Faculty Profiles - akihide Tanimoto

Izumi Yasukatsu, Yamaguchi Takehiro, Kawaguchi Hiroaki, Tawa Masashi, Shiota Masayuki, Oka Mayuko, Tanimoto Akihide, Miura Katsuyuki, Iwao Hiroshi . The establishment of a noninvasive metabolic syndrome model using an extremely small size minipig . JOURNAL OF PHARMACOLOGICAL SCIENCES124 234P - 234P 2014Reviewed

Masato Tsutsui, Hiroaki Shimokawa, Akihide Tanimoto, Nobuyuki Yanagihara, Masahito Tamura, Yutaka Otsuji . Roles of nitric oxide synthases in arteriosclerotic vascular disease: Insights from murine genetic models . Journal of Clinical and Experimental Cardiology5 ( 6 ) 2014

Publisher：OMICS Publishing Group

Nitric Oxide (NO) exerts a variety of biological actions under both physiological and pathological conditions. NO is synthesized by three distinct NO synthase (NOS) isoforms, encoded by three distinct NOS genes, including neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS), all of which are expressed in the human vascular system. Although the roles of the NOSs in arteriosclerotic vascular diseases have been described in pharmacological studies with selective and non-selective NOS inhibitors, the selectivity and specificity of the NOS inhibitors continue to be an issue of debate. To solve this issue, genetically altered animals have been established. All types of NOS gene-deficient animals have been developed, including singly, doubly, and triply NOS-deficient mice and various types of NOS Gene-Transgenic (TG) animals have also been generated, including conditional and non-conditional TG mice bearing site-specific overexpression of each NOS gene. The roles of individual NOS isoforms as well as the entire NOSs system in arteriosclerotic vascular diseases have been extensively investigated in those mice, providing pivotal insights into an understanding of the pathophysiological significance of the NOSs in human arteriosclerotic vascular diseases. The present review, which is based on studies with the murine NOS genetic models, summarizes the latest knowledge about the NOSs and arteriosclerotic vascular diseases. © 2014 Tsutsui M, et al.

DOI： 10.4172/2155-9880.1000318

Scopus

Kazuhito Hatanaka, Takako Yoshioka, Takashi Tasaki, Akihide Tanimoto . Pulmonary rhabdomyomatous dysplasia of the newborn in neurofibromatosis type 1 . PATHOLOGY RESEARCH AND PRACTICE210 ( 5 ) 318 - 320 2014Reviewed International journal

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER GMBH, URBAN & FISCHER VERLAG

Proliferation of non-neoplastic striated muscle cells in the lung is rare and has been frequently observed in cases of cardiovascular and pulmonary congenital malformations. We present an extremely rare case of pulmonary rhabdomyomatous dysplasia (RD) in neurofibromatosis type 1 (NF-1). A male neonate was born at 35 weeks' gestation after normal pregnancy. Postnatally, besides patent ductus arteriosus and posterior mediastinal mass, abnormal cystic lesions in the left upper and lower lung were detected. No bronchial atresia and stenosis were identified. Partial lobectomy specimens showed hypoplastic lung parenchyma with cystic lesions resembling terminal bronchioles and distinctive proliferation of non-neoplastic striated muscle fibers in the interstitium. The posterior mediastinal mass consisted of neurofibroma. Considering that cafe au lait spots and freckling occurred at 2 months of age, a diagnosis of NF-1 was made. The patient died of aspiration pneumonia at the age of 30 months. To the best of our knowledge, this is the first case of pulmonary RD in NF-1. (C) 2013 Elsevier GmbH. All rights reserved.

DOI： 10.1016/j.prp.2013.10.008

Atsunori Nabeshima, Sohsuke Yamada, Xin Guo, Akihide Tanimoto, Ke-Yong Wang, Shohei Shimajiri, Satoshi Kimura, Takashi Tasaki, Hirotsugu Noguchi, Shohei Kitada, Teruo Watanabe, Junichi Fujii, Kimitoshi Kohno, Yasuyuki Sasaguri . Peroxiredoxin 4 protects against nonalcoholic steatohepatitis and type 2 diabetes in a nongenetic mouse model . Antioxidants and Redox Signaling19 ( 17 ) 1983 - 1998 2013.12Reviewed International journal

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

Aims: Consumption of a high-fructose diet (HFrD) can induce the development of a metabolic syndrome, manifesting as nonalcoholic steatohepatitis (NASH) and/or type 2 diabetes mellitus (T2DM), via a process in which oxidative stress plays a critical role. Peroxiredoxin 4 (PRDX4) is a unique and only known secretory member of the PRDX antioxidant family. However, its putative roles in the development of NASH and/or T2DM have not been investigated. Results: To elucidate the functions of PRDX4 in a metabolic syndrome, we established a nongenetic mouse model of T2DM by feeding mice a HFrD after injecting a relatively low dose of streptozotocin. Compared with wild-type (WT), human PRDX4 transgenic (Tg) mice exhibited significant improvements in insulin resistance, characterized by a lower glucose and insulin concentration and faster responses in glucose tolerance tests. The liver of Tg also showed less severe vesicular steatosis, inflammation, and fibrosis, along with lower lipid concentrations, lower levels of oxidative stress markers, more decreased expression of hepatic aminotransferase, and more reduced stellate cell activation than those in the WT liver, reminiscent of human early NASH. Hepatocyte apoptosis was also significantly repressed in Tg mice. By contrast, serum adiponectin levels and hepatic adiponectin receptor expression were significantly lower in WT mice, consistent with greater insulin resistance in the peripheral liver tissue compared with Tg mice. Innovation and Conclusion: Our data for the first time show that PRDX4 may protect against NASH, T2DM, and the metabolic syndrome by ameliorating oxidative stress-induced injury. Antioxid. Redox Signal. 19, 1983-1998. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

DOI： 10.1089/ars.2012.4946

Scopus

Sohsuke Yamada, Ke-Yong Wang, Akihide Tanimoto, Xin Guo, Atsunori Nabeshima, Takeshi Watanabe, Yasuyuki Sasaguri . Histamine receptors expressed in circulating progenitor cells have reciprocal actions in ligation-induced arteriosclerosis . PATHOLOGY INTERNATIONAL63 ( 9 ) 435 - 447 2013.9Reviewed International journal

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Histamine is synthesized as a low-molecular-weight amine from L-histidine by histidine decarboxylase (HDC). Recently, we demonstrated that carotid artery-ligated HDC gene-deficient mice (HDC-/-) showed less neointimal formation than wild-type (WT) mice, indicating that histamine participates in the process of arteriosclerosis. However, little is known about the roles of histamine-specific receptors (HHRs) in arteriosclerosis. To define the roles of HHRs in arteriosclerosis, we investigated intimal remodeling in ligated carotid arteries of HHR-deficient mice (H1R(-/-) or H2R(-/-)). Quantitative analysis showed that H1R(-/-) mice had significantly less arteriosclerogenesis, whereas H2R(-/-) mice had more, as compared with WT mice. Bone marrow transplantation from H1R(-/-) or H2R(-/-) to WT mice confirmed the above observation. Furthermore, the increased expression of monocyte chemoattractant protein (MCP-1), platelet-derived growth factor (PDGF), adhesion molecules and liver X receptor (LXR)-related inflammatory signaling factors, including Toll-like receptor (TLR3), interleukin-1 receptor (IL-1R) and tumor necrosis factor receptor (TNF-R), was consistent with the arteriosclerotic phenotype of H2R(-/-) mice. Peripheral progenitor cells in H2R(-/-) mice accelerate ligation-induced arteriosclerosis through their regulation of MCP-1, PDGF, adhesion molecules and LXR-related inflammatory signaling factors. In contrast, peripheral progenitor cells act to suppress arteriosclerosis in H1R(-/-) mice, indicating that HHRs reciprocally regulate inflammation in the ligation-induced arteriosclerosis.

DOI： 10.1111/pin.12091

Hiroaki Kawaguchi, Tomonobu Yamada, Naoki Miura, Michiko Noguchi, Hiroyuki Izumi, Noriaki Miyoshi, Akihide Tanimoto . Sex Differences of Serum Lipid Profile in Novel Microminipigs . IN VIVO27 ( 5 ) 617 - 621 2013.9Reviewed International journal

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

Swine have been used extensively in biomedical research, with a significant increase in recent decades. Minipigs are increasingly becoming an especially attractive animal model in life science research because of their physiological and anatomical similarities to humans. The Microminipig (MMPig) has emerged as a novel and small minipig for non-clinical pharmacological/toxicological use. The MMPig is docile, weighs less than 10 kg in early maturity, and has an easily manageable size. In this study, we report on sex and age patterns in serum biochemistry parameters, including lipid analysis items and lipid profiles in healthy MMPigs. In total, 58 males and 67 females aged 034 months underwent serum biochemistry parameter measurements. Most parameters showed no effect of age or sex (although some did). Lipid analyses showed that the serum levels of total cholesterol, but not those of triglycerides (TG), were consistently higher in females at 0-34 months of age. Lipid profiles in 5-month-old MMPigs were investigated in greater detail. Serum low-density lipoprotein-cholesterol (LDL-C) values were higher in females. The percentage of LDL-C against total cholesterol was also higher, although high-density lipoprotein-cholesterol was lower, in females. There were no sex differences in the TG fraction. Although the sex difference in the serum lipid profile remains unexplained, the reference values obtained in this study could help facilitate the use of MMPigs in life science research.

山本謙一郎, 倉本正文, 池嶋聡, 増田稔郎, 宮田辰徳, 浦田昌幸, 吉松眞一, 江藤健一郎, 谷本昭英, 馬場秀夫, 島田信也 . 腹腔鏡下に切除した骨盤内後腹膜平滑筋肉腫の1例 . 日本外科系連合学会誌38 ( 4 ) 909 - 915 2013.8

Publisher：日本外科系連合学会

症例は63歳女性.4年前,前医における尿路結石診断のためのCT検査にて,左腸骨前面に存在する2cm大の腫瘍を指摘されていた.徐々に増大してきたため当科紹介となった.左腸骨前面に接する4cm大の腫瘍を認めたが,経過ならびにCT・MRI検査にて積極的に悪性の所見を認めないことから骨盤内良性後腹膜腫瘍の術前診断にて,腹腔鏡下に腫瘍摘出術を施行した.特に周囲への癒着・浸潤はなく,腫瘍は完全に切除しえた.切除標本の病理組織学的診断にて,紡錘形の大型核多形性細胞を混在する腫瘍が束状増殖しており,免疫染色も併施し平滑筋肉腫と診断した.後腹膜腫瘍は症状もなく,CT検査にて偶然発見されることも多く,良悪性の術前診断に苦慮する場合も少なくない.画像診断の進歩により,比較的小さな腫瘍径で診断された後腹膜腫瘍は腹腔鏡下に安全かつ低侵襲に切除が可能であるが,悪性腫瘍を念頭においた完全切除が重要である.(著者抄録)

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J01066&link_issn=&doc_id=20130904230035&doc_link_id=10.4030%2Fjjcs.38.909&url=https%3A%2F%2Fdoi.org%2F10.4030%2Fjjcs.38.909&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Kazuhito Hatanaka, Takako Yoshioka, Takashi Tasaki, Akihide Tanimoto . Paratesticular dedifferentiated liposarcoma with leiomyosarcomatous differentiation: a case report with a review of literature . DIAGNOSTIC PATHOLOGY8 142 - 142 2013.8Reviewed International journal

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Paratesticular liposarcoma is a rare neoplasm, described in single case studies or components of larger studies, as histologically well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DL). However, leiomyosarcomatous differentiation is an extremely rare occurrence in WDL and DL. We report a case of leiomyosarcomatous differentiation in a 77-year-old man. The patient presented with a painless right scrotal mass. Magnetic resonance imaging showed a large mass along the right spermatic cord. The resected mass, measuring 17.5 x 12 x 5 cm, was composed of a high-grade pleomorphic undifferentiated sarcomatous component with necrosis. Atypical smooth muscle differentiation was also detected. Additional tumor sampling revealed the presence of a WDL component. Immunohistochemical analysis of the pleomorphic sarcomatous component showed positive staining for MDM2 and CDK4, and negative staining for alpha smooth muscle actin (alpha SMA) and desmin. The smooth muscle component was positive for alpha SMA and desmin, and negative for MDM2 and CDK4. Extension from primary retroperitoneal sarcoma was not proved. We diagnosed of DL with leiomyosarcomatous differentiation.

DOI： 10.1186/1746-1596-8-142

Mayuko Sakanashi, Toshihiro Matsuzaki, Katsuhiko Noguchi, Junko Nakasone, Makiko Sakanashi, Taro Uchida, Mika Kina-Tanada, Haruaki Kubota, Kumiko Arakaki, Akihide Tanimoto, Nobuyuki Yanagihara, Matao Sakanashi, Yusuke Ohya, Hiroaki Masuzaki, Shogo Ishiuchi, Kazuhiro Sugahara, Masato Tsutsui . Long-Term Treatment With San'o-Shashin-To, a Kampo Medicine, Markedly Ameliorates Cardiac Ischemia-Reperfusion Injury in Ovariectomized Rats via the Redox-Dependent Mechanism . CIRCULATION JOURNAL77 ( 7 ) 1827 - 1837 2013.7Reviewed

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE CIRCULATION SOC

Background: Hormone replacement therapy has failed to reduce ischemic cardiovascular events in climacteric women. To explore alternative therapy, we examined whether san'o-shashin-to (TJ-113), a kampo medicine, ameliorates cardiac ischemia-reperfusion (IR) injury in a climacteric rat model.
Methods and Results: Cardiac function and infarct size after IR were significantly exacerbated in ovariectomized rats as compared with sham-operated rats, whereas long-term treatment with a clinical dosage of TJ-113 for 4 weeks markedly improved these functional and morphological changes. Myocardial inducible nitric oxide synthase (iNOS) expression and peroxynitrite levels were significantly higher in ovariectomized rats compared with sham-operated rats, and long-term TJ-113 treatment significantly reduced these oxidative changes. Furthermore, myocardial manganese superoxide dismutase (Mn-SOD) activity was significantly lower in ovariectomized than in sham-operated rats, and long-term TJ-113 treatment significantly restored antioxidant activity. Importantly, those beneficial actions of TJ-113 were significantly inhibited by the estrogen receptor antagonist, fulvestrant, and the phytoestrogen, emodin, a TJ-113 ingredient, mimicked the actions of TJ-113, suggesting involvement of emodin in the effects of TJ-113.
Conclusions: These results provide the first evidence that long-term treatment with a clinical dosage of TJ-113 markedly ameliorates cardiac IR injury in ovariectomized rats via inhibition of iNOS expression, suppression of peroxynitrite formation, and restoration of Mn-SOD activity. TJ-113 may be a novel therapeutic option in the treatment of ischemic heart disease in climacteric women.

DOI： 10.1253/circj.CJ-12-1434

Naoki Miura, Hiroaki Kawaguchi, Tomoka Nagasato, Tomonobu Yamada, Takashi Ito, Hiroyuki Izumi, Hisayo Shameshima, Noriaki Miyoshi, Akihide Tanimoto, Ikuro Maruyama . Coagulation activity and white thrombus formation in the microminipig . In Vivo27 ( 3 ) 357 - 361 2013.5Reviewed International journal

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

Swine are becoming increasingly attractive as animal models for clinical research and the recently developed Microminipig (MMPig) has emerged as a possible experimental animal model. In this study, we demonstrated age-dependent changes in hematological parameters and coagulation activity in healthy MMPigs (58 male and 67 females, aged 0-34 months), and investigated white thrombus formation (WTF) using an in vitro microchip flow-chamber system (four males and four females, aged 22-23 months). There was no clear sex or age-dependent differences in any hematological parameters. While activated partial thromboplastin time (APTT) was shorter than prothrombin time (PT), with APTT:PT of 0.88:1, microchip flow-chamber system analysis showed that WTF time was shorter than that in humans, suggesting a possible thrombotic tendency in the MMPig. These results could be useful to life science researchers in the use of the MMPig as an experimental model animal for thrombus formation.

Scopus

Mitsuru Muto, Tatsuru Kaji, Motoi Mukai, Kazuhiko Nakame, Takako Yoshioka, Akihide Tanimoto, Hiroshi Matsufuji . Ghrelin and glucagon-like peptide-2 increase immediately following massive small bowel resection . PEPTIDES43 160 - 166 2013.5Reviewed International journal

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

Children with short bowel syndrome face life-threatening complications. Therefore, there is an urgent need for a new therapy to induce effective adaptation of the remnant intestine. Adaptation occurs only during feeding. We focused on preprandial acyl ghrelin and des-acyl ghrelin, and postprandial glucagon-like peptide-2 (GLP-2), which are known to have active orexigenic and trophic actions. This study aims to clarify the secretion trends of these hormones after massive small bowel resection and to obtain basic data for developing a new treatment. Sixty-three growing male rats were used: 3 were designated as controls receiving no operation and 60 were randomized into the 80% small bowel resection (80% SBR) group and the transection and re-anastomosis group. Changes in body weight, food intake, and remnant intestine morphology were also assessed for 15 days after the operation. Acyl ghrelin and des-acyl ghrelin levels increased immediately, equivalently in both operation groups (P = 0.09 and 0.70). Interestingly, in 80% SBR animals, des-acyl ghrelin peaked on day 1 and acyl ghrelin peaked on day 4 (P = 0.0007 and P = 0.049 vs controls). GLP-2 secretion was obvious in 80% SBR animals (P = 2.25 x 10(-6)), which increased immediately and peaked on day 4 (P = 0.009 vs. controls). Body weight and food intake in 80% SBR animals recovered to preoperative levels on day 4. Morphological adaptations were evident after day 4. Our results may suggest a management strategy to reinforce these physiological hormone secretion patterns in developing a new therapy for short bowel syndrome. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.peptides.2013.03.006

Institutional Repository URL

山本謙一郎, 蔵元一崇, 倉本正文, 池嶋聡, 増田稔郎, 宮田辰徳, 吉松眞一, 浦田昌幸, 門田正貴, 谷本昭英, 馬場秀夫, 島田信也 . 内臓逆位症に合併した十二指腸乳頭部癌に対して膵頭十二指腸切除術を施行した1例 . 胆と膵34 ( 4 ) 335 - 338 2013.4

Publisher：医学図書出版(株)

症例は73歳女性。黄疸を指摘され当院受診。胸腹部造影CTにて総胆管と膵管の拡張と完全内臓逆位を認めた。上部消化管内視鏡検査では十二指腸乳頭部に表面不整で発赤腫大した易出血性の腫瘍を認めた。生検にて十二指腸乳頭部癌と診断し、亜全胃温存膵頭十二指腸切除術(Child変法再建)を施行した。病理検査所見にてtubular adenocarcinoma、pT3N0M0であった。術後4年3ヵ月無再発生存中である。内臓逆位症は内臓の一部または全部が左右逆転し正常位に対して鏡面的位置関係にある比較的まれな先天疾患であるが、それ自体に病的意義はないといわれている。悪性疾患合併の報告も散見されるが、高難度手術の一つである膵頭十二指腸切除施行例の報告は極めて少ない。今回われわれは完全内臓逆位症に合併した十二指腸乳頭部癌に対して、安全に膵頭十二指腸切除術を遂行し得たので、若干の文献的考察を加えて報告する。(著者抄録)

Takashi Tasaki, Sohsuke Yamada, Xin Guo, Akihide Tanimoto, Ke-Yong Wang, Atsunori Nabeshima, Shohei Kitada, Hirotsugu Noguchi, Satoshi Kimura, Shohei Shimajiri, Kimitoshi Kohno, Hidenori Ichijo, Yasuyuki Sasaguri . Apoptosis Signal-Regulating Kinase 1 Deficiency Attenuates Vascular Injury-Induced Neointimal Hyperplasia by Suppressing Apoptosis in Smooth Muscle Cells . AMERICAN JOURNAL OF PATHOLOGY182 ( 2 ) 597 - 609 2013.2Reviewed International journal

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

Apoptosis signal regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays a crucial role in stress-induced apoptosis. Recently, we have reported that suppressed macrophage apoptosis in ASK1 and apolipoprotein E double-knockout mice accelerates atheromatous plaques in the hyperlipidemia-induced atherosclerotic model. However, the pathogenic role of smooth muscle cell (SMC) apoptosis in atherosclerosis still remains unclear. We investigated neointimal remodeling in ligated carotid arteries of ASK1-deficient mice (ASK1(-/-)) for 3 weeks. ASK1(-/-) mice had significantly more suppressed intimal formation, inversely manifesting as potential anti-atherogenic aspects of ASK1 deficiency, characterized by fewer SMCs and Less collagen synthesis; and fewer apoptotic SMCs, infiltrating T lymphocytes, and microvessels, associated with decreased apoptosis of Luminal endothelial cells, compared with those of wild-type mice. Injured arteries of ASK1(-/-) mice also showed significantly down-regulated expression of pro-apoptotic markers, adhesion molecules, and pro-inflammatory signaling factors. Moreover, tumor necrosis factor-alpha-induced apoptosis was markedly suppressed in cultured aortic SMCs from ASK1(-/-) mice. These findings suggest that ASK1 accelerates mechanical injury-induced vascular remodeling with activated SMC migration via increased neovascularization and/or enhanced SMC and endothelial cell apoptosis. ASK1 expression, especially in the SMCs, might be crucial, and reciprocally responsible for various pro-atherogenic functions, and SMC apoptosis seems to be detrimental in this model. (Am J Pathol 2013, 182: 597-609; http://dx.doi.org/10.1016/j.ajpath.2012.10.008)

DOI： 10.1016/j.ajpath.2012.10.008