研究等業績 - 原著論文 - 小泉 幸央
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Nagaki Y.
Genes to Cells ( Genes to Cells ) 25 ( 8 ) 547 - 561 2020年08月 [査読有り]
研究論文（学術雑誌）
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Koizumi Y.
ChemBioChem ( ChemBioChem ) 20 ( 12 ) 1563 - 1568 2019年06月 [査読有り]
研究論文（学術雑誌）
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Involvement of RSK1 activation in malformin-enhanced cellular fibrinolytic activity
Koizumi Y.
Scientific Reports ( Scientific Reports ) 8 ( 1 ) 2018年12月 [査読有り]
研究論文（学術雑誌）
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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年02月 [査読有り]
研究論文（学術雑誌）
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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年03月
研究論文（学術雑誌）
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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年 [査読有り]
研究論文（学術雑誌）
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年07月
研究論文（学術雑誌）
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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年07月
研究論文（学術雑誌）
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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年05月 [査読有り]
研究論文（学術雑誌）
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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夏井 美幸, 川越 政美, 染井 正徳, 小泉 幸央, 小代田 宗一, 杉山 俊博
秋田医学 ( 秋田医学会 ) 41 ( 1 ) 23 - 33 2014年 [査読有り]
研究論文（学術雑誌）
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年 [査読有り]
研究論文（学術雑誌）
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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カバノアナタケ(Inonotus obliquus)由来の抗酸化成分の同定
熊谷 彩子, 小泉 幸央, 川越 政美, 小代田 宗一, 杉山 俊博
秋田医学 ( 秋田医学会 ) 40 ( 2 ) 113 - 119 2013年 [査読有り]
研究論文（学術雑誌）
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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夏井 美幸, 川越 政美, 永井 繁春, 喬 志偉, 佐藤 喜暁, フローレス マリア ジョリナルー, 小泉 幸央, 小代田 宗一, 杉山 俊博
秋田医学 ( 秋田医学会 ) 40 ( 1 ) 1 - 12 2013年 [査読有り]
研究論文（学術雑誌）
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年11月 [査読有り]
研究論文（学術雑誌）
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年02月 [査読有り]
研究論文（学術雑誌）
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年09月 [査読有り]
研究論文（学術雑誌）
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年08月 [査読有り]
研究論文（学術雑誌）
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年04月 [査読有り]
研究論文（学術雑誌）
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年08月 [査読有り]
研究論文（学術雑誌）
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年05月 [査読有り]
研究論文（学術雑誌）
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.
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Expression and localization of regenerating gene I in a rat liver regeneration model
Wang J.
Biochemical and Biophysical Research Communications ( Biochemical and Biophysical Research Communications ) 380 ( 3 ) 472 - 477 2009年03月 [査読有り]
研究論文（学術雑誌）
Regenerating gene (Reg) I has been identified as a regenerative/proliferative factor for pancreatic islet cells. We examined Reg I expression in the regenerating liver of a rat model that had been administered 2-acetylaminofluorene and treated with 70% partial hepatectomy (2-AAF/PH model), where hepatocyte and cholangiocyte proliferation was suppressed and the hepatic stem cells and/or hepatic progenitor cells were activated. In a detailed time course study of activation of hepatic stem cells in the 2-AAF/PH model, utilizing immunofluorescence staining with antibodies of Reg I and other cell-type-specific markers, we found that Reg I-expressing cells are present in the bile ductules and increased during regeneration. Reg I-expressing cells were colocalized with CK19, OV6, and AFP. These results demonstrate that Reg I is significantly upregulated in the liver of the 2-AAF/PH rat model, accompanied by the formation of bile ductules during liver regeneration. (C) 2009 Elsevier Inc. All rights reserved.
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KOIZUMI Yukio, TOMODA Hiroshi, KUMAGAI Ayako, ZHOU Xiao-ping, KOYOTA Souichi, SUGIYAMA Toshihiro
Cancer science 100 ( 2 ) 322 - 326 2009年02月 [査読有り]
研究論文（学術雑誌）
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Yanagimoto C.
Experimental Cell Research ( Experimental Cell Research ) 315 ( 2 ) 119 - 126 2009年01月 [査読有り]
研究論文（学術雑誌）
Wilson disease is a genetic disorder characterized by the accumulation of copper in the body by defective biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. However, copper metabolism in hepatocytes has been still unclear. Niemann-Pick disease type C (NPC) is a lipid storage disorder and the most commonly mutated gene is NPC1 and its gene product NPC1 is a late endosome protein and regulates intracellular vesicle traffic. In the present Study, we induced NPC phenotype and examined the localization of ATP7B and secretion of holo-Cp, a copper-binding mature form of Cp. The vesicle traffic was modulated using U18666A, which induces NPC phenotype, and knock down of NPC1 by RNA interference. ATP7B colocalized with the late endosome markers, but not with the trans-Golgi network markers. U18666A and NPC1 knock down decreased holo-Cp secretion to culture medium, but did not affect the secretion of other secretory proteins. Copper accumulated in the cells after the treatment with U18666A. These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via NPC1-dependent pathway and incorporated into apo-Cp to form holo-Cp. (C) 2008 Elsevier Inc. All rights reserved.
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REG I enhances chemo- and radiosensitivity in squamous cell esophageal cancer cells
HAYASHI Kaori, MOTOYAMA Satoru, KOYOTA Souichi, KOIZUMI Yukio, WANG Jingshu, TAKASAWA Shin, ITAYA HIRONAKA Asako, SAKURAMOTO TSUCHIDA Sumiyo, MARUYAMA Kiyotomi, SAITO Hajime, MINAMIYA Yoshihiro, OGAWA Jun-ichi, SUGIYAMA Toshihiro
Cancer science 99 ( 12 ) 2491 - 2495 2008年12月 [査読有り]
研究論文（学術雑誌）
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REG Iα is a reliable marker of chemoradiosensitivity in squamous cell esophageal cancer patients
Hayashi K.
Annals of Surgical Oncology ( Annals of Surgical Oncology ) 15 ( 4 ) 1224 - 1231 2008年04月 [査読有り]
研究論文（学術雑誌）
Background: A reliable marker of chemoradiosensitivity that would enable appropriate and individualized treatment of thoracic squamous cell esophageal cancer has long been sought. We investigated whether regenerating gene (REG) I alpha is such a marker.Methods: We assessed expression of REG I alpha in untreated endoscopic biopsy specimens and examined the correlation between REG I alpha expression and the clinical responses to definitive chemoradiotherapy and prognosis. We also examined the relationship between REG I alpha expression in the resected tumor and the prognosis of patients who received esophagectomy for thoracic squamous cell esophageal cancer.Results: Among the 42 patients treated with definitive chemoradiotherapy, 8 of the 23 REG I-positive patients (35%) showed complete responses to chemoradiotherapy, while only one of the 19 REG I-negative patients did so. The survival rate among the REG I-positive patients was significantly better than among the REG I-negative patients. For the 76 patients treated surgically, there was no significant difference in the survival rates among the REG I-positive and REG I-negative patients.Conclusions: REG I alpha expression in squamous cell esophageal carcinoma may be a reliable marker of chemoradiosensitivity. We anticipate that it will enable us to provide more appropriate and individualized treatment to patients of advanced esophageal squamous cell carcinoma.
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Kawagoe M.
Journal of Trace Elements in Medicine and Biology ( Journal of Trace Elements in Medicine and Biology ) 22 ( 1 ) 59 - 65 2008年03月 [査読有り]
研究論文（学術雑誌）
We evaluated tissue changes associated with cerium chloride administration via gavage to adult mice, via milk to neonatal mice and transplacentally to fetal mice. Change in adults consisted of extensive pulmonary hemorrhage, pulmonary venous congestion, thickened alveolar septae, hepatic necrosis and neutrophil infiltrations. Those in fetal mice consisted of pulmonary and hepatic congestion. These results indicate that gavage cerium administration elicited subtle tissue changes, though oral toxicity is rather low. These changes were less severe in neonatal and fetal mice. When cerium was injected into adult mice through the tail vein, cerium was distributed mainly to the liver, spleen and lung dose-dependently with the cerium concentration gradually decreasing after 3 days. A study of cerium anticoagulation in mouse plasma showed that clotting time was significantly prolonged when cerium was added to plasma. These results suggest that cerium may disturb blood coagulation and cause pulmonary and hepatic vascular congestion. (C) 2007 Elsevier GmbH. All rights reserved.
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Gadolinium chloride suppresses styrene-induced cytochrome P450s expression in rat liver
Hirasawa F.
Biomedical Research ( Biomedical Research ) 28 ( 6 ) 323 - 330 2007年12月 [査読有り]
研究論文（学術雑誌）
To assess the effect of gadolinium (Gd) on the expression of several forms of cytochrome P450 (P450s) and antioxidant enzymes, we treated rats with gadolinium chloride (25 mg as Gd/kg body weight) 4 h after styrene (a multiple P450 inducer) treatment (600 mg/kg). Gd treatment significantly suppressed styrene-inducible cytochrome P4502B1 (CYP2B1), CYP2B2, CYP2E1, and CYP3A2 mRNA expressions to 48.6%, 69.8%, 61.1%, and 38.5%, accompanying with the reduction of proteins expression to 1.42%, 31.2%, 21.1% and 21.1%, respectively, compared with styrene alone treatment. Gd suppressed styrene-inducible CYP1A2 expression, but only at the protein level. On the other hand, styrene treatment caused a decrease in reduced form of glutathione (GSH), as well as increases in lipid peroxide and serum ALT and AST activities, suggesting the occurrence of hepatic damage probably due to styrene-induced oxidative stress in rat liver. Post-treatment of Gd attenuated this styrene-caused hepatic damage. Moreover, mRNA expressions of cellular antioxidant enzymes such as catalase, CuZn-superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPX) were hardly changed by styrene and/or Gd treatment. In summary, Gd suppressed styrene-inducible expression of not only CYP2B1 but also several forms of P450 at both the mRNA and protein levels, along with attenuation of styrene-caused liver damage. These findings suggested that Gd is a chemo-preventive agent against hepatic damage caused by xenobiotics requiring biotransformation.
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LASER MICRODISSECTION IN COMBINATION WITH MICROARRAY-BASED GENE EXPRESSION ANALYSIS
Scheidl Stefan J., Wang Jing-Shu, Kawagoe Masami, SZILVIA Arany, UENO Yasuharu, KOIZUMI Yukio, KAMEDA Takashi, KOYOTA Souichi, SUGIYAMA Toshihiro
秋田医学 ( 秋田大学 ) 33 ( 2 ) 71 - 75 2006年10月 [査読有り]
研究論文（学術雑誌）
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Styrene monomer primarily induces CYP2B1 mRNA in rat liver
Hirasawa F.
Xenobiotica ( Xenobiotica ) 35 ( 12 ) 1089 - 1099 2005年12月 [査読有り]
研究論文（学術雑誌）
To determine the cytochrome P450 (CYP) primarily expressed after styrene exposure, seven forms of hepatic CYP mRNA in rats treated with 600 mg kg -1 styrene were examined. CYP1A2, CYP2B1/2, CYP2E1 and CYP3A2 mRNA were observed using real-time LightCycler PCR. The amount of CYP2B1 mRNA was significantly increased, 47-fold compared with controls, suggesting that this CYP is the primary cytochrome P450 in rats exposed to styrene. Significant increases in the amount of CYP2E1, CYP1A2 and CYP2B2 mRNA were also observed after styrene exposure, and their increase levels were 3.1-, 1.7- and 1.7-fold higher than controls, respectively. Western blot analysis also indicated that the protein levels of CYP2B1, CYP2B2, CYP2E1 and CYP1A2 showed clear increases after styrene treatment, corresponding to their mRNA expression. CYP2C11 mRNA decreased significantly in rats after styrene exposure. CYP1A1 was detected at the mRNA level in rat liver, but it was not detected at the protein level. The expression of epoxide hydrolase (EH), involved in Phase I drug metabolism, was also examined. EH mRNA increased 2-fold compared with controls after styrene exposure. Styrene thus appears to be a chemical compound that induces multiple CYPs. The results demonstrate that CYP2B1 is the primarily induced CYP form by styrene treatment to rats at acute toxic level. © 2005 Taylor & Francis.
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Transplantation of rat hepatic stem-like (HSL) cells with collagen matrices
UENO Yasuharu, NAGAI Hirokazu, WATANABE Go, ISHIKAWA Kiyoshi, YOSHIKAWA Kiwamu, KOIZUMI Yukio, KAMEDA Takashi, SUGIYAMA Toshihiro
Hepatology research : the official journal of the Japan Society of Hepatology 33 ( 4 ) 277 - 284 2005年12月 [査読有り]
研究論文（学術雑誌）
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Takahashi S.
Biomedical Research ( Biomedical Research ) 26 ( 3 ) 117 - 121 2005年06月 [査読有り]
研究論文（学術雑誌）
Our recent studies have demonstrated that the middle domain of N-acetyl-(D)-glucosamine (GlcNAc) 2-epimerase participates in the specificity for and binding of nucleotides. To identify the residue conferring nucleotide binding, amino acid substitutions were introduced in the human and rat GlcNAc 2-epimerases. The mutational analyses indicate that residue 171 of GlcNAc 2-epimerase is critical for the nucleotide binding of GlcNAc 2-epimerase.
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Boromycin abrogates bleomycin-induced G2 checkpoint
Arai M.
Journal of Antibiotics ( Journal of Antibiotics ) 57 ( 10 ) 662 - 668 2004年10月 [査読有り]
研究論文（学術雑誌）
The DNA-damaging agent bleomycin arrests the cell cycle at the G2 phase of Jurkat cells defective in the G1 checkpoint, and microtubule-acting colchicine arrests it at the M phase. Boromycin itself, an actinomycete metabolite, showed no effect on the cell cycle status of Jurkat cells at least up to 340 nM. However, the compound (3.4∼340 nM) was found to abrogate bleomycin-induced G2 arrest even at 3.4 nM, resulting in a drastic decrease in cells at the G2 phase and increase in cells at the subG1 phase. On the other hand, boromycin did not show any effect on the colchicine-induced M phase arrest in Jurkat cells, nor on the cell cycle status of the bleomycin-treated or -untreated HUVEC, normal cells conserving both G1 and G2 checkpoints. Furthermore, boromycin potentiated anti-tumor activity of bleomycin in scid mice inoculated with Jurkat cells. These data suggest that boromycin disrupts the cell cycle at the G2 checkpoint of cancer cells selectively, leading to sensitization of cancer cells to anti-cancer reagents.
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KOIZUMI YUKIO, ARAI MASAYOSHI, TOMODA HIROSHI, OMURA SATOSHI
Journal of antibiotics = An International Journal Devoted to Research on Bioactive Microbial Products 57 ( 7 ) 415 - 420 2004年07月 [査読有り]
研究論文（学術雑誌）
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Oxaline, a fungal alkaloid, arrests the cell cycle in M phase by inhibition of tubulin polymerization
Yukio Koizumi, Masayoshi Arai, Hiroshi Tomoda, Satoshi Omura
Biochimica et Biophysica Acta - Molecular Cell Research ( ELSEVIER SCIENCE BV ) 1693 ( 1 ) 47 - 55 2004年07月 [査読有り]
研究論文（学術雑誌）
Oxaline and neoxaline, fungal alkaloids, were found to inhibit cell proliferation and to induce cell cycle arrest at the G2/M phase in Jurkat cells. CBP501 (a peptide corresponding to amino acids 211-221 of Cdc25C phosphatase), which inhibits the G2 checkpoint, did not affect the G2/M arrest caused by oxaline, suggesting that oxaline causes M phase arrest but not G2 phase arrest. The Cdc2 phosphorylation level of oxaline-treated cell lysate was lower than that of the control cells, indicating that oxaline arrests the M phase. Oxaline disrupted cytoplasmic microtubule assembly in 3T3 cells. Furthermore, oxaline inhibited polymerization of microtubule protein and purified tubulin dose-dependently in vitro. In a binding competition assay, oxaline inhibited the binding of [3H]colchicine to tubulin, but not that of [3H]vinblastine. These results indicate that oxaline inhibits tubulin polymerization, resulting in cell cycle arrest at the M phase. © 2004 Elsevier B.V. All rights reserved.
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Enhancement of fibrinolytic activity of U937 cells by malformin A<inf>1</inf>
Koizumi Y.
Journal of Antibiotics ( Journal of Antibiotics ) 55 ( 1 ) 78 - 82 2002年 [査読有り]
研究論文（学術雑誌）
We have found that malformin A1, a cyclopentapeptide metabolite of Aspergillus niger, enhanced 2.0- to 3.2-fold the 125I-fibrin clot lysis when incubated at 1-10 μM with both U937 cells and blood plasma, both of which were essential to the malformin A1 action. The effect was inhibited by ε-aminocaproic acid and anti-urokinase serum, but not by anti-tissue-type plasminogen activator IgG, showing that the enhancement was mediated by urokinase-catalyzed plasminogen activator. However, malformin A1 affected neither cellular urokinase activity nor cell-free reactions involved in the fibrinolytic pathway. Malformin-treated, washed cell had an increased capacity to degrade fibrin in the presence of plasma. These results suggest that malformin A1 enhances fibrinolytic activity by affecting cell-mediated response to initiate and/or propagate fibrinolytic activity.