• IMMUNE NETWORK
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• 제13권2호
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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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• 제25권5호
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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.

• 생명과학회지
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• 제25권6호
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• pp.724-731
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• 2015

중간엽줄기세포는 성체줄기세포의 한 종류로, 자기재생산능력(self-renwal)과 다분화능(multipotency)을 가지고 있고, 다양한 자양인자(trophic factors)들을 분비한다. 뿐만 아니라, 중간엽줄기세포는 골수, 지방, 탯줄과 같은 조직에서 쉽게 얻을 수 있기 때문에 줄기세포치료에 좋은 도구로 이용되고 있다. 하지만, 줄기세포치료의 효율성을 높이기 위해 추출한 세포의 개체 수를 늘리는 과정에서 중간엽줄기세포는 점차적인 노화를 겪게 되고, 이는 줄기세포 자체의 기능적인 감소를 야기한다. 인체 내에서, 노화된 줄기세포는 조직 내의 항상성 유지에 부정적인 영향 을 미치게 되고, 이러한 상태가 지속되면 대표적인 노인성 질환인 퇴행성 질환의 원인이 된다. 최근 연구들에 의하면 중간엽줄기세포가 노화를 겪을 때, 노화 관련된 DNA 메틸화 패턴의 변화와 히스톤의 변형이 일어남을 확인하였다. 또한, 중간엽줄기세포의 노화에 있어서 DNA 메틸화효소(DNA methyltransferase) 억제제와 히스톤 아세틸화효소(histone deacetylase) 억제제가 부분적으로 노화를 개선하는 효과를 관찰한 연구사례들이 있다. 본 총설에서는, 노화에 따른 후생유전학적인 변화에 의해, 조절되는 노화 관련 유전자들과 중간엽줄기세포의 노화에 대한 연구사례들을 분석하여 서술하고자 한다.

• Interdisciplinary Bio Central
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• 제4권1호
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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.

• 생명과학회지
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• 제27권8호
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• pp.879-887
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• 2017

히스톤 탈 아세틸 효소(HDAC)와 인슐린유사성장인자(IGF-I)는 근육 관련 유전자들의 활성 및 발현을 조절하여 골격근의 성장 및 발달을 조절하지만 이들이 근신경계 발달 및 대사 기능에 중요한 역할을 담당하는 뇌신경성장인자(BDNF)의 발현에 미치는 영향에 관한 연구는 거의 이루어지지 않았다. 따라서 본 연구에서는 IGF-I과 HDAC의 억제제인 SAHA가 C2C12 골격근 세포에서 BDNF 발현에 미치는 영향을 알아보고자 하였다. 그 결과 IGF-I은 농도와 시간 의존적으로 BDNF의 mRNA 및 단백질 발현을 감소시켰지만 HDAC을 억제하자 IGF-I에 의해 감소되었던 BDNF의 발현이 증가하는 경향을 관찰할 수 있었다. 따라서 IGF-I은 BDNF의 발현을 억제하며, HDAC의 억제는 IGF-I에 의한 BDNF의 발현 억제를 감소시킬 수 있다는 사실을 확인할 수 있었다.

• Archives of Pharmacal Research
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• 제27권4호
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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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• 제15권10호
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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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• 제28권6호
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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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• 제34권2호
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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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• 제22권2호
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• pp.138-141
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• 2004

목적 : 본 연구진이 기왕에 입증한 바 있는 히스톤탈아세틸효소 억제제 trichostatin A (TSA)가 나타내는 방사선 감수성 증강 작용이 두경부암 세포주에서 발생하는 정도를 실험적으로 확인하고자 하였다. 대상 및 방법 : 인간 두경부암 세포주인 HN-3과 HN-9를 0, 50, 100, 200 nM의 TSA에 18시간 동안 전처치시킨 후 각각 0, 2, 4, 6, 8 Gy 방사선을 조사하였다. 세포생존곡선은 clonogenic assay를 이용하여 산출하였고 linear quadratic 모델에 따라 분석하였다 결과 : 방사선 조사 전 TSA처리는 HN-3과 HN-9 세포주의 방사선 감수성을 증강시켰다. 50 nM의 TSA로 처리된 HN-9 세포주에서 2 Gy 조사후 생존분획(SF2)은 유의한 수준으로 감소하였으나, HN-3 세포주는 200 nM의 TSA 처리 후 SF2가 유의하게 감소하였다. HN-3과 HN-9 세포주에서 200 nM TSA의 sensitizer enhancement ratio는 각각 1.84와 7.24였다. 결론 : 방사선 조사 전 히스톤탈아세틸효소 억제는 인간 두경부암 세포주의 방사선 감수성을 증가시켰으며, 이 증강 작용이 암세포주에서의 일반적으로 관찰되는 현상일 가능성이 크다고 제안한다.