研究等業績 - 原著論文 - 小泉 幸央
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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.