Special Issue "Epigenetic Drugs"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 15 December 2021.

Special Issue Editor

Dr. Marcin Ratajewski
E-Mail Website1 Website2
Guest Editor
Laboratory of Epigenetics, Institute of Medical Biology of the Polish of Sciences, Lodz, Poland
Interests: epigenetics , Th17 lymphocytes; autoimmunity; nuclear receptors; melanoma; drug resistance; sirtuins; plant-derived natural products

Special Issue Information

Dear Colleagues,

Many diseases (e.g., cancer, diabetes, heart, mental, and autoimmune diseases) are associated with epigenetic aberrations including DNA methylation, histone post-translational modifications, chromatin remodeling, and regulatory RNA. Until now, the DNMT inhibitors 5-azacytidine and 5-aza-20-deoxycytidine and the HDAC inhibitors belinostat, panobinostat, romidepsin, vorinostat have been approved by the FDA for the treatment of various cancers. Many of these drugs suffer from high toxicity, rapid metabolism, poor bioavailability, and limited effectiveness in monotherapy. However, in combinatorial therapy, they can be beneficial to patients. In this Special Issue, we would like to invite the submission of manuscripts containing new findings, which may contribute to the design and use of new epigenetic drugs with improved activity, functional significance of different epigenetic drugs (or candidates)-induced signaling pathways and their clinical implications, improvement of the new drugs selectivity, identification of new molecular targets of epigenetic drugs and their clinical significance, and potential combined epigenetic therapies.

We look forward to your contributions.

Dr. Marcin Ratajewski
Guest Editor

Manuscript Submission Information

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Keywords

  • epigenetic modulating agents
  • epigenetic drug discovery
  • DNA methylation
  • histone post-translational modifications
  • chromatin remodeling
  • epigenetic markers
  • cancer epigenetics
  • epigenetic therapeutics in immunotherapy
  • combined therapy

Published Papers (6 papers)

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Research

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Article
Neuroprotective Effects of Tripeptides—Epigenetic Regulators in Mouse Model of Alzheimer’s Disease
Pharmaceuticals 2021, 14(6), 515; https://doi.org/10.3390/ph14060515 - 27 May 2021
Viewed by 549
Abstract
KED and EDR peptides prevent dendritic spines loss in amyloid synaptotoxicity in in vitro model of Alzheimer’s disease (AD). The objective of this paper was to study epigenetic mechanisms of EDR and KED peptides’ neuroprotective effects on neuroplasticity and dendritic spine morphology in [...] Read more.
KED and EDR peptides prevent dendritic spines loss in amyloid synaptotoxicity in in vitro model of Alzheimer’s disease (AD). The objective of this paper was to study epigenetic mechanisms of EDR and KED peptides’ neuroprotective effects on neuroplasticity and dendritic spine morphology in an AD mouse model. Daily intraperitoneal administration of the KED peptide in 5xFAD mice from 2 to 4 months of age at a concentration of 400 μg/kg tended to increase neuroplasticity. KED and EDR peptides prevented dendritic spine loss in 5xFAD-M mice. Their action’s possible molecular mechanisms were investigated by molecular modeling and docking of peptides in dsDNA, containing all possible combinations of hexanucleotide sequences. Similar DNA sequences were found in the lowest-energy complexes of the studied peptides with DNA in the classical B-form. EDR peptide has binding sites in the promoter region of CASP3, NES, GAP43, APOE, SOD2, PPARA, PPARG, GDX1 genes. Protein products of these genes are involved in AD pathogenesis. The neuroprotective effect of EDR and KED peptides in AD can be defined by their ability to prevent dendritic spine elimination and neuroplasticity impairments at the molecular epigenetic level. Full article
(This article belongs to the Special Issue Epigenetic Drugs)
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Communication
PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance
Pharmaceuticals 2021, 14(2), 170; https://doi.org/10.3390/ph14020170 - 22 Feb 2021
Viewed by 756
Abstract
Secondary infections cause sepsis that lead to patient disability or death. Contact of macrophages with bacterial components (such as lipopolysaccharide—LPS) activates the intracellular signaling pathway downstream of Toll-like receptors (TLR), which initiate an immune proinflammatory response. However, the expression of nuclear factor-kappa B [...] Read more.
Secondary infections cause sepsis that lead to patient disability or death. Contact of macrophages with bacterial components (such as lipopolysaccharide—LPS) activates the intracellular signaling pathway downstream of Toll-like receptors (TLR), which initiate an immune proinflammatory response. However, the expression of nuclear factor-kappa B (NF-κB)-dependent proinflammatory cytokines significantly decreases after single high or multiple LPS stimulations. Knowing that poly(ADP-ribose) polymerase-1 (PARP1) serves as a cofactor of NF-κB, we aimed to verify a hypothesis of the possible contribution of PARP1 to the development of LPS-induced tolerance in human macrophages. Using TNF-α mRNA expression as a readout, we demonstrate that PARP1 interaction with the TNF-α promoter, controls macrophage immunoparalysis. We confirm that PARP1 is extruded from the gene promoter, whereas cell pretreatment with Olaparib maintains macrophage responsiveness to another LPS treatment. Furthermore, cell pretreatment with proteasome inhibitor MG132 completely abrogates the effect of Olaparib, suggesting that PARP1 acts with NF-κB in the same regulatory pathway, which controls pro-inflammatory cytokine transcription. Mechanistically, PARP1 trapping allows for the re-rebinding of p65 to the TNF-α promoter in LPS-stimulated cells. In conclusion, PARP traps prevent PARP1 extrusion from the TNF-α promoter upon macrophage stimulation, thereby maintaining chromatin responsiveness of TLR activation, allowing for the re-binding of p65 and TNF-α transcription. Full article
(This article belongs to the Special Issue Epigenetic Drugs)
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Article
Expanding the Structural Diversity of DNA Methyltransferase Inhibitors
Pharmaceuticals 2021, 14(1), 17; https://doi.org/10.3390/ph14010017 - 27 Dec 2020
Viewed by 1535
Abstract
Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with [...] Read more.
Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed extended connectivity interaction features approach, led to an excellent agreement between the experimental IC50 values and docking scores. Full article
(This article belongs to the Special Issue Epigenetic Drugs)
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Article
Atorvastatin Increases the Expression of Long Non-Coding RNAs ARSR and CHROME in Hypercholesterolemic Patients: A Pilot Study
Pharmaceuticals 2020, 13(11), 382; https://doi.org/10.3390/ph13110382 - 12 Nov 2020
Cited by 2 | Viewed by 657
Abstract
Atorvastatin is extensively used to treat hypercholesterolemia. However, the wide interindividual variability observed in response to this drug still needs further elucidation. Nowadays, the biology of long non-coding RNAs (lncRNAs) is better understood, and some of these molecules have been related to cholesterol [...] Read more.
Atorvastatin is extensively used to treat hypercholesterolemia. However, the wide interindividual variability observed in response to this drug still needs further elucidation. Nowadays, the biology of long non-coding RNAs (lncRNAs) is better understood, and some of these molecules have been related to cholesterol metabolism. Therefore, they could provide additional information on variability in response to statins. The objective of this research was to evaluate the effect of atorvastatin on three lncRNAs (lncRNA ARSR: Activated in renal cell carcinoma (RCC) with sunitinib resistance, ENST00000424980; lncRNA LASER: lipid associated single nucleotide polymorphism locus, ENSG00000237937; and lncRNA CHROME: cholesterol homeostasis regulator of miRNA expression, ENSG00000223960) associated with genes involved in cholesterol metabolism as predictors of lipid-lowering therapy performance. Twenty hypercholesterolemic patients were treated for four weeks with atorvastatin (20 mg/day). The lipid profile was determined before and after drug administration using conventional assays. The expression of lncRNAs was assessed in peripheral blood samples by RT-qPCR. As expected, atorvastatin improved the lipid profile, decreasing total cholesterol, LDL-C, and the TC/HDL-C ratio (p < 0.0001) while increasing the expression of lncRNAs ARSR and CHROME (p < 0.0001) upon completion of treatment. LASER did not show significant differences among the groups (p = 0.50). Our results indicate that atorvastatin modulates the expression of cholesterol-related lncRNAs differentially, suggesting that these molecules play a role in the variability of response to this drug; however, additional studies are needed to disclose the implication of this differential regulation on statin response. Full article
(This article belongs to the Special Issue Epigenetic Drugs)
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Review

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Review
Epigenetic Mechanisms Involved in Cisplatin-Induced Nephrotoxicity: An Update
Pharmaceuticals 2021, 14(6), 491; https://doi.org/10.3390/ph14060491 - 21 May 2021
Viewed by 590
Abstract
Cisplatin is an antineoplastic drug used for the treatment of many solid tumors. Among its various side effects, nephrotoxicity is the most detrimental. In recent years, epigenetic regulation has emerged as a modulatory mechanism of cisplatin-induced nephrotoxicity, involving non-coding RNAs, DNA methylation and [...] Read more.
Cisplatin is an antineoplastic drug used for the treatment of many solid tumors. Among its various side effects, nephrotoxicity is the most detrimental. In recent years, epigenetic regulation has emerged as a modulatory mechanism of cisplatin-induced nephrotoxicity, involving non-coding RNAs, DNA methylation and histone modifications. These epigenetic marks alter different signaling pathways leading to damage and cell death. In this review, we describe how different epigenetic modifications alter different pathways leading to cell death by apoptosis, autophagy, necroptosis, among others. The study of epigenetic regulation is still under development, and much research remains to fully determine the epigenetic mechanisms underlying cell death, which will allow leading new strategies for the diagnosis and therapy of this disease. Full article
(This article belongs to the Special Issue Epigenetic Drugs)
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Review
m6A RNA Methylation in Systemic Autoimmune Diseases—A New Target for Epigenetic-Based Therapy?
Pharmaceuticals 2021, 14(3), 218; https://doi.org/10.3390/ph14030218 - 05 Mar 2021
Viewed by 476
Abstract
The general background of autoimmune diseases is a combination of genetic, epigenetic and environmental factors, that lead to defective immune reactions. This erroneous immune cell activation results in an excessive production of autoantibodies and prolonged inflammation. During recent years epigenetic mechanisms have been [...] Read more.
The general background of autoimmune diseases is a combination of genetic, epigenetic and environmental factors, that lead to defective immune reactions. This erroneous immune cell activation results in an excessive production of autoantibodies and prolonged inflammation. During recent years epigenetic mechanisms have been extensively studied as potential culprits of autoreactivity. Alike DNA and proteins, also RNA molecules are subjected to an extensive repertoire of chemical modifications. N6-methyladenosine is the most prevalent form of internal mRNA modification in eukaryotic cells and attracts increasing attention due to its contribution to human health and disease. Even though m6A is confirmed as an essential player in immune response, little is known about its role in autoimmunity. Only few data have been published up to date in the field of RNA methylome. Moreover, only selected autoimmune diseases have been studied in respect of m6A role in their pathogenesis. In this review, I attempt to present all available research data regarding m6A alterations in autoimmune disorders and appraise its role as a potential target for epigenetic-based therapies. Full article
(This article belongs to the Special Issue Epigenetic Drugs)
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