Role of Histone Deacetylases in Monocyte Function in Health and Chronic Inflammatory Diseases.

Histone deacetylases (HDACs) are a family of 18 members that participate in the epigenetic regulation of gene expression. In addition to histones, some HDACs also deacetylate transcription factors and specific cytoplasmic proteins.Monocytes, as part of the innate immune system, maintain tissue homeostasis and help fight infections and cancer. In these cells, HDACs are involved in multiple processes including proliferation, migration, differentiation, inflammatory response, infections, and tumorigenesis. Here, a systematic description of the role that most HDACs play in these functions is reviewed. Specifically, some HDACs induce a pro-inflammatory response and play major roles in host defense. Conversely, other HDACs reprogram monocytes and macrophages towards an immunosuppressive phenotype. The right balance between both types helps monocytes to respond correctly to the different physiological/pathological stimuli. However, aberrant expressions or activities of specific HDACs are associated with autoimmune diseases along with other chronic inflammatory diseases, infections, or cancer.This paper critically reviews the interesting and extensive knowledge regarding the role of some HDACs in these pathologies. It also shows that as yet, very little progress has been made toward the goal of finding effective HDAC-targeted therapies. However, given their obvious potential, we conclude that it is worth the effort to develop monocyte-specific drugs that selectively target HDAC subtypes with the aim of finding effective treatments for diseases in which our innate immune system is involved.

Epigenetic manipulation of filamentous fungi for biotechnological applications: a systematic review.

The study of the epigenetic regulation of gene function has reached pivotal importance in life sciences in the last decades. The mechanisms and effects of processes such as DNA methylation, histone posttranslational modifications and non-coding RNAs, as well as their impact on chromatin structure and dynamics, are clearly involved in physiology homeostasis in plants, animals and microorganisms. In the fungal kingdom, studies on the model yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe contributed enormously to the elucidation of the eukaryote epigenetic landscape. Epigenetic regulation plays a central role in the expression of virulence attributes of human pathogens such as Candida albicans. In this article, we review the most recent studies on the effects of drugs capable of altering epigenetic states and on the impact of chromatin structure-related genes deletion in filamentous fungi. Emphasis is given on plant and insect pathogens, endophytes, secondary metabolites and cellulases/xylanases producing species.

Epigenetic Modifiers Induce Bioactive Phenolic Metabolites in the Marine-Derived Fungus Penicillium brevicompactum.

Fungi usually contain gene clusters that are silent or cryptic under normal laboratory culture conditions. These cryptic genes could be expressed for a wide variety of bioactive compounds. One of the recent approaches to induce production of such cryptic fungal metabolites is to use histone deacetylases (HDACs) inhibitors. In the present study, the cultures of the marine-derived fungus Penicillium brevicompactum treated with nicotinamide and sodium butyrate were found to produce a lot of phenolic compounds. Nicotinamide treatment resulted in the isolation and identification of nine compounds 1⁻9. Sodium butyrate also enhanced the productivity of anthranilic acid (10) and ergosterol peroxide (11). The antioxidant as well as the antiproliferative activities of each metabolite were determined. Syringic acid (4), sinapic acid (5), and acetosyringone (6) exhibited potent in vitro free radical scavenging, (IC50 20 to 30 µg/mL) and antiproliferative activities (IC50 1.14 to 1.71 µM) against HepG2 cancer cell line. Furthermore, a pharmacophore model of the active compounds was generated to build up a structure-activity relationship.

Design, synthesis and biological evaluation of 4-piperazinyl-containing Chidamide derivatives as HDACs inhibitors.

The synthesis and biological evaluation of a variety of 4-piperazinyl-containing Chidamide derivatives is described. Some of these compounds were shown to inhibit HDAC1 with IC50 values below micromolar range, and inhibited proliferation of several human cancer cells, not possessing toxicity to human normal cells and hERG K+ ion channels. Compound 9g, proved to be the most potent and efficacious derivative in this series, was orally active in an HCT116 xenograft model in vivo.

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods.

Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure-activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson-Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

Histone deacetylases modulate resistance to the therapy in lung cancer.

The acetylation status of histones located in both oncogenes and tumor suppressor genes modulate cancer hallmarks. In lung cancer, changes in the acetylation status are associated with increased cell proliferation, tumor growth, migration, invasion, and metastasis. Histone deacetylases (HDACs) are a group of enzymes that take part in the elimination of acetyl groups from histones. Thus, HDACs regulate the acetylation status of histones. Although several therapies are available to treat lung cancer, many of these fail because of the development of tumor resistance. One mechanism of tumor resistance is the aberrant expression of HDACs. Specific anti-cancer therapies modulate HDACs expression, resulting in chromatin remodeling and epigenetic modification of the expression of a variety of genes. Thus, HDACs are promising therapeutic targets to improve the response to anti-cancer treatments. Besides, natural compounds such as phytochemicals have potent antioxidant and chemopreventive activities. Some of these compounds modulate the deregulated activity of HDACs (e.g. curcumin, apigenin, EGCG, resveratrol, and quercetin). These phytochemicals have been shown to inhibit some of the cancer hallmarks through HDAC modulation. The present review discusses the epigenetic mechanisms by which HDACs contribute to carcinogenesis and resistance of lung cancer cells to anticancer therapies.

Clinical efficiency of epigenetic drugs therapy in bone malignancies.

A great interest in the scientific community is focused on the improvement of the cure rate in patients with bone malignancies that have a poor response to the first line of therapies. Novel treatments currently include epigenetic compounds or molecules targeting epigenetic-sensitive pathways. Here, we offer an exhaustive review of such agents in these clinical settings. Carefully designed preclinical studies selected several epigenetic drugs, including inhibitors of DNA methyltransferase (DNMTIs), such as Decitabine, histone deacetylase classes I-II (HDACIs), as Entinostat, Belinostat, lysine-specific histone demethylase (LSD1), as INCB059872 or FT-2102 (Olutasidenib), inhibitors of isocitrate dehydrogenases, and enhancer of zeste homolog 2 (EZH2), such as EPZ6438 (Tazemetostat) To enhance the therapeutic effect, the prevalent approach in phase II trial is the association of these epigenetic drug inhibitors, with targeted therapy or immune checkpoint blockade. Optimization of drug dosing and regimens of Phase II trials may improve the clinical efficiency of such novel therapeutic approaches against these devastating cancers.

Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety.

INTRODUCTION: Histone deacetylases (HDACs) represent one of the most validated cancer targets. The inhibition of HDACs has been proven to be a successful strategy for the development of novel anticancer candidates. METHODS: This work describes design and synthesis of a new set of HDAC inhibitors (7a-c and 8a, b) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition. RESULTS: The newly synthesized derivatives were evaluated for their potential inhibitory activity toward two class I histone deacetylases, namely HDAC1 and HDAC2. The tested ligustrazine-based compounds were more potent toward HDAC2 (IC50 range: 53.7-205.4 nM) than HDAC1 (IC50 range: 114.3-2434.7 nM). Furthermore, the antiproliferative activities against two HDAC-expressing cancer cell lines; HT-29 and SH-SY5Y were examined by the MTT assay. Moreover, a molecular docking study of the designed HDAC inhibitors (7a-c and 8a,b) was carried out to investigate their binding pattern within their prospective targets; HDAC1 (PDB-ID: 4BKX) and HDAC2 (PDB-ID: 6G3O). DISCUSSION: Compound 7a was found to be the most potent analog in this study toward HDAC1 and HDAC2 with IC50 values equal 114.3 and 53.7 nM, respectively. Moreover, it was the most effective counterpart (IC50 = 1.60 µM), with 4.7-fold enhanced efficiency than reference drug Gefitinib (IC50 = 7.63 µM) against SH-SY5Y cells. Whereas, compound 8a (IC50 = 1.96 µM) was the most active member toward HT-29 cells, being 2.5-times more potent than Gefitinib (IC50 = 4.99 µM). Collectively, these results suggest that 7a merits further optimization and development as an effective new HDACI lead compound.

Histone Acetylation and the Regulation of Major Histocompatibility Class II Gene Expression.

Major histocompatibility complex (MHC) class II molecules are essential for processing and presenting exogenous pathogen antigens to activate CD4+ T cells. Given their central role in adaptive immune responses, MHC class II genes are tightly regulated in a tissue- and activation-specific manner. The regulation of MHC class II gene expression involves various transcription factors that interact with conserved proximal cis-acting regulatory promoter elements, as well as MHC class II transactivator that interacts with a variety of chromatin remodeling machineries. Recent studies also identified distal regulatory elements within MHC class II gene locus that provide enormous insight into the long-range coordination of MHC class II gene expression. Novel therapeutic modalities that can modify MHC class II genes at the epigenetic level are emerging and are currently in preclinical and clinical trials. This review will focus on the role of chromatin remodeling, particularly remodeling that involves histone acetylation, in the constitutive and inducible regulation of MHC class II gene expression.