2021/12/21 更新

写真a

ウエダ ユウキ
上田 優輝
UEDA Yuki
所属
医歯薬学域 助教
職名
助教
連絡先
メールアドレス
プロフィール
1987年2月26日生まれ 2005年3月 岡山県立岡山一宮高等学校 理数科 卒業 2005年4月 岡山理科大学 理学部化学科 入学 2009年3月 同上 卒業 2009年4月 岡山大学 大学院医歯薬学総合研究科 修士課程 入学 2011年3月 同課程 修了 2011年4月 岡山大学 大学院医歯薬学総合研究科 博士課程 入学 2011年6月24日 第27回中国四国ウイルス研究会 優秀演題賞 受賞 2012年4月~2015年3月 日本学術振興会 特別研究員(DC1) 採用 2015年3月 同課程 修了 2015年4月 岡山大学 大学院医歯薬学総合研究科 助教 採用 2021年5月 教室名を腫瘍微小環境学に変更 現在に至る
外部リンク

学位

  • 学士(理学) ( 岡山理科大学 )

  • 修士(医科学) ( 岡山大学 )

  • 博士(医学) ( 岡山大学 )

研究キーワード

  • HBV

  • HCV

  • C型肝炎ウイルス

  • 分子生物学

  • B型肝炎ウイルス

  • 肝細胞癌

  • バイオインフォマティクス

  • 腫瘍微小環境

  • がん免疫療法

研究分野

  • ライフサイエンス / 分子生物学

  • ライフサイエンス / ウイルス学

  • ライフサイエンス / 免疫学

  • ライフサイエンス / 腫瘍生物学

学歴

  • 岡山大学    

    2011年4月 - 2015年3月

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    国名: 日本国

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  • 岡山大学    

    - 2015年

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  • 岡山大学    

    2009年4月 - 2011年3月

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    国名: 日本国

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  • 岡山大学    

    - 2011年

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  • 岡山理科大学   理学部   化学科

    2005年4月 - 2009年3月

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    国名: 日本国

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  • 岡山理科大学   Faculty of Science  

    - 2009年

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▼全件表示

経歴

  • - 岡山大学医歯薬学総合研究科 助教

    2015年4月

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  • - Assistant Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2015年

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  • 日本学術振興会特別研究員   DC1

    2012年4月 - 2015年3月

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  • Postdoctoral Fellowships of Japan Society for the Promotion of Science,Biopathological Sciences,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2012年 - 2015年

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所属学協会

 

論文

  • Extracellular vesicles activate ATM‐Chk2 signaling pathway through the intercellular transfer of mitochondrial DNA in HBV‐infected human hepatocytes

    Hiromichi Dansako, Youki Ueda, Shinya Satoh, Nobuyuki Kato

    The FASEB Journal   35 ( 6 )   2021年6月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1096/fj.202002678r

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1096/fj.202002678R

  • Identification of ribavirin-responsive cis-elements for GPAM suppression in the GPAM genome. 国際誌

    Daichi Onomura, Shinya Satoh, Youki Ueda, Hiromichi Dansako, Nobuyuki Kato

    Biochemical and biophysical research communications   533 ( 1 )   148 - 154   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) is a rate-limiting enzyme catalyzing triglyceride synthesis. Recently, we demonstrated that the anti-viral drug ribavirin (RBV) reduces GPAM expression by downregulating CCAAT/enhancer-binding protein α (C/EBPα). However, the precise mechanisms of GPAM suppression have remained unclear. Here, we found that RBV suppressed GPAM expression by downregulating not only C/EBPα, but also sterol regulatory element-binding protein-1c (SREBP-1c). We also found that cis-elements regulated by C/EBPα and SREBP-1c functioned as distal and proximal enhancers, respectively, to express hepatocyte- and adipocytes-specific GPAM variants. These results imply that RBV disrupts formation of the enhancer machineries on the GPAM genome by downregulating both transcription factors. Our findings may contribute to the development of treatments for fatty liver diseases caused by aberrant triglyceride synthesis.

    DOI: 10.1016/j.bbrc.2020.08.112

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  • Study of multiple genetic variations caused by persistent hepatitis C virus replication in long-term cell culture. 査読 国際誌

    Nobuyuki Kato, Youki Ueda, Hiroe Sejima, Weilin Gu, Shinya Satoh, Hiromichi Dansako, Masanori Ikeda, Kunitada Shimotohno

    Archives of virology   165 ( 2 )   331 - 343   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The most characteristic feature of the hepatitis C virus (HCV) genome in patients with chronic hepatitis C is its remarkable variability and diversity. To better understand this feature, we performed genetic analysis of HCV replicons recovered from two human hepatoma HuH-7-derived cell lines after 1, 3, 5, 7, and 9 years in culture: The cell lines 50-1 and sO harbored HCV 1B-1 and O strain-derived HCV replicons established in 2002 and 2003, respectively. The results revealed that genetic variations in both replicons accumulated in a time-dependent manner at a constant rate despite the maintenance of moderate diversity (less than 1.8% difference) between the clones and that the mutation rate in the 50-1 and sO replicons was 2.5 and 2.9 × 10-3 base substitutions/site/year, respectively. We found that the genetic distance of both replicons increased from 7.9% to 10.5% after 9 years in culture. In addition, we observed that the guanine + cytosine (GC) content of both replicon RNAs increased in a time-dependent manner, as observed in our previous studies. Finally, we demonstrated that the high sensitivity of both replicons to direct-acting antivirals was maintained even after 9 years in culture. Our results suggest that long-term cultured HCV replicon-harboring cells are a useful model for understanding the variability and diversity of the HCV genome and the drug sensitivity of HCV in patients with chronic hepatitis C.

    DOI: 10.1007/s00705-019-04461-0

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  • A new hepatoma cell line exhibiting high susceptibility to hepatitis B virus infection. 査読 国際誌

    Youki Ueda, Weilin Gu, Hiromichi Dansako, Hironori Nishitsuji, Shinya Satoh, Kunitada Shimotohno, Nobuyuki Kato

    Biochemical and biophysical research communications   515 ( 1 )   156 - 162   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hepatitis B virus (HBV) infection, which increases the risk of cirrhosis and hepatocellular carcinoma and requires lifelong treatment, has become a major global health problem. However, host factors essential to the HBV life cycle are still unclear, and the development of new drugs is needed. Cells derived from the human hepatoma cell line HepG2 and engineered to overexpress sodium taurocholate cotransporting polypeptide (NTCP: a receptor for HBV), termed HepG2/NTCP cells, are widely used as the cell-based HBV infection and replication systems for HBV research. We recently found that human hepatoma cell line Li23-derived cells overexpressing NTCP (A8 cells subcloned from Li23 cells), whose gene expression profile was distinct from that of HepG2/NTCP cells, were also sensitive to HBV infection. However, the HBV susceptibility of A8 cells was around 1/100 that of HepG2/NTCP cells. Since we considered that plural cell assay systems will be needed for the objective evaluation of anti-HBV reagents, as we previously demonstrated in hepatitis C virus research, we here attempted to develop a new Li23 cell-derived assay system equivalent to that using HepG2/NTCP cells. By repeated subcloning of A8 cells, we successfully established a new cell line (A8.15.78.10) exhibiting high HBV susceptibility equal to that of HepG2/NTCP cells. Characterization of A8.15.78.10 cells revealed that the increase of HBV susceptibility was correlated with increases in the protein and glycosylation levels of NTCP, and with decreased expression of STING, a factor contributing to innate immunity. Finally, we performed a comparative evaluation of HBV entry inhibitors (cyclosporin A and rosiglitazone) by an HBV/secNL reporter assay using A8.15.78.10 cells or HepG2/NTCP cells. The results confirmed that cyclosporin A exhibited anti-HBV activity in both cell lines, as previously reported. However, we found that rosiglitazone did not show the anti-HBV activity in A8.15.78.10 cells, although it worked in HepG2/NTCP cells as previously reported. This suggested that the difference in anti-HBV activity between cyclosporin A and rosiglitazone was due to the different types of cells used for the assay. In conclusion, plural assay systems using different types of cells are required for the objective and impartial evaluation of anti-HBV reagents.

    DOI: 10.1016/j.bbrc.2019.05.126

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  • High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction. 査読 国際誌

    Hiromichi Dansako, Hirotaka Imai, Youki Ueda, Shinya Satoh, Kunitada Shimotohno, Nobuyuki Kato

    FASEB bioAdvances   1 ( 2 )   67 - 80   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hepatitis B virus (HBV) is a hepatotropic DNA virus causing hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. To study HBV, human hepatoma HepG2 cells are currently used as an HBV infectious cell culture model worldwide. HepG2 cells exhibit susceptibility to HBV by exogenously expressing sodium taurocholate cotransporting polypeptide (NTCP). We herein demonstrated that human immortalized hepatocyte NKNT-3 cells exhibited susceptibility to HBV by exogenously expressing NTCP (NKNT-3/NTCP cells). By comparing cyclic GMP-AMP synthetase (cGAS)-stimulator of interferon genes (STING) signaling pathway in several NKNT-3/NTCP cell-derived cell clones, we found that STING was highly expressed in cell clones exhibiting resistance but not susceptibility to HBV. High-level expression of STING was implicated in HBV-triggered induction of type III IFN and a pro-inflammatory cytokine, IL-6. In contrast, RNAi-mediated knockdown of STING inhibited type III IFN induction and restored the levels of HBV total transcript in an HBV-infected cell clone exhibiting resistance to HBV. These results suggest that STING regulates susceptibility to HBV by its expression levels. STING may thus be a novel target for anti-HBV strategies.

    DOI: 10.1096/fba.1022

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    その他リンク: http://orcid.org/0000-0002-2627-8524

  • Ribavirin-induced down-regulation of CCAAT/enhancer-binding protein α leads to suppression of lipogenesis. 査読

    Satoh S, Onomura D, Ueda Y, Dansako H, Honda M, Kaneko S, Kato N

    The Biochemical journal   476 ( 1 )   137 - 149   2019年1月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1042/BCJ20180680

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  • Daunorubicin, a topoisomerase II poison, suppresses viral production of hepatitis B virus by inducing cGAS-dependent innate immune response. 査読

    Imai H, Dansako H, Ueda Y, Satoh S, Kato N

    Biochemical and biophysical research communications   504 ( 4 )   672 - 678   2018年10月

  • Multiple antiviral activities of the antimalarial and anti-hepatitis C drug candidates N-89 and N-251. 査読 国際誌

    Youki Ueda, Weilin Gu, Hiromichi Dansako, Hye-Sook Kim, Sayaka Yoshizaki, Nobuaki Okumura, Tomohiro Ishikawa, Hironori Nishitsuji, Fumihiro Kato, Takayuki Hishiki, Shinya Satoh, Koji Ishii, Michiaki Masuda, Kunitada Shimotohno, Masanori Ikeda, Nobuyuki Kato

    Biochemistry and biophysics reports   15   1 - 6   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The chemically synthesized endoperoxide compound N-89 and its derivative N-251 were shown to have potent antimalarial activity. We previously demonstrated that N-89 and N-251 potently inhibited the RNA replication of hepatitis C virus (HCV), which belongs to the Flaviviridae family. Since antimalarial and anti-HCV mechanisms have not been clarified, we were interested whether N-89 and N-251 possessed the activity against viruses other than HCV. In this study, we examined the effects of N-89 and N-251 on other flaviviruses (dengue virus and Japanese encephalitis virus) and hepatitis viruses (hepatitis B virus and hepatitis E virus). Our findings revealed that N-89 and N-251 moderately inhibited the RNA replication of Japanese encephalitis virus and hepatitis E virus, although we could not detect those anti-dengue virus activities. We also observed that N-89 and N-251 moderately inhibited the replication of hepatitis B virus at the step after viral translation. These results suggest the possibility that N-89 and N-251 act on some common host factor(s) that are necessary for viral replications, rather than the possibility that N-89 and N-251 directly act on the viral proteins except for HCV. We describe a new type of antiviral reagents, N-89 and N-251, which are applicable to multiple different viruses.

    DOI: 10.1016/j.bbrep.2018.05.007

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  • ULBP1 is induced by hepatitis C virus infection and is the target of the NK cell-mediated innate immune response in human hepatocytes 査読

    Hiromichi Dansako, Hirotaka Imai, Youki Ueda, Shinya Satoh, Takaji Wakita, Nobuyuki Kato

    FEBS Open Bio   8 ( 3 )   361 - 371   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley Blackwell  

    Natural killer (NK) cells through their NK group 2 member D (NKG2D) receptors recognize NKG2D ligands such as UL16-binding proteins (ULBPs) on virus-infected cells and subsequently trigger the host innate immune response. In the present study, we demonstrated that hepatitis C virus (HCV) induced the cell surface expression of ULBP1 in human immortalized hepatocyte PH5CH8 cells and human hepatoma HuH-7 cell-derived RSc cells. Interestingly, NK cell line NK-92 induced cytotoxicity and interferon-γ mRNA expression and subsequently reduced the levels of HCV RNA replication during co-culture with HCV-infected RSc cells. From these results, we conclude that ULBP1 is a target of the NK cell-mediated innate immune response in HCV-infected human hepatocytes.

    DOI: 10.1002/2211-5463.12373

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  • Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: involvement of adenosine monophosphate-activated protein kinase-related kinases and retinoid X receptor α. 査読

    Satoh S, Mori K, Onomura D, Ueda Y, Dansako H, Honda M, Kaneko S, Ikeda M, Kato N

    Hepatology Communications   1 ( 6 )   550 - 563   2017年8月

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/hep4.1065

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  • Evaluation of preclinical antimalarial drugs, which can overcome direct acting antivirals-resistant hepatitis C viruses, using the viral reporter assay systems 査読

    Youki Ueda, Hiromichi Dansako, Shinya Satoh, Hye-Sook Kim, Yusuke Wataya, Hiroyuki Doi, Masanori Ikeda, Nobuyuki Kato

    VIRUS RESEARCH   235   37 - 48   2017年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a major global health problem. Recently developed treatments with direct-acting antivirals (DAAs) have largely improved the sustained virologic response rate of patients with chronic hepatitis C. However, this approach is still hindered by its great expense and the problem of drug resistance. Using our cell-based HCV assay systems, we reported that the preclinical antimalarial drugs N-89 and N-251 exhibited potent anti-HCV activities. In this study we used our assay systems to evaluate the anti-HCV activities of six kinds of DAAs individually or in combination with N-89 or N-251. The results showed that the DAAs had potent anti-HCV activities and N-89 or N-251 contributed additive or synergistic effect. Using DAA-resistant HCV-RNA-replicating cells, which were prepared by continuous treatment with each DAA, we demonstrated that N-89 and N-251 could overcome all of the DAA-resistant HCVs. These preclinical drugs would have been potential as components of a therapeutic regimen that also included combinations of various DAAs. In addition, sequence analysis of the NS3-NS5B regions of the DAA-resistant HCV genomes newly found several amino acid (aa) substitutions that were suggested to contribute to DAA-resistance in addition to the aa substitutions already known to cause DAA-resistance. Among these new aa substitutions, we found that two substitutions in the NS3 region (D79G and S174Y) contributed to simeprevirand/or asunaprevir-resistance.

    DOI: 10.1016/j.virusres.2017.03.015

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  • The cyclic GMP-AMP synthetase-STING signaling pathway is required for both the innate immune response against HBV and the suppression of HBV assembly

    Hiromichi Dansako, Youki Ueda, Nobuaki Okumura, Shinya Satoh, Masaya Sugiyama, Masashi Mizokami, Masanori Ikeda, Nobuyuki Kato

    FEBS JOURNAL   283 ( 1 )   144 - 156   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    During viral replication, the innate immune response is induced through the recognition of viral replication intermediates by host factor(s). One of these host factors, cyclic GMP-AMP synthetase (cGAS), was recently reported to be involved in the recognition of viral DNA derived from DNA viruses. However, it is uncertain whether cGAS is involved in the recognition of hepatitis B virus (HBV), which is a hepatotropic DNA virus. In the present study, we demonstrated that HBV genome-derived double-stranded DNA induced the innate immune response through cGAS and its adaptor protein, stimulator of interferon genes (STING), in human hepatoma Li23 cells expressing high levels of cGAS. In addition, we demonstrated that HBV infection induced ISG56 through the cGAS-STING signaling pathway. This signaling pathway also showed an antiviral response towards HBV through the suppression of viral assembly. From these results, we conclude that the cGAS-STING signaling pathway is required for not only the innate immune response against HBV but also the suppression of HBV assembly. The cGAS-STING signaling pathway may thus be a novel target for anti-HBV strategies.

    DOI: 10.1111/febs.13563

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  • Synthesis and in vitro activity of pyrrolo[3,4-d]pyrimidine-2,5-diones as potential non-nucleoside HCV inhibitors 査読

    Amany S. Mostafa, Serry A. El Bialy, Waleed A. Bayoumi, Youki Ueda, Masanori Ikeda, Nobuyuki Kato, Ali M. Abdelal

    Current Enzyme Inhibition   12 ( 2 )   170 - 176   2016年

  • Establishment of Hepatitis C Virus RNA-Replicating Cell Lines Possessing Ribavirin-Resistant Phenotype

    Shinya Satoh, Kyoko Mori, Youki Ueda, Hiroe Sejima, Hiromichi Dansako, Masanori Ikeda, Nobuyuki Kato

    PLOS ONE   10 ( 2 )   e0118313   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Background
    Ribavirin (RBV) is a potential partner of interferon-based therapy and recently approved therapy using direct acting antivirals for patients with chronic hepatitis C. However, the precise mechanisms underlying RBV action against hepatitis C virus (HCV) replication are not yet understood. To clarify this point, we attempted to develop RBV-resistant cells from RBV-sensitive HCV RNA-replicating cells.
    Methodology/Principal Findings
    By repetitive RBV (100 mu M) treatment (10 weeks) of 3.5-year-cultured OL8 cells, in which genome-length HCV RNA (O strain of genotype 1b) efficiently replicates, dozens of colonies that survived RBV treatment were obtained. These colonies were mixed together and further treated with high doses of RBV (up to 200 mu M). By such RBV treatment, we successfully established 12 RBV-survived genome-length HCV RNA-replicating cell lines. Among them, three representative cell lines were characterized. HCV RNA replication in these cells resisted RBV significantly more than that in the parental OL8 cells. Genetic analysis of HCV found several common and conserved amino acid substitutions in HCV proteins among the three RBV-resistant cell species. Furthermore, using cDNA microarray and quantitative RT-PCR analyses, we identified 5 host genes whose expression levels were commonly altered by more than four-fold among these RBV-resistant cells compared with the parental cells. Moreover, to determine whether viral or host factor contributes to RBV resistance, we developed newly HCV RNA-replicating cells by introducing total RNAs isolated from RBV-sensitive parental cells or RBV-resistant cells into the HCV RNA-cured-parental or -RBV-resistant cells using an electroporation method, and evaluated the degrees of RBV resistance of these developed cells. Consequently, we found that RBV-resistant phenotype was conferred mainly by host factor and partially by viral factor.
    Conclusions/Significance
    These newly established HCV RNA-replicating cell lines should become useful tools for further understanding the anti-HCV mechanisms of RBV.

    DOI: 10.1371/journal.pone.0118313

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  • Synthesis of 3 ',4 '-difluoro-3 '-deoxyribonucleosides and its evaluation of the biological activities: Discovery of a novel type of anti-HCV agent 3 ',4 '-difluorocordycepin

    Hisashi Shimada, Kazuhiro Haraguchi, Kumi Hotta, Tomoko Miyaike, Yasuyuki Kitagawa, Hiromichi Tanaka, Ryutaro Kaneda, Hiroshi Abe, Satoshi Shuto, Kyoko Mori, Youki Ueda, Nobuyuki Kato, Robert Snoeck, Graciela Andrei, Jan Balzarini

    BIOORGANIC & MEDICINAL CHEMISTRY   22 ( 21 )   6174 - 6182   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Upon reacting 3',4'-unsaturated cytosine (8 and 9) and adenine nucleosides (13 and 14) with XeF2/BF3 center dot OEt2, the respective novel 3',4'-difluoro-3'-deoxyribofuranosyl nucleosides (10-12 and 15-18) could be obtained. Formation of anti-adducts (11, 16 and 18) revealed that the fluorination involved oxonium ions as incipient intermediates. TBDMS-protected 3',4'-unsaturated adenosine provided the beta-face adducts as sole stereoisomers whereas a-face-selectivity was observed with the TBDPS-protected adenosine 14. The evaluation of the novel 3'-deoxy-3',4'-difluororibofuranosylcytosine-(19-21) and adenine nucleosides (22-25) against antitumor and antiviral activities revealed that 3',4'-difluorocordycepin (24) was found to possess anti-HCV activity. The SI of 24 was comparable to that of the anti-HCV drug ribavirin. However, sofosbuvir, FDA-approved novel anti-HCV drug, showed better SI value. Our finding revealed that the introduction of the fluoro-substituent into the 4'-position of cordycepin derivatives decreased the cytotoxicity to the host cell with retention of the antiviral activity. (C) 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.bmc.2014.08.024

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  • Synthesis and inhibitory activity on hepatitis C virus RNA replication of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)aniline analogs

    Kenji Matsuno, Youki Ueda, Miwa Fukuda, Kenji Onoda, Minoru Waki, Masanori Ikeda, Nobuyuki Kato, Hiroyuki Miyachi

    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS   24 ( 17 )   4276 - 4280   2014年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Using our recently developed assay system for full-genome-length hepatitis C virus (HCV) RNA replication in human hepatoma-derived Li23 cells (ORL8), we identified 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)aniline analog la as a novel HCV inhibitor. Structural modifications of la provided a series of sulfonamides 7 with much more potent HCV RNA replication-inhibitory activity than ribavirin. Compound 7a showed an additive anti-HCV effect in combination with standard anti-HCV therapy (IFN-alpha plus ribavirin). Since 7a generated reactive oxygen species (ROS) in the ORL8 system and its anti-HCV activity was blocked by vitamin E, its anti-HCV activity may be mediated at least in part by ROS. (C) 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.bmcl.2014.07.019

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  • Anti-HCV activity of the Chinese medicinal fungus Cordyceps militaris

    Youki Ueda, Kyoko Mori, Shinya Satoh, Hiromichi Dansako, Masanori Ikeda, Nobuyuki Kato

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   447 ( 2 )   341 - 345   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although the sustained virologic response rate in the treatment of genotype 1 using new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has been improved by more than 70%, several severe side effects such as skin rash/ageusia and advanced anemia have become a problem. Under these circumstances, a new type of anti-HCV oral drug with few side effects is needed. Our recently developed HCV drug assay systems, including the HuH-7 cell line-derived OR6 and AH1R, and the Li23 cell line derived ORL8 and ORL11, allow genome-length HCV RNAs (several strains of genotype 1b) encoding renilla luciferase to replicate efficiently. Using these systems as anti-HCV candidates, we have identified numerous existing medicines that can be used against HCV with few side effects, such as statins and teprenon. To obtain additional anti-HCV candidates, we evaluated a number of oral health supplements, and found that the capsule but not the liquid form of Cordyceps militaris (CM) (Ascomycotinanorth, North Chinese caterpillar fungus), which is used as a Chinese herbal medicine, exhibited moderate anti-HCV activity. In combination with interferon-a or ribavirin, CM exhibited an additive inhibitory effect. Among the main components of CM, cordycepin, but not ergosterol, contributed to the anti-HCV activity of CM. In consideration of all these results, we suggest that CM would be useful as an oral anti-HCV agent in combination with interferon-alpha and/or ribavirin. (C) 2014 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2014.03.150

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  • Genetic Characterization of Hepatitis C Virus in Long-Term RNA Replication Using Li23 Cell Culture Systems

    Nobuyuki Kato, Hiroe Sejima, Youki Ueda, Kyoko Mori, Shinya Satoh, Hiromichi Dansako, Masanori Ikeda

    PLOS ONE   9 ( 3 )   91156 - 91156   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Background: The most distinguishing genetic feature of hepatitis C virus (HCV) is its remarkable diversity and variation. To understand this feature, we previously performed genetic analysis of HCV in the long-term culture of human hepatoma HuH-7-derived HCV RNA-replicating cell lines. On the other hand, we newly established HCV RNA-replicating cell lines using human hepatoma Li23 cells, which were distinct from HuH-7 cells.
    Methodology/Principal Findings: Li23-derived HCV RNA-replicating cells were cultured for 4 years. We performed genetic analysis of HCVs recovered from these cells at 0, 2, and 4 years in culture. Most analysis was performed in two separate parts: one part covered from the 5'-terminus to NS2, which is mostly nonessential for RNA replication, and the other part covered from NS3 to NS5B, which is essential for RNA replication. Genetic mutations in both regions accumulated in a timedependent manner, and the mutation rates in the 5'-terminus-NS2 and NS3-NS5B regions were 4.0-9.0x10(-3) and 2.7-4.0x10(-3) base substitutions/site/year, respectively. These results suggest that the variation in the NS3-NS5B regions is affected by the pressure of RNA replication. Several in-frame deletions (3-105 nucleotides) were detected in the structural regions of HCV RNAs obtained from 2-year or 4-year cultured cells. Phylogenetic tree analyses clearly showed that the genetic diversity of HCV was expanded in a time-dependent manner. The GC content of HCV RNA was significantly increased in a time-dependent manner, as previously observed in HuH-7-derived cell systems. This phenomenon was partially due to the alterations in codon usages for codon optimization in human cells. Furthermore, we demonstrated that these long-term cultured cells were useful as a source for the selection of HCV clones showing resistance to anti-HCV agents.
    Conclusions/Significance: Long-term cultured HCV RNA-replicating cells are useful for the analysis of evolutionary dynamics and variations of HCV and for drug-resistance analysis.

    DOI: 10.1371/journal.pone.0091156

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  • Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication

    Shintaro Ban, Youki Ueda, Masao Ohashi, Kenji Matsuno, Masanori Ikeda, Nobuyuki Kato, Hiroyuki Miyachi

    Bioorganic and Medicinal Chemistry Letters   23 ( 17 )   4774 - 4778   2013年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    It has been reported that ligand-mediated transcription factor peroxisome proliferator-activated receptor alpha (hPPARα) is involved in hepatitis C virus (HCV) RNA replication, whereas hPPARγ is not, and the effect of hPPARδ is unknown. Here, we show that hPPARδ-selective antagonists effectively inhibit HCV RNA replication. We describe the design, synthesis and pharmacological evaluation of a series of biphenyl-4-carboxylic acid-type hPPARδ antagonists, including previously reported compounds, as candidate anti-HCV agents. A representative compound (4c) dose-dependently inhibited HCV RNA replication (EC50 0.22 μM), while exhibiting relatively weak cytotoxicity to the host cells (CC50 2.5 μM). It also showed an additive and dose-dependent effect on the inhibition of HCV RNA replication by pegylated interferon alpha (Peg-IFNα) alone and by both Peg-IFNα and ribavirin (currently the clinical treatment of choice for HCV infection). Thus, combination of a hPPARδ antagonist with current therapy may improve the efficacy of treatment for HCV infection. © 2013 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.bmcl.2013.07.005

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  • New Preclinical Antimalarial Drugs Potently Inhibit Hepatitis C Virus Genotype 1b RNA Replication

    Youki Ueda, Midori Takeda, Kyoko Mori, Hiromichi Dansako, Takaji Wakita, Hye-Sook Kim, Akira Sato, Yusuke Wataya, Masanori Ikeda, Nobuyuki Kato

    PLOS ONE   8 ( 8 )   e72519   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Background: Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed.
    Methodology/Principal Findings: Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8) were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251) showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-alpha demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-alpha-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-alpha and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect.
    Conclusions/Significance: We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.

    DOI: 10.1371/journal.pone.0072519

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  • Development of a drug assay system with hepatitis C virus genome derived from a patient with acute hepatitis C

    Kyoko Mori, Youki Ueda, Yasuo Ariumi, Hiromichi Dansako, Masanori Ikeda, Nobuyuki Kato

    VIRUS GENES   44 ( 3 )   374 - 381   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    We developed a new cell culture drug assay system (AH1R), in which genome-length hepatitis C virus (HCV) RNA (AH1 strain of genotype 1b derived from a patient with acute hepatitis C) efficiently replicates. By comparing the AH1R system with the OR6 assay system that we developed previously (O strain of genotype 1b derived from an HCV-positive blood donor), we demonstrated that the anti-HCV profiles of reagents including interferon-gamma and cyclosporine A significantly differed between these assay systems. Furthermore, we found unexpectedly that rolipram, an anti-inflammatory drug, showed anti-HCV activity in the AH1R assay but not in the OR6 assay, suggesting that the anti-HCV activity of rolipram differs depending on the HCV strain. Taken together, these results suggest that the AH1R assay system is useful for the objective evaluation of anti-HCV reagents and for the discovery of different classes of anti-HCV reagents.

    DOI: 10.1007/s11262-012-0712-2

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  • Plural assay systems derived from different cell lines and hepatitis C virus strains are required for the objective evaluation of anti-hepatitis C virus reagents 査読

    Youki Ueda, Kyoko Mori, Yasuo Ariumi, Masanori Ikeda, Nobuyuki Kato

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   409 ( 4 )   663 - 668   2011年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. HuH-7 hepatoma-derived cells are widely used as the only cell-based HCV replication system for HCV research, including drug assays. Recently, using different hepatoma Li23-derived cells, we developed an HCV drug assay system (ORL8), in which the genome-length HCV RNA (O strain of genotype 1b) encoding renilla luciferase replicates efficiently. In this study, using the HuH-7-derived OR6 assay system that we developed previously and the ORL8 assay system, we evaluated 26 anti-HCV reagents, which other groups had reported as anti-HCV candidates using HuH-7-derived assay systems other than ORB. The results revealed that more than half of the reagents showed different anti-HCV activities from those in the previous studies, and that anti-HCV activities evaluated by the ORB and ORL8 assays were also frequently different. In further evaluation using the HuH-7-derived AH1R assay system, which was developed using the AH1 strain of genotype 1b, several reagents showed different anti-HCV activities in comparison with those evaluated by the OR6 and ORL8 assays. These results suggest that the different activities of anti-HCV reagents are caused by the differences in cell lines or HCV strains used for the development of assay systems. Therefore, we conclude that plural HCV assay systems developed using different cell lines or HCV strains are required for the objective evaluation of anti-HCV reagents. (C) 2011 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2011.05.061

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  • 抗HCV剤の活性評価には複数の細胞株由来のHCVアッセイ系が必要である 査読

    上田 優輝, 森 京子, 池田 正徳, 有海 康雄, 加藤 宣之

    肝臓   52 ( Suppl.1 )   A230 - A230   2011年4月

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    記述言語:日本語   出版者・発行元:(一社)日本肝臓学会  

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  • Mechanism of freezing of water in contact with mesoporous silicas MCM-41, SBA-15 and SBA-16: role of boundary water of pore outlets in freezing

    Shigeharu Kittaka, Yuki Ueda, Fumika Fujisaki, Taku Iiyama, Toshio Yamaguchi

    PHYSICAL CHEMISTRY CHEMICAL PHYSICS   13 ( 38 )   17222 - 17233   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ROYAL SOC CHEMISTRY  

    The freezing mechanism of water contacted with mesoporous silicas with uniform pore shapes, both cylindrical and cagelike, was studied by thermodynamic and structural analyses with differential scanning calorimetry (DSC) and X-ray diffraction (XRD) together with adsorption measurements. In the DSC data extra exothermic peaks were found at around 230 K for water confined in SBA-15, in addition to that due to the freezing of pore water. These peaks are most likely to be ascribed to the freezing of water present over the micropore and/or mesopore outlets of coronas in SBA-15. Freezing of water confined in SBA-16 was systematically analysed by DSC with changing the pore size. The freezing temperature was found to be around 232 K, close to the homogeneous nucleation temperature of bulk water, independent of the pore size when the pore diameter (d) < 7.0 nm. Water confined in the cagelike pores of SBA-16 is probably surrounded by a water layer (boundary water) at the outlets of channels to interconnect the pores and of fine corona-like pores, which is similar to that present at the outlet of cylindrical pores in MCM-41 and of cylindrical channels in SBA-15. The presence of the boundary water would be a key for water in SBA-16 to freeze at the homogeneous nucleation temperature. This phenomenon is similar to those well known for water droplets in oil and water droplets of clouds in the sky. The XRD data showed that the cubic ice I(c) was formed in SBA-16 as previously found in SBA-15 when d < 8.0 nm.

    DOI: 10.1039/c1cp21458f

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講演・口頭発表等

  • 抗HCV薬として開発中のN-89とN-251に対する抵抗性の獲得に寄与する宿主側とウイルス側因子の解析

    第33回中国四国ウイルス研究会  2018年 

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  • 抗HCV薬リバビリンによるGPAM発現抑制機序の解明

    第33回中国四国ウイルス研究会  2018年 

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  • 抗HCV薬リバビリンによる中性脂質合成抑制機序の解明

    第33回中国四国ウイルス研究会  2018年 

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  • HCV以外の広範なウイルスにも有効性を示した抗マラリア薬候補N-89とN-251

    第33回中国四国ウイルス研究会  2018年 

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  • 抗マラリア及び抗HCV薬候補N-89とN-251が有する幅広い抗ウイルス活性

    第28回抗ウイルス療法学会学術集会・総会  2018年 

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  • ヒト不死化肝NKNT-3細胞におけるB型肝炎ウイルスの感染増殖性を制御する宿主因子の探索

    第33回中国四国ウイルス研究会  2018年 

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  • ヒト不死化肝NKNT-3細胞におけるtopoisomerase II阻害剤によるcGAS依存的な自然免疫応答の誘導

    第33回中国四国ウイルス研究会  2018年 

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  • Downregulation of C/EBPα by anti-HCV drug ribavirin leads to the suppression of triglyceride synthesis pathway.

    The 65th Annual Meeting of The Japanese Society for Virology  2017年 

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  • Development of HBV infection system using human immortalized hepatocyte NKNT-3 cells.

    The 65th Annual Meeting of The Japanese Society for Virology  2017年 

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  • Screening of FDA-approved drugs activating cyclic GMP-AMP synthase promoter.

    The 65th Annual Meeting of The Japanese Society for Virology  2017年 

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  • Resistant acquistion mechanism for anti-HCV drug candidates, N-89 and its derivative N-251.

    The 65th Annual Meeting of The Japanese Society for Virology  2017年 

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  • Identification of new amino acid substitusions contributing to DAA-resistance, using HCV reporter assay systems.

    The 65th Annual Meeting of The Japanese Society for Virology  2017年 

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  • HCVポリメラーゼ/プロテアーゼ二重阻害活性を有するフラーレン誘導体の細胞内HCV複製阻害及び酸化ストレス抑制効果

    日本薬学会第137年会  2017年 

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  • Development of human hepatoma cell line, Li23-derived cells possessing high susceptibility to HBV.

    The 2017 international HBV meeting  2017年 

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  • 抗HCV薬として開発中のN-89とN-251に対する抵抗性獲得機序の解析

    第32回中国四国ウイルス研究会  2017年 

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  • ヒトcGASの発現を亢進するインターフェロンγと新規薬剤の探索

    第32回中国四国ウイルス研究会  2017年 

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  • 抗HCV薬リバビリンの脂質生合成抑制機序の解明

    第32回中国四国ウイルス研究会  2017年 

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  • ヒト不死化肝細胞株を用いた新規HBV感染増殖システムの開発

    第32回中国四国ウイルス研究会  2017年 

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  • HCVレポーターアッセイ系を用いたDAAに抵抗性を示す新規アミノ酸置換の同定

    第32回中国四国ウイルス研究会  2017年 

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  • DAA製剤による新治療時代におけるN-89/N-251の有用性とそれらの作用機序の解析

    第4回肝炎ウイルス研修会  2016年 

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  • DAA製剤によるHCV治療におけるN-89/N-251の有用性とそれらの作用機序の解析

    第26回抗ウイルス療法学会  2016年 

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  • Mechanism for suppression of hepatic lipogenesis by anti-HCV drug ribavirin.

    The 64th Annual Meeting of The Japanese Society for Virology  2016年 

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  • The mechanism of natural killer cell-mediated recognition against hepatitis C virus in human immortalized hepatocyte cells.

    The 64th Annual Meeting of The Japanese Society for Virology  2016年 

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  • Both host and viral factors contribute to the resistance to preclinical anti-HCV drugs, N-89 and N-251.

    The 64th Annual Meeting of The Japanese Society for Virology, Sapporo  2016年 

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  • Genetic characterization of HCVs obtained from HCV-RNA-replicating cells possessing a DAA-, N-89-, or N-251-resistant phenotype.

    The 64th Annual Meeting of The Japanese Society for Virology  2016年 

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  • 全長HCV-RNA複製細胞におけるexosome産生量の増加

    第3回日本細胞外小胞学会及び第8回日本RNAi研究会  2016年 

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  • 核酸アナログ型抗HCV薬によるAMPK活性への影響

    第31回中国四国ウイルス研究会  2016年 

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  • B型肝炎ウイルスに対する感染受容性を有するヒト肝がんLi23細胞のサブクローニングとその有用性

    第31回中国四国ウイルス研究会  2016年 

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  • ヒト不死化肝細胞を用いたナチュラルキラー細胞によるC型肝炎ウイルス認識機構の解析

    第31回中国四国ウイルス研究会  2016年 

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  • 抗HCV薬候補として開発中のN-89とN-251に対する抵抗性の獲得には宿主とウイルス側両方が関与する

    第31回中国四国ウイルス研究会  2016年 

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  • N-89或いはN-251に耐性を示すHCV-RNA複製細胞から得られたHCV遺伝子の性状解析

    第31回中国四国ウイルス研究会  2016年 

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  • Improved ExoQuick protocol for the preparation of exosomes released from human hepatoma cells.

    The 63rd Annual Meeting of The Japanese Society for Virology  2015年 

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  • Antimalarial preclinical drugs, N-89 and N-251, overcome various DAAs-resistant HCVs.

    22nd International Symposium on Hepatitis C Virus and Related Viruses  2015年 

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  • Function and transcriptional regulation mechanism of CPB2 gene downregulated by persistent HCV RNA replication.

    The 63rd Annual Meeting of The Japanese Society for Virology  2015年 

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  • New function of anti-HCV drug ribavirin: supprssive effect in hepatic lipogenesis.

    The 63rd Annual Meeting of The Japanese Society for Virology  2015年 

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  • The cGAS-STING signaling pathway is required for both the innate immune against HBV and suppression of HBV assembly.

    The 63rd Annual Meeting of The Japanese Society for Virology  2015年 

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  • Antimalarial preclinical drugs, N-89 and N-251, overcome various DAAs-resistant HCVs.

    The 63rd Annual Meeting of The Japanese Society for Virology  2015年 

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  • Antimalarial preclinical drugs, N-89 and N-251, overcome various DAAs-resistant HCVs.

    22nd International Symposium on Hepatitis C Virus and Related Viruses  2015年 

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  • HCV-RNAの長期複製により顕著な発現低下を示したCPB2遺伝子の機能解析と発現制御機構の解析

    第30回中国四国ウイルス研究会  2015年 

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  • HCVの細胞内複製を許容する肝がん細胞におけるエクソソーム調製法の確立

    第30回中国四国ウイルス研究会  2015年 

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  • cGAS-STINGシグナル経路はB型肝炎ウイルスの感染と会合を制御する

    第30回中国四国ウイルス研究会  2015年 

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  • 抗HCV薬リバビリンの脂質生合成系における新規機能解析

    第30回中国四国ウイルス研究会  2015年 

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  • 強い抗HCV活性が見出された抗マラリア化合物の臨床応用に向けた研究とDAAとの併用効果

    第30回中国四国ウイルス研究会  2015年 

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  • HCV RNAの複製や抗HCV活性に対するビタミンEによる制御機構

    第26回ビタミンE研究会  2015年 

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  • Characterization of anti-HCV activity of N-251, a preclinical antimalarial drug, and its combination effect with DAA.

    21st International Symposium on Hepatitis C Virus and Related Viruses  2014年 

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  • C型肝炎治療薬を指向したPPARα/δデュアルアンタゴニストの創製

    第32回メディシナルケミストリーシンポジウム  2014年 

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  • ヘキサフルオロイソプロピルベンズアミド誘導体による抗C型肝炎ウィルス(HCV)活性

    第32回メディシナルケミストリーシンポジウム  2014年 

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  • 抗マラリア薬候補で強い抗HCV活性を示すN-251の臨床応用に向けた研究とDAAとの併用効果

    第62回日本ウイルス学会学術集会  2014年 

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  • 臨床応用に向けた抗マラリア薬候補N-251の抗HCV活性作用機序の解析

    第18回日本肝臓学会大会  2014年 

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  • Characterization of anti-HCV activity of N-251, a preclinical antimalarial drug, and its combination effect with DAA.

    21st International Symposium on Hepatitis C Virus and Related Viruses  2014年 

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  • 抗マラリア薬候補N-251の抗HCV活性作用機序の解析と臨床応用に向けた研究

    第29回中国四国ウイルス研究会  2014年 

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  • リバビリン耐性全長HCV-RNA複製細胞株の樹立と特性解析

    第29回中国四国ウイルス研究会  2014年 

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  • HCV RNA評価系により見出したN-251等の抗HCV化合物とその利用について

    第2回肝炎ウイルス研修会  2013年 

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  • リバビリン耐性全長HCV-RNA複製細胞株の樹立

    第61回日本ウイルス学会学術総会  2013年 

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  • 抗HCV活性を有する中国由来の漢方薬であるサナギタケ(北冬虫夏草)

    第61回日本ウイルス学会学術総会  2013年 

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  • Anti-HCV activity of Cordyceps militaris used as a chinese herbal medicine.

    20th International Symposium on Hepatitis C Virus and Related Viruses  2013年 

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  • 中国由来の漢方薬であるサナギタケ(北冬虫夏草)が有する抗HCV活性

    第28回中国四国ウイルス研究会  2013年 

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  • 中国由来の漢方薬であるサナギタケ(北冬虫夏草)に見出された抗HCV活性

    第49回日本肝臓学会総会  2013年 

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  • Anti-HCV activity of Cordyceps militaris used as a chinese herbal medicine.

    20th International Symposium on Hepatitis C Virus and Related Viruses  2013年 

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  • Plural assay systems derived from different cell lines and hepatitis C virus strains are required for the objective evaluation of anti-hepatitis C virus reagents.

    Ueda Y, Mori K, Ariumi Y, Ikeda M, Kato N

    Biochemical and Biophysical Research Communications  2011年 

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受賞

  • 第27回中国四国ウイルス研究会・優秀演題賞

    2011年   中国四国ウイルス研究会   強力な抗HCV活性が見出された抗マラリア薬として開発中の化合物

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    受賞国:日本国

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担当授業科目

  • 腫瘍ウイルス学I(演習・実習) (2020年度) 特別  - その他

  • 腫瘍ウイルス学I(講義・演習) (2020年度) 特別  - その他

  • 腫瘍ウイルス学II(演習・実習) (2020年度) 特別  - その他

  • 腫瘍ウイルス学II(講義・演習) (2020年度) 特別  - その他