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약품개발연구지

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수록정보
수록범위 : 3권0호(1995)~25권0호(2016) |수록논문 수 : 731
약품개발연구지
25권0호(2016년 12월) 수록논문
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1Osterix represses adipogenesis by negatively regulating PPARγ transcriptional activity

저자 : Younho Han , Chae Yul Kim , Heesun Cheong , Kwang Youl Lee

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 1-11 (11 pages)

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Osterix is a novel bone-related transcription factor involved in osteoblast differentiation, and bone maturation. Because a reciprocal relationship exists between adipocyte and osteoblast differentiation of bone narrow derived mesenchymal stem cells, we hypothesized that Osterix might have a role in adipogenesis. Ablation of Osterix enhanced adipogenesis in 3T3-L1 cells, whereas overexpression suppressed this process and inhibited the expression of adipogenic markers including CCAAT/enhancer-binding protein alpha(C/EBPα) and peroxisome proliferator-activated receptor gamma(PPARγ).
Further studies indicated that Osterix significantly decreased PPARγ-induced transcriptional activity. Using co-immunoprecipitation and GST-pull down analysis, we found that Osterix directly interacts With PPARγ. The ligand-binding domain(LBD)of PPARγ was responsible for this interaction, which was followed by repression of PPARγ-induced transcriptional activity, even in the presence of rosiglitazone. Taken together, we identified the Osterix has an important regulatory role on PPARγ activity, which contributed to the mechanism of adipogenesis.

2Pin1 enhances adipocyte differentiation by positively regulating the transcriptional activity of PPARγ

저자 : Younho Han , Sung Ho Lee , Minjin Bahn , Chang-yeol Yeo , Kwang Youl Lee

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 12-20 (9 pages)

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Pin1 is a peptidylprolyl cis/trans isomerase and it has a unique enzymatic activity of catalyzing isom-erization of the peptide bond between phospho-serine/threonine and proline. Through the conforma-tional change of its substrates, Pin1 regulates diverse biological processes including adipogenesis. In mouse embryonic fibroblasts and 3T3-L1 preadipocytes, overexpression of Pin1 enhances adipocyte differentiation whereas inhibition of Pin1 activity suppresses it. However, the precise functions of Pin1 during adipogenesis are not clear. In the present study, we investigated the potential targets of Pin1 during adipogenesis. We found that Pin1 interacts directly with and regulates the transcriptional activity of PPARγ, a key regulator of adipogenesis. In addition, ERK activity and Ser273 of PPARγ, a potential ERK phosphorylation target site, are important for the regulation of PPARγ function by Pin1 3T3-L1 cells. Taken together our results suggest a novel regulatory mechanism of pin1 during adipogensis. In which Pin1 enhances adipocyte differentiation by regulating the function of PPARΥ.
ⓒ 2016 Elsevier lreland Ltd. All rights reserved.

3Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects

저자 : Yifeng Jin , Younho Han , Daulat Bikram Khadka , Chao Zhao , Kwang Youl Lee , Won-jea Cho

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 21-30 (10 pages)

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Conformational change in helix 12 can alter ligand-in duced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays showed that this new series of PPARγ antagonists more strongly inhibit adipocyte differentiation and PPARγ2-induced transcriptional activity than GW9662.

4Estrogen Receptor α Regulates Dlx3-Mediated Osteoblast Differentiation

저자 : Sung Ho Lee , Kyo-nyeo Oh , Younho Han , You Hee Choi , Kwang-youl Lee

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 31-31 (1 pages)

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Estrogen receptor α (ER-α), which is involved in bone me-Tabolism and breast cancer, has been shown to have tran-scriptional targets. Dlx3 is essential for the skeletal devel-opment and plays an important role in osteoblast differen-tiation. Various osteogenic stimulators and transcription factors can induce the protein expression of Dlx3. Howev-er, the regulatory function of ER-α in the Dlx3 mediated osteogenic process remains unknown. Therefore, we in-vestigated the regulation of Dlx3 and found that ER-α is a positive regulator of Dlx3 transcription in BMP2-induced osteoblast differentiation. We also found that ER-α inter-acts with Dlx3 and increases its transcriptional activity and DNA binding affinity. Furthermore, we demonstrated that the regulation of Dlx3 activity by ER-α is independent of cate that Dlx3 is a novel target of ER-α, and that ER-α regu-lates the osteoblast differentiation through modulation of Dlx3 expression and/or interaction with Dlx3.

5Osterix plays a critical role in BMP4-induced promoter activity of connexin43

저자 : Younho Han , Dong Hyeok Cho , Dong Jin Chung , Kwang Youl Lee

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 37-37 (1 pages)

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Osterix is an essential transcription factor for osteogenesis and is expressed in osteoblasts. Although Osterix has been shown to be induced by bone morphogenetic protein 4, the molecular mechanism underlying Osterix function during osteoblast differentiation remains unclear. Connexin43 (Cx43) is the most abundant gap junction protein in bone cells and plays a critical role in osteoblast differentiation. However, little is known about the functional interactions between Osterix and the Cx43 promoter. In the present study, we investigated the relationship between Osterix and Cx43 in HEK293 and C2C12 cells. Cx43 expression was significantly repressed by the addition of shRNA against Osterix, whereas over- expression of Osterix resulted in enhanced Cx43 expression. Furthermore, Osterix directly occupied the promoter region of Cx43 and subsequently increased Cx43 promoter activity in a dose-dependent manner. In addition, phosphorylation of the Ser76 and Ser80 residues in Osterix were found to be critical for its activity on the Cx43 promoter. Our results suggest that Osterix plays an important role in increasing bone morphogenetic protein 4-induced Cx43 activity.
ⓒ 2016 Elsevier Inc. All rights reserved.

6Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility

저자 : Yi Yang , Thanh Thi Nguyen , Min-hye Jeong , Florin Crisan , Young Hyun Yu , Hyung-ho Ha , Kyung Hee Choi , Hye Gwang Jeong , Tae Cheon Jeong , Kwang Youl Lee , Kyung Keun Kim , Jae-seoun Hur , Hangun Kim

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 43-43 (1 pages)

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Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit Cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer Cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KlTENlN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that(+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with(+)-usnic acid. Interest-ingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that(+)-usnic acid might have potential activity in inhibiyion of cancer cell metastasis, and(+)-usnic acid could be used for anti-can-cer therapy with a distinct mechanisms of action.

7Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells

저자 : Nguyen Thi Thuy Phuong , Sang Kyum Kim , Ji Hye Im , Jin Won Yang , Min Chang Choi , Sung Chul Lim , Kwang Yeol Lee , Young-mi Kim , Jeong Hoon Yoon , Keon Wook Kang

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 59-59 (1 pages)

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We previously showed that-S-adenosylmethionine-mediated hypermethylation of the PTEN promoter was important for the growth of tamoxifen-resistant MCF-7 (TAMR-MCF-7) cancer cells. Here, we found that the basal expression level of methionine adenosyltransferase 2A (MAT2A), a critical enzyme for the biosynthesis of S-adenosylmethionine, was up-regulated in TAMR-MCF-7 cells compared with control MCF-7 cells. Moreover, the basal expression level of MAT2A in T47D cells, a TAM-resistant estrogen receptor-positive cell line was higher compared to MCF-7 cells. Immunohistochemistry confirmed that MAT2A expression in TAM-resistant human breast cancer tissues was higher than that in TAM-responsive cases. The promoter region of human MAT2A contains binding sites for nuclear factor-кB, activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2), and the activities of these three transcription factors were enhanced in TAMR-MCF-7 cells. Both the protein expression and transcriptional activity of MAT2A in TAMR-MCF-7 cells were potently suppressed by NF-кB inhibition but not by c-Jun/AP-1 or Nrf2 Knock-down. Interestingly, the expression levels of microRNA (miR)-146a and-146b were diminished in TAMR-MCF-7 cells, and miR-146b transduction decreased Nf-кB-mediated MAT2A expression. miR-146b restored PTEN expression via the suppression of PTEN promoter methylation In TAMR-MCF-7 cells. Additionally, miR-146b overexpression inhibited cell proliferation and reversed chemoresistance to-hydroxyramoxifen in TAMR-MCF-7 cells.

8Design and synthesis of novel androgen receptor antagonists via molecular modeling

저자 : Chao Zhao , You Hee Choi , Daulat Bikram Khadka , Yifeng Jin , Kwang-youl Lee , Won-jea Cho

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 66-66 (1 pages)

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Several androgen receptor (AR) antagonists are clinically prescribed to treat prostate cancer. Unfortunately, many patients become resistant to the existing AR antagonists. To overcome this, a novel AR antagonist candidate called DIMN was discovered by our research group in 2013. In order to develop compounds with improved potency, we designed novel DIMN derivatives based on a docking study and substituted carbons with heteroatom moieties. Encouraging in vitro results for compounds 1b, 1c, 1e, 3c, and 4c proved that the new design was successful. Among the newly synthesized compounds. 1e exhib-ited the strongest inhibitory effect on LNCaP cell growth (IC-50=0.35 μm) and also acted as a competitive AR antagonist with selectivity over the estrogen receptor (ER) and the glucocorticoid receptor (GR). A docking study of compound 1e fully supported these biological results. Compound 1e is considered to be a novel, potent and AR-specific antagonist for treating prostate cancer. Thus, our study successfully applied molecular modeling and bioisosteric replacement for hit optimization. The methods here provide a guide for future development of drug candidates through structure-based drug discovery and chemical Modifications.
ⓒ 2015 Elsevier Ltd. All rights reserved.

9Yin-Yang 1 and Yin-Yang 2 exert opposing effects on the promoter activity of interleukin 4

저자 : Sung Ho Lee , Young-chang Cho , Hyung Min Jeong , Kyung Hee Kim , Hyun Jin Choi , Kwang Youl Lee , Bok Yun Kang

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 79-79 (1 pages)

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Interleukin (IL)-4 acts on T cells as a growth And activation factor, and promotes the differentiation of Type 2 T helper cells. In T cells, expression of the gene Encoding IL-4 is regulated by inducible or constitutive factors. Yin-Yang (YY)-1 is one of constitutive transcrip-tion factors binding to the IL-4 promoter. The recently identified YY2 protein is similar to YY1, with both sharing high levels of homology in their zinc finger motifs. How-ever, the role of YY2 in T cells is unclear. YY1 and YY2 were constitutively expressed in EL4 T cells, and their expression was not dependent on stimulation. IL-4 pro-moter (-741/+56 fragment) activity was enhanced by YY1, but inhibited by YY2, The enhanced IL-4 promoter activity by YY1 was reduced by simultaneous expression of YY2. In addition, the DNA binding affinity of YY1 to the IL-4 promoter was adversely affected by YY2. Our results suggest that YY1 and YY2 exert opposing effects on the IL-4 promoter as they compete for the same DNA binding sites.

10아연이 면역에 미치는 영향

저자 : 김경은 , 강복윤

발행기관 : 전남대학교 약품개발연구소 간행물 : 약품개발연구지 25권 0호 발행 연도 : 2016 페이지 : pp. 87-91 (5 pages)

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