Faculty Profiles - TSUKAHARA Hirokazu

Papers - TSUKAHARA Hirokazu

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Therapeutic effects of redox-active protein thioredoxin(TRX)-1 in influenza-virus-induced pneumonia in mice

125 ( 2 ) 109 - 112 2013.8

川谷正男, 巨田元礼, 米谷博, 大嶋勇成, 平谷美智夫, 友田明美, 塚原宏一

脳と発達 45 ( Suppl. ) S339 - S339 2013.5

Metabolic improvements in intrahepatic porto-systemic venous shunt presenting various metabolic abnormalities by 4-phenylacetate Reviewed

Nagasaka H, Miida T, Yorifuji T, Hirano K.-I, Inui A, Fujisawa T, Tsukahara H, Hayashi H, Inomata Y

Clin Chim Acta 419 52 - 56 2013.4

Oxysterol changes along with cholesterol and vitamin D changes in adult phenylketonuric patients diagnosed by newborn mass-screening. Reviewed

Nagasaka H, Okano Y, Kimura A, Mizuochi T, Sanayama Y, Takatani T, Nakagawa S, Hasegawa E, Hirano K, Mochizuki H, Ohura T, Ishige-Wada M, Usui H, Yorifuji T, Tsukahara H, Hirayama S, Ohtake A, Yamato S, Miida T

Clinica chimica acta; international journal of clinical chemistry 416 54 - 59 2013.2

Sustained high plasma mannose less sensitive to fluctuating blood glucose in glycogen storage disease type Ia children Reviewed

Nagasaka H, Yorifuji T, Bandsma R.H.J, Takatani T, Asano H, Mochizuki H, Takuwa M, Tsukahara H, Inui A, Tsunoda T, Komatsu H, Hiejima E, Fujisawa T, Hirano K.-I, Miida T, Ohtake A, Taguchi T, Miwa I

J Inherit Metab Dis 36 ( 1 ) 75 - 81 2013.1

Thioredoxin-1 and oxidative stress status in pregnant women at early third trimester of pregnancy: relation to maternal and neonatal characteristics.

Yoko Nakatsukasa, Hirokazu Tsukahara, Kazuhisa Tabuchi, Masako Tabuchi, Tomoko Magami, Mutsuko Yamada, Yosuke Fujii, Masato Yashiro, Mitsuru Tsuge, Tsuneo Morishima

Journal of clinical biochemistry and nutrition 52 ( 1 ) 27 - 31 2013.1

Language：English Publishing type：Research paper (scientific journal)

This study examined the clinical and biological importance of thioredoxin-1, a redox-active defensive protein that controls multiple biological functions, in pregnant women. We measured serum concentrations of thioredoxin-1, total hydroperoxides, and redox potential in 60 pregnant women at the early third trimester: gestational age of 27-29 weeks. The thioredoxin-1 concentration (mean ± SD) was 90 ± 42 ng/ml. Total hydroperoxides was 471 ± 105 U.CARR (1 U.CARR = 0.08 mg/dl H(2)O(2)). Redox potential was 2142 ± 273 µmol/l. The total hydroperoxides: redox potential ratio (oxidative stress index) was 0.23 ± 0.08. Thioredoxin-1, total hydroperoxides, and oxidative stress index were higher and redox potential was lower than in blood of healthy adults. Total hydroperoxides and redox potential were mutually correlated significantly and negatively. Thioredoxin-1 correlated significantly and negatively and redox potential correlated significantly and positively with body weight and body mass index. Thioredoxin-1 and redox potential correlated significantly and positively with uric acid and albumin, respectively. Thioredoxin-1 and oxidative stress index correlated significantly and negatively and redox potential significantly and positively with neonatal birth weight. These results suggest that high concentrations of thioredoxin-1 are linked to high oxidative stress status in pregnant women and that neonatal birth weight is affected by the maternal oxidative condition during later pregnancy.

DOI： 10.3164/jcbn.12-71

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Redox-active protein thioredoxin-1 administration ameliorates influenza A virus (H1N1)-induced acute lung injury in mice. International journal

Masato Yashiro, Hirokazu Tsukahara, Akihiro Matsukawa, Mutsuko Yamada, Yosuke Fujii, Yoshiharu Nagaoka, Mitsuru Tsuge, Nobuko Yamashita, Toshihiro Ito, Masao Yamada, Hiroshi Masutani, Junji Yodoi, Tsuneo Morishima

Critical care medicine 41 ( 1 ) 171 - 81 2013.1

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: Influenza virus infections can cause severe acute lung injury leading to significant morbidity and mortality. Thioredoxin-1 is a redox-active defensive protein induced in response to stress conditions. Animal experiments have revealed that thioredoxin-1 has protective effects against various severe disorders. This study was undertaken to evaluate the protective effects of recombinant human thioredoxin-1 administration on influenza A virus (H1N1)-induced acute lung injury in mice. DESIGN: Prospective animal trial. SETTING: Research laboratory. SUBJECTS: Nine-week-old male C57BL/6 mice inoculated with H1N1. INTERVENTION: The mice were divided into a vehicle-treated group and recombinant human thioredoxin-1-treated group. For survival rate analysis, the vehicle or recombinant human thioredoxin-1 was administered intraperitoneally every second day from day -1 to day 13. For lung lavage and pathological analyses, vehicle or recombinant human thioredoxin-1 was administered intraperitoneally on days -1, 1, and 3. MEASUREMENTS AND MAIN RESULTS: Lung lavage and pathological analyses were performed at 24, 72, and 120 hrs after inoculation. The recombinant human thioredoxin-1 treatment significantly improved the survival rate of H1N1-inoculated mice, although the treatment did not affect virus propagation in the lung. The treatment significantly attenuated the histological changes and neutrophil infiltration in the lung of H1N1-inoculated mice. The treatment significantly attenuated the production of tumor necrosis factor-α and chemokine (C-X-C motif) ligand 1 in the lung and oxidative stress enhancement, which were observed in H1N1-inoculated mice. H1N1 induced expressions of tumor necrosis factor-α and chemokine (C-X-C motif) ligand 1 in murine lung epithelial cells MLE-12, which were inhibited by the addition of recombinant human thioredoxin-1. The recombinant human thioredoxin-1 treatment started 30 mins after H1N1 inoculation also significantly improved the survival of the mice. CONCLUSIONS: Exogenous administration of recombinant human thioredoxin-1 significantly improved the survival rate and attenuated lung histological changes in the murine model of influenza pneumonia. The protective mechanism of thioredoxin-1 might be explained by its potent antioxidative and anti-inflammatory actions. Consequently, recombinant human thioredoxin-1 might be a possible pharmacological strategy for severe influenza virus infection in humans.

DOI： 10.1097/CCM.0b013e3182676352

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Characteristics of NO cycle coupling with urea cycle in non-hyperammonemic carriers of ornithine transcarbamylase deficiency Reviewed

H. Nagasaka, T. Yorifuji, H. Egawa, A. Inui, T. Fujisawa, H. Komatsu, H. Tsukahara, S. Uemoto, Y. Inomata

Molecular Genetics and Metabolism 109 ( 3 ) 251 - 254 2013

Fatty liver and anti-oxidant enzyme activities along with peroxisome proliferator-activated receptors γ and α expressions in the liver of Wilson's disease Reviewed

Nagasaka H, Miida T, Inui A, Inoue I, Tsukahara H, Komatsu H, Hiejima E, Fujisawa T, Yorifuji T, Hiranao K.-I, Okajima H, Inomata Y

Mol Genet Metab 107 ( 3 ) 542 - 547 2012.11

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia. Reviewed International journal

Naoto Morishita, Hirokazu Tsukahara, Kosuke Chayama, Toshiaki Ishida, Kana Washio, Takako Miyamura, Nobuko Yamashita, Megumi Oda, Tsuneo Morishima

Pediatric blood & cancer 59 ( 1 ) 83 - 9 2012.7

Language：English Publishing type：Research paper (scientific journal)

Background: Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. Procedure: We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. Results: P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. Conclusion: These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL. © 2011 Wiley Periodicals, Inc.

DOI： 10.1002/pbc.24034

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Oxidative stress biomarkers in pediatric medicine - A 2013 update Reviewed

Hirokazu Tsukahara

Systems Biology of Free Radicals and Antioxidants 689 - 715 2012.5

Language：English Publishing type：Part of collection (book) Publisher：Springer-Verlag Berlin Heidelberg

A large body of circumstantial evidence emphasizes the critical role of reactive oxygen species (ROS), including superoxide anion and nitric oxide (NO), in acute and chronic pediatric diseases. About 15 years ago, measurement of oxidative damage affecting tissues and organs using specific biomarkers was introduced into the field of pediatric medicine. This chapter is intended to describe recent progress in clinical application of oxidative stress biomarkers in pediatric medicine. First, this chapter briefly presents the biochemistry and pathophysiology of ROS and antioxidative defense systems. Second, it discusses the interrelationship of endothelial dysfunction, NO system blockade, and oxidative stress. Third, it presents a list of clinically applicable biomarkers, along with pediatric diseases in which enhanced oxidative stress might be involved. The discussion emphasizes that many good biomarkers are readily measurable using enzyme-linked immunosorbent assay. Fourth, this chapter presents age-related reference normal ranges of oxidative stress biomarkers, including urinary acrolein-lysine, 8-hydroxy-2′-deoxyguanosine, nitrite/nitrate, and pentosidine. Furthermore, our new and interesting data related to oxidative stress and antioxidative defenses in congenital metabolic disorders, such as Wilson disease, urea cycle defects, citrin deficiency, and phenylketonuria, are presented. Rapid diagnostic tests for measuring blood levels of total hydroperoxides and biological antioxidative potential and urinary levels of 8-hydroxy-2′-deoxyguanosine are also explained. Finally, this chapter describes recent clinical studies that have evaluated the efficacy of antioxidative intervention for oxidative-stress-related diseases. Repeated measurement of multiple appropriate parameters will enable us to discern the pathophysiological patterns of pediatric diseases and guide our therapies appropriately.

DOI： 10.1007/978-3-642-30018-9_36

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Focal EEG abnormalities might reflect neuropathological characteristics of pervasive developmental disorder and attention-deficit/hyperactivity disorder

Kawatani M, Hiratani M, Kometani H, Nakai A, Tsukahara H, Tomoda A, Mayumi M, Ohshima Y

Brain & Development 34 ( 9 ) 723 - 730 2012

Cross-sectional study of bone metabolism with nutrition in adult classical phenylketonuric patients diagnosed by neonatal screening Reviewed

Hironori Nagasaka, Hirokazu Tsukahara, Tomozumi Takatani, Yoshitami Sanayama, Masaki Takayanagi, Toshihiro Ohura, Osamu Sakamoto, Tetsuya Ito, Mika Wada, Makoto Yoshino, Akira Ohtake, Tohru Yorifuji, Satoshi Hirayama, Takashi Miida, Hiroki Fujimoto, Hiroshi Mochizuki, Toshikazu Hattori, Yoshiyuki Okano

JOURNAL OF BONE AND MINERAL METABOLISM 29 ( 6 ) 737 - 743 2011.11

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

The mechanism underlying the development of osteopenia or osteoporosis in longstanding phenylketonuria (PKU) remains to be clarified. We investigated the details of bone metabolism in 21 female and 13 male classical PKU patients aged 20-35 years. Vitamin D (VD), parathyroid hormone (PTH), bone turnover markers, and daily nutrient intake were examined. The patients had lower daily energy and protein intake than did the age-matched controls (22 women, 14 men), but their respective fat, VD, and calcium intake did not differ. Serum 1,25-dihydroxy VD and 25-hydroxy VD levels in female and male patient groups were significantly higher and lower than those in respective control groups (females, P < 0.001; males, P < 0.05 and P < 0.01, respectively). Serum intact PTH levels were significantly higher in the female patient group (P < 0.05). Urinary calcium levels in the patient groups were significantly higher than those of the control subjects (females, P < 0.001; males, P < 0.05). Bone resorption markers were significantly higher in patients than in controls, although bone formation markers were not different. Patient serum levels of osteoprotegerin-inhibiting bone resorption were significantly lower (females, P < 0.001; males, P < 0.01). None of the bone parameters correlated significantly with serum phenylalanine or nutrient intake. PKU patients exhibited lower VD status and more rapid bone resorption despite normal calcium-VD intakes.

DOI： 10.1007/s00774-011-0276-6

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Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria Reviewed

Yoshitami Sanayama, Hironori Nagasaka, Masaki Takayanagi, Toshihiro Ohura, Osamu Sakamoto, Tetsuya Ito, Mika Ishige-Wada, Hiromi Usui, Makoto Yoshino, Akira Ohtake, Tohru Yorifuji, Hirokazu Tsukahara, Satoshi Hirayama, Takashi Miida, Mitsuru Fukui, Yoshiyuki Okano

MOLECULAR GENETICS AND METABOLISM 103 ( 3 ) 220 - 225 2011.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Few studies have looked at optimal or acceptable serum phenylalanine levels in later life in patients with phenylketonuria (PKU). This study examined the oxidative stress status of adolescents and adults with PKU. Forty PKU patients aged over fifteen years were enrolled, and were compared with thirty age-matched controls. Oxidative stress markers, anti-oxidant enzyme activities in erythrocytes, and blood anti-oxidant levels were examined. Nitric oxide (NO) production was also examined as a measure of oxidative stress. Plasma thiobarbituric acid reactive species and serum malondialdehyde-modified LDL levels were significantly higher in PKU patients than control subjects, and correlated significantly with serum phenylalanine level (P<0.01). Plasma total anti-oxidant reactivity levels were significantly lower in the patient group, and correlated negatively with phenylalanine level (P<0.001). Erythrocyte superoxide dismutase and catalase activities were higher and correlated significantly with phenylalanine level (P<0.01). Glutathione peroxidase activity was lower and correlated negatively with phenylalanine level (P<0.001). The oxidative stress score calculated from these six parameters was significantly higher in patients with serum phenylalanine of 700-800 mu mol/l. Plasma anti-oxidant substances, beta-carotene, and coenzyme Q(10) were also lower (P<0.001), although the decreases did not correlate significantly with the phenylalanine level. Serum nitrite/nitrate levels, as stable NO products, were higher together with low serum asymmetric dimethylarginine, as an endogenous NO inhibitor. Oxidative stress status is closely linked with serum phenylalanine levels. Phenylalanine level in should be maintained PKU below 700-800 mu mol/l even in adult patients. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ymgme.2011.03.019

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CD36 deficiency predisposing young children to hypoglycemia. Reviewed

Nagasaka H, Yorifuji T, Okano Y, Tsukahara H, Yanai H, Hirano K, Hui SP, Hirayama S, Chiba H, Miida T

Metabolism. 60 ( 6 ) 881 - 887 2011.6

水痘帯状疱疹ウイルスの再活性化により無疱性帯状疱疹と髄膜炎を発症した急性リンパ性白血病の1例

藤井洋輔, 宮村能子, 茶山公祐, 長岡義晴, 津下充, 八代将登, 齊藤有希恵, 森下直人, 石田敏章, 鷲尾佳奈, 山下信子, 塚原宏一, 小田慈, 森島恒雄

小児科臨床 64 ( 6 ) 1111 - 1115 2011.6

Language：Japanese Publisher：(株)総合医学社

無疱性帯状疱疹は皮疹を欠く無疱性の水痘帯状疱疹ウイルス(VZV)感染症であるが、その診断は困難であることが少なくない。今回、急性リンパ性白血病(ALL)の寛解期維持療法中にVZV再活性化により無疱性帯状疱疹と髄膜炎を発症した小児例を経験した。症例は15歳男児で、B前駆細胞性ALLの維持療法中に発熱、嘔吐を来して入院した。経過中、脳脊髄液細胞増加と左末梢性顔面神経麻痺が出現した。皮疹は出現しなかったが、髄液と唾液よりVZV-DNAが検出されたため、VZV再活性化による無疱性帯状疱疹および髄膜炎と診断した。プレドニゾロンとアシクロビルの併用により、諸症状は改善した。白血病の経過中に生じる顔面神経麻痺は、原病の再発と関連する場合が多いが、ウイルスの再活性化に伴う場合もあり、その鑑別診断は適切な治療を行ううえで重要である。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J00643&link_issn=&doc_id=20110603230013&doc_link_id=%2Fag1snrsd%2F2011%2F006406%2F013%2F1111-1115%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag1snrsd%2F2011%2F006406%2F013%2F1111-1115%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

A case of intracranial saccular aneurysm after primary varicella zoster virus infection. Reviewed

Kawatani M, Nakai A, Okuno T, Tsukahara H, Ohshima Y, Mayumi M

Brain & development 34 ( 1 ) 80 - 82 2011.3

Images in emergency medicine. Pregnant woman with gastric pain. Hypertriglyceridemia-induced pancreatitis. Reviewed

Nishijima K, Takahashi J, Yamamoto M, Orisaka M, Suzuki C, Tsukahara H, Shukunami K, Kurokawa T, Yoshida Y, Kotsuji F

Annals of emergency medicine 55 ( 5 ) 483, 490 2010.5

MRIにて脳梁膨大部に可逆性の変化が認められたロタウイルス脳症の1例

古畑律代, 塚原宏一, 中井昭夫, 谷澤昭彦, 眞弓光文, 石森佳幸, 河村泰孝, 朱蕾, 牛島廣治

小児感染免疫 15 ( 3 ) 344 - 344 2003.10

呼吸器系における一酸化窒素(NO)の病態生理学的役割

塚原宏一

日本小児アレルギー学会誌 = The Japanese journal of pediatric allergy and clinical immunology 16 ( 5 ) 475 - 485 2002.12

Language：Japanese Publisher：THE JAPANESE SOCIETY OF PEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

一酸化窒素 (NO) はNO合成酵素の働きにより L-arginine を基質として生合成されるフリーラジカルである. 呼吸器系を構成するほぼすべての細胞がNOを産生することから, NOは生理的にも様々な呼吸器疾患においても重要な役割を果たすと考えられる.<br>著者らは, 以前より血管内皮の病態生理について臨床的および実験的研究を推進してきた. 本論文では, それらの研究成果に基づいて血管内皮, NOを軸とした呼吸器系の病態生理について論じる.<br>肺の血管内皮は肺血流や換気血流均衡を調節することで血液の効率的な酸素化に寄与している. また, 血管内皮は気道―血管関門を構築し白血球の接着浸潤を抑制することで気道のホメオスターシスを維持している. ところが, 気管支喘息などの炎症性肺疾患では誘導合成されたNOは活性酸素種と相互作用し組織障害性の強い活性窒素種に変化する. このような酸化ストレスが亢進すると血管内皮機能は低下し, 肺の組織障害はさらに進展する. こうしたパラダイムに基づいて, 近年NOが創薬ターゲットとして注目されている. NOガス吸入療法はその代表である.

DOI： 10.3388/jspaci.16.475

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