Current concepts in the epigenetic regulation of cardiac fibrosis.

Cardiac fibrosis is a significant driver of congestive heart failure, a syndrome that continues to affect a growing patient population globally. Cardiac fibrosis results from a constellation of complex processes at the transcription, receptor, and signaling axes levels. Various mediators and signaling cascades, such as the transformation growth factor-beta pathway, have been implicated in the pathophysiology of cardiac tissue fibrosis. Our understanding of these markers and pathways has improved in recent years as more advanced technologies and assays have been developed, allowing for better delineation of the crosstalk between specific factors. There is mounting evidence suggesting that epigenetic modulation plays a pivotal role in the progression of cardiac fibrosis. Transcriptional regulation of key pro- and antifibrotic pathways can accentuate or blunt the rate and extent of fibrosis at the tissue level. Exosomes, micro-RNAs, and long noncoding RNAs all belong to factors that can impact the epigenetic signature in cardiac fibrosis. Herein, we comprehensively review the latest literature about exosomes, their contents, and cardiac fibrosis. In doing so, we highlight the specific transcriptional factors with pro- or antifibrotic properties. We also assimilate the data supporting these mediators' potential utility as diagnostic or prognostic biomarkers. Finally, we offer insight into where further work can be done to fill existing gaps to translate preclinical findings better and improve clinical outcomes.

A Hydrogen-Bonded Organic Framework-Based Mitochondrion-Targeting Bioorthogonal Platform for the Modulation of Mitochondrial Epigenetics.

Bioorthogonal chemistry represents a powerful tool in chemical biology, which shows great potential in epigenetic modulation. As a proof of concept, the epigenetic modulation model of mitochondrial DNA (mtDNA) is selected because mtDNA establishes a relative hypermethylation stage under oxidative stress, which impairs the mitochondrion-based therapeutic effect during cancer therapy. Herein, we design a new biocompatible hydrogen-bonded organic framework (HOF) for a HOF-based mitochondrion-targeting bioorthogonal platform TPP@P@PHOF-2. PHOF-2 can activate a prodrug (pro-procainamide) in situ, which can specifically inhibit DNA methyltransferase 1 (DNMT1) activity and remodel the epigenetic modification of mtDNA, making it more susceptible to ROS damage. In addition, PHOF-2 can also catalyze artemisinin to produce large amounts of ROS, effectively damaging mtDNA and achieving better chemodynamic therapy demonstrated by both in vitro and in vivo studies. This work provides new insights into developing advanced bioorthogonal therapy and expands the applications of HOF and bioorthogonal catalysis.

Next-generation sequencing reveals that miR-16-5p, miR-19a-3p, miR-451a, and miR-25-3p cargo in plasma extracellular vesicles differentiates sedentary young males from athletes.

A sedentary lifestyle and Olympic participation are contrary risk factors for global mortality and incidence of cancer and cardiovascular disease. Extracellular vesicle miRNAs have been described to respond to exercise. No molecular characterization of young male sedentary people versus athletes is available; so, our aim was to identify the extracellular vesicle miRNA profile of chronically trained young endurance and resistance male athletes compared to their sedentary counterparts. A descriptive case-control design was used with 16 sedentary young men, 16 Olympic male endurance athletes, and 16 Olympic male resistance athletes. Next-generation sequencing and RT-qPCR and external and internal validation were performed in order to analyze extracellular vesicle miRNA profiles. Endurance and resistance athletes had significant lower levels of miR-16-5p, miR-19a-3p, and miR-451a compared to sedentary people. Taking all together, exercise-trained miRNA profile in extracellular vesicles provides a differential signature of athletes irrespective of the type of exercise compared to sedentary people. Besides, miR-25-3p levels were specifically lower in endurance athletes which defines its role as a specific responder in this type of athletes. In silico analysis of this profile suggests a role in adaptive energy metabolism in this context that needs to be experimentally validated. Therefore, this study provides for the first time basal levels of circulating miRNA in extracellular vesicles emerge as relevant players in intertissue communication in response to chronic exercise exposure in young elite male athletes.

Role of Epigenetic Modulation in Neurodegenerative Diseases: Implications of Phytochemical Interventions.

Epigenetics defines changes in cell function without involving alterations in DNA sequence. Neuroepigenetics bridges neuroscience and epigenetics by regulating gene expression in the nervous system and its impact on brain function. With the increase in research in recent years, it was observed that alterations in the gene expression did not always originate from changes in the genetic sequence, which has led to understanding the role of epigenetics in neurodegenerative diseases (NDDs) including Alzheimer's disease (AD) and Parkinson's disease (PD). Epigenetic alterations contribute to the aberrant expression of genes involved in neuroinflammation, protein aggregation, and neuronal death. Natural phytochemicals have shown promise as potential therapeutic agents against NDDs because of their antioxidant, anti-inflammatory, and neuroprotective effects in cellular and animal models. For instance, resveratrol (grapes), curcumin (turmeric), and epigallocatechin gallate (EGCG; green tea) exhibit neuroprotective effects through their influence on DNA methylation patterns, histone acetylation, and non-coding RNA expression profiles. Phytochemicals also aid in slowing disease progression, preserving neuronal function, and enhancing cognitive and motor abilities. The present review focuses on various epigenetic modifications involved in the pathology of NDDs, including AD and PD, gene expression regulation related to epigenetic alterations, and the role of specific polyphenols in influencing epigenetic modifications in AD and PD.

Advances in Hodgkin Lymphoma Treatment: From Molecular Biology to Clinical Practice.

Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field.

Epigenetic modulations in triple-negative breast cancer: Therapeutic implications for tumor microenvironment.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors, progesterone receptors and lacks HER2 overexpression. This absence of critical molecular targets poses significant challenges for conventional therapies. Immunotherapy, remarkably immune checkpoint blockade, offers promise for TNBC treatment, but its efficacy remains limited. Epigenetic dysregulation, including altered DNA methylation, histone modifications, and imbalances in regulators such as BET proteins, plays a crucial role in TNBC development and resistance to treatment. Hypermethylation of tumor suppressor gene promoters and the imbalance of histone methyltransferases such as EZH2 and histone deacetylases (HDACs) profoundly influence tumor cell proliferation, survival, and metastasis. In addition, epigenetic alterations critically shape the tumor microenvironment (TME), including immune cell composition, cytokine signaling, and immune checkpoint expression, ultimately contributing to immune evasion. Targeting these epigenetic mechanisms with specific inhibitors such as EZH2 and HDAC inhibitors in combination with immunotherapy represents a compelling strategy to remodel the TME, potentially overcoming immune evasion and enhancing therapeutic outcomes in TNBC. This review aims to comprehensively elucidate the current understanding of epigenetic modulation in TNBC, its influence on the TME, and the potential of combining epigenetic therapies with immunotherapy to overcome the challenges posed by this aggressive breast cancer subtype.

Non-Coding Ribonucleic Acids as Diagnostic and Therapeutic Targets in Cardiac Fibrosis.

PURPOSE OF REVIEW: Cardiac fibrosis is a crucial juncture following cardiac injury and a precursor for many clinical heart disease manifestations. Epigenetic modulators, particularly non-coding RNAs (ncRNAs), are gaining prominence as diagnostic and therapeutic tools. RECENT FINDINGS: miRNAs are short linear RNA molecules involved in post-transcriptional regulation; lncRNAs and circRNAs are RNA sequences greater than 200 nucleotides that also play roles in regulating gene expression through a variety of mechanisms including miRNA sponging, direct interaction with mRNA, providing protein scaffolding, and encoding their own products. NcRNAs have the capacity to regulate one another and form sophisticated regulatory networks. The individual roles and disease relevance of miRNAs, lncRNAs, and circRNAs to cardiac fibrosis have been increasingly well described, though the complexity of their interrelationships, regulatory dynamics, and context-specific roles needs further elucidation. This review provides an overview of select ncRNAs relevant in cardiac fibrosis as a surrogate for many cardiac disease states with a focus on crosstalk and regulatory networks, variable actions among different disease states, and the clinical implications thereof. Further, the clinical feasibility of diagnostic and therapeutic applications as well as the strategies underway to advance ncRNA theranostics is explored.

ncRNAs Orchestrate Chemosensitivity Induction by Neddylation Blockades.

We performed an integrative transcriptomic in silico analysis using lung adenocarcinoma A549 cells treated with the neddylation inhibitor MLN4924 and the gefitinib-resistant PC9 cell line (PC9GR). We focused on the transcriptional effects of the top differentially expressed ncRNA biotypes and their correlating stemness factors. Interestingly, MLN4924-treated cells showed a significant upregulation of mRNAs involved in carcinogenesis, cell attachment, and differentiation pathways, as well as a parallel downregulation of stemness maintenance and survival signaling pathways, an effect that was inversely observed in PC9GR cells. Moreover, we found that stemness factor expression could be contrasted by selected up-regulated ncRNAs upon MLN4924 treatment in a dose and time-independent manner. Furthermore, upregulated miRNAs and lncRNA-targeted mRNAs showed an evident enrichment of proliferation, differentiation, and apoptosis pathways, while downregulated ncRNA-targeted mRNAs were implicated in stem cell maintenance. Finally, our results proved that stemness (KLF4 and FGFR2) and epithelial-mesenchymal transition (ZEB2, TWIST2, SNAI2, CDH2, and VIM) factors, which are highly expressed in PC9GR cells compared to gefitinib-sensitive PC9 cells, could be abrogated with the neddylation inhibitor MLN4924 mainly through activation of epithelial differentiation pathways, thus exerting a protective role in lung cancer cells and chemosensitivity against lung tumorigenic transformation.

Antimicrobial activity and acetylcholinesterase inhibition by extracts from chromatin modulated fungi

ABSTRACT Major health challenges as the increasing number of cases of infections by antibiotic multiresistant microorganisms and cases of Alzheimer's disease have led to searching new control drugs. The present study aims to verify a new way of obtaining bioactive extracts from filamentous fungi with potential antimicrobial and acetylcholinesterase inhibitory activities, using epigenetic modulation to promote the expression of genes commonly silenced. For such finality, five filamentous fungal species (Talaromyces funiculosus, Talaromyces islandicus, Talaromyces minioluteus, Talaromyces pinophilus, Penicillium janthinellum) were grown or not with DNA methyltransferases inhibitors (procainamide or hydralazine) and/or a histone deacetylase inhibitor (suberohydroxamic acid). Extracts from T. islandicus cultured or not with hydralazine inhibited Listeria monocytogenes growth in 57.66 ± 5.98% and 15.38 ± 1.99%, respectively. Increment in inhibition of acetylcholinesterase activity was observed for the extract from P. janthinellum grown with procainamide (100%), when compared to the control extract (39.62 ± 3.76%). Similarly, inhibition of acetylcholinesterase activity increased from 20.91 ± 3.90% (control) to 92.20 ± 3.72% when the tested extract was obtained from T. pinophilus under a combination of suberohydroxamic acid and procainamide. Concluding, increases in antimicrobial activity and acetylcholinesterase inhibition were observed when fungal extracts in the presence of DNA methyltransferases and/or histone deacetylase modulators were tested.