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Epigenetics and Beyond: New Advances in Drug Discovery

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 20 March 2025 | Viewed by 5764

Special Issue Editors


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Guest Editor
Department of Life Sciences, University of Siena, 53100 Siena, Italy
Interests: HDAC; vasorelaxant agents; antioxidant and anti-inflammatory nutraceuticals; leukemia; Pseudomonas aeruginosa; hybrid compounds; retinitis pigmentosa
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Interests: medicinal chemistry; HIV; anticancer compounds; antimicrobial agents; nitrogen-based compounds; Pseudomonas aeruginosa
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Interests: drug design; drug synthesis; drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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

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Published Papers (3 papers)

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Research

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12 pages, 4438 KiB  
Article
Preparation, Characterization, and Oral Bioavailability of Solid Dispersions of Cryptosporidium parvum Alternative Oxidase Inhibitors
by Yongxiang Zhang, Minglang Ma, Jinyu Yang, Xiaotong Qiu, Lin Xin, Yixing Lu, Huiguo Huang, Zhenling Zeng and Dongping Zeng
Int. J. Mol. Sci. 2024, 25(13), 7025; https://doi.org/10.3390/ijms25137025 - 27 Jun 2024
Viewed by 835
Abstract
The phenylpyrazole derivative 5-amino-3-[1-cyano-2-(3-phenyl-1H-pyrazol-4-yl) vinyl]-1-phenyl-1H-pyrazole-4-carbonitrile (LN002), which was screened out through high-throughput molecular docking for the AOX target, exhibits promising efficacy against Cryptosporidium. However, its poor water solubility limits its oral bioavailability and therapeutic utility. In this study, [...] Read more.
The phenylpyrazole derivative 5-amino-3-[1-cyano-2-(3-phenyl-1H-pyrazol-4-yl) vinyl]-1-phenyl-1H-pyrazole-4-carbonitrile (LN002), which was screened out through high-throughput molecular docking for the AOX target, exhibits promising efficacy against Cryptosporidium. However, its poor water solubility limits its oral bioavailability and therapeutic utility. In this study, solid dispersion agents were prepared by using HP-β-CD and Soluplus® and characterized through differential scanning calorimetry, Fourier transform infrared, powder X-ray diffraction, and scanning electron microscopy. Physical and chemical characterization showed that the crystal morphology of LN002 transformed into an amorphous state, thus forming a solid dispersion of LN002. The solid dispersion prepared with an LN002/HP-β-CD/Soluplus® mass ratio of 1:3:9 (w/w/w) exhibited significantly increased solubility and cumulative dissolution. Meanwhile, LN002 SDs showed good preservation stability under accelerated conditions of 25 °C and 75% relative humidity. The complexation of LN002 with HP-β-CD and Soluplus® significantly improved water solubility, pharmacological properties, absorption, and bioavailability. Full article
(This article belongs to the Special Issue Epigenetics and Beyond: New Advances in Drug Discovery)
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24 pages, 7786 KiB  
Article
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
Cited by 1 | Viewed by 2246
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 [...] Read more.
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  
Review
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
Viewed by 1999
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 [...] Read more.
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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