Removal Of Acetyl Groups Research Articles

A novel esterase regulates Klebsiella pneumoniae hypermucoviscosity and virulence.

Klebsiella pneumoniae, an emerging multidrug-resistant pathogen, exhibits hypermucoviscosity (HMV) as a critical virulence trait mediated by its capsular polysaccharide (CPS). Recent discoveries have determined acetylation as a significant modification for CPS, although its impact on HMV and virulence was previously unknown. This study elucidates the roles of two enzymes: Klebsiella pneumoniae Acetylated CPS Esterase (KpACE), an esterase that removes acetyl groups from CPS, and WcsU, an acetyltransferase that adds acetyl groups to CPS. KpACE is highly upregulated in an ompR-deficient mutant lacking HMV, and its overexpression consistently reduces HMV and diminishes virulence in a mouse model of pneumonia. The esterase domain-containing KpACE effectively deacetylates model sugar substrates and CPS-K2. Site-directed mutagenesis of the conserved catalytic histidine residue at position 370 significantly reduces its enzymatic activity. This reduction correlates with decreased HMV, affecting key virulence traits including biofilm formation and serum resistance. Similarly, a deficiency in the wcsU gene abolishes CPS acetylation, and reduces HMV and virulence. These results highlight the importance of the delicate balance between CPS acetylation by WcsU and deacetylation by KpACE in regulating the pathogenicity of K. pneumoniae. Understanding this balance provides new insights into the modulation of virulence traits and potential therapeutic targets for combating K. pneumoniae infections.

Histone Deacetylases in Metabolism: The Known and the Unexplored.

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from key lysine residues on histone and non-histone proteins and thereby regulate gene transcription. They have been implicated in several biological processes in both healthy and pathologic settings. This review discusses the role of HDACs in multiple metabolically active tissues and highlights their contribution to the pathogenesis of tissue-specific maladaptation and diseases. We also summarize the current knowledge gaps and potential ways to address them in future studies.

Regulation of Fumonisin B1 Production and Pathogenicity in Fusarium verticillioides by Histone Deacetylases

Transcriptional regulation mediated by the balance of histone acetylation and deacetylation is fundamental in responding to environmental cues by impacting chromatin remodeling. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone and non-histone proteins, thus restoring a tight chromatin structure. In pathogenic fungi, HDACs have been implicated in growth, secondary metabolite biosynthesis, and virulence. However, the role of HDACs in the mycotoxin fumonisin B1 (FB1)-producing fungus Fusarium verticillioides is poorly understood. In this study, we systematically characterized six F. verticillioides HDACs. An increased level of H4K16ac was observed in the deletion mutant of FvHOS2, which was associated with vegetative growth, conidiation, and virulence when infecting sugarcane and maize. FvRpd3 appeared to be essential for vegetative growth, while FvHda1 promoted growth, and both contributed to conidiation and pathogenicity. In contrast, FvSirt4 displayed a negative correlation with these processes. Additionally, the FB1 production was positively affected by FvHos2 and FvRpd3, but negatively impacted by Fvhda1, FvSir2, FvHst2, and FvSirt4 through the regulation of different key fumonisin biosynthetic (FUM) genes. Further findings indicate an association between FvSirt4 and FvSkb1, which is a histone methylase that positively regulates FB1 and pathogenicity. Moreover, as a global transcriptional regulator, over 2365 genes (~15% of the genome) enriched in multiple metabolic pathways were significantly downregulated in the ΔFvhos2 mutants relative to the wild type. Overall, our results suggest distinct roles of HDACs in regulating the growth, virulence, mycotoxin FB1 production, and gene expression in F. verticillioides.

Stack-HDAC3i: A high-precision identification of HDAC3 inhibitors by exploiting a stacked ensemble-learning framework

Epigenetics involves reversible modifications in gene expression without altering the genetic code itself. Among these modifications, histone deacetylases (HDACs) play a key role by removing acetyl groups from lysine residues on histones. Overexpression of HDACs is linked to the proliferation and survival of tumor cells. To combat this, HDAC inhibitors (HDACi) are commonly used in cancer treatments. However, pan-HDAC inhibition can lead to numerous side effects. Therefore, isoform-selective HDAC inhibitors, such as HDAC3i, could be advantageous for treating various medical conditions while minimizing off-target effects. To date, computational approaches that use only the SMILES notation without any experimental evidence have become increasingly popular and necessary for the initial discovery of novel potential therapeutic drugs. In this study, we develop an innovative and high-precision stacked-ensemble framework, called Stack-HDAC3i, which can directly identify HDAC3i using only the SMILES notation. Using an up-to-date benchmark dataset, we first employed both molecular descriptors and Mol2Vec embeddings to generate feature representations that cover multi-view information embedded in HDAC3i, such as structural and contextual information. Subsequently, these feature representations were used to train baseline models using nine popular ML algorithms. Finally, the probabilistic features derived from the selected baseline models were fused to construct the final stacked model. Both cross-validation and independent tests showed that Stack-HDAC3i is a high-accuracy prediction model with great generalization ability for identifying HDAC3i. Furthermore, in the independent test, Stack-HDAC3i achieved an accuracy of 0.926 and Matthew’s correlation coefficient of 0.850, which are 0.44–6.11% and 0.83–11.90% higher than its constituent baseline models, respectively.

Alkali pretreatment-assisted catalytic pyrolysis of waste cellulose acetate for selective preparation of levoglucosenone

With the increasing demand for cellulose acetate (CA) in industrial and daily applications, the disposal of its waste has emerged as an environmental concern. In this study, a novel and sustainable method for value-added utilization of waste CA was proposed, which involved NaOH pretreatment and subsequent catalytic pyrolysis using phosphoric acid-activated carbon (PAC) to prepare levoglucosone (LGO). The effects of pretreatment temperatures and NaOH concentrations on the physicochemical characteristics of CA were thoroughly investigated. Furthermore, the pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) experiments were conducted to methodically assess the impacts of both pretreatment and pyrolysis conditions on the production of LGO. The results indicated that NaOH pretreatment could effectively hydrolyze the ester bonds in CA, leading to the removal of acetyl groups and a decrease in thermal stability. At a pretreatment temperature of 40 °C, a NaOH concentration of 0.5 mol/L, a catalyst/sample ratio of 1/3, and a pyrolysis temperature of 400 °C, the LGO yield could reach 11.52 wt%, much higher than that obtained from catalytic pyrolysis of CA (2.70 wt%). This study provides an efficient method for treating waste CA and demonstrates its potential for conversion into high-value chemicals, laying a solid foundation for the green recycling of waste plastics.

Current Status and Applications of Gamma Radiation-induced Graft Copolymerized Chitosan

Chitosan (CS) is a natural polymer obtained by removing acetyl groups from chitin through alkaline hydrolysis. It possesses biodegradable properties and exhibits immunological, antibacterial, and wound-healing activities. This polysaccharide has undergone modification through radiation-induced graft copolymerization to broaden its application scope. The potential applications of CS can be expanded by introducing side chains through grafting. This article aims to review the innovative alternatives of gamma-graft-copolymerized CS and, for the first time, comprehensively examines the current applications of CS derivatives in dye removal, metal adsorption, antibacterial interventions, biomedical practices, drug delivery systems, and tissue engineering.

Enhancing cellulose acetate biodegradability in cigarette filters: an in-depth analysis of thermal alkaline pretreatment, microbial dynamics, and breakdown pathway prediction

BackgroundThe demand for bioplastics has increased exponentially as they have emerged as alternatives to petrochemical plastics. However, there is a substantial lack of knowledge regarding bioplastic degradation. This study developed a novel pretreatment method to improve the accessibility of a bioplastic substrate for biodegradation. In this study, cellulose acetate, a bioplastic found in the world’s most littered waste, e.g. cigarette filters, was selected as a potential substrate. Before anaerobic digestion, three thermal alkaline pretreatments: TA 30 °C, TA 90 °C, and TA 121 °C, were used to evaluate their effects on the chemical alterations of cellulose acetate.ResultThe ester groups in cellulose acetate were significantly reduced by the TA 30 °C pretreatment, as seen by a decrease in C = O stretching vibrations and shortening of C − O stretches (1,270 ∼ 1,210 cm− 1), indicating effective removal of acetyl groups. This pretreatment significantly enhanced cellulose acetate biodegradability to a maximum of 91%, surpassing the previously reported cellulose acetate degradation. Methane production increased to 695.0 ± 4 mL/g of volatile solid after TA 30 °C pretreatment, indicating enhanced cellulose acetate accessibility to microorganisms, which resulted in superior biogas production compared to the control (306.0 ± 10 mL/g of volatile solid). Diverse microbes in the anaerobic digestion system included hydrolytic (AB240379_g, Acetomicrobium, FN436103_g, etc.), fermentative, and volatile fatty acids degrading bacteria (JF417922_g, AB274492_g, Coprothermobacter, etc.), with Methanobacterium and Methanothermobacter being the sole hydrogenotrophic methanogens in the anaerobic digestion system. Additionally, an attempt to predict the pathway for the effective degradation of cellulose acetate from the microbial community in different pretreatment conditions.ConclusionsTo the best of our knowledge, this is the first study to estimate the maximum cellulose acetate degradation rate, with a simple and cost-effective pretreatment procedure. This approach holds promise for mitigating the environmental impact of cellulose acetate of cigarette filters and presents a sustainable and economically viable waste management strategy.

Optimizing cellulose acetate microbead formation through premixed membrane emulsification: Unraveling critical parameters

This study explores the fabrication of cellulose acetate microbeads using the premix membrane emulsification technique and their subsequent conversion to cellulose microbeads through deacetylation, emphasizing the need for environmentally friendly alternatives to conventional synthetic microbeads. By systematically investigating critical processing parameters such as oil-to-water phase ratio, cellulose acetate concentration, dispersion solvent, drying temperature, and flux rate, we optimized the conditions for producing uniform and well-dispersed microbeads. The optimal oil-to-water phase ratio was identified at 6:1, with higher concentrations of cellulose acetate yielding better dispersion and reduced bead size. The flux rate significantly influenced the morphology of the microbeads, with lower rates favoring spherical shapes. Non-polar solvents like hexane were found to enhance bead dispersion, whereas the drying temperature showed no significant impact. The successful transformation from cellulose acetate to cellulose microbeads was confirmed by FT-IR spectroscopy, demonstrating the removal of acetyl groups and indicating complete deacetylation. Our findings provide valuable insights into the production of cellulose-based microbeads, offering a sustainable alternative for various industrial and environmental applications.

Deletion of myeloid HDAC3 promotes efferocytosis to ameliorate retinal ischemic injury

Ischemia-induced retinopathy is a hallmark finding of common visual disorders including diabetic retinopathy (DR) and central retinal artery and vein occlusions. Treatments for ischemic retinopathies fail to improve clinical outcomes and the design of new therapies will depend on understanding the underlying disease mechanisms. Histone deacetylases (HDACs) are an enzyme class that removes acetyl groups from histone and non-histone proteins, thereby regulating gene expression and protein function. HDACs have been implicated in retinal neurovascular injury in preclinical studies in which nonspecific HDAC inhibitors mitigated retinal injury. Histone deacetylase 3 (HDAC3) is a class I histone deacetylase isoform that plays a central role in the macrophage inflammatory response. We recently reported that myeloid cells upregulate HDAC3 in a mouse model of retinal ischemia-reperfusion (IR) injury. However, whether this cellular event is an essential contributor to retinal IR injury is unknown. In this study, we explored the role of myeloid HDAC3 in ischemia-induced retinal neurovascular injury by subjecting myeloid-specific HDAC3 knockout (M-HDAC3 KO) and floxed control mice to retinal IR. The M-HDAC3 KO mice were protected from retinal IR injury as shown by the preservation of inner retinal neurons, vascular integrity, and retinal thickness. Electroretinography confirmed that this neurovascular protection translated to improved retinal function. The retinas of M-HDAC3 KO mice also showed less proliferation and infiltration of myeloid cells after injury. Interestingly, myeloid cells lacking HDAC3 more avidly engulfed apoptotic cells in vitro and after retinal IR injury in vivo compared to wild-type myeloid cells, suggesting that HDAC3 hinders the reparative phagocytosis of dead cells, a process known as efferocytosis. Further mechanistic studies indicated that although HDAC3 KO macrophages upregulate the reparative enzyme arginase 1 (A1) that enhances efferocytosis, the inhibitory effect of HDAC3 on efferocytosis is not solely dependent on A1. Finally, treatment of wild-type mice with the HDAC3 inhibitor RGFP966 ameliorated the retinal neurodegeneration and thinning caused by IR injury. Collectively, our data show that HDAC3 deletion enhances macrophage-mediated efferocytosis and protects against retinal IR injury, suggesting that inhibiting myeloid HDAC3 holds promise as a novel therapeutic strategy for preserving retinal integrity after ischemic insult.

Bacterial protein acetylation: mechanisms, functions, and methods for study.

Lysine acetylation is an evolutionarily conserved protein modification that changes protein functions and plays an essential role in many cellular processes, such as central metabolism, transcriptional regulation, chemotaxis, and pathogen virulence. It can alter DNA binding, enzymatic activity, protein-protein interactions, protein stability, or protein localization. In prokaryotes, lysine acetylation occurs non-enzymatically and by the action of lysine acetyltransferases (KAT). In enzymatic acetylation, KAT transfers the acetyl group from acetyl-CoA (AcCoA) to the lysine side chain. In contrast, acetyl phosphate (AcP) is the acetyl donor of chemical acetylation. Regardless of the acetylation type, the removal of acetyl groups from acetyl lysines occurs only enzymatically by lysine deacetylases (KDAC). KATs are grouped into three main superfamilies based on their catalytic domain sequences and biochemical characteristics of catalysis. Specifically, members of the GNAT are found in eukaryotes and prokaryotes and have a core structural domain architecture. These enzymes can acetylate small molecules, metabolites, peptides, and proteins. This review presents current knowledge of acetylation mechanisms and functional implications in bacterial metabolism, pathogenicity, stress response, translation, and the emerging topic of protein acetylation in the gut microbiome. Additionally, the methods used to elucidate the biological significance of acetylation in bacteria, such as relative quantification and stoichiometry quantification, and the genetic code expansion tool (CGE), are reviewed.

HDAC6 inhibition as a mechanism to prevent neurodegeneration in the mSOD1G93A mouse model of ALS

The loss of upper and lower motor neurons, and their axons is central to the loss of motor function and death in amyotrophic lateral sclerosis (ALS). Due to the diverse range of genetic and environmental factors that contribute to the pathogenesis of ALS, there have been difficulties in developing effective therapies for ALS. One emerging dichotomy is that protection of the neuronal cell soma does not prevent axonal vulnerability and degeneration, suggesting the need for targeted therapeutics to prevent axon degeneration. Post-translational modifications of protein acetylation can alter the function, stability and half-life of individual proteins, and can be enzymatically modified by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), which add, or remove acetyl groups, respectively. Maintenance of post-translational microtubule acetylation has been suggested as a mechanism to stabilize axons, prevent axonal loss and neurodegeneration in ALS. This study used an orally dosed potent HDAC6 inhibitor, ACY-738, prevent deacetylation and stabilize microtubules in the mSOD1G93A mouse model of ALS. Co-treatment with riluzole was performed to determine any effects or drug interactions and potentially enhance preclinical research translation. This study shows ACY-738 treatment increased acetylation of microtubules in the spinal cord of mSOD1G93A mice, reduced lower motor neuron degeneration in female mice, ameliorated reduction in peripheral nerve axon puncta size, but did not prevent overt motor function decline. The current study also shows peripheral nerve axon puncta size to be partially restored after treatment with riluzole and highlights the importance of co-treatment to measure the potential effects of therapeutics in ALS.

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.

Heterocycles-Containing HDAC Inhibitors Active in Cancer: An Overview of the Last Fifteen Years.

Cancer is one of the primary causes of mortality worldwide. Despite nowadays are numerous therapeutic treatments to fight tumor progression, it is still challenging to completely overcome it. It is known that Histone Deacetylases (HDACs), epigenetic enzymes that remove acetyl groups from lysines on histone's tails, are overexpressed in various types of cancer, and their inhibition represents a valid therapeutic strategy. To date, some HDAC inhibitors have achieved FDA approval. Nevertheless, several other potential drug candidates have been developed. This review aims primarily to be comprehensive of the studies done so far regarding HDAC inhibitors bearing heterocyclic rings since their therapeutic potential is well known and has gained increasing interest in recent years. Hence, inserting heterocyclic moieties in the HDAC-inhibiting scaffold can be a valuable strategy to provide potent and/or selective compounds. Here, in addition to summarizing the properties of novel heterocyclic HDAC inhibiting compounds, we also provide ideas for developing new, more potent, and selective compounds for treating cancer.

Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective.

Sirtuins (SIRTs) are classified as class III histone deacetylases (HDACs), a family of enzymes that catalyze the removal of acetyl groups from the ε-N-acetyl lysine residues of histone proteins, thus counteracting the activity performed by histone acetyltransferares (HATs). Based on their involvement in different biological pathways, ranging from transcription to metabolism and genome stability, SIRT dysregulation was investigated in many diseases, such as cancer, neurodegenerative disorders, diabetes, and cardiovascular and autoimmune diseases. The elucidation of a consistent number of SIRT-ligand complexes helped to steer the identification of novel and more selective modulators. Due to the high diversity and quantity of the structural data thus far available, we reviewed some of the different ligands and structure-based methods that have recently been used to identify new promising SIRT1/2 modulators. The present review is structured into two sections: the first includes a comprehensive perspective of the successful computational approaches related to the discovery of SIRT1/2 inhibitors (SIRTIs); the second section deals with the most interesting SIRTIs that have recently appeared in the literature (from 2017). The data reported here are collected from different databases (SciFinder, Web of Science, Scopus, Google Scholar, and PubMed) using "SIRT", "sirtuin", and "sirtuin inhibitors" as keywords.

Development of a fluorescence-based excipient screening for improved stability and shelf-life of recombinant chitin deacetylase

Chitin deacetylase (CDA) modifies chitin into chitosan by removing acetyl groups, but its inherent instability poses a challenge for successful crystallisation. Despite limited successes in crystallizing CDAs, prior attempts with recombinant chitin deacetylase (BaCDA) failed due to poor stability. To address this, we propose an enzyme buffer formulation as a cost-effective strategy to enhance stability, prolong shelf life, and increase the likelihood of crystallisation. Utilizing the high-throughput screening technique FTSA, we developed a screening method correlating BaCDA stability with its activity. The optimised formulation comprises 50 mM Tris-HCl buffer pH 7, 1 M NaCl, 20 % glycerol, and 1 mM Mg2+ as excipients. This formulation significantly improves BaCDA's thermostability (140.47 % increase) and enzyme activity (2.9-fold enhancement). BaCDA remains stable in the formulated buffer at −20 °C and −80 °C for 30 days and at 4 °C for 15 days. The current study has designed a high-throughput screening method approach to assess the stability of CDA enzyme formulations. The results of this study could contribute to the exploration of formulation elements that enhance the structural stability of CDA, thereby facilitating investigations into the enzyme's structure-function relationships.

Investigating Potential Cancer Therapeutics: Insight into Histone Deacetylases (HDACs) Inhibitions.

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from ɛ-amino of histone, and their involvement in the development and progression of cancer disorders makes them an interesting therapeutic target. This study seeks to discover new inhibitors that selectively inhibit HDAC enzymes which are linked to deadly disorders like T-cell lymphoma, childhood neuroblastoma, and colon cancer. MOE was used to dock libraries of ZINC database molecules within the catalytic active pocket of target HDACs. The top three hits were submitted to MD simulations ranked on binding affinities and well-occupied interaction mechanisms determined from molecular docking studies. Inside the catalytic active site of HDACs, the two stable inhibitors LIG1 and LIG2 affect the protein flexibility, as evidenced by RMSD, RMSF, Rg, and PCA. MD simulations of HDACs complexes revealed an alteration from extended to bent motional changes within loop regions. The structural deviation following superimposition shows flexibility via a visual inspection of movable loops at different timeframes. According to PCA, the activity of HDACs inhibitors induces structural dynamics that might potentially be utilized to define the nature of protein inhibition. The findings suggest that this study offers solid proof to investigate LIG1 and LIG2 as potential HDAC inhibitors.

Abstract 4487: Simple modifications of 3-HPT for improved in-vivo activtiy

Abstract One of the key targets in the treatment of castration resistant prostate cancer is HDAC6. HDAC6 removes acetyl groups from Heat shock protein 90 (HSP90), which is a protein chaperone that folds the androgen receptor. By inhibiting HDAC6 it is possible to prevent the expression of mutated androgen receptors, that are no longer responsive to androgen deprivation therapy, treating castration resistant prostate cancer. The Oyelere lab has previously demonstrated that 3-Hydroxypyridin-2-thione (3-HPT) can serve as a scaffold for HDAC6 inhibitors. While the unaltered 3-HPT has been shown on its own to inhibit HDAC6 in enzyme specific assays. The unaltered 3-HPT had no effect in whole cell assays. This work investigated simple modification of the 3-HPT scaffold to improve the in-vivo activity of 3-HPT. This work is an extension of work previously done in the Oyelere lab. The aim of this work is to apply simple modifications to the 3-HPT scaffold to improve the in-vitro activity. Previously 3-HPT was shown on its own to inhibit HDAC6 with an IC50 of 681nM but have no effect on cell assays. The hypothesis was that by converting the secondary amine into a tertiary amine the pharmacokinetic-properties of 3-HPT allowing can be improved focusing on cellular entry. The specific modification was the addition of alkanes and fluorinated alkanes at the secondary amine. This addition should improve the charge of the compounds improving the invitro activity. Based on molecular docking studies using Autodock vina, the introduction of fluorines improves the binding to HDAC6 by interacting with a hydrophilic pocket near the zinc ion. The preliminary in-vivo results in LnCAP and DU145 cells demonstrate that the addition of fluorinated alkanes has substantially improved the IC50 compared to the base 3-HPT compound. The base 3-HPT compound has an IC50 of greater than 100µM while the compounds with fluorinated alkanes have IC50 values in the range of 2-15µM. this data indicates improved drug likeness. Preliminary IC50 values of compounds in prostate cancer cell lines Compound Name LNCaPIC50 (µM) DU145IC50 (µM) Vero IC50 (µM) SH-1-78 >100 >100 >100 SH-1-94 2.50 19.29 22.53 RK-1-187 96.95 95.45 88.57 SH-1-110 1.27 21.47 17.41 RK-2-16 2.09 62.86 18.76 RK-2-17 >100 >100 >100 RK-2-64 78.36 >100 76.45 RK-2-67 14.19 26.95 11.38 Citation Format: Ryan E. Kern, Susanna Huang, Uche Arunsi, Adegboyega Oyelere. Simple modifications of 3-HPT for improved in-vivo activtiy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4487.

The Development of HDAC and Tubulin Dual-Targeting Inhibitors for Cancer Therapy.

Histone deacetylases (HDACs) are a class of enzymes that are responsible for the removal of acetyl groups from the ε-N-acetyl lysine of histones, allowing histones to wrap DNA more tightly. HDACs play an essential role in many biological processes, such as gene regulation, transcription, cell proliferation, angiogenesis, migration, differentiation and metastasis, which make it an excellent target for anticancer drug discovery. The search for histone deacetylase inhibitors (HDACis) has been intensified, with numerous HDACis being discovered, and five of them have reached the market. However, currently available HDAC always suffers from several shortcomings, such as limited efficacy, drug resistance, and toxicity. Accordingly, dual-targeting HDACis have attracted much attention from academia to industry, and great advances have been achieved in this area. In this review, we summarize the progress on inhibitors with the capacity to concurrently inhibit tubulin polymerization and HDAC activity and their application in cancer treatment.

Genome-wide identification of HDAC members and function analysis of PnHDT1/2 in salt stress response in Phyla nodiflora (L.) Greene

Reversible histone acetylation and deacetylation play an essential role in regulating chromatin structure and gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysine residues of core histones, resulting in closed chromatin structure and transcription repression. Although the HDCAs have been extensively studied in model plants, the HDAC members have not been identified in Phyla nodiflora (L.) Greene (P. nodiflora), a salt-tolerant plant species. Here, 17 PnHDAC genes were identified in the genome of P. nodiflora. Phylogenetic analysis displayed that the PnHDACs were classified into three groups, the RPD3/HDA1-group (11 members), the SIR2-group (2 members) and the plant-specific HD2-group (4 members). Transcription analysis displayed that the gene expression patterns of PnHDACs were affected by salt stress in P. nodiflora seedlings. PnHDT1 and PnHDT2, two HD2-type HDAC proteins were found to be subcellular localized in the nucleolus. Furthermore, overexpressing PnHDT1 and PnHDT2 in Arabidopsis decreased the sensitivity to plant hormone abscisic acid whereas reduced the tolerance to salt stress during seed germination and seedling stages. Overall, our work identified the PnHDAC gene family for the first time in P. nodiflora and revealed an involvement of PnHDT1 and PnHDT2 in salt stress tolerance, which may contribute to uncover the mechanism of P. nodiflora in adaption to salt environments.

Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and, as such, provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may result in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in epigenetic regulation primarily by modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extranuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases, and we will discuss the potential of their inhibitors for lung injury prevention.