Research Achievements - Original paper -
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Nagaki Y.
Genes to Cells ( Genes to Cells ) 25 ( 8 ) 547 - 561 2020.08 [Refereed]
Research paper (journal)
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Koizumi Y.
ChemBioChem ( ChemBioChem ) 20 ( 12 ) 1563 - 1568 2019.06 [Refereed]
Research paper (journal)
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Involvement of RSK1 activation in malformin-enhanced cellular fibrinolytic activity
Koizumi Y.
Scientific Reports ( Scientific Reports ) 8 ( 1 ) 2018.12 [Refereed]
Research paper (journal)
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The CCR4-NOT deadenylase complex controls atg7-dependent cell death and heart function
Yamaguchi T.
Science Signaling ( Science Signaling ) 11 ( 516 ) 2018.02 [Refereed]
Research paper (journal)
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Analysis for the role of CCR4-NOT complex in regulation of adenine nucleotide metabolism in the hearts
Tomokazu Yamaguchi, Takashi Suzuki, Teruki Sato, Miyuki Natsui, Ayumi Kadowaki, Chitose Sato, Yukio Koizumi, Akinori Takahashi, Tadashi Yamamoto, Yumiko Imai, Keiji Kuba
JOURNAL OF PHARMACOLOGICAL SCIENCES ( JAPANESE PHARMACOLOGICAL SOC ) 130 ( 3 ) S78 - S78 2016.03
Research paper (journal)
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Structure–activity relationship of cyclic pentapeptide malformins as fibrinolysis enhancers
Koizumi Y.
Bioorganic and Medicinal Chemistry Letters ( Bioorganic and Medicinal Chemistry Letters ) 26 ( 21 ) 5267 - 5271 2016 [Refereed]
Research paper (journal)
The formation of blood clots in blood vessels causes severe ischemic diseases such as cerebral infarction and myocardial infarction. While searching for microbial products that increase fibrinolytic activity using an in vitro fibrin degradation assay, we found malformin Al, a disulfide form of cyclo(-D-Cys-n-Cys-L-Valn-Leu-L-Ile-), as an active compound. In this study, we synthesized malformin derivatives using a solid phase peptide synthesis method and evaluated their fibrinolytic activity and cytotoxicity. Reduction of the disulfide bond and linearization of the cyclic peptide frame decreased the pro-fibrinolytic activity. Substitution of a branched-chain amino acid with lysine resulted in loss of activity. However, protection of the amino group in the lysine derivatives by the tert-butoxycarbonyl (Boc) group rescued the inactivity. Furthermore, the phenylalanine derivatives also exhibited a similar pro-fibrinolytic effect compared to malformin Al. These results suggest that the disulfide bond, the cyclic peptide frame, and the bulky hydrophobic side chains play a crucial role in the pro-fibrinolytic activity of malformin. The effective dose of the active derivatives for the in vitro fibrin degradation showed similar ranges (1-5 mu M), while the order of cytotoxic potency for the active derivatives was as follows: Phe-derivatives > BocLys-derivatives > malformin Al > reduced form. These results showed no correlation between pro-fibrinolytic activity and cytotoxicity, suggesting the possibility of the synthesis for non-toxic malformin derivatives possessing the activity. (C) 2016 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.
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A crucial role of CNOT3 in stem cell proliferation and early embryonic development
Yukio Koizumi, Tomokazu Yamaguchi, Ayumi Kadowaki, Miyuki Natsui, Chitose Sato, Yumiko Imai, Keiji Kuba
JOURNAL OF PHARMACOLOGICAL SCIENCES ( JAPANESE PHARMACOLOGICAL SOC ) 128 ( 3 ) S250 - S250 2015.07
Research paper (journal)
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Dissecting the role of CCR4-NOT-associated ubiquitin converting enzyme in controlling heart functions
Tomokazu Yamaguchi, Ayumi Kadowaki, Yukio Koizumi, Miyuki Natsui, Chitose Satou, Yumiko Imai, Keiji Kuba
JOURNAL OF PHARMACOLOGICAL SCIENCES ( JAPANESE PHARMACOLOGICAL SOC ) 128 ( 3 ) S147 - S147 2015.07
Research paper (journal)
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Cadmium-coordinated supramolecule suppresses tumor growth of T-cell leukemia in mice
Zhou X.
Cancer Science ( Cancer Science ) 106 ( 5 ) 635 - 641 2015.05 [Refereed]
Research paper (journal)
Cadmium is a toxic pollutant with occupational and environmental significance, due to its diverse toxic effects. Supramolecules that conjugate and decontaminate toxic metals have potential for use in treatment of cadmium intoxication. In addition, metal-coordinating ability has been postulated to contribute to the cytotoxic effects of anti-tumor agents such as cisplatin or bleomycin. Thiacalixarenes, cyclic oligomers of p-alkylphenol bridged by sulfur atoms, are supramolecules known to have potent coordinating ability to metal ions. In this study, we show that cadmium-coordinated thiacalix[4]arene tetrasulfate (TC4ATS-Cd) exhibits an anti-proliferative effect against T-cell leukemia cells. Cadmium exhibited cytotoxicity with IC50 values ranging from 36 to 129M against epithelia-derived cancer cell lines, while TC4ATS-Cd elicited no significant cytotoxicity (IC50>947M). However, a number of T-cell leukemia cell lines exhibited marked sensitivity to TC4ATS-Cd. In Jurkat cells, toxicity of TC4ATS-Cd occurred with an IC50 of 6.9M, which is comparable to that of 6.5M observed for cadmium alone. TC4ATS-Cd induced apoptotic cell death through activation of caspase-3 in Jurkat cells. In a xenograft model, TC4ATS-Cd (13mg/kg) treatment significantly suppressed the tumor growth of Jurkat cells in mice. In addition, TC4ATS-Cd-treated mice exhibited significantly less cadmium accumulation in liver and kidney compared to equimolar cadmium-treated mice. These results suggest that cadmium-coordinated supramolecules may have therapeutic potential for treatment of T-cell leukemia.
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Stimulation of the hair growth by α2-blocker SST-VED
Natsui Miyuki, Kawagoe Masami, Somei Masanori, Koizumi Yukio, Koyota Souichi, Sugiyama Toshihiro
Akita journal of medicine ( Akita University ) 41 ( 1 ) 23 - 33 2014 [Refereed]
Research paper (journal)
The hair follicle was picked from the beard of a C57BL/6J mouse, and the influence on hair follicle extension was measured by hair follicle organ culture under the addition of SST-VED1. Compared with control( solvent of SST-VED1), the hair growth by SST-VED1 addition was observed in dose-dependent manner. When SST-VED1 was compared with SST-VED2, SST-VED1 promotes the hair growth significantly. Moreover, it turned out that growth is large in order of RiUP^<(R)>, SST-VED1, and Glechoma hederacea extract. In this research, it was shown clearly that new molecular chemicals of SST-VED 1 and 2 have a hair growth action. Furthermore, by using it together with the extract obtained from Glechoma hederacea of product-of-nature origin, it turned out that a hair growth action is amplified.
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Flores Maria Jolina Lou N., Koyota Souichi, Qiao Zhiwei, Koizumi Yukio, Sugiyama Toshihiro
秋田医学 ( 秋田医学 ) 40 ( 3 ) 163 - 173 2013 [Refereed]
Research paper (journal)
Aim : Ceruloplasmin (Cp) is an acute-phase protein and a member of the multicopper oxidase family of enzymes. It has been implicated in iron metabolism because of its ferroxidase activity. It is expressed as soluble (sCp) or glycosylphosphatidylinositol-anchored ceruloplasmin (GPI-Cp) form ; the former is primarily synthesized in the liver, and the latter is primarily found in the brain. Although recent studies reported GPI-Cp expression on hepatocytes, little is known regarding its presence in specific liver cell compartments and its possible involvement in liver pathophysiology. This study aimed to characterize the distribution of GPI-Cp in liver cells and specifically in the apical part of the plasma membrane. Methods : We assessed GPI-Cp expression in the liver using immunohistochemistry and immunoblotting techniques. Furthermore, we isolated apical and basolateral membrane fraction from the total liver membrane using sucrose discontinuous gradient centrifugation, and GPI-Cp were detected using immunoblotting. Results : GPI-Cp was detected in purified apical membranes of rat liver cells. Immunoreactive Cp protein was released after incubation with phosphatidylinositol-specific phospholipase C, and the free protein demonstrated ferroxidase activity. Conclusion : These findings suggest that majority of GPI-Cp present in the liver is primarily located on the apical surface of cells because of transcytosis.
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Identification of antioxidants derived from Inonotus obliquus
Kumagai Ayako, Koizumi Yukio, Kawagoe Masami, Koyota Souichi, Sugiyama Toshihiro
Akita journal of medicine ( Akita University ) 40 ( 2 ) 113 - 119 2013 [Refereed]
Research paper (journal)
The medicinal mushroom Inonotus obliquus is a traditional and widely used multi-functional fungus. In the present study, the lipophilic fraction of Inonotus obliquus were investigated for their antioxidative activity with hydroxyl radical scavenging activity assays. As a result, two acidic materials had higher antioxidative activity than basic or neutral materials. Furthermore, antioxidative acidic materials including organic acids were isolated by silica gel column chromatography and subsequent preparative high-performance liquid chromatography. Two purified antioxidants, designated compound 1 and 2, were identified as vanillic acid and syringic acid, respectively. Vanillic acid and syringic acid were showed the antioxidative activities with IC_50 values of 59.0 and 2.8 μg/ml, respectively.
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Sitmulation of the hair growth by a natural origin Glechoma hederacea extract
Natsui Miyuki, Kawagoe Masami, Nagai Shigeharu, Qiao Zhiwei, Sato Yoshiaki, Flores Maria Jolina, Koizumi Yukio, Koyota Souichi, Sugiyama Toshihiro
Akita journal of medicine ( Akita University ) 40 ( 1 ) 1 - 12 2013 [Refereed]
Research paper (journal)
The glechoma hederacea subsp. grandis( G. grandis) is used as an herbal medicine and is supposed that the extract at the time of the bloom shade-drying is effective against a child's convulsion. Moreover, it may be considered as reduction of blood sugar level. In this study, the clinical test of the hair growth facilitatory effect of the G. grandis extract in human during one to three years showed remarkable improvement or a little improvement by evaluation at 95%(41 persons among 43 persons). With the mice, the tendency for hair growth was promoted compared with a control( physiological saline). Furthermore, we used the hair follicle organ culture system for the hair growth promoting substance from G. grandis extract. As a result, G. grandis in the growth phase after the bloom had remarkable growth effect, and found out having the remarkable hair growth effect in a fraction of aqueous phase from the extract especially. This aims at the establishment of the hair regenerative technology which utilizes the natural plant, G. grandis. It is possible to apply to the baldness and the alopecia caused by various factors, and preventive effect for the depilation, trichogenous, and the hair restoration action improve synergistic and it is effective as the external application medicine for the head with high safety compared with the scalp.
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Anti-melanogenesis effect of Glechoma hederacea L. extract on B16 murine melanoma cells
Qiao Z.
Bioscience, Biotechnology and Biochemistry ( Bioscience, Biotechnology and Biochemistry ) 76 ( 10 ) 1877 - 1883 2012.11 [Refereed]
Research paper (journal)
Glechoma hederacea L. (Labiatae) has been used in folk medicine to treat various ailments for centuries. We investigated the effects of G. hederacea extract on melanogenesis in B16 melanoma cells. It significantly reduced both the cellular melanin content and tyrosinase activity in a concentration-dependent manner. An MTT assay did not reveal any obvious cytotoxicity. Furthermore, we found that G. hederacea extract decreased tyrosinase and microphthalmia-associated transcription factor protein expression, but did not inhibit tyrosinase-related protein-1 and tyrosinase-related protein-2 expression. RT-PCR analysis indicated that the antimelanogenic effect of G. hederacea extract might be due to inhibition of tyrosinase gene transcription. Moreover, this effect is regulated via suppression of microphthalmia-associated transcription factor protein expression. Our data indicate that G. hederacea extract inhibits melanin synthesis in B16 melanoma cells but is not cytotoxic. Hence it might prove a useful therapeutic agent for treating hyperpigmentation and an effective component of whitening cosmetics.
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Ma L.
Biochemical and Biophysical Research Communications ( Biochemical and Biophysical Research Communications ) 418 ( 4 ) 628 - 633 2012.02 [Refereed]
Research paper (journal)
Mucin-type O-glycosylation is initiated by a large number of UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (GalNAc-T). Although extensive in vitro studies using synthetic peptides as substrates suggest that most GalNAc-Ts exhibit overlapping substrate specificities, many studies have shown that individual GalNAc-Ts play an important role in both animals and humans. Further investigations of the functions of individual GalNAc-Ts including in vivo substrate proteins and O-glycosylation sites are necessary.In this study, we attempted to generate single-chain variable fragment (scFv) antibodies to bind to GalNAc-T1, T2, T3, and T4 using a yeast two-hybrid system for screening a naive chicken scFv library. Several different scFvs were isolated against a single target GalNAc-T isoform specifically under expressed in yeast and were confirmed to be expressed in mammalian cells and to retain binding activity inside the cells. Generation of these specific antibodies provides an opportunity to modify and exploit antibodies for specific applications in investigations of GalNAc-T functions. (C) 2012 Elsevier Inc. All rights reserved.
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Koizumi Y.
Biological and Pharmaceutical Bulletin ( Biological and Pharmaceutical Bulletin ) 34 ( 9 ) 1426 - 1431 2011.09 [Refereed]
Research paper (journal)
Malformin A(1), a cyclopentapeptide of fungal origin, enhances cellular fibrinolytic activity depending on the existence of a cofactor in blood plasma. However, the nature of this cofactor remains unknown. Here, we report that vitronectin acts as a plasma cofactor of malformin A(1). We purified the cofactor from bovine plasma by activity-based fractionation, and confirmed that vitronectin in conjunction with plasminogen supports the activity of malformin A(1) to promote the fibrinolytic activity of U937 cells. Malformin A(1) action was abolished by Arg-Gly-Asp peptide (a competitor of vitronectin integrin binding), wortmannin (an inhibitor of signaling kinases), and cytochalasin B (an inhibitor of actin polymerization). Changes in actin organization and a decrease in filopodia were observed in cells treated with malformin A(1) and plasma. A focal localization of plasminogen on the cell surface was augmented by malformin A(1), whereas the amount of cell-surface-bound plasminogen was minimally altered by the treatment. Our results suggest the involvement of cytoskeletal reorganization via vitronectin signaling in the cellular fibrinolytic activity-enhancing action of malformin A(1).
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In vitro prominent bone regeneration by release zinc ion from Zn-modified implant
Yusa K.
Biochemical and Biophysical Research Communications ( Biochemical and Biophysical Research Communications ) 412 ( 2 ) 273 - 278 2011.08 [Refereed]
Research paper (journal)
Zinc is one of the trace elements which induce the proliferation and the differentiation of the osteoblast. In the previous study, we found that zinc ions (Zn2(+) ion)-releasing titanium implants had excellent bone fixation using a rabbit femurs model. In this study, we isolated the Zn2(+) ions (eluted Zn2(+) ion; EZ) released from the implant surface, and evaluated the effect of EZ on the osteogenesis of human bone marrowderived mesenchymal cells (hBMCs). In the result, it was found that the EZ stimulated cell viability, osteoblast marker gene (type I collagen, osteocalcin (OC), alkaline phosphatase (ALP) and bone sialoprotein (BSP)) expressions and calcium deposition in hBMCs. (C) 2011 Elsevier Inc. All rights reserved.
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Kuhara M.
Biomedical Research ( Biomedical Research ) 32 ( 2 ) 111 - 117 2011.04 [Refereed]
Research paper (journal)
We examined age-related changes in the protein expression of carbonic anhydrase Ill (CAIII) in livers of Long-Evans with a cinnamon-like color (LEC) rats using an agouti color (LEA) rats as controls. The levels of the protein of CAIII in the liver of LEC male rats increased before 20 weeks of age, at the stage of acute hepatitis, and were decreased at 54 weeks of age, while those of CAIII in the liver of LEA male rats were highly expressed at all ages. In the normal LEA rats, CAIII showed sexual dimorphism. The level of CAIII in LEA male rat liver relative to female was four times higher. On the other hand, young LEC rat (at 4-12 weeks) showed a higher protein level of CAM than LEA rats, and then decreased during development of hepatitis. CAIII mRNA also decreased in the LEC rat liver during hepatocarcinogenesis. The level of CAIII in the tumor region was lower than that in the tumor-free region. Immunohistochemical analysis showed that glutathione S-transferase P (GST-P) was positive and CAIII was negative in the precancerous region. The expression of CAM was suppressed in cancerous lesions in hepatoma-bearing LEC rat liver compared to uninvolved surrounding tissues. These results indicated that suppression of CAIII accompanied hepatocarcinogenesis and it is a secondary consequence of the high copper levels in the liver.
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Hasegawa T.
Bioorganic and Medicinal Chemistry ( Bioorganic and Medicinal Chemistry ) 17 ( 16 ) 6015 - 6019 2009.08 [Refereed]
Research paper (journal)
Two kinds of rhodamine modified beta-cyclodextrins (R-1 and R-2), which are coupled up ethylene diamine (EDA) and tetraethylene pentamine (TEPA) between Rh B and beta-cyclodextrin, respectively, have been synthesized. R-1 and 2 work as a new fluorogenic probe for monitoring pH of Hela cells, and MTT of assay R-1, R-2, and rhodamine B indicate that less a cytotoxicity of those R-1 and R-2 than that of rhodamine B, where R-1 has much less one than that of R-2. The fluorogenetic probe capability of R-2 was recognized in an area of acidic area in living cell, which is lysosome. (C) 2009 Elsevier Ltd. All rights reserved.
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Lys17 in the 'lasso' peptide lariatin A is responsible for anti-mycobacterial activity
Iwatsuki M.
Bioorganic and Medicinal Chemistry Letters ( Bioorganic and Medicinal Chemistry Letters ) 19 ( 10 ) 2888 - 2890 2009.05 [Refereed]
Research paper (journal)
C-terminal-lacking fragments of the anti-mycobacterial peptide lariatin A were obtained by hydrolysis using carboxypeptidase P and their anti-mycobacterial activities were evaluated. Lys17 was found to be essential for their antimicrobial activity. A molecular dynamics simulation, with explicit water molecules, helped determine the structural characteristics of Lys17 of lariatin A. The simulation revealed the dynamic formation and deformation of a salt bridge between the N-xi atom of Lys17 and the carboxyl group of C-terminal Pro18, which is deemed to be crucial for the compound's anti-mycobacterial activity. (C) 2009 Elsevier Ltd. All rights reserved.