QSAR Studies on the Inhibitory Activityof Levofloxacin-thiadiazole HDACi Conjugates to Histone Deacetylases

A molecular electronegativity distance vector(M)based on 13 atomic types has been used to describe the structures of 19 conjugates(LHCc)of levofloxacin-thiadiazole HDAC inhibitor(HDACi)and related inhibitory activities(pH,i=1,2,6)of LHCc against histone deacetylases(HDACs,such as HDAC1,HDAC2 and HDAC6).The quantitative structure-activity relationships(QSAR)were established by using leaps-and-bounds regression analysis for the inhibitory activities(pH)of 19 above compounds to HDAC1,HDAC2 and HDAC6 along with M.The correlation coefficients(R~2)and the leave-one-out(LOO)cross validation Rfor the pH,pHand pHmodels were 0.976 and 0.949;0.985 and 0.977;0.976 and 0.932,respectively.The QSAR models had favorable correlations,as well as robustness and good prediction capability by R~2,F,R~2,A,Fand Vtests.Validated by using 3876 training sets,the models have good external prediction ability.The results indicate that the molecular structural units:–CH–(g=1,2),–NH,–OH,=O,–O–and–S–are the main factors which can affect the inhibitory activity of pH,pHas well as pHbioactivities of these compounds directly.Accordingly,the main interactions between HDACs inhibitor and HDACs are hydrophobic interaction,hydrogen bond,and coordination with Znto form compounds,which is consistent with the results in reports.

Histone deacetylases and cardiovascular cell lineage commitment

Cardiovascular diseases(CVDs), which include alldiseases of the heart and circulation system, are the leading cause of deaths on the globally. During the development of CVDs, choric inflammatory, lipid metabolism disorder and endothelial dysfunction are widely recognized risk factors. Recently, the new treatment for CVDs that designed to regenerate the damaged myocardium and injured vascular endothelium and improve recovery by the use of stem cells, attracts more and more public attention. Histone deacetylases(HDACs) are a family of enzymes that remove acetyl groups from lysine residues of histone proteins allowing the histones to wrap the DNA more tightly and commonly known as epigenetic regulators of gene transcription. HDACs play indispensable roles in nearly all biological processes, such as transcriptional regulation, cell cycle progression and developmental events, and have originally shown to be involved in cancer and neurological diseases. HDACs are also found to play crucial roles in cardiovascular diseases by modulating vascular cell homeostasis(e.g., proliferation, migration, and apoptosis of both ECs and SMCs). This review focuses on the roles of different members of HDACs and HDAC inhibitor on stem cell/ progenitor cell differentiation toward vascular cell lineages(endothelial cells, smooth muscle cells and Cardiomyocytes) and its potential therapeutics.

Histone deacetylases,microRNA and leptin crosstalk in pancreatic cancer

Because pancreatic cancer(PC) historically has had poor prognosis and five year survival rates,it has been intensely investigated.Analysis of PC incidence and biology has shown a link between different risk factors such as smoking,alcoholism,and obesity and disease progression.Important factors affecting PC include the epigenomic changes driven by DNA methylation and histone acetylation,and actions of microRNA inducing oncogenic or tumor suppressor effects.Studies have identified markers whose dysregulation seem to play important roles in PC progression.PC markers involve classical histone deacetylases(HDAC),PC stem cell(PCSC),and leptin.In this review,we discuss the role of several PC biomarkers,and the potential crosstalk between HDAC,microRNA,and leptin in PC progression.Dysregulated expression of these molecules can increase proliferation,survival,PCSC,resistance to chemotherapy and tumor angiogenesis.The potential relationships between these molecules are further analyzed using data from The Cancer Genome Atlas and crosstalk pathways generated by the Pathway Studio Platform(Ariadne Genomics,Inc.).Oncogenic miRNA21 and tumor suppressor miRNA200 have been previously linked to leptin signaling.Preliminary analysis of PC biopsies and signaling crosstalk suggests that the main adipokine leptin could affect the expression of microRNA and HDAC in PC.Data analysis suggests that HDAC-microRNA-leptin signaling crosstalk may be a new target for PC therapy.

Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases

The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.

The expression of histone deacetylases and the regenerative abilities of spinal-projecting neurons after injury

Epigenetic control of regeneration after spinal cord injury： Com- plete spinal cord injury （SCI） in humans and other mammals leads to irreversible paralysis below the level of injury, due to failure of axonal regeneration in the central nervous system （CNS）. Previous work has shown that successful axon regeneration is dependent upon transcription of a large number of regeneration-associated genes （RAGs） and transcription factors （TFs） （Van Kesteren et al., 2011）. A prominent theory in the field of axon regeneration is that the large differences in regenerative potential between peripheral nervous system （PNS） neurons, which regenerate well, and CNS neurons, which do not, reflect differences in intrinsic transcriptional net- works, rather than individual genes （Van Kesteren et al., 2011）.

Targeting histone deacetylases： perspectives for epigenetic-based therapy in cardio-cerebrovascular disease

Although the pathogenesis of cardio-cerebrovascular disease （CCVD） is multifactorial, an increasing number of experimental and clinical studies have highlighted the importance of histone deacetylase （HDAC）-mediated epigenetic processes in the development of cardio-cerebrovascular injury. HDACs are a family of enzymes to balance the acetylation activities of histone acetyltransferases on chromatin remodeling and play essential roles in regulating gene transcription. To date, 18 mammalian HDACs are identified and grouped into four classes based on similarity to yeast orthologs. The zinc-dependent HDAC family currently consists of 11 members divided into three classes （class I, II, and IV） on the basis of structure, sequence homology, and domain organization. In comparison, class III HDACs （also known as the sirtuins） are composed of a family of NAD＋-dependent protein-modifying enzymes related to the Sir2 gene. HDAC inhibitors are a group of compounds that block HDAC activities typically by binding to the zinc-containing catalytic domain of HDACs and have displayed an- ti-inflammatory and antifibrotic effects in the cardio-cerebrovascular system. In this review, we summarize the current knowledge about classifications, functions of HDACs and their roles and regulatory mechanisms in the cardio-cerebrovascular system. Pharmacological tar- geting of HDAC-mediated epigenetic processes may open new therapeutic avenues for the treatment of CCVD.

Histone deacetylases in hearing loss: Current perspectives for therapy

Hearing loss is one of the most frequent health issues in industrialized countries. The pathogenesis and molecular mechanisms of hearing loss are still unclear. Histone deacetylases(HDACs) are emerging as key enzymes in many physiological processes, including chromatin remodeling,regulation of transcription, DNA repair, metabolism, genome stability and protein secretion. Recent studies indicated that HDACs are associated with the development and progression of hearing loss. Dysfunction of HDACs could promote the oxidative stress and aging in the inner ear. In light of considering the current stagnation in the development of therapeutic options, the need for new strategies in the treatment of hearing loss has never been so pressing. In this review, we will summarize the reported literatures for HDACs in hearing loss and discuss how HDAC family members show different performances for the possibility of process of diseases development. The possibility of pharmacological intervention on hearing loss opens a novel path in the treatment of hearing loss.

Histone deacetylases:Regulation of vascular homeostasis via endothelial cells and vascular smooth muscle cells and the role in vascular pathogenesis

tHistone deacetylases(HDACs)are proteases that play a key role in chromosome structural modification and gene expression regulation,and the involvement of HDACs in can-cer,the nervous system,and the metabolic and immune system has been well reviewed.Our understanding of the function of HDACs in the vascular system has recently progressed,and a significant variety of HDAC inhibitors have been shown to be effective in the treatment of vascular diseases.However,few reviews have focused on the role of HDACs in the vascular sys-tem.In this study,the role of HDACs in the regulation of the vascular system mainly involving endothelial cells and vascular smooth muscle cells was discussed based on recent updates,and the role of HDACs in different vascular pathogenesis was summarized as well.Furthermore,the therapeutic effects and prospects of HDAC inhibitors were also addressed in this review.

Transcriptional Repression by Histone Deacetylases in Plants

Reversible histone acetylation and deacetylation at the N-terminus of histone tails play crucial roles in regulation of eukaryotic gene activity. Acetylation of core histones usually induces an ＇open＇ chromatin structure and is associated with gene activation, whereas deacetylation of histone is often correlated with ＇closed＇ chromatin and gene repression. Histone deacetylation is catalyzed by histone deacetylases （HDACs）. A growing number of studies have demonstrated the importance of histone deacetylation/acetylation on genome stability, transcriptional regulation, and development in plants. Furthermore, HDACs were shown to interact with various chromatin remolding factors and transcription factors involved in transcriptional repression in multiple developmental processes. In this review, we summarized recent findings on the transcriptional repression mediated by HDACs in plants.

Functions and mechanisms of plant histone deacetylases

Lysine acetylation, one of the major types of post-translational modifications, plays critical roles in regulating gene expression and protein function. Histone deacetylases(HDACs) are responsible for removing acetyl groups from lysines of both histone and non-histone proteins. While tremendous progress has been made in understanding the function and mechanism of HDACs in animals in the past two decades, nearly half of the HDAC studies in plants were reported within the past five years. In this review,we summarize the major findings on plant HDACs, with a focus on the model plant Arabidopsis thaliana, and highlight the components, regulatory mechanisms, and biological functions of HDAC complexes.

Histone deacetylases and their inhibitors:molecular mechanisms and therapeutic implications in diabetes mellitus

Epigenetic mechanisms such as DNA methylation,histone modification and microRNA changes have been shown to be important for the regulation of cellular functions.Among them,histone deacetylases(HDACs)are enzymes that balance the acetylation activities of histone acetyltransferases in chromatin remodeling and play essential roles in gene transcription to regulate cell proliferation,migration and death.Recent studies indicate that HDACs are promising drug targets for a wide range of diseases including cancer,neurodegenerative and psychiatric disorders,cardiovascular dysfunction,autoimmunity and diabetes mellitus.This review highlights the role of HDACs in diabetes mellitus and outlines several important cellular and molecular mechanisms by which HDACs regulate glucose homeostasis and can be targeted for the treatment of dia betic microvascular complications.It is hoped that our understanding of the role of HDACs in diabetes.mellitus will lead to the development of better diagnostic tools and the design of more potent and specific drugs targeting selective HDAC proteins for the treatment of the disease.

Multifaceted Influence of Histone Deacetylases on DNA Damage Repair:Implications for Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is one of the most commonly diagnosed cancers and a leading cause of cancerrelated mortality worldwide,but its pathogenesis remains largely unknown.Nevertheless,genomic instability has been recognized as one of the facilitating characteristics of cancer hallmarks that expedites the acquisition of genetic diversity.Genomic instability is associated with a greater tendency to accumulate DNA damage and tumor-specific DNA repair defects,which gives rise to gene mutations and chromosomal damage and causes oncogenic transformation and tumor progression.Histone deacetylases(HDACs)have been shown to impair a variety of cellular processes of genome stability,including the regulation of DNA damage and repair,reactive oxygen species generation and elimination,and progression to mitosis.In this review,we provide an overview of the role of HDAC in the different aspects of DNA repair and genome instability in HCC as well as the current progress on the development of HDAC-specific inhibitors as new cancer therapies.

Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

Molecular mechanism revealing therapeutic opportunities of histone deacetylases inhibitors in triple-negative breast cancer

Subject Code:H31With the support by the National Natural Science Foundation of China,Ministry of Science and Technology of China and Chinese Academy of Sciences,the research team led by Prof.Geng Meiyu(耿美玉)and Ding Jian(丁健)from Shanghai Institute of Materia Medica,Chinese Academy of Sciences,demonstrated the therapeutic opportunities of histone deacetylases(HDACs)inhibitors in

Arabidopsis RPD3-like histone deacetylases form multiple complexes involved in stress response

The Arabidopsis thaliana RPD3-type histone deacetylases have been known to form conserved SIN3-type histone deacetylase complexes,but whether they form other types of complexes is unknown.Here,we perform affinity purification followed by mass spectrometry and demonstrate that the Arabidopsis RPD3-type histone deacetylases HDA6 and HDA19 interact with several previously uncharacterized proteins,thereby forming three types of plant-specific histone deacetylase complexes,which we named SANT,ESANT,and ARID.RNA-seq indicates that the newly identified components function together with HDA6 and HDA19 and coregulate the expression of a number of genes.HDA6 and HDA19 were previously thought to repress gene transcription by histone deacetylation.We find that the histone deacetylase complexes can repress gene expression via both histone deacetylation-dependent and-independent mechanisms.In the mutants of histone deacetylase complexes,the expression of a number of stressinduced genes is up-regulated,and several mutants of the histone deacetylase complexes show severe retardation in growth.Considering that growth retardation is thought to be a trade-off for an increase in stress tolerance,we infer that the histone deacetylase complexes identified in this study prevent overexpression of stress-induced genes and thereby ensure normal growth of plants under nonstress conditions.

Nucleolar histone deacetylases HDT1,HDT2,and HDT3 regulate plant reproductive development

Nucleolus is a membrane-less organelle where ribosomes are assembled, and ribosomal RNAs(r RNAs)transcribed and processed. The assembled ribosomes composed of ribosomal proteins and r RNAs synthesize proteins for cell survival. In plants, the loss of nucleolar ribosomal proteins often causes gametophytically or embryonically lethality. The amount of r RNAs are under stringent regulation according to demand and partially switched off by epigenetic modifications. However, the molecular mechanism for the selective activation or silencing is still unclear, and the transcriptional coordination of r RNAs and ribosomal proteins is also unknown. Here, we report the critical role of three Arabidopsis nucleolar proteins HDT1,HDT2, and HDT3 in fertility and transcription of r DNAs and r RNA processing-related genes through histone acetylation. This study highlights the important roles of transcriptional repression of ribosome biogenesisrelated genes for plant reproductive development.

Bhlhe40 protects cochlear hair cell-like HEI-OC1 cells against H_(2)O_(2) ‑triggered oxidative injury

Background:Cochlear hair cell injury is a common pathological feature of hearing loss.The basic helix-loop-helix family,member e40(Bhlhe40),a gene belonging to the basic helix-loop-helix(bHLH)family,exhibits strong transcriptional repression activity.Methods:Oxidative damage,in House Ear Institute-Organ of Corti 1(HEI-OC1)cells,was caused using hydrogen peroxide(H2O2).The Ad-Bhlhe40 particles were constructed to overexpress Bhlhe40 in HEI-OC1 cells.Various assays including cell counting kit-8(CCK-8),terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay(TUNEL),flow cytometry,immunofluorescence,and corresponding commercial kits were employed to investigate the impacts of Bhlhe40 on cell viability,apoptosis,oxidative stress levels,mitochondrial membrane potential and cellular senescence.Additionally,a dual-luciferase reporter assay was performed to confirm the targeting of the histone deacetylases 2(Hdac2)by Bhlhe40.Results:The results revealed that Bhlhe40 was downregulated in H_(2)O_(2)-treated HEI-OC1 cells,but its overexpression improved cell viability and mitigated H_(2)O_(2)-induced oxidative injury in HEI-OC1 cells with increase of superoxide dismutase(SOD),catalase(CAT)and glutathione peroxidase(GPx)activities and decrease of reactive oxygen species(ROS)levels.Besides,overexpression of Bhlhe40 suppressed H_(2)O_(2)-triggered cell senescence,as evidenced by the fact that the upregulation of P53,P21,and P16 in HEI-OC1 cells treated with H2O2 were all alleviated by Bhlhe40 overexpression.And we further verified that overexpression of Bhlhe40 could inhibit the expression of Hdac2,which may be related to the repression of Hdac2 transcription.Conclusion:This study suggests that Bhlhe40 plays a protective role against senescence and oxidative damage in cochlear hair cells exposed to H2O2.

Repressing iron overload ameliorates central poststroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.

Current evidence for histone deacetylase inhibitors in pancreatic cancer

Pancreatic cancer is one of the most aggressive human cancers,with more than 200 000 deaths worldwide every year.Despite recent efforts,conventional treatment approaches,such as surgery and classic chemotherapy,have only slightly improved patient outcomes.More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm.Among new agents,histone deacetylase inhibitors (HDACIs) are now being tested.HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression,apoptosis,cell cycle progression and angiogenesis.HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines.In the present review,the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro,as well as their antiproliferative effects in animal models are presented.HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor ef-fects,at well-tolerated doses.

Novel epigenetic-based therapies useful in cardiovascular medicine

Epigenetic modifications include DNA methylation, his-tone modifications, and micro RNA. Gene alterations have been found to be associated with cardiovascular diseases, and epigenetic mechanisms are continuously being studied to find new useful strategies for the clinical management of afflicted patients. Numerous cardiovascular disorders are characterized by the abnormal methylation of Cp G islands and so specific drugs that could inhibit DNA methyltransferase directly or by reducing its gene expression(e.g., hydralazine and procainamide) are currently under investigation. The anti-proliferative and anti-inflammatory properties of histone deacetylase inhibitors and their cardio-protective effects have been confirmed in preclinical studies. Furthermore, the regulation of the expression of micro RNA targets through pharmacological tools is still under development. Indeed, large controlled trials are required to establish whether current possible candidate antisense micro RNAs could offer better therapeutic benefits in clinical practice. Here, we updated therapeutic properties, side effects, and feasibility of eme-rging epigenetic-based strategies in cardiovascular diseases by highlighting specific problematic issues that still affect the development of large scale novel therapeutic protocols.