• BMB Reports
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• v.52 no.3
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• pp.175-180
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• 2019

Telomeres are nucleoprotein complexes at the physical ends of linear eukaryotic chromosomes. They protect the chromosome ends from various external attacks to avoid the loss of genetic information. Telomeres are maintained by cellular activities associated with telomerase and telomere-binding proteins. In addition, epigenetic regulators have pivotal roles in controlling the chromatin state at telomeres and subtelomeric regions, contributing to the maintenance of chromosomal homeostasis in yeast, animals, and plants. Here, we review the recent findings on chromatin modifications possibly associated with the dynamic states of telomeres in Arabidopsis thaliana.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.310.1-310.1
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• 2003

SD-2007 ia an apicidin analogue, possessing a potent histone deacetylase inhibiting activity. A rapid and senstive LC/MS method was developed for the determination of SD-2007 and its major active metabolite. apicidin. in rat serum. SD-2007 and apicidin was extracted by liquid-liquid extraction using methyl t-butyl ether. SD-2007 and apicidin were monitored in a SIM mode at m/z of 679 and 622, respectively. (omitted)

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2503-2508
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• 2013

Histone deacetylation mediated by histone deacetylases (HDACs) has been reported as one of the epigenetic mechanisms associated with tumorigenesis. The poor responsiveness of anticancer drugs found with cholangiocarcinoma (CCA) leads to short survival rate. We aimed to investigate mRNA expression of HDACs class I and II, and the effect of HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), in CCA in vitro. Expression of HDACs was studied in CCA cell lines (M213, M214 and KKU-100) and an immortal cholangiocyte (MMNK1) by semi-quantitative reverse transcription-PCR. SAHA and VPA, as well as a classical chemotherapeutic drug 5 -fluorouacil (5-FU) were used in this study. Cell proliferation was determined by sulforhodamine assay. $IC_{50}$ and $IC_{20}$ were then analyzed for each agent and cell line. Moreover, synergistic potentional of VPA or SAHA in combination with 5-FU at sub toxic does ($IC_{20}$) of each agent was also evaluated. Statistic difference of HDACs expression or cell proliferation in each experimental condition was analyzed by Student's t-test. The result demonstrated that HDACs were expressed in all studied cell types. Both SAHA and VPA inhibited cell proliferation in a dose-dependent manner. Interestingly, KKU-100 which was less senstitive to classical chemotheraoeutic 5-FU was highly was sensitive to HDAC inhibitors. Simultaneous combination of subtoxic doses of HDAC inhibitors and 5-FU signiicantly inhibited cell proliferation in CCA cell lines compared to single sgent treatment($P{\leq}0.01$), while sequentially combined treatments were less effective. The present study showed inhibitory effects of HDACIs on cell proliferation in CCA cell lines, with synergistic antitumor potential demonstrated by simultaneous combination of VPA or SAHA with 5-FU, suggesting a novel alternative therapeutic strategy in effective treatment of CCA.

• Interdisciplinary Bio Central
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• v.4 no.1
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• pp.2.1-2.7
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• 2012

Introduction: Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups from ${\varepsilon}$-N-acetyl lysine amino acids of histone proteins. Their action is opposite to that of histone acetyltransferase that adds acetyl groups to these lysines. Only few HDAC inhibitors are approved and used as anti-cancer therapeutics. Thus, discovery of new and potential HDAC inhibitors are necessary in the effective treatment of cancer. Materials and Methods: This study proposed a method using support vector machine (SVM) to classify HDAC8 inhibitors and non-inhibitors in early-phase virtual compound filtering and screening. The 100 experimentally known HDAC8 inhibitors including 52 inhibitors and 48 non-inhibitors were used in this study. A set of molecular descriptors was calculated for all compounds in the dataset using ADRIANA. Code of Molecular Networks. Different kernel functions available from SVM Tools of free support vector machine software and training and test sets of varying size were used in model generation and validation. Results and Conclusion: The best model obtained using kernel functions has shown 75% of accuracy on test set prediction. The other models have also displayed good prediction over the test set compounds. The results of this study can be used as simple and effective filters in the drug discovery process.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3605-3610
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• 2016

Background: Histone acetylation in chromatin structures plays a key role in regulation of gene transcription and is strictly controlled by histone acetyltransferase (HAT) and deacetylase (HDAC) activities. HDAC deregulation has been reported in several cancers. Materials and Methods: The expression of 10 HDACs (including HDAC class I and II) was studied by quantitative reverse transcription-PCR (qRT-PCR) in a cohort of mesenchymal stem cells (MM-MSCs) from 10 multiple myeloma patients with a median age 60y. The results were compared with those obtained for normal donors. Then, a coculture system was performed between MM-MSCs and u266 cell line, in the presence or absence of sodium butyrate (NaBT), to understand the effects of HDAC inhibitors (HDACi) in MM-MSCs on multiple myeloma cases. Also, the interleukin-6 (IL-6) and vascular endothelial growth factor (VEGFA) gene expression level and apoptotic effects were investigated in MM-MSCs patients and control group following NaBT treatment. Results: The results indicated that upregulated (HDACs) and downregulated (IL6 and VEGFA) genes were differentially expressed in the MM-MSCs derived from patients with multiple myeloma and ND-MSCs from normal donors. Comparison of the MM-MSCs and ND-MSCs also showed distinct HDACs expression patterns. For the first time to our knowledge, a significant increase of apoptosis was observed in coculture with MM-MSCs treated with NaBT. Conclusions: The obtained findings elucidate a complex set of actions in MSCs in response to HDAC inhibitors, which may be responsible for anticancer effects. Also, the data support the idea that MSCs are new therapeutic targets as a potential effective strategy for MM.

• Journal of Plant Biotechnology
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• v.31 no.2
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• pp.175-178
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• 2004

Transgenic tobacco (Nicotiana tabacum L. cv Bright Yellow-2) cell lines expressing a human histone H1.5 (referred to as hH1.5), which suppress collagen-induced rheumatoid arthritis, were developed under the oxidative stress-inducible peroxidase (SWPA2) promoter. Tobacco BY-2 cells were transformed by Agrobacterium-mediated method. The kanamycin-resistant calli were selected on the modified MS medium containing 150mg/L kanamycin and 300mg/L claforan. Transgenic cell lines were confirmed by PCR and northern blot analysis. Recombinant hH1.5 (rhH1.5) protein (42 kDa) was also detected by Western blot analysis, showing a different molecular weight of human hH1.5 (32 kDa). These results suggested that a hH1.5 gene was properly introduced in tobacco cultured cells under the control of SWPA2 promoter. The further characterization of rhH1.5 protein remains to be studied.

• Molecules and Cells
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• v.26 no.1
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• pp.93-99
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• 2008

Transcriptional silencing is regulated by promoter methylation and histone modifications such as methylation and acetylation. We constructed a Schizosaccaromyces pombe reporter strain, KCT120a, to identify modifiers of transcriptional silencing, by inserting the $ura4^+$ gene into a heterochromatic telomere region. Two compounds inhibited the activity of histone deacetylases, induced acetylation of histone H3 and caused apoptotic cell death in HeLa cells. Expression of gelsolin and $p21^{waf1/cip1}$ also increased, as it does in response to HDAC inhibitors such as TSA. Therefore, these compounds appear to be potent inhibitors of HDACs, and hence potential anti-cancer drugs. Our observations suggest that a yeast cell-based assay system for transcriptional silencing may be useful for identifying histone deacetylase inhibitors and other agents affecting chromatin remodeling.

• The Korean Journal of Zoology
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• v.36 no.3
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• pp.367-372
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• 1993

We have found a protein kinase activity that is tightly associated with type II DNA topoisomerase purified from regenerating rat liver. The activities of protein kinase and topoisomerase II were not separable when the enzyme was subjected to analytical chromatographies (Hydroxyapatite, phosphocellulose, and double strand DNA cellulose) and glycerol gradient sedimentation. The kinase activity from purified rat topoisomerase II was also inactivated by the topoisomerase II inhibitors such as N-ethylmaleimide or novobiocin. The evidences, however, do not rule out a possibility that the kinase activity resides in a polypeptide other than the topoisomerase II protein. The topoisomerase II-associated protein kinase required Mg++ for its activity, and this requirement was not substituted by any other mono- or divalent ions. Histone H1 act as a strong stimulator and a good substrate for the kinase activity and other histones and ${\alpha}$-casein could not substitute the effect of histone H1.

• Nutrition Research and Practice
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• v.17 no.1
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• pp.164-173
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• 2023

BACKGROUND/OBJECTIVES: Hyperglycemia is a major cause of diabetes and diabetesrelated diseases. Sodium butyrate (NaB) is a short-chain fatty acid derivative that produces dietary fiber by anaerobic bacterial fermentation in the large intestine and occurs in foods, such as Parmesan cheese and butter. Butyrate has been shown to prevent obesity, improve insulin sensitivity, and ameliorate dyslipidemia in diet-induced obese mice. Therefore, this study examined the effects and mechanism of NaB on the secretion of inflammatory cytokines induced by high glucose (HG) in THP-1 cells. MATERIALS/METHODS: THP-1 cells were used as an in vitro model for HG-induced inflammation. The cells were cultured under normal glycemic or hyperglycemic conditions with or without NaB (0-25 μM). Western blotting and quantitative polymerase chain reaction were used to evaluate the protein and mRNA levels of nuclear factor-κB (NF-κB), interleukin-6, tumor necrosis factor-α, acetylated p65, acetyl CREB-binding protein/p300 (CBP/p300), and p300 using THP-1 cells. Histone acetyltransferase (HAT), histone deacetylase (HDAC), and pro-inflammatory cytokine secretion activity were analyzed using an enzyme-linked immunosorbent assay. RESULTS: HG significantly upregulated histone acetylation, acetylation levels of p300, NF-κB activation, and inflammatory cytokine release in THP-1 cells. Conversely, the NaB treatment reduced cytokine release and NF-κB activation in HG-treated cells. It also significantly reduced p65 acetylation, CBP/p300 HAT activity, and CBP/p300 gene expression. In addition, NaB decreased the interaction of p300 in acetylated NF-κB and TNF-α. CONCLUSIONS: These results suggest that NaB suppresses HG-induced inflammatory cytokine production through HAT/HDAC regulation in monocytes. NaB has the potential for preventing and treating diabetes and its related complications.

• Parasites, Hosts and Diseases
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• v.62 no.1
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• pp.98-116
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• 2024

Epigenetic writers including DNA and histone lysine methyltransferases (DNMT and HKMT, respectively) play an initiative role in the differentiation and development of eukaryotic organisms through the spatiotemporal regulation of functional gene expressions. However, the epigenetic mechanisms have long been suspected in helminth parasites lacking the major DNA methyltransferases DNMT1 and DNMT3a/3b. Very little information on the evolutionary status of the epigenetic tools and their role in regulating chromosomal genes is currently available in the parasitic trematodes. We previously suggested the probable role of a DNMT2-like protein (CsDNMT2) as a genuine epigenetic writer in a trematode parasite Clonorchis sinensis. Here, we analyzed the phylogeny of HKMT subfamily members in the liver fluke and other platyhelminth species. The platyhelminth genomes examined conserved genes for the most of SET domain-containing HKMT and Disruptor of Telomeric Silencing 1 subfamilies, while some genes were expanded specifically in certain platyhelminth genomes. Related to the high gene dosages for HKMT activities covering differential but somewhat overlapping substrate specificities, variously methylated histones were recognized throughout the tissues/organs of C. sinensis adults. The temporal expressions of genes involved in eggshell formation were gradually decreased to their lowest levels proportionally to aging, whereas those of some epigenetic tool genes were re-boosted in the later adult stages of the parasite. Furthermore, these expression levels were significantly affected by treatment with DNMT and HKMT inhibitors. Our data strongly suggest that methylated histones are potent epigenetic markers that modulate the spatiotemporal expressions of C. sinensis genes, especially those involved in sexual reproduction.