Details of a Researcher - Mashino, Tadahiko

Papers - Mashino, Tadahiko

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

Watanabe Tadashi, Nakamura Shigeo, Ono Toshiya, Ui Sadaharu, Yagi Syota, Kagawa Hiroki, Watanabe Hisami, Ohe Tomoyuki, Mashino Tadahiko, Fujimuro Masahiro

Biochemical and Biophysical Research Communications 451 ( 1 ) 93 - 100 2014.08

Research paper (scientific journal), ISSN 0006-291X

Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin's B-cell lymphoma and is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated whether pyrrolidinium fullerene in combination with the HSP90 inhibitor (geldanamycin; GA) or valproate, potentiated the cytotoxic effects on PEL cells. Compared to treatment with pyrrolidinium fullerene alone, the addition of low-concentration GA or valproate enhanced the cytotoxic activity of pyrrolidinium fullerene. These results indicate that pyrrolidinium fullerene could be used as a novel therapy for the treatment of PEL. © 2014 Elsevier Inc. All rights reserved.

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Effect of chemical modification on the ability of pyrrolidinium fullerene to induce apoptosis of cells transformed by JAK2 V617F mutant

Funakoshi-Tago, Megumi, Tsukada, Masaki, Watanabe, Toshiro, Mameda, Yuka, Tago, Kenji, Ohe, Tomoyuki, Nakamura, Shigeo, Mashino, Tadahiko, Kasahara, Tadashi

INTERNATIONAL IMMUNOPHARMACOLOGY 20 ( 1 ) 258 - 263 2014.05

Research paper (scientific journal), ISSN 1567-5769

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Antioxidant activities of 5-hydroxyoxindole and its 3-hydroxy-3-phenacyl derivatives: The suppression of lipid peroxidation and intracellular oxidative stress.

Yasuda D, Takahashi K, Ohe T, Nakamura S, Mashino T.

Bioorg Med Chem 21 7709-7714 2013.12

Research paper (scientific journal), Joint Work, Accepted

Anti-influenza activity of c60 fullerene derivatives.

Shoji M, Takahashi E, Hatakeyama D, Iwai Y, Morita Y, Shirayama R, Echigo N, Kido H, Nakamura S, Mashino T, Okutani T, Kuzuhara T.

PLoS One 8 1-10 2013.06

Research paper (scientific journal), Joint Work, Accepted

Synthesis, radical scavenging activity and structure-activity relationship of uric acid analogs

Yasuda Daisuke, Takahashi Kyoko, Kakinoki Tomohiro, Tanaka Yoko, Ohe Tomoyuki, Nakamura Shigeo, Mashino Tadahiko

MedChemComm 4 ( 3 ) 527 - 529 2013.03

Research paper (scientific journal), ISSN 2040-2503

Uric acid (UA) is known to play an important role as an endogenous antioxidant. However, its insolubility in the serum is a risk for hyperuricemia. We assume that UA is an equivalent to hydroquinone or p-aminophenol, which can be oxidized to quinone/quinoimine and thus acts as a radical scavenger. Based on this hypothesis, a series of UA analogs was designed and synthesized. In the chemical radical scavenging assay, active compounds were considered as hydroquinone or p-aminophenol equivalents. A highly functionalized UA structure is not essential to have radical scavenging activity. Potent active 5-hydroxyindolinones (1a, 2a, and 3a) showed sufficient activity with high solubility and low cytotoxicity. © 2013 The Royal Society of Chemistry.

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Fullerene derivative prevents cellular transformation induced by JAK2 V617F mutant through inhibiting c-Jun N-terminal kinase pathway

Funakoshi-Tago Megumi, Nagata Tatsuaki, Tago Kenji, Tsukada Masaki, Tanaka Kazuyuki, Nakamura Shigeo, Mashino Tadahiko, Kasahara Tadashi

Cellular Signalling 24 ( 11 ) 2024 - 2034 2012.11

Research paper (scientific journal), ISSN 0898-6568

The constitutively activated mutation (V617F) of tyrosine kinase Janus kinase 2 (JAK2) is found in the majority of patients with myeloproliferative neoplasms (MPNs). The development of a novel chemical compound to suppress JAK2 V617F mutant-induced onset of MPNs and clarification of the signaling cascade downstream of JAK2 V617F mutant will provide clues to treat MPNs. Here we found that a water-soluble pyrrolidinium fullerene derivative, C₆₀-bis (N, N-dimethylpyrrolidinium iodide), markedly induced apoptosis of JAK2 V617F mutant-induced transformed cells through a novel mechanism, inhibiting c-Jun N-terminal kinase (JNK) activation pathway but not generation of reactive oxygen species (ROS). Pyrrolidinium fullerene derivative significantly reduced the protein expression level of apoptosis signal-regulating kinase 1 (ASK1), one of the mitogen-activated protein kinase kinase kinases (MAPKKK), resulting in the inhibition of upstream molecules of JNK, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7). Strikingly, the knockdown of ASK1 enhanced the sensitivity to pyrrolidinium fullerene derivative-induced apoptosis, and the treatment with a JNK inhibitor, SP600125, also induced apoptosis of the transformed cells by JAK2 V617F mutant. Furthermore, administration of both SP600125 and pyrrolidinium fullerene derivative markedly inhibited JAK2 V617F mutant-induced tumorigenesis in nude mice. Taking these findings together, JAK2 V617F mutant-induced JNK signaling pathway is an attractive target for MPN therapy, and pyrrolidinium fullerene derivative is now considered a candidate potent drug for MPNs. © 2012 Elsevier Inc.

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Water-soluble fullerene derivatives for drug discovery

Shigeo Nakamura; Tadahiko Mashino

Journal of Nippon Medical School 79 ( 4 ) 248 - 254 2012.08

Research paper (scientific journal)

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Impairment of heme biosynthesis induces short circadian period in body temperature rhythms in mice

Reiko Iwadate; Yoko Satoh; Yukino Watanabe; Hiroshi Kawai; Naomi Kudo; Yoichi Kawashima; Tadahiko Mashino; Atsushi Mitsumoto

American Journal of Physiology - Regulatory Integrative and Comparative Physiology 303 ( 1 ) R8 - R18 2012.07

Research paper (scientific journal)

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Isolation and structural identification of a direct-acting mutagen derived from N-nitroso-N-methylpentylamine and Fenton's reagent with copper ion

Miura Motofumi, Inami Keiko, Yoshida Masafumi, Yamaguchi Kentaro, Mashino Tadahiko, Mochizuki Masataka

Bioorganic and Medicinal Chemistry 19 ( 18 ) 5693 - 5697 2011.09

Research paper (scientific journal), ISSN 0968-0896

N-Nitrosodialkylamines show their mutagenicity by forming α-hydroxynitrosamines in the presence of rat S9 mix in the Ames assay. The hydroxyl radical derived from Fe ²⁺-H ₂O ₂ (Fenton's reagent) with Cu ²⁺ activates N-nitrosamines, with an alkyl chain longer than a propyl constituent, to a direct-acting mutagen. The reactivity of Fe ²⁺-Cu ²⁺-H ₂O ₂ on nitrosamines in relation to their metabolic activation is not fully characterized. Here, we report the identification of the direct-acting mutagen derived from N-nitroso-N-methylpentylamine (NMPe) in the presence of Fe ²⁺, Cu ²⁺, H ₂O ₂ and nitric oxide (NO), which is a product of nitrosamine metabolism. A dichloromethane extract of the NMPe reaction mixtures was fractionated by silica gel column chromatography several times and by a preparative high performance liquid chromatography (HPLC); we obtained white crystals as a product. The direct-acting mutagen that was isolated was provisionally identified as 5-ethyl-5-nitro-1-pyrazoline 1-oxide by ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy and X-ray crystallography. To confirm the structure of the mutagen, the authentic compound was synthesized from 2-nitrobutene and diazomethane, followed by N-oxidation with m-chloroperoxybenzoic acid. The ¹H NMR spectral data from the direct-acting mutagen that was synthesized was identical to the data from the isolated mutagen. Furthermore, the authentic 5-ethyl-5-nitro-1-pyrazoline 1-oxide was mutagenic in Salmonella typhimurium TA1535. The results showed that 5-ethyl-5-nitro-1-pyrazoline 1-oxide was a direct-acting mutagen derived from the reaction of NMPe and Fe ²⁺-Cu ²⁺-H ₂O ₂-NO. © 2011 Elsevier Ltd. All rights reserved.

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Anti-inflammatory activity of structurally related flavonoids, Apigenin, Luteolin and Fisetin.

Funakoshi-Tago M*, Nakamura K, Tago K, Mashino T, Kasahara T.

Int Immunopharmacol 11(9) 1150-1159 2011.09

Research paper (scientific journal), Joint Work, Accepted

Ipso Substitution of bisphenol A catalyzed by microsomal cytochrome P450 and Enhancement of estrogenic activity.

Nakamura S, Tezuka Y, Ushiyama A, Kawashima C, Kitagawara Yumina Takahashi K, Ohto S, Mashino T.

Toxicology Letters 203 92-95 2011.05

Research paper (scientific journal), Joint Work, Accepted

The fixed structure of Licochalcone A by α, β-unsaturated ketone is necessary for anti-inflammatory activity through the inhibition of NF-κB activation

Funakoshi-Tago Megumi, Nakamura Kei, Tsuruya Rina, Hatanaka Masashi, Mashino Tadahiko, Sonoda Yoshiko, Kasahara Tadashi

International Immunopharmacology 10 ( 5 ) 562 - 571 2010.05

Research paper (scientific journal), ISSN 1567-5769

Glycyrrhiza inflata has been used as a traditional medicine with anti-inflammatory activity. Previously, we reported that a major component, Licochalcone A, potently inhibited TNFα-induced NF-κB activation by inhibiting IKKβ activation. In this study, we investigated whether the fixed structure of Licochalcone A by α, β-unsaturated ketone is required for its inhibitory effect of NF-κB activation. Interestingly, reduced Licochalcone A, which lacks a double bond, failed to inhibit TNFα-induced NF-κB activation. Whereas Licochalcone A potently inhibited TNFα-induced IKK activation, IκBα degradation, nuclear localization of NF-κB and its DNA binding activity, no inhibitory effect was observed by reduced Licochalcone A. In addition, TNFα-induced expression of inflammatory cytokines, CCL2/MCP-1 and CXCL1/KC, was clearly inhibited by Licochalcone A but not reduced Licochalcone A. As a result, culture media pretreated with Licochalcone A but not reduced Licochalcone A following TNFα stimulation significantly inhibited the chemotactic activity of neutrophils. Furthermore, acute carrageenan-induced paw edema in mice was markedly inhibited by administration of Licochalcone A but not reduced Licochalcone A. Taken together, it is suggested that Licochalcone A is a promising anti-inflammatory drug in vivo and its fixed structure is critical for anti-inflammatory activity. © 2010 Elsevier B.V. All rights reserved.

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Biological safety of water-soluble fullerenes evaluated using tests for genotoxicity, phototoxicity, and pro-oxidant activity

Aoshima Hisae, Yamana Shuichi, Nakamura Shigeo, Mashino Tadahiko

Journal of Toxicological Sciences 35 ( 3 ) 401 - 409 2010

Research paper (scientific journal), ISSN 0388-1350

We evaluated the safety of water-soluble polymer-enwrapped fullerenes (PVP/fullerenes) as antioxidants in cosmetic and pharmaceutical preparations by studying the genotoxicity, phototoxicity, and pro-oxidant effects of these fullerenes. These materials were not mutagenic to any of the tested bacterial strains and did not induce chromosomal aberrations in cultured mammalian cells. The PVP/fullerenes did not exhibit cytotoxicity under ultraviolet or sham irradiation in the alternative phototoxicity test. Moreover, they did not show any pro-oxidant effect in the presence of Fe2+ or Cu2+. Thus, we concluded that PVP/fullerenes are safe for use in cosmetic and pharmaceutical applications. This is the first study in which toxicity tests were performed on PVP/fullerenes.

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Pyrrolidinium-type fullerene derivative-induced apoptosis by the generation of reactive oxygen species in HL-60 cells.

Nishizawa C, Hashimoto N, Yokoo S, Funakoshi-Tago M, Kasahara T, Takahashi K, Nakamura S, Mashino T*.

Free Radical Res 43(12) 1240-1247 2009.12

Research paper (scientific journal), Joint Work, Accepted

Licochalcone A potently inhibits tumor necrosis factor alpha-induced nuclear factor-kappaB activation through the direct inhibition of IkappaB kinase complex activation.

Funakoshi-Tago M*, Tanabe S, Tago K, Itoh H, Mashino T, Sonoda Y, Kasahara T.

Molecular Pharmacology 76(4) 745-753 2009.10

Research paper (scientific journal), Joint Work, Accepted

Licochalcone A significantly suppresses LPS signaling pathway through the inhibition of NF-κB p65 phosphorylation at serine 276

Furusawa Jun ichi, Funakoshi-Tago Megumi, Tago Kenji, Mashino Tadahiko, Inoue Hideo, Sonoda Yoshiko, Kasahara Tadashi

Cellular Signalling 21 ( 5 ) 778 - 785 2009.05

Research paper (scientific journal), ISSN 0898-6568

Licorice root, Glycyrrhiza inflata, has been used as a traditional medicine for the treatment of bronchial asthma and inflammation; however, the mechanism of its anti-inflammatory activity has not been clarified. Here, we investigated the effect of Licochalcone A, a major component of G. inflata, on the LPS signaling pathway. We found that Licochalcone A remarkably inhibited LPS-induced NO production, and TNFα expression and MCP-1 expression in both RAW264.7 cells and primary macrophages. Furthermore, when injected with Licochalcone A prior to injection of LPS, the serum level of TNFα and MCP-1 in C57BL/6 mice was clearly decreased, indicating that Licochalcone A has a potent anti-inflammatory effect both in vitro and in vivo. Strikingly, Licochalcone A significantly inhibited LPS-induced NF-κB transcriptional activation; however, it had no effect on not only the phosphorylation and degradation of IκBα but also nuclear translocation and DNA binding activity of NF-κB p65. Interestingly, Licochalcone A markedly inhibited the phosphorylation of p65 at serine 276. As a result, it reduced NF-κB transactivation by preventing the interaction of p65 with p300. Taken together, Licochalcone A might contribute to the potent anti-inflammatory effect of G. inflata through the unique mechanism of NF-κB inhibition. © 2009 Elsevier Inc. All rights reserved.

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Glycyrrhiza inflata-derived chalcones, Licochalcone A, Licochalcone B and Licochalcone D, inhibit phosphorylation of NF-κB p65 in LPS signaling pathway

Furusawa Jun ichi, Funakoshi-Tago Megumi, Mashino Tadahiko, Tago Kenji, Inoue Hideo, Sonoda Yoshiko, Kasahara Tadashi

International Immunopharmacology 9 ( 4 ) 499 - 507 2009.04

Research paper (scientific journal), ISSN 1567-5769

Licorice root has been used as a traditional medicine for the treatment of gastric ulcer, bronchial asthma and inflammation. Licochalcone A is a major component of Xinjiang licorice, Glycyrrhiza inflata. Previously we showed that Licochalcone A significantly inhibited LPS-induced NF-κB transcriptional activation by abrogating the phosphorylation of NF-κB p65 at serine 276. Glycyrrhiza inflata contains not only Licochalcone A but also Licochalcone B, Licochalcone C, Licochalcone D, Echinatin and Isoliquiritigenin, harboring the common structure of chalcones. No chalcones had any effect on LPS-induced IκB degradation, nuclear translocation and DNA binding activity of NF-κB p65; however, we observed that Licochalcone B and Licochalcone D significantly inhibited LPS-induced phosphorylation at serine 276 and transcriptional activation of NF-κB, the same as Licochalcone A. Interestingly, we also found that Licochalcone A, Licochalcone B and Licochalcone D effectively inhibited LPS-induced activation of PKA, which is required for the phosphorylation of NF-κB p65 at serine 276. Consequently, Licochalcone B and Licochalcone D significantly reduced the LPS-induced production of NO, TNFα and MCP-1. On the other hand, Licochalcone C, Echinatin and Isoliquitigenin failed to inhibit LPS-induced NF-κB activation. These findings suggest that the anti-inflammatory effect of Glycyrrhiza inflata is ascribable to the potent inhibition of NF-κB by Licochalcone A, Licochalcone B and Licochalcone D. © 2009 Elsevier B.V. All rights reserved.

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Glycyrrhiza inflata-derived chalcones, Licochalcone A, Licochalcone B and Licochalcone D, inhibit phosphorylation of NF-kappaB p65 in LPS signaling pathway.

Furusawa J, Funakoshi-Tago M*, Mashino T, Tago K, Inoue H, Sonoda Y, Kasahara T.

International Immunopharmacology 9(4) 499-507 2009.04

Research paper (scientific journal), Joint Work, Accepted

Fullerene nanowhiskers and related fullerene nanomaterials.

Miyazawa K*, Kato R, Saito K, Kizuka T, Mashino T, Nakamura S.

J Phys Conf Series 159 012007 2009.04

Research paper (scientific journal), Joint Work, Accepted

Biological activities of water-soluble fullerene derivatives

S. Nakamura; T. Mashino

Journal of Physics: Conference Series 159 2009.01

Research paper (scientific journal)

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