Epigenetic mechanisms, including DNA methylation, hydroxymethylation, histone modifications, and the regulation of microRNAs and long non-coding RNAs, are demonstrably dysregulated in individuals with Alzheimer's disease. Epigenetic mechanisms are essential to memory development, where the epigenetic tags of DNA methylation and histone tail post-translational modifications are prominent. The transcriptional level is a key site of action for genes related to AD (Alzheimer's Disease) where altered versions cause the disease process. The current chapter focuses on epigenetics' contribution to the emergence and advancement of Alzheimer's disease (AD) and examines the therapeutic potential of epigenetic interventions in ameliorating the impact of AD.
Histone modifications and DNA methylation, two key epigenetic processes, play a role in determining the higher-order DNA structure and consequent gene expression. The emergence of numerous illnesses, prominently cancer, is demonstrably linked to dysfunctional epigenetic mechanisms. In the past, chromatin abnormalities were considered isolated to precise DNA sequences, commonly associated with rare genetic syndromes. However, current research suggests extensive genome-wide modifications in epigenetic mechanisms, offering a more comprehensive understanding of the underlying causes of developmental and degenerative neuronal conditions, including Parkinson's disease, Huntington's disease, epilepsy, and multiple sclerosis. This chapter explores epigenetic changes affecting diverse neurological disorders, and subsequently examines their potential to influence the development of new treatment approaches.
Different diseases and mutations in epigenetic components often display consistent changes in DNA methylation levels, histone modifications, and the functions of non-coding RNAs (ncRNAs). By distinguishing the contributions of driving and passenger epigenetic factors, one can identify diseases where epigenetics has a critical impact on the assessment of disease, forecasting its progression, and guiding its treatment. Furthermore, a combined intervention strategy will be devised by scrutinizing the interplay between epigenetic elements and other disease pathways. Through a comprehensive examination of specific cancer types, the cancer genome atlas project has revealed a high incidence of mutations in genes responsible for epigenetic components. The effects on the cell include mutations in DNA methylase and demethylase enzymes, along with cytoplasmic modifications, and changes in the composition of the cytoplasm. Genes involved in chromatid restoration and chromosome structure are also affected, as are metabolic genes, isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), which modulate histone and DNA methylation, thereby disrupting the architecture of the 3D genome, also affecting the metabolic pathways involving IDH1 and IDH2. Cancerous growth can be triggered by the presence of recurring DNA motifs. Epigenetic research in the 21st century has accelerated dramatically, engendering legitimate enthusiasm and hope, and generating a noticeable degree of excitement. The deployment of novel epigenetic tools signifies a potential revolution in disease prevention, diagnosis, and therapy. Specific epigenetic systems that control gene expression are the focus of drug development, which seeks to bolster gene expression. The development and use of epigenetic tools constitute a suitable and effective strategy for clinical management of diverse diseases.
The past few decades have witnessed the rise of epigenetics as a key area of study, contributing to a greater understanding of gene expression and its complex mechanisms of control. Epigenetic mechanisms have enabled the manifestation of stable phenotypic variations without modifications to the underlying DNA sequences. DNA methylation, acetylation, phosphorylation, and other such regulatory processes can bring about epigenetic changes, thereby influencing gene expression levels without altering the underlying DNA sequence. CRISPR-dCas9-facilitated epigenome modifications, enabling the regulation of gene expression, are explored in this chapter as potential therapies for human diseases.
Histone deacetylases (HDACs) are responsible for the removal of acetyl groups from lysine residues, found in both histone and non-histone proteins. Cancer, neurodegeneration, and cardiovascular disease are just a few of the conditions potentially influenced by the presence of HDACs. Gene transcription, cell survival, growth, and proliferation are intricately linked to the activities of HDACs, with histone hypoacetylation serving as a key downstream event. The restoration of acetylation levels is a crucial epigenetic mechanism employed by HDAC inhibitors (HDACi) to influence gene expression. While a few HDAC inhibitors have received FDA approval, the majority of them are still in clinical trials to evaluate their effectiveness in preventing and treating diseases. Institute of Medicine This chapter meticulously details the diverse HDAC classes and their roles in disease progression, encompassing conditions like cancer, cardiovascular ailments, and neurodegenerative disorders. Moreover, we delve into innovative and promising HDACi therapeutic approaches within the context of the current clinical landscape.
The mechanisms of epigenetic inheritance include DNA methylation, post-translational modifications to chromatin structures, and the roles of non-coding RNA molecules. The emergence of new traits in various organisms, a consequence of epigenetic modifications impacting gene expression, is linked to a range of diseases, including cancer, diabetic kidney disease, diabetic nephropathy, and renal fibrosis. Bioinformatics provides an effective methodology for characterizing epigenetic patterns. These epigenomic datasets can be dissected and examined using a vast array of bioinformatics tools and software. A wealth of online databases contain extensive information on these modifications. Methodologies have been expanded to incorporate a variety of sequencing and analytical techniques for the extraction of different types of epigenetic data. To develop drugs for ailments connected to epigenetic changes, this data is instrumental. This chapter succinctly introduces epigenetic databases (MethDB, REBASE, Pubmeth, MethPrimerDB, Histone Database, ChromDB, MeInfoText database, EpimiR, Methylome DB, dbHiMo) and tools (compEpiTools, CpGProD, MethBlAST, EpiExplorer, BiQ analyzer), which are essential for accessing and mechanistically understanding epigenetic modifications.
Regarding the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, the European Society of Cardiology (ESC) has issued new guidelines. This guideline extends the recommendations of the 2017 AHA/ACC/HRS guideline and the 2020 CCS/CHRS position statement, providing evidence-based support for clinical practice decisions. The periodic updating of these recommendations with the latest scientific evidence nevertheless results in numerous shared characteristics. In spite of certain convergences, notable disparities in recommendations arise from several factors such as differences in research methodologies, data selection approaches, interpretations of the data, and regional disparities in drug availability across various geographical locations. This paper seeks to evaluate specific recommendations, emphasizing points of divergence and convergence, and provide a survey of current guidance. It will also analyze research gaps and outline prospective avenues for future research initiatives. From the perspective of the recent ESC guidelines, cardiac magnetic resonance, genetic testing for cardiomyopathies and arrhythmia syndromes, and risk calculator utilization in risk stratification are increasingly valued. Varied approaches are evident in the diagnosis of genetic arrhythmia syndromes, the care of well-tolerated ventricular tachycardia, and the utilization of primary preventative implantable cardioverter-defibrillators.
The difficulty of implementing strategies to prevent right phrenic nerve (PN) injury during catheter ablation often leads to ineffectiveness and risks. A novel, pneumo-sparing technique, involving a single lung ventilation followed by an intentional pneumothorax, was prospectively evaluated in patients with multidrug-refractory periphrenic atrial tachycardia. Effective phrenic nerve (PN) relocation from the target site during the PHRENICS (phrenic nerve relocation by endoscopy, intentional pneumothorax using carbon dioxide, and single lung ventilation) procedure led to successful AT catheter ablation in all cases, free from procedural complications or arrhythmia recurrences. The PHRENICS hybrid ablation procedure efficiently mobilizes the PN, thus minimizing pericardium encroachment, ultimately increasing the safety of periphrenic AT catheter ablation.
Cryoballoon pulmonary vein isolation (PVI), alongside posterior wall isolation (PWI), has been proven, in prior research, to produce favourable clinical results in cases of persistent atrial fibrillation (AF). Hepatoprotective activities Nevertheless, the function of this strategy in individuals experiencing intermittent atrial fibrillation (PAF) continues to be enigmatic.
The investigation explored the short-term and long-term effects of cryoballoon PVI versus PVI+PWI ablation in patients with symptomatic paroxysmal atrial fibrillation.
This long-term follow-up retrospective study (NCT05296824) investigated the outcomes of cryoballoon PVI (n=1342) compared to cryoballoon PVI combined with PWI (n=442) in patients experiencing symptomatic PAF. Through the nearest-neighbor method, a sample of 11 patients was selected, encompassing those treated with PVI alone and those receiving PVI plus PWI.
The matched cohort comprised 320 patients, specifically 160 patients with PVI and 160 patients with co-occurrence of PVI and PWI. JNJ-26481585 cost Procedure times and cryoablation times were found to be longer when PVI+PWI was not present; cryoablation times increased from 23 10 minutes to 42 11 minutes, and procedure times from 103 24 minutes to 127 14 minutes (P<0.0001 for both comparisons).