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Epigenetics and Beyond: New Advances in Drug Discovery

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Dear Colleagues,

Epigenetics studies heritable or acquired changes in gene expression. Changes are caused by non-genetic mechanisms without alterations in gene structure or sequence. Typical mechanisms are histone modifications, DNA methylation, and chromatin remodelling, which are essential in the regulation of many physiological processes. Alterations in these mechanisms can have implications in a number of cancers, as well as in immunological and neurodegenerative conditions. Several targets have emerged as tools to treat different diseases. Among these targets, histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs), histone demethylases (KDMs), protein kinases (PTKs), protein phosphatases (PPs), ubiquitin ligases and deubiquitinating enzymes (DUBs) are druggable and offer the opportunity to study different diseases, including infectious diseases. In this context, we welcome review articles and original articles from chemical and biological points of view, ranging from drug discovery to biological/pharmacological studies, in order to fully cover topics related to the molecular sciences.

Dr. Gabriele Carullo
Dr. Valeria Tudino
Dr. Maria Dichiara
Guest Editors

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Keywords

epigenetic modifications
epigenetic targets
drug design
drug discovery
cancer
infectious disease
immunology
inflammation
neurological diseases
fibrosis
wound repair and regeneration

Published Papers (2 papers)

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Research

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24 pages, 7786 KiB

Open AccessArticle

Sitagliptin Induces Tolerogenic Human Dendritic Cells

by Marija Drakul, Sergej Tomić, Marina Bekić, Dušan Mihajlović, Miloš Vasiljević, Sara Rakočević, Jelena Đokić, Nikola Popović, Dejan Bokonjić and Miodrag Čolić

Int. J. Mol. Sci. 2023, 24(23), 16829; https://doi.org/10.3390/ijms242316829 - 27 Nov 2023

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Abstract

Sitagliptin, an anti-diabetic drug, is a dipeptidyl peptidase (DPP)-4/CD26 inhibitor with additional anti-inflammatory and immunomodulatory properties. In this study, we investigated for the first time the effect of sitagliptin on the differentiation and functions of human dendritic cells generated from monocytes (MoDCs) for 4 days using the standard GM-CSF/IL-4 procedure. LPS/IFN-γ treatment for an additional 24 h was used for maturation induction of MoDCs. Sitagliptin was added at the highest non-cytotoxic concentration (500 µg/mL) either at the beginning (sita 0d protocol) or after MoDC differentiation (sita 4d protocol). Sitagliptin impaired differentiation and maturation of MoDCs as judged with the lower expression of CD40, CD83, CD86, NLRP3, and HLA-DR, retention of CD14 expression, and inhibited production of IL-β, IL-12p70, IL-23, and IL-27. In contrast, the expression of CD26, tolerogenic DC markers (ILT4 and IDO1), and production of immunoregulatory cytokines (IL-10 and TGF-β) were increased. Generally, the sita 0d protocol was more efficient. Sitagliptin-treated MoDCs were poorer allostimulators of T-cells in MoDC/T-cell co-culture and inhibited Th1 and Th17 but augmented Th2 and Treg responses. Tolerogenic properties of sitagliptin-treated MoDCs were additionally confirmed by an increased frequency of CD4+CD25+CD127- FoxP3+ Tregs and Tr1 cells (CD4+IL-10+FoxP3-) in MoDC/T-cell co-culture. The differentiation of IL-10+ and TGF-β+ Tregs depended on the sitagliptin protocol used. A Western blot analysis showed that sitagliptin inhibited p65 expression of NF-kB and p38MAPK during the maturation of MoDCs. In conclusion, sitagliptin induces differentiation of tolerogenic DCs, and the effect is important when considering sitagliptin for treating autoimmune diseases and allotransplant rejection. Full article

(This article belongs to the Special Issue Epigenetics and Beyond: New Advances in Drug Discovery)

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Review

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17 pages, 1073 KiB

Open AccessReview

Epigenetic Landscape and Therapeutic Implication of Gene Isoforms of Doublecortin-Like Kinase 1 for Cancer Stem Cells

by Landon L. Moore and Courtney W. Houchen

Int. J. Mol. Sci. 2023, 24(22), 16407; https://doi.org/10.3390/ijms242216407 - 16 Nov 2023

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Abstract

While significant strides have been made in understanding cancer biology, the enhancement in patient survival is limited, underscoring the urgency for innovative strategies. Epigenetic modifications characterized by hereditary shifts in gene expression without changes to the DNA sequence play a critical role in producing alternative gene isoforms. When these processes go awry, they influence cancer onset, growth, spread, and cancer stemness. In this review, we delve into the epigenetic and isoform nuances of the protein kinase, doublecortin-like kinase 1 (DCLK1). Recognized as a hallmark of tumor stemness, DCLK1 plays a pivotal role in tumorigenesis, and DCLK1 isoforms, shaped by alternative promoter usage and splicing, can reveal potential therapeutic touchpoints. Our discussion centers on recent findings pertaining to the specific functions of DCLK1 isoforms and the prevailing understanding of its epigenetic regulation via its two distinct promoters. It is noteworthy that all DCLK1 isoforms retain their kinase domain, suggesting that their unique functionalities arise from non-kinase mechanisms. Consequently, our research has pivoted to drugs that specifically influence the epigenetic generation of these DCLK1 isoforms. We posit that a combined therapeutic approach, harnessing both the epigenetic regulators of specific DCLK1 isoforms and DCLK1-targeted drugs, may prove more effective than therapies that solely target DCLK1. Full article

(This article belongs to the Special Issue Epigenetics and Beyond: New Advances in Drug Discovery)

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