• IMMUNE NETWORK
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• v.13 no.2
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• pp.75-79
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• 2013

Evidence for immunoregulatory roles of prostaglandins (PGs) is accumulating. Since our observation of PG production by human follicular dendritic cells (FDCs), we investigated the regulatory mechanism of PG production in FDC and attempted to understand the functions of released PGs in the responses of adjacent lymphocytes. Here, using FDC-like cells, HK cells, we analyzed protein expression alterations in cyclooxygenase-2 (COX-2) in the presence of IL-4 or histone deacetylase (HDAC) inhibitors. Both IL-4 and HDAC inhibitors suppressed COX-2 expression in dose-dependent manners. Their effect was specific to COX-2 and did not reach to COX-1 expression. Interestingly, HDAC inhibitors gave rise to an opposing effect on COX-2 expression in peripheral blood monocytes. Our results suggest that IL-4 may regulate COX-2 expression in FDCs by affecting chromatin remodeling and provide insight into the role of cellular interactions between T cells and FDC during the GC reaction. Given the growing interests in wide-spectrum HDAC inhibitors, the differential results on COX-2 expression in HK cells and monocytes raise cautions on their clinical use.

• Journal of Microbiology and Biotechnology
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• v.25 no.5
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• pp.579-588
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• 2015

Fungi of the genus Pestalotiopsis have drawn attention for their capability to produce an array of bioactive secondary metabolites that have potential for drug development. Here, we report the determination of a polyketide derivative compound, pestalotiollide B, in the culture of the saprophytic fungus Pestalotiopsis microspora NK17. Structural information acquired by analyses with a set of spectroscopic and chromatographic techniques suggests that pestalotiollide B has the same skeleton as the penicillide derivatives, dibenzodioxocinones, which are inhibitors of cholesterol ester transfer protein (CETP), and as purpactins A and C', inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). Strain NK17 can make a fairly high yield of pestalotiollide B (i.e., up to 7.22 mg/l) in a constitutive manner in liquid culture. Moreover, we found that a putative histone deacetylase gene, designated as hid1, played a role in the biosynthesis of pestalotiollide B. In the hid1 null mutant, the yield of pestalotiollide B increased approximately 2-fold to 15.90 mg/l. In contrast, deletion of gene hid1 led to a dramatic decrease of conidia production of the fungus. These results suggest that hid1 is a modulator, concerting secondary metabolism and development such as conidiation in P. microspora. Our work may help with the investigation into the biosynthesis of pestalotiollide B and the development for new CETP and ACAT inhibitors.

• Journal of Life Science
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• v.25 no.6
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• pp.724-731
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• 2015

Mesenchymal stem cells (MSCs) are characterized by their multipotency capacity, which allows them to differentiate into diverse cell types (bone, cartilage, fat, tendon, and neuron-like cells) and secrete a variety of trophic factors (ANG, FGF-2, HGF, IGF-1, PIGF, SDF-1α, TGF-β, and VEGF). MSCs can be easily isolated from human bone-marrow, fat, and umbilical-cord tissues. These features indicate that MSCs might be of use in stem-cell therapy. However, MSCs undergo cellular senescence during long-term expansion, and this is accompanied by functional declines in stem-cell potency. In the human body, because of their senescence and declines in their microenvironmental niches stem cells fail to maintain tissue homeostasis, and as a result, senescent cells accumulate in tissues. This can lead to age-related diseases, including degenerative disorders and cancers. Recent studies suggest that the number of histone modifications to stem cells’ genomes and aberrant alterations to their DNA methylation increase as stem cells progress into senescence. These epigenetic alterations have been partly reversed with treatments in which DNA methyltransferase (DNMT) inhibitors or histone deacetylase (HDAC) inhibitors are introduced into replicative senescent-MSCs. This review focuses on epigenetic alteration in replicative senescent-MSCs and explains how epigenetic modifications are widely associated with stem-cell senescences such as differentiation, proliferation, migration, calcium signaling, and apoptosis.

• 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.

• Journal of Life Science
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• v.27 no.8
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• pp.879-887
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• 2017

It is well established that brain-derived neurotrophic factor (BDNF) is expressed not only in the brain but also in skeletal muscle, and is required for normal neuromuscular system function. Histone deacetylases (HDACs) and insulin-like growth factor-I (IGF-I) are potent regulators of skeletal muscle myogenesis and muscle gene expression, but the mechanisms of HDAC and IGF-I in skeletal muscle-derived BDNF expression have not been examined. In this study, we examined the effect of IGF-I and suberoylanilide hydroxamic acid (SAHA), a pan-HDAC inhibitor, on BDNF induction. Proliferating or differentiating C2C12 skeletal muscle cells were treated with increasing concentrations (0-50 ng/ml) of IGF-I in the absence or presence of $5{\mu}M$ SAHA for various time periods (3-24 hr). Treatment of C2C12 cells with IGF-I resulted in a dose- and time-dependent decrease in BDNF mRNA expression. However, inhibition of HDAC led to a significant increase in the expression of BDNF mRNA levels. In addition, immunocytochemistry revealed high BDNF protein levels in undifferentiated C2C12 skeletal muscle cells, whether untreated, IGF-I-treated, or exposed to SAHA. These results represent the first evidence that IGF-I can suppress the mRNA and protein expression of BDNF; conversely, SAHA attenuates the effects of IGF-I. Consequently, SAHA upregulates BDNF expression in C2C12 skeletal muscle cells.

• Archives of Pharmacal Research
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• v.27 no.4
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• pp.407-414
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• 2004

The expression of CYP3A4 gene is induced by a variety of structurally unrelated xenobiotics including the antibiotic rifampicin, pregnenolone 16-carbonitrile (PCN), and endogenous hormones, that might mediate through steroid and xenobiotic receptor (SXR) system. The molecular mechanisms underlying regulation of CYP3A4 gene expression have not been understood. In order to gain the insight of the molecular mechanism of CYP3A4 gene expression, study has been undertaken to investigate if the histone deacetylation is involved in the regulation of CYP3A4 gene expression by proximal promoter in human hepatoma HepG2 cells. Also we have investigated to see if SXR is involved in the regulation of CYP3A4 proximal promoter activity in human hepatoma HepG2 cells. HepG2 cells were transfected with a plasmid PCYP3A4-Luc containing ${\~}1kb$ of the CYP3A4 proximal promoter region (-863 to +64 bp) in front of a reporter gene, luciferase, in the presence or absence of pSAP-SXR. In HepG2 cells, CYP3A4 inducers, such as rifampicin, PCN and RU486 showed minimal stimulation of CYP3A4 proximal promoter activity in the absence of SXR and histone deacetylase (HDAC) inhibitors. 4-Dimethylamino-H-[4-(2-hydroxycarbamoylvinyl)benzyl]benzamide (IN2001), a new class HDAC inhibitor significantly increased CYP3A4 proximal promoter activity over untreated control cells and rifampicin concomitant treatment with IN2001 increased further CYP3A4 proximal promoter activity that was stimulated by IN2001 The results of this study demon-strated that both HDAC inhibitors and SXR are essential to increase of CYP3A4 proximal promoter activity by CYP3A4 inducers such as PCN, rifampicin, and RU486. Especially SXR seems to be important for the dose dependent response of CYP3A4 inducing chemicals to stimulate CYP3A4 proximal promoter activity. Also this data suggested that HDAC inhibitors seemed to facilitate the CYP3A4 proximal promoter to be activated by chemicals.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.10
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• pp.4331-4338
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• 2014

$N^1$-(2, 5-dimethoxyphenyl)-$N^8$-hydroxyoctanediamide (N25) is a novel SAHA cap derivative of HDACi, with a patent (No. CN 103159646). This invention is a hydroxamic acid compound with a structural formula of $RNHCO(CH_2)6CONHOH$ (wherein R=2, 5dimethoxyaniline), a pharmaceutically acceptable salt which is soluble. In the present study, we investigated the effects of N25 with regard to drug distribution and molecular docking, and anti-proliferation, apoptosis, cell cycling, and $LD_{50}$. First, we designed a molecular approach for modeling selected SAHA derivatives based on available structural information regarding human HDAC8 in complex with SAHA (PDB code 1T69). N25 was found to be stabilized by direct interaction with the HDAC8. Anti-proliferative activity was observed in human glioma U251, U87, T98G cells and human lung cancer H460, A549, H1299 cells at moderate concentrations ($0.5-30{\mu}M$). Compared with SAHA, N25 displayed an increased antitumor activity in U251 and H460 cells. We further analyzed cell death mechanisms activated by N25 in U251 and H460 cells. N25 significantly increased acetylation of Histone 3 and inhibited HDAC4. On RT-PCR analysis, N25 increased the mRNA levels of p21, however, decreased the levels of p53. These resulted in promotion of apoptosis, inducing G0/G1 arrest in U251 cells and G2/M arrest in H460 cells in a time-dependent and dose-dependent manner. In addition, N25 was able to distribute to brain tissue through the blood-brain barrier of mice ($LD_{50}$: 240.840mg/kg). In conclusion, our findings demonstrate that N25 will provide an invaluable tool to investigate the molecular mechanism with potential chemotherapeutic value in several malignancies, especially human glioma.

• Molecules and Cells
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• v.28 no.6
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• pp.553-558
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• 2009

In the periphery, a galectin-1 receptor, CD7, plays crucial roles in galectin-1-mediated apoptosis of activated T-cells as well as progression of T-lymphoma. Previously, we demonstrated that $NF-{\kappa}B$ downregulated CD7 gene expression through the p38 MAPK pathway in developing immature thymocytes. However, its regulatory pathway is not well understood in functional mature T-cells. Here, we show that CD7 expression was downregulated by Twist2 in Jurkat cells, a human acute T-cell lymphoma cell line, and in EL4 cells, a mature murine T-cell lymphoma cell line. Furthermore, ectopic expression of Twist2 in Jurkat cells reduced galectin-1-induced apoptosis. While full-length Twist2 decreased CD7 promoter activity, a C-terminal deletion form of Twist2 reversed its inhibition, suggesting an important role of the C-terminus in CD7 regulation. In addition, CD7 expression was enhanced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate, which indicates that Twist2 might be one of candidate factors involved in histone deacetylation. Based on these results, we conclude that upregulation of Twist2 increases the resistance to galectin-1-mediated-apoptosis, which may have significant implications for the progression of some T-cells into tumors such as Sezary cells.

• Toxicological Research
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• v.34 no.2
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• pp.173-182
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• 2018

Valproic acid (VPA) plays a role in histone modifications that eventually inhibit the activity of histone deacetylase (HDAC), and will affect the expressions of genes Pdx1, Nkx6.1, and Ngn3 during pancreatic organogenesis. This experiment was designed to study the effect of VPA exposure in pregnant rats on the activity of HDAC that controls the expression of genes regulating the development of beta cells in the pancreas to synthesize and secrete insulin. This study used 30 pregnant Sprague-Dawley rats, divided into 4 groups, as follows: (1) a control group of pregnant rats without VPA administration, (2) pregnant rats administered with 250 mg VPA on day 10 of pregnancy, (3) pregnant rats administered with 250 mg VPA on day 13 of pregnancy, and (4) pregnant rats administered with 250 mg VPA on day 16 of pregnancy. Eighty-four newborn rats born to control rats and rats administered with VPA on days 10, 13, and 16 of pregnancy were used to measure serum glucose, insulin, DNA, RNA, and ratio of RNA/DNA concentrations in the pancreas and to observe the microscopical condition of the pancreas at the ages of 4 to 32 weeks postpartum with 4-week intervals. The results showed that at the age of 32 weeks, the offspring of pregnant rats administered with 250 mg VPA on days 10, 13, and 16 of pregnancy had higher serum glucose concentrations and lower serum insulin concentrations, followed by decreased concentrations of RNA, and the ratio of RNA/DNA in the pancreas. Microscopical observations showed that the pancreas of the rats born to pregnant rats administered with VPA during pregnancy had low immunoreaction to insulin. The exposure of pregnant rats to VPA during pregnancy disturbs organogenesis of the pancreas of the embryos that eventually disturb the insulin production in the beta cells indicated by the decreased insulin secretion during postnatal life.

• Radiation Oncology Journal
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• v.22 no.2
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• pp.138-141
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• 2004

Purpose : We have previously reported that human glioblastoma cells are sensitized to radiation-induced death after their exposure to trichostatin A (TSA), a histone deacetylase inhibitor (HDAC-1), prior to the irradiation. We aimed to measure the magnitude of the radiosensitizing effect of TSA in human head and neck cancer cell lines. Materials and Methods : Human head and neck cancer cell lines, HN-3 and HN-9, were exposed to 0, 50, 100, and 200 nM TSA for 18 hr prior to irradiation. Then, the TSA-treated cells were irradiated with 0, 2, 4, 6, and 8 Gy, and cell survival was measured by clonogenic assay. Results : Pre-irradiation exposure to TSA was found to radiosensitize HN-3 and HN-9 cell lines. In HN-9 cells, the fraction surviving after 2 Gy (SF2) was significantly reduced by treatment of TSA at concentration as low as 50 nM. However, a treatment with 200 nM TSA was required to significantly decrease SF2 in the HN-3 cell line. SER of pre-irradiation treatment with 200 nM TSA was 1.84 in HN-3 and 7.24 in HN-9, respectively. Conclusions : Our results clearly showed that human head and neck cancer cell lines can be sensitized to ionizing radiation by pre-irradiation inhibition of histone deacetylase (HDAC) using TSA, and that this potentiation might well be a general phenomenon.