Regulation Of Histone Deacetylase Activity Research Articles

Valeric acid delays aril breakdown of longan (Dimocarpus longan Lour.) fruit in relation to the regulation of histone deacetylase activity

Aril breakdown results in the loss of nutrition and commodity value, thereby limits the postharvest storage of longan fruit. Histone deacetylases (HDACs) are important epigenetic regulators in many biological processes. Results in the current study showed that application of valeric acid (VA), which belongs to HDAC inhibitors, suppressed longan aril breakdown during postharvest storage. Meanwhile, lower contents of malondialdehyde, H2O2, and O2−., but higher activities of superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and glutathione peroxidase (GPX) were observed in VA-treated fruit. Western blotting (WB) assay confirmed enhancement of histone H3 and H4 acetylation in VA-treated fruit, suggesting the possible inhibition of HDAC activity by VA. Furthermore, VA regulated DlHDACs expressions, with DlHDA5 and DlHDA8 expressions apposite of WB results. These results revealed that VA inhibited longan aril breakdown through enhancing the reactive oxygen species scavenging ability in relation to HDAC inhibitor activity. Our findings suggested that VA treatment delayed aril breakdown of longan fruit in relation to histone deacetylase-mediated epigenetic regulation and highlighted DlHDA5 and DlHDA8 potentially be important candidates for further research.

Comprehensive Analysis of Pertinent Genes and Pathways in Atrial Fibrillation.

Purpose Atrial fibrillation (AF) is the most frequent arrhythmia in clinical practice. The pathogenesis of AF is not yet clear. Therefore, exploring the molecular information of AF displays much importance for AF therapy. Methods The GSE2240 data were acquired from the Gene Expression Omnibus (GEO) database. The R limma software package was used to screen DEGs. Based on the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) databases, we conducted the functions and pathway enrichment analyses. Then, the STRING and Cytoscape software were employed to build Protein-Protein Interaction (PPI) network and screen for hub genes. Finally, we used the Cell Counting Kit-8 (CCK-8) experiment to explore the effect of hub gene knockdown on the proliferation of AF cells. Result 906 differentially expressed genes (DEGs), including 542 significantly upregulated genes and 364 significantly downregulated genes, were screened in AF. The genes of AF were mainly enriched in vascular endothelial growth factor-activated receptor activity, alanine, regulation of histone deacetylase activity, and HCM. The PPI network constructed of significantly upregulated DEGs contained 404 nodes and 514 edges. Five hub genes, ASPM, DTL, STAT3, ANLN, and CDCA5, were identified through the PPI network. The PPI network constructed by significantly downregulated genes contained 327 nodes and 301 edges. Four hub genes, CDC42, CREB1, AR, and SP1, were identified through this PPI network. The results of CCK-8 experiments proved that knocking down the expression of CDCA5 gene could inhibit the proliferation of H9C2 cells. Conclusion Bioinformatics analyses revealed the hub genes and key pathways of AF. These genes and pathways provide information for studying the pathogenesis, treatment, and prognosis of AF and have the potential to become biomarkers in AF treatment.

Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding.

Histone modifications through acetylation are fundamental for remodelling chromatin and consequently activating gene expression. The imbalance between acetylation and deacetylation activity causes transcriptional dysregulation associated with several disorders. Flavones, small molecules of plant origin, are known to interfere with class I histone deacetylase (HDAC) enzymes and to enhance acetylation, restoring cell homeostasis. To investigate the possible physical interactions of flavones on human HDAC1 and 2, we carried out in silico molecular docking simulations. Our data have revealed how flavone, and other two flavones previously investigated, i.e., apigenin and luteolin, can interact as ligands with HDAC1 and 2 at the active site binding pocket. Regulation of HDAC activity by dietary flavones could have important implications in developing epigenetic therapy to regulate the cell gene expression.

Molecular characterization of the grape seeds extract\u2019s effect against chemically induced liver cancer: In vivo and in vitro analyses

The purpose of this study was to investigate the anti-cancer property of grape seed extract (GSE) during early stages of developing liver cancer using a two-stage carcinogenic model combining diethylnitrosamine (DEN) and 2-Acetyl Aminofluorene (2-AAF). Administration of GSE at doses 25, 50 and 100 mg/kg per day started at the beginning of promotion periods and continued for 14 weeks. GSE dramatically inhibited pre-neoplastic foci formation as well as significantly decreased the number and the area of placental glutathione-S-transferase in livers of DEN-2AAF-treated rats by approximately 4 & 10 fold deductions, respectively. GSE’s effects were associated with induced apoptosis, reduced cell proliferation, decreased oxidative stress and down regulation of histone deacetylase activity and inflammation makers, such as cyclooxygenase 2, inducible nitric oxide synthase, nuclear factor-kappa B-p65 and p- phosphorylated tumor necrosis factor receptor expressions in liver. GSE treatment also decreased the viability of HepG2 cells and induced early and late apoptosis through activating caspase-3 and Bax. Furthermore, GSE induced G2/M and G1/S cell cycle arrest. The present study provides evidence that the GSE’s anticancer effect is mediated through the inhibition of cell proliferation, induction of apoptosis, modulating oxidative damage and suppressing inflammatory response.

In vivo effects of Trichostatin A – A histone deacetylase inhibitor – On chromatin remodeling during Triturus cristatus spermatogenesis

A major challenge in developmental biology field is to decipher the molecular mechanisms involved in cellular differentiation and to understand the processes that control and regulate genes expression. The study of nuclear molecular architecture during gametogenesis represents one approach toward deciphering the molecular organization and function of the eukaryotic chromatin. As spermatogenesis progresses, there is a widespread reorganization of the haploid genome followed by extensive DNA compaction. It is becoming increasingly evident that the dynamic composition of chromatin plays an important role in the activities of enzymes and in the processes that act upon it.As the information in the existing literature regarding the epigenetic modifications occurring in the advanced stages of spermatogenesis of crested newt is still scarce, we have investigated the effect of a Histone Deacetylase (HDAC) inhibitor, Trichostatin A (TSA), at the cytological level (by transmission electron microscopy – TEM, immunohistochemistry technique, fluorescence microscopy) and at the molecular level (AUT-PAGE and ChIP assay) on Triturus cristatus spermatogenesis. Our results have revealed an important role for regulation of histone deacetylase activity in controlling histone hyperacetylation and the replacement with sperm nuclear basic proteins during spermiogenesis.

Improving Insulin Sensitivity With HDAC Inhibitor

Histone deacetylase (HDAC) has emerged as a new molecular target in the control of obesity and type 2 diabetes. HDAC is an enzyme with well-known functions in the regulation of chromatin structure and gene transcription in the nucleus, where HDAC interacts with corepressor proteins such as NcoR and SMRT to form active corepressor complexes. In the corepressor complex, HDAC catalyzes removal of acetyl groups from histone proteins to inhibit gene expression. Recent studies have consistently suggested that HDAC also exhibits activity in the cytosol and mitochondria to regulate acetylation of metabolic enzymes (1). More than 20% of mitochondria proteins are regulated by acetylation (2,3). Regulation of HDAC activity is a new approach to modify glucose and fatty acid metabolism in the treatment of type 2 diabetes. In HDAC, HDAC3 and sirtuin (SIRT)1 are well-known players in regulation of fatty acid and glucose metabolism. In mammals, HDACs are divided into three classes: class I HDACs (1–3,8,10), class II HDACs (4–7,9,11), and class III HDACs (SIRTs 1–7 and NAD-dependent histone deacetylases). Class I HDACs have strong catalytic activities, and they are targets of most HDAC inhibitors, such as trichostatin A (TSA), sodium butyrate, and suberoylanilide hydroxamic acid. HDAC3 regulates metabolism in genetic and pharmacological studies. NcoR is required by HDAC3 in the regulation of transcription factors including peroxisome proliferator–activated receptor (PPAR)γ. NcoR knockout in fat tissue led to enhanced PPARγ function in adipose tissue, increased insulin sensitivity, …

A phase I trial of romidepsin in combination with gemcitabine in patients with pancreatic and other advanced solid tumors

2567 Background: Romidepsin is a histone deacetylase (HDAC) inhibitor that inhibits ras-mediated and MAP kinase signal transduction causing cell cycle arrest. Preclinical studies of romidepsin and gemcitabine in xenografts of ras transformed pancreatic cancer demonstrated significant antitumor activity for the combination compared to gemcitabine alone. Long-term effects were observed on tumor cell growth and cell cycle regulators following treatment cessation, suggesting down regulation of HDAC activity. This trial evaluated the safety and tolerability of romidepsin in combination with gemcitabine. Methods: Premedications consisted of a serotonin antagonist plus dexamethasone. Romidepsin was administered as a 4 hour infusion followed by gemcitabine over 30 minutes on days 1, 8, and 15 of a 28 day cycle. Results: Thirty-three patients (9 pancreatic, 8 breast, 7 NSCLC, 3 ovarian, 6 other; 23 F/10M) have received 104+ cycles (median 2, range 1 - 8). The initial romidepsin/gemcitabine dose level was 10/800 mg/m2, but 4/7 patients required dose omissions on days 8 or 15 due to thrombocytopenia (<75,000) or neutropenia (≤ 1,000) and were considered to have dose-limiting toxicity (DLT). Subsequently, the romidepsin was decreased to 7 mg/m2. At this dose level, 6/7 patients missed doses due to DLTs of thrombocytopenia and/or neutropenia. As a result, the day 8 dose was eliminated. Three dose levels have been explored on the every other week schedule. Ten patients were enrolled at 10/800 mg/m2 and 2/10 experienced a DLT (grade 4 thrombocytopenia, ↑LFTs). Six patients were enrolled at 10/1,000 mg/m2 with 2/6 experiencing dose-limiting grade 4 thrombocytopenia. Concurrently, the romidepsin was increased to 12 mg/m2 in combination with gemcitabine 800 mg/m2 and no DLTs were reported in 3 patients. Nonhematologic toxicities have been mild to moderate and consist primarily of nausea, vomiting, and fatigue. One patient with ovarian cancer experienced a minor response (29% ↓) and 12 pts experienced stable disease for ≥ 4 cycles (5 pancreatic, 4 breast, 1 NHL, 1 ovarian, 1 ampullary cancer). Conclusions: The recommended phase II dose (romidepsin 12 mg/m2 and gemcitabine 800 mg/m2 every other week) is being expanded to further assess the safety and activity of the regimen. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Gloucester Pharmaceuticals Gloucester Pharmaceuticals

A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma

8000 Background: MGCD0103 is a non-hydroxamate, isotype-selective, inhibitor of human HDACs. Abnormal regulation of HDAC activity is associated with malignant disease in humans, and small molecule HDAC inhibitors are a novel drug class with anticancer potential. Their proposed anti-Hodgkin activity is through regulation of aberrant gene expression at the transcriptional level by inhibiting proliferation, inducing apoptosis, and/or initiating differentiation in cancer cells. Methods: A phase II trial of MGCD0103 (110 mg 3x/week in 4- week cycles) is ongoing in patients (pts) with relapsed/refractory Hodgkin Lymphoma (RRHL). The primary endpoint is a composite of objective response and stable disease. Results: As of Dec 15th, 2006, 18 pts out of a planned 12–35 have been enrolled; median age 28 (range: 21–62). All pts were previously treated with autologous and/or allogeneic stem cell transplant. The median number of cycles received to date is 2 (range: 1–4). Seven pts have completed =8 weeks (2 cycles) of therapy and are evaluable for response analysis; 5 of these had tumor reduction ranging between 21% and 70% by CT, which is associated with a significant reduction in FDG-PET activity in 4 pts. Of the 18 pts, 5 have had dose reductions/discontinuations due to: mucositis (n=1); fatigue/nausea/diarrhea (n=1); nausea/vomiting (n=1); fatigue (n=1) and pancreatitis/hypotension (n=1). Significant HDAC inhibition (&gt;20% of total activity), was seen in PBMCs from 7/9 pts with samples. Treatment is ongoing in 14 pts; including those with tumor reduction. Criteria have been met to expand to the second stage of the study (&gt;1 response demonstrated in the first 12 patients). Conclusions: Preliminary results suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in RRHL and is well tolerated at a Phase II dose of 110mg in this ongoing trial. No significant financial relationships to disclose.