ABSTRACT
OBJECTIVES: Dravet syndrome (DS) is a rare form of refractory epilepsy that begins in the first year of life. Approximately 85% of patients have a mutation in the SCN1A gene, which encodes a voltage-gated sodium channel. The main objective of the present work was to assess the degree of knowledge of DS among Spanish primary care (PC) professionals, the communication flow between them and the pediatric neurologists (PNs), and the services available and resources offered to patients in Spain when searching for a diagnosis and adequate treatment. METHODS: Two anonymized online surveys on DS diagnosis and patient management in PC were conducted with Spanish PC pediatricians (PCPs) and caregivers of DS patients in Spain. RESULTS: Most PCPs are aware of genetic epilepsy but lack full knowledge of DS and patient advocacy groups (PAGs). Access to epilepsy treatments varies among regions, with many referrals to hospitals and pediatric neurologists. Diagnosis is often delayed, with misdiagnoses and frequent emergency room (ER) visits. Treatment involves multiple drugs, and sodium channel blockers are used, which are contraindicated in DS treatment. Improved training, resources, and communication are needed for early diagnosis. SIGNIFICANCE: To improve the care and treatment of DS patients in Spain, early diagnosis is required and, possibly, specific efforts aimed at identifying patients in adulthood, generating socio-sanitary structures that integrate social and health services to provide comprehensive care, taking into account the different features and comorbidities of the disease. PLAIN LANGUAGE SUMMARY: Dravet syndrome (DS) is a form of genetic epilepsy that starts within the first year of life. We present a study showing that, while family doctors are aware of genetic epilepsies, many don't have a complete understanding of DS. Unfortunately, getting the right diagnosis can take a long time, leading to unnecessary visits to the emergency room. Patients often need several medications, and sometimes they're given drugs that aren't recommended for DS. The takeaway is that training for doctors, more resources, and improved communication could help creating better healthcare systems and therefore give easier access to the right therapies.
ABSTRACT
Epigenetic mechanisms contribute to the maintenance of both type 2 diabetes mellitus (T2DM) and psychiatric disorders. Emerging evidence suggests that molecular pathways and neurocognitive performance regulate epigenetic dynamics in these disorders. The current combined and transdiagnostic study investigated whether inflammatory, oxidative stress, adhesion molecule, neurocognitive and functional performance are significant predictors of telomere dynamics in a sample stratified by global DNA methylation levels. Peripheral blood inflammation, oxidative stress and adhesion molecule biomarkers and neurocognitive function were assessed twice over a 1-year period in 80 individuals, including 16 with schizophrenia (SZ), 16 with bipolar disorder (BD), 16 with major depressive disorder (MDD), 15 with T2DM, and 17 healthy controls (HCs). Leukocyte telomere length (LTL) was measured by qRT-PCR using deoxyribonucleic acid (DNA) extracted from peripheral blood samples. A posteriori, individuals were classified based on their global methylation score (GMS) at baseline into two groups: the below-average methylation (BM) and above-average methylation (AM) groups. Hierarchical and k-means clustering methods, mixed one-way analysis of variance and linear regression analyses were performed. Overall, the BM group showed a significantly higher leukocyte telomere length (LTL) than the AM group at both time points (p = 0.02; η2p = 0.06). Moreover, the BM group had significantly lower levels of tumor necrosis factor alpha (TNF-α) (p = 0.03; η2p = 0.06) and C-reactive protein (CRP) (p = 0.03; η2p = 0.06) than the AM group at the 1-year follow-up. Across all participants, the regression models showed that oxidative stress (reactive oxygen species [ROS]) (p = 0.04) and global cognitive score [GCS] (p = 0.02) were significantly negatively associated with LTL, whereas inflammatory (TNF-α) (p = 0.04), adhesion molecule biomarkers (inter cellular adhesion molecule [ICAM]) (p = 0.009), and intelligence quotient [IQ] (p = 0.03) were significantly positively associated with LTL. Moreover, the model predictive power was increased when tested in both groups separately, explaining 15.8% and 28.1% of the LTL variance at the 1-year follow-up for the AM and BM groups, respectively. Heterogeneous DNA methylation in individuals with T2DM and severe mental disorders seems to support the hypothesis that epigenetic dysregulation occurs in a transdiagnostic manner. Our results may help to elucidate the interplay between epigenetics, molecular processes and neurocognitive function in these disorders. DNA methylation and LTL are potential therapeutic targets for transdiagnostic interventions to decrease the risk of comorbidities.
Subject(s)
DNA Methylation , Inflammation , Oxidative Stress , Schizophrenia , Telomere , Humans , Male , Female , Inflammation/blood , Inflammation/genetics , Adult , Middle Aged , Telomere/genetics , Telomere/metabolism , Schizophrenia/genetics , Schizophrenia/blood , Diabetes Mellitus, Type 2/genetics , Biomarkers/blood , Bipolar Disorder/genetics , Bipolar Disorder/blood , Depressive Disorder, Major/genetics , Depressive Disorder, Major/blood , Leukocytes/metabolism , Epigenesis, Genetic , Telomere Homeostasis , Cognition , Case-Control StudiesABSTRACT
Cancer cells employ adaptive mechanisms to survive various stressors, including genotoxic drugs. Understanding the factors promoting survival is crucial for developing effective treatments. In this study, we unveil a previously unexplored long non-coding RNA, JUNI (JUN-DT, LINC01135), which is upregulated by genotoxic drugs through the activation of stress-activated MAPKs, JNK, and p38 and consequently exerts positive control over the expression of its adjacent gene product c-Jun, a well-known oncoprotein, which transduces signals to multiple transcriptional outputs. JUNI regulates cellular migration and has a crucial role in conferring cellular resistance to chemotherapeutic drugs or UV radiation. Depletion of JUNI markedly increases the sensitivity of cultured cells and spheroids to chemotherapeutic agents. We identified 57 proteins interacting with JUNI. The activity of one of them the MAPK phosphatase and inhibitor, DUSP14, is counteracted by JUNI, thereby, facilitating efficient JNK phosphorylation and c-Jun induction when cells are exposed to UV radiation. The antagonistic interplay with DUSP14 contributes not only to c-Jun induction but also augments the survival of UV-exposed cells. In summary, we introduce JUNI as a novel stress-inducible regulator of c-Jun, positioning it as a potential target for enhancing the sensitivity of cancer cells to chemotherapy.
Subject(s)
Cell Movement , Cell Survival , Dual-Specificity Phosphatases , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Dual-Specificity Phosphatases/metabolism , Dual-Specificity Phosphatases/genetics , Cell Movement/genetics , Cell Survival/radiation effects , Cell Survival/genetics , Cell Survival/drug effects , Proto-Oncogene Proteins c-jun/metabolism , Proto-Oncogene Proteins c-jun/genetics , Cell Line, Tumor , Ultraviolet Rays/adverse effects , MAP Kinase Signaling System/genetics , Gene Expression Regulation, Neoplastic , JNK Mitogen-Activated Protein Kinases/metabolismABSTRACT
A wide range of approaches can be used to detect micro RNA (miRNA)-target gene pairs (mTPs) from expression data, differing in the ways the gene and miRNA expression profiles are calculated, combined and correlated. However, there is no clear consensus on which is the best approach across all datasets. Here, we have implemented multiple strategies and applied them to three distinct rare disease datasets that comprise smallRNA-Seq and RNA-Seq data obtained from the same samples, obtaining mTPs related to the disease pathology. All datasets were preprocessed using a standardized, freely available computational workflow, DEG_workflow. This workflow includes coRmiT, a method to compare multiple strategies for mTP detection. We used it to investigate the overlap of the detected mTPs with predicted and validated mTPs from 11 different databases. Results show that there is no clear best strategy for mTP detection applicable to all situations. We therefore propose the integration of the results of the different strategies by selecting the one with the highest odds ratio for each miRNA, as the optimal way to integrate the results. We applied this selection-integration method to the datasets and showed it to be robust to changes in the predicted and validated mTP databases. Our findings have important implications for miRNA analysis. coRmiT is implemented as part of the ExpHunterSuite Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite.
Subject(s)
MicroRNAs , Consensus , Databases, Factual , MicroRNAs/genetics , Odds Ratio , RNA-SeqABSTRACT
BACKGROUND: As leading contributors to worldwide morbidity and mortality, sepsis and septic shock are considered a major global health concern. Proactive biomarker identification in patients with sepsis suspicion at any time remains a daunting challenge for hospitals. Despite great progress in the understanding of clinical and molecular aspects of sepsis, its definition, diagnosis, and treatment remain challenging, highlighting a need for new biomarkers with potential to improve critically ill patient management. In this study we validate a quantitative mass spectrometry method to measure circulating histone levels in plasma samples for the diagnosis and prognosis of sepsis and septic shock patients. METHODS: We used the mass spectrometry technique of multiple reaction monitoring to quantify circulating histones H2B and H3 in plasma from a monocenter cohort of critically ill patients admitted to an Intensive Care Unit (ICU) and evaluated its performance for the diagnosis and prognosis of sepsis and septic shock (SS). RESULTS: Our results highlight the potential of our test for early diagnosis of sepsis and SS. H2B levels above 121.40 ng/mL (IQR 446.70) were indicative of SS. The value of blood circulating histones to identify a subset of SS patients in a more severe stage with associated organ failure was also tested, revealing circulating levels of histones H2B above 435.61 ng/ml (IQR 2407.10) and H3 above 300.61 ng/ml (IQR 912.77) in septic shock patients with organ failure requiring invasive organ support therapies. Importantly, we found levels of H2B and H3 above 400.44 ng/mL (IQR 1335.54) and 258.25 (IQR 470.44), respectively in those patients who debut with disseminated intravascular coagulation (DIC). Finally, a receiver operating characteristic curve (ROC curve) demonstrated the prognostic value of circulating histone H3 to predict fatal outcomes and found for histone H3 an area under the curve (AUC) of 0.720 (CI 0.546-0.895) p < 0.016 on a positive test cut-off point at 486.84 ng/mL, showing a sensitivity of 66.7% and specificity of 73.9%. CONCLUSIONS: Circulating histones analyzed by MS can be used to diagnose SS and identify patients at high risk of suffering DIC and fatal outcome.
Subject(s)
Sepsis , Shock, Septic , Humans , Histones , Critical Illness , Prognosis , Early Diagnosis , Mass SpectrometryABSTRACT
Lafora disease is a rare, fatal form of progressive myoclonus epilepsy characterized by continuous neurodegeneration with epileptic seizures, characterized by the intracellular accumulation of aberrant polyglucosan granules called Lafora bodies. Several works have provided numerous evidence of molecular and cellular alterations in neural tissue from experimental mouse models deficient in either laforin or malin, two proteins related to the disease. Oxidative stress, alterations in proteostasis, and deregulation of inflammatory signals are some of the molecular alterations underlying this condition in both KO animal models. Lafora bodies appear early in the animal's life, but many of the aforementioned molecular aberrant processes and the consequent neurological symptoms ensue only as animals age. Here, using small RNA-seq and quantitative PCR on brain extracts from laforin and malin KO male mice of different ages, we show that two different microRNA species, miR-155 and miR-146a, are overexpressed in an age-dependent manner. We also observed altered expression of putative target genes for each of the microRNAs studied in brain extracts. These results open the path for a detailed dissection of the molecular consequences of laforin and malin deficiency in brain tissue, as well as the potential role of miR-155 and miR-146a as specific biomarkers of disease progression in LD.
Subject(s)
Lafora Disease , MicroRNAs , Mice , Male , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Lafora Disease/genetics , Lafora Disease/metabolism , Neuroinflammatory Diseases , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Protein Tyrosine Phosphatases, Non-Receptor/metabolism , Oxidative Stress/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Sepsis management remains one of the most important challenges in modern clinical practice. Rapid progression from sepsis to septic shock is practically unpredictable, hence the critical need for sepsis biomarkers that can help clinicians in the management of patients to reduce the probability of a fatal outcome. Circulating nucleoproteins released during the inflammatory response to infection, including neutrophil extracellular traps, nucleosomes, and histones, and nuclear proteins like HMGB1, have been proposed as markers of disease progression since they are related to inflammation, oxidative stress, endothelial damage, and impairment of the coagulation response, among other pathological features. The aim of this work was to evaluate the actual potential for decision making/outcome prediction of the most commonly proposed chromatin-related biomarkers (i.e., nucleosomes, citrullinated H3, and HMGB1). To do this, we compared different ELISA measuring methods for quantifying plasma nucleoproteins in a cohort of critically ill patients diagnosed with sepsis or septic shock compared to nonseptic patients admitted to the intensive care unit (ICU), as well as to healthy subjects. Our results show that all studied biomarkers can be used to monitor sepsis progression, although they vary in their effectiveness to separate sepsis and septic shock patients. Our data suggest that HMGB1/citrullinated H3 determination in plasma is potentially the most promising clinical tool for the monitoring and stratification of septic patients.
Subject(s)
Biomarkers/metabolism , Chromatin/metabolism , Shock, Septic/metabolism , Animals , Antibodies, Monoclonal/metabolism , Citrulline/metabolism , Cohort Studies , Female , HMGB1 Protein/metabolism , Histones/metabolism , Humans , Immunoassay , Male , Mice , Middle Aged , Nucleoproteins/blood , Pilot ProjectsABSTRACT
Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/- mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.
Subject(s)
Aging/pathology , Cochlea/pathology , Haploinsufficiency/genetics , Hearing Loss, Noise-Induced/pathology , Inflammation/pathology , Insulin-Like Growth Factor I/metabolism , Animals , Auditory Threshold , Biomarkers/metabolism , Cell Death/genetics , Cochlea/physiopathology , Cytokines/genetics , Cytokines/metabolism , Gene Expression Profiling , Gene Expression Regulation , Hearing Loss, Noise-Induced/blood , Hearing Loss, Noise-Induced/genetics , Hearing Loss, Noise-Induced/physiopathology , Heterozygote , Inflammation/blood , Inflammation/genetics , Inflammation/physiopathology , Insulin-Like Growth Factor I/genetics , Mice , Noise , Oxidative Stress/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Synapses/metabolismABSTRACT
High-throughput gene expression analysis is widely used. However, analysis is not straightforward. Multiple approaches should be applied and methods to combine their results implemented and investigated. We present methodology for the comprehensive analysis of expression data, including co-expression module detection and result integration via data-fusion, threshold based methods, and a Naïve Bayes classifier trained on simulated data. Application to rare-disease model datasets confirms existing knowledge related to immune cell infiltration and suggest novel hypotheses including the role of calcium channels. Application to simulated and spike-in experiments shows that combining multiple methods using consensus and classifiers leads to optimal results. ExpHunter Suite is implemented as an R/Bioconductor package available from https://bioconductor.org/packages/ExpHunterSuite . It can be applied to model and non-model organisms and can be run modularly in R; it can also be run from the command line, allowing scalability with large datasets. Code and reports for the studies are available from https://github.com/fmjabato/ExpHunterSuiteExamples .
Subject(s)
Gene Expression Profiling/methods , Gene Expression Regulation/genetics , RNA-Seq/methods , Software , Algorithms , Arabidopsis/genetics , Bayes Theorem , Calcium Channels/genetics , Humans , Rare Diseases/genetics , Rare Diseases/metabolismABSTRACT
Writing an editorial about rare diseases can become a messy subject from the biological perspective [...].
ABSTRACT
Epigenetic regulation of gene expression provides a finely tuned response capacity for cells when undergoing environmental changes. However, in the context of human physiology or disease, any cellular imbalance that modulates homeostasis has the potential to trigger molecular changes that result either in physiological adaptation to a new situation or pathological conditions. These effects are partly due to alterations in the functionality of epigenetic regulators, which cause long-term and often heritable changes in cell lineages. As such, free radicals resulting from unbalanced/extended oxidative stress have been proved to act as modulators of epigenetic agents, resulting in alterations of the epigenetic landscape. In the present review we will focus on the particular effect that oxidative stress and free radicals produce in histone post-translational modifications that contribute to altering the histone code and, consequently, gene expression. The pathological consequences of the changes in this epigenetic layer of regulation of gene expression are thoroughly evidenced by data gathered in many physiological adaptive processes and in human diseases that range from age-related neurodegenerative pathologies to cancer, and that include respiratory syndromes, infertility, and systemic inflammatory conditions like sepsis.
Subject(s)
Epigenesis, Genetic , Histones , DNA Methylation , Gene Expression , Histones/genetics , Histones/metabolism , Humans , Oxidative Stress , Protein Processing, Post-TranslationalABSTRACT
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. Specifically, in the context of Friedreich's ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.
ABSTRACT
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 mechanisms underlying alterations in the innate and adaptive immune responses described in sepsis and septic shock, and their consequences for immunosuppression states, providing several candidates to become epigenetic biomarkers that could improve sepsis management and help predict immunosuppression in postseptic patients.
Subject(s)
Epigenesis, Genetic , Immunosuppression Therapy , Sepsis/genetics , Shock, Septic/genetics , Adaptive Immunity , Biomarkers , DNA Methylation , Histones , Humans , Immunity, Innate , RNA, Untranslated , Sepsis/immunology , Shock, Septic/immunologyABSTRACT
Recent observations related to the structure of the cytoskeleton in neurons and novel cytoskeletal abnormalities involved in the pathophysiology of some neurological diseases are changing our view on the function of the cytoskeletal proteins in the nervous system. These efforts allow a better understanding of the molecular mechanisms underlying neurological diseases and allow us to see beyond our current knowledge for the development of new treatments. The neuronal cytoskeleton can be described as an organelle formed by the three-dimensional lattice of the three main families of filaments: actin filaments, microtubules, and neurofilaments. This organelle organizes well-defined structures within neurons (cell bodies and axons), which allow their proper development and function through life. Here, we will provide an overview of both the basic and novel concepts related to those cytoskeletal proteins, which are emerging as potential targets in the study of the pathophysiological mechanisms underlying neurological disorders.
Subject(s)
Cytoskeletal Proteins/metabolism , Nervous System Diseases/metabolism , Actin Cytoskeleton/metabolism , Axons/metabolism , Growth Cones/metabolism , Humans , Mutation/geneticsABSTRACT
Lafora disease (LD) is a rare, fatal form of progressive myoclonus epilepsy. The molecular basis of this devastating disease is still poorly understood, and no treatment is available yet, which leads to the death of the patients around 10 years from the onset of the first symptoms. The hallmark of LD is the accumulation of insoluble glycogen-like inclusions in the brain and peripheral tissues, as a consequence of altered glycogen homeostasis. In addition, other determinants in the pathophysiology of LD have been suggested, such as proteostasis impairment, with reduction in autophagy, and oxidative stress, among others. In order to gain a general view of the genes involved in the pathophysiology of LD, in this work, we have performed RNA-Seq transcriptome analyses of whole-brain tissue from two independent mouse models of the disease, namely Epm2a-/- and Epm2b-/- mice, at different times of age. Our results provide strong evidence for three major facts: first, in both models of LD, we found a common set of upregulated genes, most of them encoding mediators of inflammatory response; second, there was a progression with the age in the appearance of these inflammatory markers, starting at 3 months of age; and third, reactive glia was responsible for the expression of these inflammatory genes. These results clearly indicate that neuroinflammation is one of the most important traits to be considered in order to fully understand the pathophysiology of LD, and define reactive glia as novel therapeutic targets in the disease.
Subject(s)
Age Factors , Lafora Disease/metabolism , Myoclonic Epilepsies, Progressive/metabolism , Neuroglia/metabolism , Protein Tyrosine Phosphatases, Non-Receptor/metabolism , Animals , Disease Models, Animal , Disease Progression , Glycogen/metabolism , Inclusion Bodies/metabolism , Lafora Disease/genetics , Mice, Knockout , Myoclonic Epilepsies, Progressive/genetics , Oxidative Stress/physiologyABSTRACT
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 field of research with potential important consequences for the treatment of many pathologies.
Subject(s)
Epigenesis, Genetic , Histones/metabolism , Protein Processing, Post-Translational , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Animals , Glutathione/metabolism , Histones/genetics , Humans , Mice , Nitroso Compounds/metabolism , Oxidation-Reduction , Oxidative Stress , Protein Carbonylation , Signal Transduction , Sulfur Compounds/metabolismABSTRACT
No disponible
Subject(s)
Humans , Health Education/methods , Vaccination , Communicable Disease Control/methods , Concept Formation , Health Promotion/methods , Vaccination Refusal/trendsABSTRACT
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 cultured human endothelial cells. In addition, we describe how histones regulate these pathways via Sestrin2/AMPK/ULK1-mTOR and AKT/mTOR. Furthermore, we evaluate the effect of Toll-like receptors in mediating autophagy and apoptosis demonstrating how TLR inhibitors do not prevent apoptosis and/or autophagy induced by histones. Our results confirm that histones and autophagic pathways can be considered as novel targets to design therapeutic strategies in endothelial damage.
Subject(s)
Histones/pharmacology , Human Umbilical Vein Endothelial Cells/cytology , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinases/metabolism , Autophagy , Autophagy-Related Protein-1 Homolog/metabolism , Cell Survival/drug effects , Dose-Response Relationship, Drug , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Nuclear Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
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 control of proliferation. METHODS: The previous years have produced a high increase in data that refine our understanding of the role of ROS, and their relationship with epigenetic events, in determining cellular fate. RESULTS: The accumulating evidence regarding the epigenetic regulation of ROS-mediated processes provides promising tools to deepen in our comprehension of the process of senescence, and to develop novel therapeutic strategies. In this review, we aim to provide an overview of the relationships between oxidative stress and cell senescence. CONCLUSION: We provide information about the role of epigenetic regulation in senescence and aging, collecting recent data from some examples of progeroid syndromes in which cell senescence, oxidative stress and epigenetic mechanisms are severely impaired. Finally, a collection of data is presented regarding current pharmacological approaches that either target or use oxidative stress-related factors or epigenetic regulators as strategies for disease treatment.
Subject(s)
Cellular Senescence/genetics , Epigenesis, Genetic/genetics , Oxidative Stress/genetics , Animals , Cellular Senescence/drug effects , Epigenesis, Genetic/drug effects , Humans , Oxidative Stress/drug effects , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , SyndromeABSTRACT
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 to use. Laboratory professionals can easily acquire experience and techniques are becoming more affordable. A high number of epigenetic biomarker candidates are being continuously proposed, making now the moment to adopt epigenetics in the clinical laboratory and convert epigenetic marks into reliable biomarkers. In this review, we describe some current promising epigenetic biomarkers and technologies being applied in clinical practice. Furthermore, we will discuss some laboratory strategies and kits to accelerate the adoption of epigenetic biomarkers into clinical routine. The likelihood is that over time, better markers will be identified and will likely be incorporated into future multi-target assays that might help to optimize its application in a clinical laboratory. This will improve cost-effectiveness, and consequently encourage the development of theragnosis and the application of precision medicine.