating miRNAs as diagnostic biomarkers for adolescent idiopathic scoliosis

AbstractThe aetiology of adolescent idiopathic scoliosis (AIS) has been linked to many factors, such as asymmetric growth, neuromuscular condition, bone strength and genetic background. Recently, epigenetic factors have been proposed as contributors of AIS physiopathology, but information about the molecular mechanisms and pathways involved is scarce. Regarding epigenetic factors, microRNAs (miRNAs) are molecules that contribute to gene expression modulation by regulating important cellular pathways. We herein used Next-Generation Sequencing to discover a series of circulating miRNAs detected in the blood samples of AIS patients, which yielded a unique miRNA biomarker signature that diagnos…

Oxidative Stress and the Epigenetics of Cell Senescence: Insights from Progeroid Syndromes.

Background: Cell senescence constitutes a critical process to respond to a variety of insults and adverse circumstances. Senescence involves the detention of DNA replication and cell proliferation, and hence, genetic programs associated with DNA damage response, chromosome stability, chromatin rearrangement, epigenetic reprogramming, and cell cycle are tightly linked to the senescent phenotype. Although senescence increases with age, the real implication of senescence regulation in the progress of aging in humans is largely discussed. In this context, reactive oxygen species (ROS) accumulation has also been postulated to play a critical role in cell homeostasis, aging processes, and contro…

Could thiazolidinediones increase the risk of heart failure in Friedreich's ataxia patients?

Clinical evidence and the recent decisions of the European Medicines Agency and the Food and Drug Administration challenge the safety of thiazolidinediones treatment. Recently, this treatment has been suggested for Friedreich's ataxia because thiazolidinediones improve neurological symptoms. Hypertrophic cardiomyopathy is the most prevalent cardiac feature and the cause of premature death in Friedreich's ataxia patients. We recommend that therapy with peroxisome proliferator-activated receptor-gamma agonists like thiazolidinediones be taken with caution, as they cause a decrease in the number of fast fibers and an increase in mitochondrial biogenesis in cardiac muscle because of the inducti…

Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells.

Circulating histones have been proposed as targets for therapy in sepsis and hyperinflammatory symptoms. However, the proposed strategies have failed in clinical trials. Although different mechanisms for histone-related cytotoxicity are being explored, those mediated by circulating histones are not fully understood. Extracellular histones induce endothelial cell death, thereby contributing to the pathogenesis of complex diseases such as sepsis and septic shock. Therefore, the comprehension of cellular responses triggered by histones is capital to design effective therapeutic strategies. Here we report how extracellular histones induce autophagy and apoptosis in a dose-dependent manner in cu…

Impact of periodontal treatment on the RANKL/OPG ratio in crevicular fluid.

Aim Alveolar resorption is one of the most important events in periodontitis. Osteoclast activity is regulated by the ratio between receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). The aim of this study was to evaluate changes in the RANKL/OPG ratio in crevicular fluid after periodontal treatment. Material and methods A total of 15 patients with periodontitis were included in the study group. Samples were collected from an area with active periodontitis and a healthy area. The RANKL and OPG levels were measured before and after periodontal scaling and root planing (SRP) treatment. The study group was compared to the control group, which included 10 patients without peri…

Extracellular Histones Activate Endothelial NLRP3 Inflammasome and are Associated with a Severe Sepsis Phenotype

Jesús Beltrán-García,1– 3 Rebeca Osca-Verdegal,1,3 Daniel Pérez-Cremades,2,3 Susana Novella,2,3 Carlos Hermenegildo,2,3 Federico V Pallardó,1– 3 José Luis García-Giménez1– 3 1Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; 2Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain; 3Departamento de Fisiología, Facultad de Medicina y Odontología, Universitat de València, València, SpainCorrespondence: José Luis García-Giménez, Departamento de Fisiología, Facultad de Medicina y Odontología, Universitat de València, València, 46010, Spain, Tel +34 963 864 646, Email j.luis.garcia@uv.esIntrod…

Corrigendum to “A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration” [Biochim. Biophys. Acta 1863 (2017) 801–809]

Expression of the genetic suppressor element 24.2 (GSE24.2) decreases DNA damage and oxidative stress in X-linked dyskeratosis congenita cells.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.

The Intricate Role of Non-Coding RNAs in Sepsis-Associated Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulation (DIC) is a type of tissue and organ dysregulation in sepsis, due mainly to the effect of the inflammation on the coagulation system. Unfortunately, the underlying molecular mechanisms that lead to this disorder are not fully understood. Moreover, current biomarkers for DIC, including biological and clinical parameters, generally provide a poor diagnosis and prognosis. In recent years, non-coding RNAs have been studied as promising and robust biomarkers for a variety of diseases. Thus, their potential in the diagnosis and prognosis of DIC should be further studied. Specifically, the relationship between the coagulation cascade and non-coding RNAs should…

Epigenetic Regulation in the Pathogenesis of Sjögren Syndrome and Rheumatoid Arthritis

Autoimmune rheumatic diseases, such as Sjögren syndrome (SS) and rheumatoid arthritis (RA), are characterized by chronic inflammation and autoimmunity, which cause joint tissue damage and destruction by triggering reduced mobility and debilitation in patients with these diseases. Initiation and maintenance of chronic inflammatory stages account for several mechanisms that involve immune cells as key players and the interaction of the immune cells with other tissues. Indeed, the overlapping of certain clinical and serologic manifestations between SS and RA may indicate that numerous immunologic-related mechanisms are involved in the physiopathology of both these diseases. It is widely accept…

Oxidative nuclease activity of ferromagnetically coupled μ-hydroxo-μ-propionato copper(II) complexes [Cu3(L)2(μ-OH)2(μ-propionato)2] (L=N-(pyrid-2-ylmethyl)R-sulfonamidato, R=benzene, toluene, naphthalene)

Three doubly-bridged, trinuclear copper(II) compounds with hydroxo and carboxylato bridges, ∞ 1 [Cu 3 (L1) 2 (μ-OH) 2 (μ-propionato) 2 ] ∞ 1 [ Cu 3 ( L 1 ) 2 ( μ - OH ) 2 ( μ - propionato ) 2 ] (1) , [Cu 3 (L2) 2 (μ-OH) 2 (μ-propionato) 2 (DMF) 2 ] (2) and ∞ 1 {[Cu 3 (L3) 2 (μ-OH) 2 (μ-propionato) 2 ]} ∞ 1 { [ Cu 3 ( L 3 ) 2 ( μ - OH ) 2 ( μ - propionato ) 2 ] } [Cu 3 (L3) 2 (μ-OH) 2 (μ-propionato) 2 (DMF) 2 ]} (3) [HL1 =  N -(pyrid-2-ylmethyl)benzenesulfonylamide, HL2 =  N -(pyrid-2-ylmethyl)toluenesulfonylamide, HL3 =  N -(pyrid-2-ylmethyl)naphthalenesulfonylamide], have been synthesized and characterized. 1 is built from [Cu 3 (L1) 2 (μ-OH) 2 (μ-propionato) 2 ] clusters. Each unit contai…

Epigenetic biomarkers: Current strategies and future challenges for their use in the clinical laboratory

Epigenetic modifications and regulators represent potential molecular elements which control relevant physiological and pathological features, thereby contributing to the natural history of human disease. These epigenetic modulators can be employed as disease biomarkers, since they show several advantages and provide information about gene function, thus explaining differences among patient endophenotypes. In addition, epigenetic biomarkers can incorporate information regarding the effects of the environment and lifestyle on health and disease, and monitor the effect of applied therapies. Technologies used to analyze these epigenetic biomarkers are constantly improving, becoming much easier…