Shin-ichi Tsunoda

National Institute of Biomedical Innovation, Ibaragi, Ōsaka, Japan

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Publications (167)587.41 Total impact

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    ABSTRACT: Hypoxia-adapted cancer cells in tumors contribute to the pathological progression of cancer. Cancer research has therefore focused on the identification of molecules responsible for hypoxia adaptation in cancer cells, as well as the development of new compounds with action against hypoxia-adapted cancer cells. The marine natural product furospinosulin-1 (1) displays hypoxia-selective growth inhibition against cultured cancer cells, and showed in vivo anti-tumor effects, whereas its precise in vivo mode of action and molecular targets remain unclear. In this study, we found that 1 is selectively effective against hypoxic regions of tumors, and also showed that it directly binds to the transcriptional regulators p54nrb and LEDGF/p75, which have not been previously identified as mediators of hypoxia adaptation in cancer cells.
    ChemBioChem 11/2015; DOI:10.1002/cbic.201500519 · 3.09 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):4377-4377. DOI:10.1158/1538-7445.AM2015-4377 · 9.33 Impact Factor
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    ABSTRACT: The skin is a key route of human exposure to nanomaterials, which typically occurs simultaneously with exposure to other chemical and environmental allergen. However, little is known about the hazards of nanomaterial exposure via the skin, particularly when accompanied by exposure to other substances. Repeated topical treatment of both ears and the shaved upper back of NC/Nga mice, which are models for human atopic dermatitis (AD), with a mixture of mite extract and silica nanoparticles induced AD-like skin lesions. Measurements of ear thickness and histologic analyses revealed that cutaneous exposure to silica nanoparticles did not aggravate AD-like skin lesions. Instead, concurrent cutaneous exposure to mite allergens and silica nanoparticles resulted in the low-level production of allergen-specific IgGs, including both the Th2-related IgG1 and Th1-related IgG2a subtypes, with few changes in allergen-specific IgE concentrations and in Th1 and Th2 immune responses. In addition, these changes in immune responses increased the sensitivity to anaphylaxis. Low-level IgG production was induced when the mice were exposed to allergen-silica nanoparticle agglomerates but not when the mice exposed to nanoparticles applied separately from the allergen or to well-dispersed nanoparticles. Our data suggest that silica nanoparticles themselves do not directly affect the allergen-specific immune response after concurrent topical application of nanoparticles and allergen. However, when present in allergen-adsorbed agglomerates, silica nanoparticles led to a low IgG/IgE ratio, a key risk factor of human atopic allergies. We suggest that minimizing interactions between nanomaterials and allergens will increase the safety of nanomaterials applied to skin.
    Particle and Fibre Toxicology 06/2015; 12(1):16. DOI:10.1186/s12989-015-0095-3 · 7.11 Impact Factor
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    ABSTRACT: Here, we describe the enzymatic construction of a new larger base pair formed between adenine (A) and a 4-hydroxy-2-mercaptobenzimidazole (SB) nucleobase analogue. We investigated the enzymatic incorporation of 2'-deoxynucleoside-5'-triphosphate bearing a SB nucleobase analogue (dSBTP) into oligonucleotides (ONs) by DNA polymerases. dSBTP could be effectively incorporated at the site opposite a dA in a DNA template by several B family DNA polymerases. These findings provide new insights into various aspects of biotechnology, including the design of non-natural base pairs. Copyright © 2015. Published by Elsevier Ltd.
    Bioorganic & medicinal chemistry letters 05/2015; 25(15). DOI:10.1016/j.bmcl.2015.05.075 · 2.42 Impact Factor
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    ABSTRACT: Recently, nanomaterial-mediated biological effects have been shown to be governed by the interaction of nanomaterials with some kinds of proteins in biological fluids, and the physical characteristics of the nanomaterials determine the extent and type of their interactions with proteins. Here, we examined the relationships between the surface properties of amorphous silica nanoparticles with diameters of 70 nm (nSP70), their interactions with some proteins in biological fluids, and their toxicity in mice after intravenous administration. The surface modification of nSP70 with amino groups (nSP70-N) prevented acute lethality and abnormal activation of the coagulation cascade found in the nSP70-treated group of mice. Since our previous study showed that coagulation factor XII played a role in the nSP70-mediated abnormal activation of the coagulation cascade, we examined the interaction of nSP70 and nSP70-N with coagulation factor XII. Coagulation factor XII bonded to the surface of nSP70 to a greater extent than that observed for nSP70-N, and consequently more activation of coagulation factor XII was observed for nSP70 than for nSP70-N. Collectively, our results suggest that controlling the interaction of nSP70 with blood coagulation factor XII by modifying the surface properties would help to inhibit the nSP70-mediated abnormal activation of the blood coagulation cascade.
    Nanotechnology 05/2015; 26(24):245101. DOI:10.1088/0957-4484/26/24/245101 · 3.82 Impact Factor
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    ABSTRACT: Metastasis is an important prognosis factor in lung cancer, therefore, it is imperative to identify target molecules and elucidate molecular mechanism of metastasis for developing new therapeutics and diagnosis methods. We searched for metastasis-related proteins by utilizing a novel antibody proteome technology developed in our laboratory that facilitated efficient screening of useful target proteins. Two-dimensional differential in-gel electrophoresis (2D-DIGE) analysis identified sixteen proteins, which were highly expressed in metastatic lung cancer cells, as protein candidates. Monoclonal single-chain variable fragments (scFvs) binding to candidates were isolated from a scFv-displaying phage library by affinity selection. Tissue microarray analysis of scFvs binding to candidates revealed that oxysterol binding protein-like 5 (OSBPL5) and calumenin (CALU) were expressed at a significantly higher levels in the lung tissues of metastasis-positive cases than that in the metastasis-negative cases (OSBPL5; p=0.0156, CALU; p=0.0055). Furthermore, 80% of OSBPL5 and CALU double-positive cases were positive for lymph node metastasis. Consistent with these observations, overexpression of OSBPL5 and CALU promoted invasiveness of lung cancer cells. Conversely, knockdown of these proteins using respective siRNAs reversed the invasiveness of the lung cancer cells. Moreover, these proteins were expressed in lung tumor tissues, but not in normal lung tissues. In conclusion, OSBPL5 and CALU are related to metastatic potential of lung cancer cells, and they could be useful targets for cancer diagnosis and also for development of drugs against metastasis.
    International Journal of Oncology 05/2015; 47(1). DOI:10.3892/ijo.2015.3000 · 3.03 Impact Factor
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    Shohei Mori · Kunihiko Morihiro · Yuuya Kasahara · Shin-Ichi Tsunoda · Satoshi Obika ·
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    ABSTRACT: Nucleic acids that change their properties upon photo-irradiation could be powerful materials for molecular sensing with high spatiotemporal resolution. Recently, we reported a photo-isomeric nucleoside bearing azobenzene at the C5 position of 2'-deoxyuridine (dU Az), whose hybridization ability could be reversibly controlled by the appropriate wavelength of light. In this paper, we synthesized and evaluated dU Az analogues that have various para-substitutions on the azobenzene moiety. Spectroscopic measurements and HPLC analyses revealed that the para-substitutions of the azobenzene moiety strongly affect the photo-isomerization ability and thermal stability of the cis-form. The results suggest that proper substitution of the azobenzene moiety can improve the properties of dU Az as a light-responsive nucleic acid probe.
    03/2015; 2015(3):36-54. DOI:10.3390/chemosensors3020036
  • Kunihiko Morihiro · Osamu Hasegawa · Shohei Mori · Shin-ichi Tsunoda · Satoshi Obika ·
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    ABSTRACT: Oligonucleotides (ONs) modified with locked nucleic acid (LNA) are widely used in the fields of therapeutics, diagnosis, and nanotechnology. There has been significant effort towards developing LNA analogues bearing modified bridges to improve hybridization ability, nuclease resistance, and pharmacokinetic profiles. Moreover, nucleobase modifications of LNA are useful strategies for the functionalization of ONs. Modifications of the C5-position of pyrimidine nucleobases are particularly interesting because they enable predictable positioning of functional groups in the major groove of the duplex. Here we report the synthesis of C5-azobenzene-functionalized LNA uridine (LNA-UAz) and properties of LNA-UAz-modified ONs, including isomerization property, hybridization ability, and enzyme stability. LNA-UAz in ON is photo-isomerized effectively and reversibly by irradiation at 365 nm (trans to cis) and 450 nm (cis to trans). LNA-UAz-modified ONs show RNA-selective hybridization ability despite the large hydrophobic azobenzene moiety extending into the major groove of the duplex. The enzymatic stability of LNA-UAz-modified ONs is higher than that of natural and LNA-modified ONs with or without photo-irradiation. Our results indicate that LNA-UAz holds promise for RNA targeting and photo-switchable technologies.
    Organic & Biomolecular Chemistry 03/2015; 13(18). DOI:10.1039/C5OB00477B · 3.56 Impact Factor
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    ABSTRACT: Tumor necrosis factor (TNF) is an important mediator that triggers onset of autoimmune diseases and exerts its biological effects by interacting through two types of receptors, TNFR1 and TNFR2. The TNFR2 signaling has significant potential to exert pro-survival and protective roles in several disorders. Unlike TNFR1 signaling, however, the mechanism of TNFR2 signal transduction is poorly understood, and few of its adapter molecules are known. The present study utilized a proteomics approach to search for adapter molecules in the TNFR2 signaling complex and identified aminopeptidase P3 (APP3) to be a key molecule. One of its two isoforms, mitochondrial APP3 (APP3m) but not cytosolic APP3 (APP3c), was recruited to TNFR2 and shown to regulate TNF/TNFR2-dependent JNK phosphorylation. Furthermore, APP3m was released from mitochondria upon TNF stimulation in the absence of mitochondrial outer membrane permeabilization (MOMP). The observation of increased cell death by down-regulation of APP3m also suggested that APP3m exerts an anti-apoptotic function. These findings reveal that APP3m is a new member of the TNF/TNFR2 signaling complex and characterize an APP3-mediated TNFR2 signal transduction mechanism that induces JNK activation.
    Journal of Cell Science 01/2015; 128(4). DOI:10.1242/jcs.149385 · 5.43 Impact Factor
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    ABSTRACT: The EPH receptor A10 (EphA10) is up-regulated in breast cancer but is not normally expressed in healthy tissue, thus it has been suggested that EphA10 may be a useful target for cancer therapy. This study reports a diabody, an antibody derivative binding two different target molecules, EphA10 expressed in tumor cells and CD3 expressed in T cells, which showed T cell dependent-cytotoxicity. The diabody, which has His-tagged and FLAG-tagged chains, was expressed in E. coli and purified in both heterodimer (Db-1) and homodimer (Db-2) formulations by liquid chromatography. Flow cytometry analysis using EphA10-expressing cells showed that binding activity of heterodimers was stronger than that of homodimers. Addition of diabodies to PBMC cultures resulted in T-cell mediated redirected lysis, and the bioactivity was consistent with the stronger binding activity of heterodimeric diabody formulations. Our results indicate that diabodies recognizing both EphA10 and CD3 could have a range of potential applications in cancer therapy, such as breast cancers that express the EPH receptor A10, especially triple negative breast cancer. Copyright © 2014 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 12/2014; 456(4). DOI:10.1016/j.bbrc.2014.12.030 · 2.30 Impact Factor
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    ABSTRACT: Because of their useful chemical and physical properties, nanomaterials are widely used around the world - for example, as additives in food and medicines - and such uses are expected to become more prevalent in the future. Therefore, collecting information about the effects of nanomaterials on metabolic enzymes is important. Here, we examined the effects of amorphous silica particles with various sizes and surface modifications on cytochrome P450 3A4 (CYP3A4) activity by means of two different in vitro assays. Silica nanoparticles with diameters of 30 and 70 nm (nSP30 and nSP70, respectively) tended to inhibit CYP3A4 activity in human liver microsomes (HLMs), but the inhibitory activity of both types of nanoparticles was decreased by carboxyl modification. In contrast, amine-modified nSP70 activated CYP3A4 activity. In HepG2 cells, nSP30 inhibited CYP3A4 activity more strongly than the larger silica particles did. Taken together, these results suggest that the size and surface characteristics of the silica particles determined their effects on CYP3A4 activity and that it may be possible to develop silica particles that do not have undesirable effects on metabolic enzymes by altering their size and surface characteristics.
    Nanoscale Research Letters 12/2014; 9(1):651. DOI:10.1186/1556-276X-9-651 · 2.78 Impact Factor
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    ABSTRACT: Nanomaterials are used for various biomedical applications because they are often more effective than conventional materials. Recently, however, it has become clear that the protein corona that forms on the surface of nanomaterials when they make contact with biological fluids, such as blood, influences the pharmacokinetics and biological responses induced by the nanomaterials. Therefore, when evaluating nanomaterial safety and efficacy, it is important to analyze the interaction between nanomaterials and proteins in biological fluids and to evaluate the effects of the protein corona. Here, we evaluated the interaction of silica nanoparticles, a commonly used nanomaterial, with the human blood proteins albumin, transferrin, fibrinogen, and IgG. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis showed that the amount of albumin, transferrin, and IgG binding to the silica particles increased as the particle size decreased under conditions where the silica particle mass remained the same. However, under conditions in which the specific surface area remained constant, there were no differences in the binding of human plasma proteins to the silica particles tested, suggesting that the binding of silica particles with human plasma proteins is dependent on the specific surface area of the silica particles. Furthermore, the amount of albumin, transferrin, and IgG binding to silica nanoparticles with a diameter of 70 nm (nSP70) and a functional amino group was lower than that with unmodified nSP70, although there was no difference in the binding between nSP70 with the surface modification of a carboxyl functional group and nSP70. These results suggest that the characteristics of nanomaterials are important for binding with human blood proteins; this information may contribute to the development of safe and effective nanomaterials.
    Nanoscale Research Letters 12/2014; 9(1):668. DOI:10.1186/1556-276X-9-668 · 2.78 Impact Factor
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    ABSTRACT: Although amorphous silica nanoparticles are widely used in the production of food products (e.g., as anticaking agents), there is little information available about their absorption and biological effects after oral exposure. Here, we examined the in vitro intestinal absorption and in vivo biological effects in mice of orally administered amorphous silica particles with diameters of 70, 300, and 1,000 nm (nSP70, mSP300, and mSP1000, respectively) and of nSP70 that had been surface-modified with carboxyl or amine groups (nSP70-C and nSP70-N, respectively). Analysis of intestinal absorption by means of the everted gut sac method combined with an inductively coupled plasma optical emission spectrometer showed that the intestinal absorption of nSP70-C was significantly greater than that of nSP70. The absorption of nSP70-N tended to be greater than that of nSP70; however, the results were not statistically significant. Our results indicate that silica nanoparticles can be absorbed through the intestine and that particle diameter and surface properties are major determinants of the degree of absorption. We also examined the biological effects of the silica particles after 28-day oral exposure in mice. Hematological, histopathological, and biochemical analyses showed no significant differences between control mice and mice treated with the silica particles, suggesting that the silica nanoparticles evaluated in this study are safe for use in food production.
    Nanoscale Research Letters 09/2014; 9(1):532. DOI:10.1186/1556-276X-9-532 · 2.78 Impact Factor

  • Toxicology Letters 09/2014; 229:S186-S187. DOI:10.1016/j.toxlet.2014.06.634 · 3.26 Impact Factor

  • Toxicology Letters 09/2014; 229:S193. DOI:10.1016/j.toxlet.2014.06.655 · 3.26 Impact Factor
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    ABSTRACT: Ephrin receptor A10 (EphA10) is a relatively uncharacterized protein which is expressed in many breast cancers but not expressed in normal breast tissues. Here, we examined the potential of EphA10 as a drug target in breast cancer. Immunohistochemical staining of clinical tissue sections revealed that EphA10 was expressed in various breast cancer subtypes, including triple negative breast cancers (TNBCs), with no expression observed in normal tissues apart from testis. Ligand-dependent proliferation was observed in EphA10-transfected MDA-MB-435 cells (MDA-MB-435(EphA10)) and native TNBC cells (MDA-MB-436). However, this phenomenon was not observed in parental MDA-MB-435 cells which express a low level of EphA10. Finally, tumor growth was significantly suppressed by administration of an anti-EphA10 monoclonal antibody in a xenograft mouse model. These results suggest that inhibition of EphA10 signaling may be a novel therapeutic option for management of breast cancer, including TNBCs which are currently not treated with molecularly targeted agents.
    Journal of Controlled Release 06/2014; 189. DOI:10.1016/j.jconrel.2014.06.010 · 7.71 Impact Factor
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    ABSTRACT: We recently identified Eph receptor A10 (EphA10) as a novel breast cancer-specific protein. Moreover, we also showed that an in-house developed anti-EphA10 monoclonal antibody (mAb) significantly inhibited proliferation of breast cancer cells, suggesting EphA10 as a promising target for breast cancer therapy. However, the only other known report for EphA10 was its expression in the testis at the mRNA level. Therefore, the potency of EphA10 as a drug target against cancers other than the breast is not known. The expression of EphA10 in a wide variety of cancer cells was studied and the potential of EphA10 as a drug target was evaluated. Screening of EphA10 mRNA expression showed that EphA10 was overexpressed in breast cancer cell lines as well as in prostate and colon cancer cell lines. Thus, we focused on prostate cancers in which EphA10 expression was equivalent to that in breast cancers. As a result, EphA10 expression was clearly shown in clinical prostate tumor tissues as well as in cell lines at the mRNA and protein levels. In order to evaluate the potential of EphA10 as a drug target, we analyzed complement-dependent cytotoxicity effects of anti-EphA10 mAb and found that significant cytotoxicity was mediated by the expression of EphA10. Therefore, the idea was conceived that the overexpression of EphA10 in prostate cancers might have a potential as a target for prostate cancer therapy, and formed the basis for the studies reported here.
    Biochemical and Biophysical Research Communications 06/2014; 450(1). DOI:10.1016/j.bbrc.2014.06.007 · 2.30 Impact Factor
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    ABSTRACT: Asian dust is a springtime meteorological phenomenon that originates in the deserts of China and Mongolia. The dust is carried by prevailing winds across East Asia where it causes serious health problems. Most of the information available on the impact of Asian dust on human health is based on epidemiological investigations, so from a biological standpoint little is known of its effects. To clarify the effects of Asian dust on human health, it is essential to assess inflammatory responses to the dust and to evaluate the involvement of these responses in the pathogenesis or aggravation of disease. Here, we investigated the induction of inflammatory responses by Asian dust particles in macrophages. Treatment with Asian dust particles induced greater production of inflammatory cytokines interleukin-6 and tumor necrosis factor- α (TNF- α ) compared with treatment with soil dust. Furthermore, a soil dust sample containing only particles ≤10 μ m in diameter provoked a greater inflammatory response than soil dust samples containing particles >10 μ m. In addition, Asian dust particles-induced TNF- α production was dependent on endocytosis, the production of reactive oxygen species, and the activation of nuclear factor- κ B and mitogen-activated protein kinases. Together, these results suggest that Asian dust particles induce inflammatory disease through the activation of macrophages.
    Research Journal of Immunology 05/2014; 2014(4464):856154. DOI:10.1155/2014/856154
  • Yasuo Yoshioka · Kazuma Higashisaka · Shin-ichi Tsunoda · Yasuo Tsutsumi ·
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    ABSTRACT: Advances in nanotechnology have led to the recent development of many nanoparticles. With the growing commercialization of nanoparticles, opportunities for human exposure to nanoparticles will increase substantially. For the development of nanoparticles with efficacy and safety, a systematic and thorough analysis of the absorption, distribution, metabolism, and excretion (ADME) of nanoparticles is essential. In this chapter, we present the current understanding regarding the ADME profile of nanoparticles.
    Engineered Cell Manipulation for Biomedical Application, 01/2014: pages 259-271;

Publication Stats

2k Citations
587.41 Total Impact Points


  • 2006-2015
    • National Institute of Biomedical Innovation
      • Laboratory of Biopharmaceutical Research
      Ibaragi, Ōsaka, Japan
  • 1995-2015
    • Osaka University
      • • Laboratory of Toxicology and Safety Science
      • • Graduate School of Pharmaceutical Sciences
      • • Center for Advanced Medical Engineering and Informatics
      • • Department of Pharmaceutical Sciences
      • • Division of Molecular Pharmaceutical Science
      Suika, Ōsaka, Japan
  • 2011
    • Ankara University
      • Department of Medical Oncology
      Engüri, Ankara, Turkey
  • 2010
    • Teikyo University
      Edo, Tōkyō, Japan
  • 1997-2001
    • Osaka University of Pharmaceutical Sciences
      • Faculty of Pharmaceutical Sciences
      Ōsaka, Ōsaka, Japan
  • 1999
    • Kobe Gakuin University
      • Faculty of Pharmaceutical Sciences
      Kōbe, Hyōgo, Japan
    • Chugai pharmceutical