Hirofumi Tachibana

Kyushu University, Hukuoka, Fukuoka, Japan

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Publications (206)433.84 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: An epidemiological study showed that green tea consumption is associated with a reduced risk of hematopoietic malignancy. The major green tea polyphenol epigallocatechin‑3-O-gallate (EGCG) is reported to have anticancer effects. Chronic myeloid leukemia (CML) is a major hematopoietic malignancy characterized by expansion of myeloid cells. In the present study, we showed EGCG-induced acid sphingomyelinase (ASM) activation and lipid raft clustering in CML cells. The ASM inhibitor desipramine significantly reduced EGCG-induced cell death. Protein kinase Cδ is a well‑known kinase that plays an important role in ASM activation. We observed EGCG-induced phosphorylation of protein kinase Cδ at Ser664. Importantly, EGCG-induced ASM activation was significantly reduced by pretreatment of CML cells with the soluble guanylate cyclase inhibitor NS2028, suggesting that EGCG induced ASM activation through the cyclic guanosine monophosphate (cGMP)-dependent pathway. Indeed, pharmacological inhibition of a cGMP-negative regulator enhanced the anti-CML effect of EGCG. These results indicate that EGCG-induced cell death via the cGMP/ASM pathway in CML cells.
    Oncology Reports 06/2015; DOI:10.3892/or.2015.4086 · 2.19 Impact Factor
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    ABSTRACT: Green tea extract (GTE) induces apoptosis of cancer cells without adversely affecting normal cells. Several clinical trials reported that GTE was well tolerated and had potential anti-cancer efficacy. Epigallocatechin-3-O-gallate (EGCG) is the primary compound responsible for the anti-cancer effect of GTE; however, the effect of EGCG alone is limited. To identify GTE compounds capable of potentiating EGCG bioactivity, we performed metabolic profiling of 43 green tea cultivar panels by liquid chromatography-mass spectrometry (LC-MS). Here, we revealed the polyphenol eriodictyol significantly potentiated apoptosis induction by EGCG in vitro and in a mouse tumour model by amplifying EGCG-induced activation of the 67-kDa laminin receptor (67LR)/protein kinase B/endothelial nitric oxide synthase/protein kinase C delta/acid sphingomyelinase signalling pathway. Our results show that metabolic profiling is an effective chemical-mining approach for identifying botanical drugs with therapeutic potential against multiple myeloma. Metabolic profiling-based data mining could be an efficient strategy for screening additional bioactive compounds and identifying effective chemical combinations.
    Scientific Reports 03/2015; 5:9474. DOI:10.1038/srep09474 · 5.58 Impact Factor
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    ABSTRACT: 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose (PGG) is a gallotannin isolated from various plants. In a previous study, it was reported that PGG suppressed interleukin (IL)-4 induced signal pathway in B cell which is indispensable for immunoglobulin E (IgE) production. However, the suppressive effect of PGG on IgE production in allergen-sensitized mice remains unclear. Therefore, the aim of this study was to investigate the inhibitory effect of PGG on IgE production in ovalbumin (OVA)-sensitized mice. Mice orally administered PGG showed a decrease in total and OVA-specific IgE levels in serum. Oral administration of PGG strongly suppressed production of type 2 T helper (IL-4 and IL-13), type 1 T helper (IFN-γ), and pro-inflammatory cytokines (TNF-α and IL-6), but not anti-inflammatory cytokine (IL-10) from splenocytes of OVA-sensitized mice against OVA re-stimulation. A population of T regulatory (Treg) cells with immunosuppressive properties was increased in mesenteric lymph nodes and spleen of PGG-fed mice. PGG administration not only reduced expression levels of eotaxin, tissue inhibitors of metalloproteinases-1, and TNF-α, which assisted with IgE production, but also increased the expression of insulin-like growth factor binding protein-3 which inhibits IgE production. Additionally, PGG increased the levels of Treg cell-inducing factors such as IL-2, IL-10 and platelet factor-4 in serum. These data suggest that the inhibitory effect of PGG on IgE production could be partially caused by increasing a population of Treg cells in conjunction with Treg-inducing factors. Copyright © 2015. Published by Elsevier B.V.
    International Immunopharmacology 02/2015; 26(1). DOI:10.1016/j.intimp.2015.02.025 · 2.71 Impact Factor
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    ABSTRACT: The Ras/Raf/MEK/ERK pathway has been identified as a major, druggable regulator of melanoma. Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, resulting in constitutive melanoma hyperproliferation. A selective BRAF inhibitor showed remarkable clinical activity in patients with mutated-BRAF. Unfortunately, most patients acquire resistance to the BRAF inhibitor, highlighting the urgent need for new melanoma treatment strategies. Green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) inhibits cell proliferation independently of BRAF inhibitor sensitivity, suggesting that increased understanding of the anti-melanoma activity of EGCG may provide a novel therapeutic target. Here, by performing functional genetic screening, we identified protein phosphatase 2A (PP2A) as a critical factor in the suppression of melanoma cell proliferation. We demonstrated that tumor-overexpressed 67-kDa laminin receptor (67LR) activates PP2A through adenylate cyclase/cAMP pathway eliciting inhibitions of oncoproteins and activation of tumor suppressor Merlin. Activating 67LR/PP2A pathway leading to melanoma-specific mTOR inhibition shows strong synergy with the BRAF inhibitor PLX4720 in the drug-resistant melanoma. Moreover, SET, a potent inhibitor of PP2A, is overexpressed on malignant melanoma. Silencing of SET enhances 67LR/PP2A signaling. Collectively, activation of 67LR/PP2A signaling may thus be a novel rational strategy for melanoma-specific treatment.
  • Mika Takai, Yoshiyuki Miyazaki, Hirofumi Tachibana, Koji Yamada
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    ABSTRACT: In this study, we revealed that a Mekabu (Udaria pinnantifida) extract enhanced immunoglobulin (Ig) production of mouse spleen lymphocytes. Furthermore, it was suggested that water-soluble and high molecular weight ingredients in the Mekabu extract have significant enhancing effect on Ig production. Therefore, fucoidan was estimated as the active component.
    Bioscience Biotechnology and Biochemistry 10/2014; 78(10):1743-7. DOI:10.1080/09168451.2014.930323 · 1.21 Impact Factor
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    ABSTRACT: Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a powerful technique for visualizing the distribution of a wide range of biomolecules within tissue sections. However, methodology for visualizing a bioactive ellagitannin has not yet been established. Here, we present a novel in situ label-free MALDI-MSI technique for visualizing the distribution of strictinin, a bioactive ellagitannin found in green tea, within mammalian kidney after oral dosing. Among nine representative matrix candidates, we found that 1,5-diaminonaphthalene (1,5-DAN), harmane and ferulic acid showed higher sensitivity to strictinin spotted onto a MALDI sample plate. Of these, 1,5-DAN enables visualization of a two-dimensional image of strictinin directly spotted on mouse kidney sections with the highest sensitivity. Furthermore, 1,5-DAN-based MALDI-MSI could detect the unique distribution of orally dosed strictinin within kidney sections. This in situ label-free imaging technique will contribute to the localization analysis of strictinin and its biological mechanisms.
    Journal of Agricultural and Food Chemistry 09/2014; 62(38). DOI:10.1021/jf503143g · 3.11 Impact Factor
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    ABSTRACT: Keywords:chronic lymphocytic leukaemia;67-kDa laminin receptor;phosphodiesterase 5;protein kinase C delta;apoptosis
    British Journal of Haematology 09/2014; 168(4). DOI:10.1111/bjh.13135 · 4.96 Impact Factor
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    ABSTRACT: Strictinin has been shown to suppress interleukin (IL)-4-induced signal transducer and activator of transcription (STAT)-6 phosphorylation, which is a critical event for IgE class switching. However, it is unclear how strictinin inhibits STAT6 activation. Strictinin inhibited STAT6 phosphorylation by suppressing IL-4 receptor α (IL-4Rα) activation. Strictinin was bound to the cell surface and only localized in non-lipid raft fraction of the cells where IL-4Rα was also located. In addition, strictinin directly bound to IL-4Rα and inhibited binding of IL-4 to IL-4Rα. These results suggest that IL-4Rα locating in non-lipid raft region is a target molecule for stirctinin in inhibiting STAT6 activation.
    Biochemical and Biophysical Research Communications 06/2014; 450(1). DOI:10.1016/j.bbrc.2014.06.069 · 2.28 Impact Factor
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    ABSTRACT: Interleukin (IL)-4 is a critical stimulator that induces ɛ germline transcripts (ɛGT) for switch recombination to initiate immunoglobulin (Ig) E and is important in allergic disease pathogenesis. We found pentagalloylglucose (PGG) inhibited IL-4-induced ɛGT expression. PGG exerted its inhibitory function by suppressing IL-4-induced activation of IL-4Rα, JAK3 and STAT6. Furthermore, tannic acid, a higher galloylated PGG, attenuated ovalbumin-induced IgE production in vivo by inhibiting IL-4-induced ɛGT expression and the IL-4 signaling pathway. In conclusion, our results suggest that tannic acid may attenuate allergic diseases by suppressing IgE production by inhibiting IL-4-induced signaling.
    FEBS Open Bio 12/2013; 3:341-5. DOI:10.1016/j.fob.2013.07.008 · 1.52 Impact Factor
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    ABSTRACT: We examined the anti-allergic effect of strawberry extract on human peripheral blood mononuclear cells (PBMCs) and atopic dermatitis model mice NC/NgaTndCrlj. The addition of strawberry extract suppressed total IgE production in the cedar pollen antigen Cry j 1-stimulated PBMCs. Flow cytometric analysis showed that strawberry extract decreased the rate of CD3(+)CD4(+) helper T cells by 17.3% and increased the rate of CD3(+)CD8(+) cytotoxic T cells by 19.7% in PBMCs. Moreover, the extract inhibited the expression level of GATA3 that is the master regulator of type 2 helper T cells (Th2) in human primary pan T cells isolated from PBMCs. Oral administration of strawberry extract lowered dermatitis scores and serum IgE levels in mice. In addition, it also decreased the GATA3 expression level in mouse blood cells. These results revealed that strawberry extract suppressed the severity of atopic dermatitis through the down-regulation of serum IgE by inhibition of Th2 differentiation.
    Journal of Functional Foods 10/2013; 5(4):1947-1955. DOI:10.1016/j.jff.2013.09.016 · 4.48 Impact Factor
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    ABSTRACT: Although understanding the high-resolution spatial distribution of bioactive small molecules is indispensable for elucidating their biological or pharmacological effects, there has been no analytical technique that can easily detect the naïve molecular localization in mammalian tissues. We herein present a novel in situ label-free imaging technique for visualizing bioactive small molecules, using a polyphenol. We established a 1,5-diaminonaphthalene (1,5-DAN)-based matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) technique for visualizing epigallocatechin-3-O-gallate (EGCG), the major bioactive green tea polyphenol, within mammalian tissue micro-regions after oral dosing. Furthermore, the combination of this label-free MALDI-MSI method and a standard-independent metabolite identification method, an isotopic fine structure analysis using ultrahigh-resolution mass spectrometer, allows for the visualization of spatially-resolved biotransformation based on simultaneous mapping of EGCG and its phase II metabolites. Although this approach has limitations of the detection sensitivity, it will overcome the drawbacks associated with conventional molecular imaging techniques, and could contribute to biological discovery.
    Scientific Reports 09/2013; 3:2805. DOI:10.1038/srep02805 · 5.58 Impact Factor
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    ABSTRACT: We investigated the effects of extracts of Benifuuki (a tea cultivar that contains methylated catechins such as epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3"Me)) in mice fed a high-fat/high-sucrose (HF/HS) diet. This tea cultivar was then compared with an extract of Yabukita (a popular tea cultivar that lacks methylated catechins). For 6 weeks, C57BL/6J mice were fed either HF/HS diet with or without tea extracts from tea cultivars, which contained almost identical ingredients except for methylated catechins (i.e., Yabukita (0.2% and 1%) or Benifuuki (0.2% and 1%) extract powders). Supplementation with Benifuuki 0.2% markedly lowered plasma levels of TG and NEFAs compared with mice supplemented with Yabukita 0.2%. The diet containing Benifuuki 1% decreased adipose tissue weights, liver TG, and expression of lipogenic genes in the liver. These results suggested that Benifuuki had much greater lipid-lowering effects than Yabukita. Taken together, these data suggest that methylated catechins direct the strong lipid-lowering activity of Benifuuki.
    Scientific Reports 09/2013; 3:2749. DOI:10.1038/srep02749 · 5.58 Impact Factor
  • Motofumi Kumazoe, Hirofumi Tachibana
    08/2013; 14(Suppl 1):O33-O33. DOI:10.1186/2050-6511-14-S1-O33
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    ABSTRACT: (-)-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors.
    FEBS letters 07/2013; 587(18). DOI:10.1016/j.febslet.2013.07.041 · 3.34 Impact Factor
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    ABSTRACT: The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.
    The Journal of clinical investigation 01/2013; 123(2). DOI:10.1172/JCI64768 · 13.77 Impact Factor
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    ABSTRACT: The flower of the chrysanthemum plant Shiranui Himekiku has been used as a folk medicine for a variety of diseases including cancer, and cytotoxic effects in some cancer lines have been reported. However, little is known about the anti-cancer activity of the leaf extract and its active compounds. Therefore, to clarify the anti-cancer activity of Shiranui Himekiku leaf and flower, the anti-proliferative effects of the extracts on human cancer cells were examined. Both leaf and flower water extracts dose-dependently suppressed the proliferation of the human breast cancer cell line MCF-7 at concentrations > 25 μg/ml. Furthermore, the anti-proliferative effect in MCF-7 is more than four times that in normal human dermal fibroblast cells. When heated at 100°C for 30 minutes, the proliferation inhibitory activity of the flower extract was unchanged. In contrast, under identical conditions, the activity of the leaf extract was lost. The extracts were separated into two fractions ; one with a molecular weight (MW) > 10 000 (high molecular weight fraction) (HMW) and the other with a MW < 10 000 (low molecular weight fraction) (LMW). A significant proliferation inhibitory effect can be seen in the LMW fraction of both extracts, but the HMW fraction of the leaf extract also slightly inhibits cell growth. Both polyphenols and non-polyphenols are candidate active compounds because the anti-cancer effect was seen in the polyphenol- and non-polyphenol-fractions. These results suggest that the extracts contain several types of anti-cancer components and that both leaves and flowers can be useful.
    Nippon Shokuhin Kagaku Kogaku Kaishi 01/2013; 60(2):80-86. DOI:10.3136/nskkk.60.80 · 0.13 Impact Factor
  • Nippon Shokuhin Kagaku Kogaku Kaishi 01/2013; 60(7):357-361. DOI:10.3136/nskkk.60.357 · 0.13 Impact Factor
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    ABSTRACT: Celastrol has been reported to possess anticancer effects in various cancers; however, the precise mechanism underlying ROS-mediated mitochondria-dependent apoptotic cell death triggered by celastrol treatment in melanoma cells remains unknown. We showed that celastrol effectively induced apoptotic cell death and inhibited tumor growth using tissue culture and in vivo models of B16 melanoma. In addition to apoptotic cell death in B16 cells, several apoptotic events such as PARP cleavage and activation of caspase were confirmed. Pretreatment with caspase inhibitor modestly attenuated the celastrol-induced increase in PARP cleavage and sub-G1 cell population, implying that caspases play a partial role in celastrol-induced apoptosis. Moreover, ROS generation was detected following celastrol treatment. Blocking of ROS accumulation with ROS scavengers resulted in inhibition of celastrol-induced Bcl-2 family-mediated apoptosis, indicating that celastrol-induced apoptosis involves ROS generation as well as an increase in the Bax/Bcl-2 ratio leading to release of cytochrome c and AIF. Importantly, silencing of AIF by transfection of siAIF into cells remarkably attenuated celastrol-induced apoptotic cell death. Moreover, celastrol inhibited the activation of PI3K/AKT/mTOR signaling cascade in B16 cells. Our data reveal that celastrol inhibits growth and induces apoptosis in melanoma cells via the activation of ROS-mediated caspase-dependent and -independent pathways and the suppression of PI3K/AKT signaling.
    Apoptosis 10/2012; 17(12). DOI:10.1007/s10495-012-0767-5 · 3.61 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate the effects of leaf order or crop season on anthocyanins and other chemicals in the anthocyanin-rich tea cultivar 'Sunrouge' (Camellia sinensis x C. taliensis) by using high-performance liquid chromatography, and to study the effect of 'Sunrouge' extract on acetylcholinesterase (AChE) activity in human neuroblastoma SK-N-SH cells. The total anthocyanin content was higher in the third (3.09 mg g(-1)) than in the second (2.24 mg g(-1) ) or first crop season (1.79 mg g(-1)). The amount of anthocyanins contained in the stem was high (1.61 mg g(-1)). In the third crop season, the concentrations of delphinidin-3-O-β-D-(6-(E)-p-coumaroyl)galactopyranoside (DCGa), cyanidin-3-O-β-D-(6-(E)-p-coumaroyl)galactopyranoside, delphinidin-3-O-β-D-galactopyranoside, delphinidin-3-O-β-D-(6-O-(Z)-p-coumaroyl)galactopyranoside, cyanidin-3-O-β-D-galactoside, and delphinidin-3-O-β-D-glucoside were 1.57 mg g(-1), 0.52 mg g(-1), 0.40 mg g(-1), 0.22 mg g(-1), 0.14 mg g(-1), and 0.11 mg g(-1), respectively. DCGa accounted for about 50% of the anthocyanins present. The suppressive effect of 'Sunrouge' water extract on AChE activity in human neuroblastoma SK-N-SH cells was the strongest among the three tea cultivars ('Sunrouge', 'Yabukita' and 'Benifuuki'). These results suggested that 'Sunrouge' might protect humans from humans from AChE-related diseases by suppressing AChE activity. To obtain sufficient amounts of anthocyanins, catechins and/or caffeine for a functional food material, 'Sunrouge' from the third crop season should be used.
    Journal of the Science of Food and Agriculture 08/2012; 92(11):2379-86. DOI:10.1002/jsfa.5644 · 1.88 Impact Factor
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    ABSTRACT: Isoflavones found in soybeans and soy products possess clinically relevant properties. However, the anti-allergic effect of isoflavones has been poorly studied. We examined the effects of isoflavones, genistein, daidzein, and equol, on the expression of the high-affinity immunoglobulin E (IgE) receptor, FcεRI, which plays a central role in IgE-mediated allergic response. Flow cytometric analysis showed that all of these isoflavones reduced the cell surface expression of FcεRI on mouse bone-marrow-derived mast cells and human basophilic KU812 cells. All isoflavones decreased the levels of the FcεRIα mRNA in the cells. Genistein reduced the mRNA expression of the β chain, and daidzein and equol downregulated that of the γ chain. The suppressive effects of isoflavones on FcεRI expression were unaffected by ICI 182,780, an estrogen receptor antagonist, suggesting that these effects were independent of estrogen receptors.
    Journal of Agricultural and Food Chemistry 08/2012; 60(34). DOI:10.1021/jf301759s · 3.11 Impact Factor

Publication Stats

3k Citations
433.84 Total Impact Points


  • 1970–2015
    • Kyushu University
      • • Department of Bioscience and Biotechnology
      • • Department of Applied Chemistry
      • • Graduate School of Bioresource and Bioenvironmental Sciences
      • • Faculty of Agriculture
      Hukuoka, Fukuoka, Japan
  • 2002
    • University of California, Davis
      • Department of Environmental Toxicology
      Davis, CA, United States
  • 2001–2002
    • University of Shizuoka
      Sizuoka, Shizuoka, Japan
  • 1998–2001
    • Prefectural University of Kumamoto
      Kumamoto, Kumamoto, Japan