Circulating Histones and Nucleosomes as Biomarkers in Sepsis and Septic Shock

Sepsis, severe sepsis, and septic shock are among the leading causes of death worldwide and their incidence is constantly increasing. Despite early intervention in intensive care units (ICUs) mortality remains high. There is great interest in understanding the genetics and epigenetics of the host in response to infection because of two reasons: the peculiarities of each patient, and the unclear associations identified between genetic polymorphisms and susceptibility to sepsis. In addition, chromatin remodeling and epigenetic changes occur in crucial genes involved in the inflammatory response and also in the immunosuppression found in sepsis. The early and accurate diagnosis of sepsis is a …

Acute telomerase components depletion triggers oxidative stress as an early event previous to telomeric shortening

Loss of function of dyskerin (DKC1), NOP10 and TIN2 are responsible for different inheritance patterns of Dyskeratosis congenita (DC; ORPHA1775). They are key components of telomerase (DKC1 and NOP10) and shelterin (TIN2), and play an important role in telomere homeostasis. They participate in several fundamental cellular processes by contributing to Dyskeratosis congenita through mechanisms that are not fully understood. Presence of oxidative stress was postulated to result from telomerase ablation. However, the resulting disturbed redox status can promote telomere attrition by generating a vicious circle, which promotes cellular senescence. This fact prompted us to study if acute loss of …

A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration

[EN] Charcot-Marie-Tooth disease is a rare peripheral neuropathy for which there is no specific treatment. Some forms of Charcot-Marie-Tooth are due to mutations in the GDAP1 gene. A striking feature of mutations in GDAP1 is that they have a variable clinical manifestation, according to disease onset and progression, histology and mode of inheritance. Studies in cellular and animal models have revealed a role of GDAP1 in mitochondrial morphology and distribution, calcium homeostasis and oxidative stress. To get a better understanding of the disease mechanism we have generated models of over-expression and RNA interference of the Drosophila Gdapl gene. In order to get an overview about the c…

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

Oxidative stress is an imbalance between production and accumulation of oxygen reactive species and/or reactive nitrogen species in cells and tissues, and the capacity of detoxifying these products, using enzymatic and non-enzymatic components, such as glutathione. Oxidative stress plays roles in several pathological processes in the nervous system, such as neurotoxicity, neuroinflammation, ischemic stroke, and neurodegeneration. The concepts of oxidative stress and rare diseases were formulated in the eighties, and since then, the link between them has not stopped growing. The present review aims to expand knowledge in the pathological processes associated with oxidative stress underlying …

Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot–Marie–Tooth neuropathy

One of the genes involved in Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is GDAP1. In this work, we show that there is a true ortholog of this gene in Drosophila, which we have named Gdap1. By up- and down-regulation of Gdap1 in a tissue-specific manner, we show that altering its levels of expression produces changes in mitochondrial size, morphology and distribution, and neuronal and muscular degeneration. Interestingly, muscular degeneration is tissue-autonomous and not dependent on innervation. Metabolic analyses of our experimental genotypes suggest that alterations in oxidative stress are not a primary cause of the neuromuscular degeneration but a long-term c…

Glutathione and cellular redox control in epigenetic regulation.

Epigenetics is defined as the mitotically/meiotically heritable changes in gene expression that are not due to changes in the primary DNA sequence. Over recent years, growing evidence has suggested a link between redox metabolism and the control of epigenetic mechanisms. The effect of the redox control, oxidative stress, and glutathione (GSH) on the epigenetic mechanisms occur at different levels affecting DNA methylation, miRNAs expression, and histone post-translational modifications (PTMs). Furthermore, a number of redox PTMs are being described, so enriching the histone code. Pioneer works showed how oxidized GSH inhibits the activity of S-adenosyl methionine synthetase, MAT1A, a key en…

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)

Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich’s ataxia patients

AbstractMicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich’s ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich’s ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated. We found seven differentially expressed miRNAs, and we propose that these miRNAs represent …

Increased oxidative stress and impaired antioxidant response in Lafora disease.

15 páginas, 10 figuras

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…

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…

Acute depletion of telomerase components DKC1 and NOP10 induces oxidative stress and disrupts ribosomal biogenesis via NPM1 and activation of the P53 pathway.

Mutations in DKC1, NOP10, and TINF2 genes, coding for proteins in telomerase and shelterin complexes, are responsible for diverse diseases known as telomeropathies and ribosomopathies, including dyskeratosis congenita (DC, ORPHA 1775). These genes contribute to the DC phenotype through mechanisms that are not completely understood. We previously demonstrated in models of DC that oxidative stress is an early and independent event that occurs prior to telomere shortening. To clarify the mechanisms that induce oxidative stress, we silenced genes DKC1, NOP10, and TINF2 with siRNA technology. With RNA array hybridisation, we found several altered pathways for each siRNA model. Afterwards, we ide…

Epigenetics in spine curvature disorders

Abstract Scoliosis is a three-dimensional (3D) structural deformity of the spine with a radiological lateral Cobb angle of ≥ 10°. Several classification systems exist, dividing different types regarding the age of onset or the type of etiology. The minority of cases are secondary to congenital, syndromic of neuromosucular diseases. Most of the cases are classified “idiopathic” due to unknown etiology. These were formally divided by the age of onset into “Infantile Idiopathic Scoliosis” (0–3 years), “Juvenile Idiopathic Scoliosis” (JIS—4–10 years), and “Adolescent Idiopathic Scoliosis” (AIS → 10 years). Since the initiative of the Scoliosis Research Society in 2014 all kind of scoliosis with…

Is the Macrophage Phenotype Determinant for Fibrosis Development?

Fibrosis is a pathophysiological process of wound repair that leads to the deposit of connective tissue in the extracellular matrix. This complication is mainly associated with different pathologies affecting several organs such as lung, liver, heart, kidney, and intestine. In this fibrotic process, macrophages play an important role since they can modulate fibrosis due to their high plasticity, being able to adopt different phenotypes depending on the microenvironment in which they are found. In this review, we will try to discuss whether the macrophage phenotype exerts a pivotal role in the fibrosis development in the most important fibrotic scenarios.

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…

Epigenetic biomarkers for disease diagnosis

Abstract Epigenetic dysregulation plays an important role in the initiation and progression of human diseases; therefore, because of the dynamic nature of this orchestrated regulation of epigenetic marks and epigenetic mechanisms, it is possible to use these marks as biomarkers. In this context, an epigenetic biomarker is “any epigenetic mark or altered epigenetic mechanism” which generally serves to evaluate health or disease status, progression or treatment response and is particularly stable and reproducible during sample processing. Advances in precision medicine, with better diagnostic and treatment strategies are the hope to improve the management of diseases, comorbidities, and morta…

Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia

The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifical…

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]

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…

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…

miR-1226 detection in GCF as potential biomarker of chronic periodontitis: a pilot study

Background The study and identification of new biomarkers for periodontal disease, such as microRNAs (miRNAs), may give us more information about the location and severity of the disease and will serve as a basis for treatment planning and disease-monitoring. miRNAs are a group of small RNAs which are involved in gene regulation by binding to their messenger RNA target (mRNA). In this pilot study, the procedure for purifying miRNAs from gingival crevicular fluid (GCF) was, for the first time, described. In addition, the concentration of miRNAs in GCF was analyzed and compared between patients with moderate or severe chronic periodontitis (CP) and healthy controls. Material and Methods GCF s…