論文 - 渡部　匡史

Synthesis and biological evaluation of novel imidazole nucleosides as potential anti-dengue virus agents.

Okano Y, Saito-Tarashima N, Kurosawa M, Iwabu A, Ota M, Watanabe T, Kato F, Hishiki T, Fujimuro M, Minakawa N

Bioorganic & medicinal chemistry   27 ( 11 ) 2181 - 2186   2019年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

In this work, we developed imidazole nucleoside derivatives with anti-dengue virus (DENV) activity was examined. First, compounds in a nucleosides library were screened to find lead compounds which inhibit replication of DENV. As a result, 5-ethynyl-(1-β-d-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) and its 4-carbonitrile derivative EICNR (2) were selected as promising antiviral compounds. However, both of them also exhibited cytotoxicity. In order to develop an effective and less toxic compound, 4'-thio and 4'-seleno derivatives of EICAR and EICNR 3-6 were prepared. The resulting 4'-thioEICAR and 4'-thioEICNR showed inhibitory effect on DENV replication without cytotoxicity as potent as ribavirin, a positive control.

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Sulforaphane Exhibits Cytotoxic Effects against Primary Effusion Lymphoma Cells by Suppressing p38MAPK and AKT Phosphorylation.

Ishiura Y, Ishimaru H, Watanabe T, Fujimuro M

Biological & pharmaceutical bulletin   42 ( 12 ) 2109 - 2112   2019年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Primary effusion lymphoma (PEL) is a rare subtype of non-Hodgkin's B-cell lymphoma and is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive lymphoma and is frequently resistant to conventional chemotherapies. Sulforaphane (SFN), a natural compound found in cruciferous vegetables and broccoli sprouts, modulates signaling pathways and epigenetic gene expression. However, the anti-proliferative effects of SFN on PEL cells and the underlying mechanisms have not been identified. Here, we found that SFN decreased the viability of KSHV-infected PEL cells compared to KSHV-uninfected B-lymphoma cells. The anti-proliferative effects of SFN on PEL cells were mediated by apoptosis with activating caspases. In addition, SFN inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and AKT in PEL cells. We also showed that p38MAPK and AKT inhibitors reduced PEL cell growth. The constitutive and/or transient activation of p38MAPK and AKT signaling are necessary for the survival and proliferation of PEL cells. Our data and previous literature indicate that SFN represses the phosphorylation of p38MAPK and AKT, which results in PEL cell apoptosis. Moreover, we investigated whether MG132 or sangivamycin (Sangi) in combination with SFN potentiated the cytotoxic effects of SFN on PEL cells. Compared to treatment with SFN alone, the addition of MG132 or Sangi enhanced the cytotoxic activity of SFN in a synergistic manner. In conclusion, the anti-proliferative effects of SFN indicate its potential as a new substance for the treatment of PEL.

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No enhancing effects of plasmid-specific histone acetyltransferase recruitment system on transgene expression in vivo.

Suzuki T, Wakao Y, Watanabe T, Hori M, Ikeda Y, Tsuchiya H, Kogure K, Harada-Shiba M, Fujimuro M, Kamiya H

Nucleosides, nucleotides & nucleic acids   38 ( 12 ) 942 - 949   2019年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Altered levels of histone acetylation are associated with changes in chromosomal gene expression. Thus, the specific acetylation of histones bound to plasmid DNA might increase transgene expression. Previously, the expression of the histone acetyltransferase domain of CREB-binding protein fused to the sequence-dependent DNA binding domain of GAL4 (GAL4-HAT) successfully improved reporter gene expression in cultured cells [ 123, 277-280 (2017)]. In this study, the same approach was applied for transgene expression in mice. The activator and reporter plasmid DNAs bearing the genes for GAL4-HAT and luciferase, respectively, were co-administered into the mouse liver by hydrodynamics-based tail vein injection, and the luciferase activity in serum was measured for two weeks. Unexpectedly, the co-injection of the GAL4-HAT and luciferase plasmid DNAs seemed to decrease, rather than increase, luciferase expression. Moreover, the co-injection apparently reduced the amount of luciferase DNA in the liver. These results indicated that this system is ineffective in vivo and suggested the exclusion of hepatic cells expressing GAL4-HAT.

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Capsaicin Induces ATF4 Translation with Upregulation of CHOP, GADD34 and PUMA.

Moriguchi M, Watanabe T, Fujimuro M

Biological & pharmaceutical bulletin   42 ( 8 ) 1428 - 1432   2019年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Capsaicin Induces Apoptosis in KSHV-Positive Primary Effusion Lymphoma by Suppressing ERK and p38 MAPK Signaling and IL-6 Expression.

Moriguchi M, Watanabe T, Kadota A, Fujimuro M

Frontiers in oncology   9   83 - 83   2019年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Primary effusion lymphoma (PEL) is defined as a rare subtype of non-Hodgkin's B-cell lymphoma which is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. PEL is an aggressive lymphoma and is frequently resistant to conventional chemotherapies. Therefore, it is critical to investigate novel therapeutic options for PEL. Capsaicin is a pungent component of chili pepper and possesses unique pharmacological effects, such as pain relief, anti-microbial and anti-cancer properties. Here, we demonstrate that capsaicin markedly inhibited the growth of KSHV latently infected PEL cells by inhibiting ERK, p38 MAPK and expression hIL-6, which are known to contribute to PEL growth and survival. The underlying mechanism of action by capsaicin was through the inhibition of ERK and p38 MAPK phosphorylation and signaling that affected hIL-6 expression. As a result, capsaicin induced apoptosis in PEL cells in a caspase-9 dependent manner. In line with these results, ERK (U0126) and p38 MAPK (SB203580) specific signaling inhibitors suppressed hIL-6 expression and attenuated cell growth in PEL cells. Furthermore, the addition of hIL-6 neutralizing antibody to culture medium suppressed the growth of PEL cells. We also demonstrate that capsaicin suppressed PEL cell growth in the absence of nascent viral replication. Finally, we confirmed ex vivo treatment of capsaicin attenuated PEL development in SCID mice. Taken together, capsaicin could represent a lead compound for PEL therapy without the risk of de novo KSHV infection.

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Arctigenin induces the apoptosis of primary effusion lymphoma cells under conditions of glucose deprivation.

Baba Y, Shigemi Z, Hara N, Moriguchi M, Ikeda M, Watanabe T, Fujimuro M

International journal of oncology   52 ( 2 ) 505 - 517   2018年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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KSHV episomes reveal dynamic chromatin loop formation with domain-specific gene regulation.

Campbell M, Watanabe T, Nakano K, Davis RR, Lyu Y, Tepper CG, Durbin-Johnson B, Fujimuro M, Izumiya Y

Nature communications   9 ( 1 ) 49   2018年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Methylseleninic acid and sodium selenite induce severe ER stress and subsequent apoptosis through UPR activation in PEL cells.

Shigemi Z, Manabe K, Hara N, Baba Y, Hosokawa K, Kagawa H, Watanabe T, Fujimuro M

Chemico-biological interactions ( ELSEVIER IRELAND LTD )  266   28 - 37   2017年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Selenium compounds such as methylseleninic acid (MSA) and sodium selenite (SS) have been widely evaluated as potential anti-cancer agents in the clinical setting. Primary effusion lymphoma (PEL) is a non-Hodgkin's B-cell lymphoma, associated with immunosuppressed individuals, such as post-transplant or AIDS patients. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of PEL and Kaposi's sarcoma. Here, we found that MSA and SS markedly inhibited the growth of PEL cells compared with KSHV-uninfected B cells. MSA and SS caused ER stress, inducing the unfolded protein response (UPR) pathway in PEL cells that resulted in pro-apoptotic UPR, and finally apoptosis. The expression of UPR-related molecules (GRP78 and GADD34) and pro-apoptotic UPR molecules (CHOP, Bim, or Puma) were augmented in PEL cells treated with MSA or SS. In addition, these compounds induced the activation of caspase-4, an ER stress specific caspase, as well as caspase-3,-7, and -9 in PEL cells. We confirmed that thapsigargin which is an inducer of ER stress, dramatically decreased the viability of PEL cells, compared with KSHV-uninfected Ramos cells. We also investigated whether MSA or SS caused oxidization of cellular proteins in PEL cells. MSA and SS increased the levels of oxidative proteins in PEL cells, and the anti-oxidant agent (N-acetyl-L-cysteine) restored cell viability and suppressed caspase-7 activation in PEL cells treated with MSA or SS. Finally, we confirmed that MSA and SS induced neither lytic replication nor viral production in PEL cells. Taken together, MSA and SS could serve as lead compounds for the development of novel and effective drugs against PEL without the risk of de novo KSHV production. (C) 2017 Elsevier B.V. All rights reserved.

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Kaposi's sarcoma-associated herpesvirus ORF34 is essential for late gene expression and virus production.

Nishimura M, Watanabe T, Yagi S, Yamanaka T, Fujimuro M

Scientific reports ( NATURE PUBLISHING GROUP )  7 ( 1 ) 329   2017年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. KSHV establishes a life-long infection in its host and alternates between a latent and lytic infection state. During lytic infection, lytic-related genes are expressed in a temporal manner and categorized as immediate early, early, and late gene transcripts. ORF34 is an early-late gene that interacts with several viral transcription-associated factors, however its physiological importance remains poorly understood. Here, we investigated the role of ORF34 during KSHV infection by generating ORF34-deficient KSHV, using a bacterial artificial chromosome system. Our results reveal that ORF34-deficient KSHV exhibited significantly attenuated late gene expression and viral production but did not affect viral DNA replication. ORF34 interacted with transcription factors ORF18, ORF24, ORF31, and ORF66, and a novel ORF34-interaction partner, ORF23. The C-terminal region of ORF34 was important for interaction with ORF24 and viral production. Our data support a model, in which ORF34 serves as a hub for recruiting a viral transcription complex to ORF24 to promote late viral gene expression.

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Asymptomatic malaria, growth status, and anaemia among children in Lao People's Democratic Republic: a cross-sectional study.

Akiyama T, Pongvongsa T, Phrommala S, Taniguchi T, Inamine Y, Takeuchi R, Watanabe T, Nishimoto F, Moji K, Kano S, Watanabe H, Kobayashi J

Malaria journal ( BIOMED CENTRAL LTD )  15 ( 1 ) 499 - 8   2016年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Background: Asymptomatic malaria can be observed in both stable endemic areas and unstable transmission areas. However, although much attention has been given to acute malaria infections, relatively little attention has been paid to asymptomatic malaria. Nonetheless, because the asymptomatic host serves as a reservoir for the malaria parasite, asymptomatic malaria is now recognized as an important obstacle to malaria elimination. Asymptomatic malaria is also associated with anaemia, a global public health problem with serious consequences on human health as well as social and economic development. In Lao People's Democratic Republic (Lao PDR), malaria, anaemia, and malnutrition are serious public health concerns. However, few studies have focused on the relationship between these variables. Therefore, this study investigated the relationship between asymptomatic malaria, growth status, and the prevalence of anaemia among children aged 120 months old or younger in rural villages in Lao PDR. Methods: In December 2010 and March 2011, data were collected from five villages in Savannakhet province. Anthropometric measurements, blood samples, and malaria rapid diagnostic tests were conducted. The presence of malaria was confirmed with polymerase chain reaction assays for Plasmodium falciparum. Underweight status, stunting, and anaemia were defined according to World Health Organization standards. Results: The mean age of participants (n = 319) was 88.3 months old (Standard Deviation: 20.6, ranged from 30-119 months old), and 20 participants (6.3 %) had an asymptomatic malaria infection, 92 (28.8 %) were anaemic, 123 (38.6 %) were underweight, and 137 (42.9 %) were stunted. Stunted children were more likely to be infected with asymptomatic malaria [odds ratio (OR) 3.34, 95 % confidence interval (CI) 1.25-8.93], and asymptomatic malaria was associated with anaemia [OR 5.17, 95 % CI 1.99-13.43]. Conclusions: These results suggest a significant association between asymptomatic malaria and anaemia in children. Furthermore, stunted children were more likely to have lower Hb levels and to be infected with asymptomatic malaria than children without stunting. However, further studies examining the impact of asymptomatic malaria infection on children's nutritional and development status are necessary.

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The dynamics of histone H2A ubiquitination in HeLa cells exposed to rapamycin, ethanol, hydroxyurea, ER stress, heat shock and DNA damage.

Nakata S, Watanabe T, Nakagawa K, Takeda H, Ito A, Fujimuro M

Biochemical and biophysical research communications ( ACADEMIC PRESS INC ELSEVIER SCIENCE )  472 ( 1 ) 46 - 52   2016年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Polyubiquitination plays key roles in proteasome-dependent and independent cellular events, whereas monoubiquitination is involved in gene expression, DNA repair, protein protein interaction, and protein trafficking. We previously developed an FK2 antibody, which specifically recognizes poly-Ub moieties but not free Ub. To elucidate the role of Ub conjugation in response to cellular stress, we used FK2 to investigate whether chemical stress (rapamycin, ethanol, or hydroxyurea), ER stress (thapsigargin or tunicamycin), heat shock or DNA damage (H2O2 or methyl methanesulfonate) affect the formation of Ub conjugates including histone H2A (hH2A) ubiquitination. First, we found that all forms of stress tested increased poly-ubiquitinated proteins in HeLa cells. Furthermore, rapamycin and hydroxyurea treatment, and ER stress increased ubiquitination of hH2A, while methyl methanesulfonate (MMS) treatment induced deubiquitination of hH2A. The ethanol and H2O2 treatments, and heat shock transiently induced hH2A de-ubiquitination, although deubiquitinated hH2A were ubiquitinated again by subsequent cultivation. We also revealed that FK2 reacts with not only polyubiquitinated proteins but also monoubiquitinated hH2A. With the exception of MMS, all forms of stress tested increased the acetylation of K5-hH2A, K9-hH3 and K8-hH4 in addition to ubiquitination. K118 and 1(119 of hH2A were ubiquitinated in cells under normal conditions, and 1(119 was the major ubiquitination site. The MMS-treatment and heat shock induced the deubiquitination of both K118 and K119-histone H2A. Interestingly, MMS treatment did not affect cell HeLa cell viability expressing double-mutant hH2A (KK118,119AA-hH2A), while heat shock slightly but significantly decreased viability of double-mutant hH2A expressing cells, indicating that ubiquitination of both sites associates with recovery from heat shock but not MMS treatment. Thus, we characterized FK2 reactivity and demonstrated that various stresses alter the ubiquitination status, particularly ubiquitinated hH2A and with histone acetylation, and highlight the physiological importance of hH2A ubiquitination after exposure to stress stimuli. (C) 2016 Elsevier Inc. All rights reserved.

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Effects of ER stress on unfolded protein responses, cell survival, and viral replication in primary effusion lymphoma.

Shigemi Z, Baba Y, Hara N, Matsuhiro J, Kagawa H, Watanabe T, Fujimuro M

Biochemical and biophysical research communications ( ACADEMIC PRESS INC ELSEVIER SCIENCE )  469 ( 3 ) 565 - 72   2016年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-lymphoma, is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. Endoplasmic reticulum (ER) stress induces activation of the unfolded protein response (UPR), which induces expression of ER chaperones, which in turn decrease ER stress, leading to ER homeostasis. The UPR is necessary for not only ER homeostasis but also persistent infection by, and replication of, many viruses. However, the precise roles and regulation of the UPR in KSHV infection remain poorly understood. Here, we found that IRE1 alpha and PERK were significantly downregulated in PEL cells cultured under normal conditions, compared with KSHV-uninfected B-lymphoma cells. IRE1 alpha and PERK mRNA levels were decreased in PEL cells, and KSHV-encoded LANA and v-cyclin D led to suppressed IRE1 alpha transcription. Thapsigargin-induced ER stress activated the UPR and increased the mRNA levels of UPR-related molecules, including IRE1 alpha and PERK, in PEL cells. However the IRE1 alpha and PERK mRNA levels in PEL cells were lower than those in KSHV-uninfected cells. Furthermore, ER stress induced by brefeldin A and thapsigargin dramatically reduced the viability of PEL cells, compared with KSHV-uninfected cells, and induced apoptosis of PEL cells via the pro-apoptotic UPR through expression of CHOP and activation of caspase-9. In addition to the pro-apoptotic UPR, thapsigargin-induced ER stress enhanced transcription of lytic genes, including RTA, K-bZIP and K8.1, and viral production in PEL cells resulted in induction of the lytic cycle. Thus, we demonstrated downregulation of IRE1 alpha and PERK in PEL cells, transcriptional suppression of IRE1 alpha by LANA and v-cyclin D, apoptosis induction in PEL cells by ER stress, and potentiation of lytic replication by ER stress. (C) 2015 Elsevier Inc. All rights reserved.

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Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma.

Shigemi Z, Furukawa Y, Hosokawa K, Minami S, Matsuhiro J, Nakata S, Watanabe T, Kagawa H, Nakagawa K, Takeda H, Fujimuro M

International journal of oncology   48 ( 1 ) 293 - 304   2016年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma.

Watanabe T, Nakamura S, Ono T, Ui S, Yagi S, Kagawa H, Watanabe H, Ohe T, Mashino T, Fujimuro M

Biochemical and biophysical research communications   451 ( 1 ) 93 - 100   2014年08月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells.

Wakao K, Watanabe T, Takadama T, Ui S, Shigemi Z, Kagawa H, Higashi C, Ohga R, Taira T, Fujimuro M

Biochemical and biophysical research communications   444 ( 2 ) 135 - 40   2014年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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The hematopoietic cell-specific Rho GTPase inhibitor ARHGDIB/D4GDI limits HIV type 1 replication

Watanabe T., Urano E., Miyauchi K., Ichikawa R., Hamatake M., Misawa N., Sato K., Ebina H., Koyanagi Y., Komano J.

AIDS Research and Human Retroviruses ( Mary Ann Liebert, Inc., publishers )  28 ( 8 ) 913 - 922   2012年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Hyrtioreticulins A-E, indole alkaloids inhibiting the ubiquitin-activating enzyme, from the marine sponge Hyrtios reticulatus.

Yamanokuchi R, Imada K, Miyazaki M, Kato H, Watanabe T, Fujimuro M, Saeki Y, Yoshinaga S, Terasawa H, Iwasaki N, Rotinsulu H, Losung F, Mangindaan RE, Namikoshi M, de Voogd NJ, Yokosawa H, Tsukamoto S

Bioorganic & medicinal chemistry   20 ( 14 ) 4437 - 42   2012年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Physical and functional interactions between Daxx and STAT3

Muromoto R., Nakao K., Watanabe T., Sato N., Sekine Y., Sugiyama K., Oritani K., Shimoda K., Matsuda T.

Oncogene ( Springer Nature )  25 ( 14 ) 2131 - 2136   2006年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Phosphorylation of threonine-265 in Zipper-interacting protein kinase plays an important role in its activity and is induced by IL-6 family cytokines

Sato N., Kamada N., Muromoto R., Kawai T., Sugiyama K., Watanabe T., Imoto S., Sekine Y., Ohbayashi N., Ishida M., Akira S., Matsuda T.

Immunology Letters ( Elsevier )  25   127 - 134   2006年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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