Faculty Profiles - akihide Tanimoto

Noguchi M, Miura N, Ando T, Kubota C, Hobo S, Kawaguchi H, Tanimoto A. . Profiles of reproductive hormone in the microminipig during the normal estrous cycle. . In Vivo.29 ( 1 ) 176 - 22 2015.1Reviewed

Yamada S, Wang KY, Tanimoto A, Sasaguri Y. . Novel function of histamine signaling in hyperlipidemia-induced atherosclerosis: Histamine H1 receptors protect and H2 receptors accelerate atherosclerosis. . Pathol Int.65 ( 2 ) 67 - 80 2015.1Reviewed

Masato Tsutsui, Akihide Tanimoto, Masahito Tamura, Hiroshi Mukae, Nobuyuki Yanagihara, Hiroaki Shimokawa, Yutaka Otsuji . Significance of nitric oxide synthases: Lessons from triple nitric oxide synthases null mice . JOURNAL OF PHARMACOLOGICAL SCIENCES127 ( 1 ) 42 - 52 2015.1Reviewed

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

Nitric oxide (NO) is synthesized by three distinct NO synthases (neuronal, inducible, and endothelial NOSs), all of which are expressed in almost all tissues and organs in humans. The regulatory roles of NOSs in vivo have been investigated in pharmacological studies with non-selective NOS inhibitors. However, the specificity of the inhibitors continues to be an issue of debate, and the authentic significance of NOSs is still poorly understood. To address this issue, we generated mice in which all three NOS genes are completely disrupted. The triple NOSs null mice exhibited cardiovascular abnormalities, including hypertension, arteriosclerosis. myocardial infarction, cardiac hypertrophy, diastolic heart failure, and reduced EDHF responses, with a shorter survival. The triple NOSs null mice also displayed metabolic abnormalities, including metabolic syndrome and high-fat diet-induced severe dyslipidemia. Furthermore, the triple NOSs null mice showed renal abnormalities (nephrogenic diabetes insipidus and pathological renal remodeling), lung abnormalities (accelerated pulmonary fibrosis), and bone abnormalities (increased bone mineral density and bone turnover). These results provide evidence that NOSs play pivotal roles in the pathogenesis of a wide variety of disorders. This review summarizes the latest knowledge on the significance of NOSs in vivo, based on lessons learned from experiments with our triple mutant model. (C) 2015 Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.

DOI： 10.1016/j.jphs.2014.10.002

Michiko Noguchi, Naoki Miura, Takaaki Ando, Chikara Kubota, Seiji Hobo, Hiroaki Kawaguchi, Akihide Tanimoto . Profiles of Reproductive Hormone in the Microminipig During the Normal Estrous Cycle . IN VIVO29 ( 1 ) 17 - 22 2015.1Reviewed

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

We investigated changes in the peripheral plasma concentrations of ovarian steroids and gonadotropins throughout the estrous cycle of the Microminipig (MMpig), a novel experimental animal model. The mean (+/- standard error of the mean (SEM)) duration of estrous and the estrous cycle in seven animals was 66.0 +/- 5.2 h and 20.6 +/- 0.3 days, respectively. A luteinizing hormone (LH) surge was observed 16.5 +/- 6.5 h after the onset of estrous in six out of the seven animals. The LH peak and the duration of the LH surge were 14.0 +/- 4.5 ng/ml and 34.0 +/- 2.0 h, respectively. Plasma progesterone concentrations started to decline on Day 7 (Day 0 = the day of the LH peak) and increased from Day 4. Estradiol-17 beta levels increased from Day 3 and reached a maximum (37.0 +/- 1.6 pg/ml) on Day 0.75. Follicle-stimulating hormone (FSH) concentrations showed a first and second surge on Days 0 and 1.75. An inverse relationship between FSH and estradiol-17 beta concentrations was noted before the LH surge. The characteristics of estrous and the gonadotropin and ovarian steroid profiles throughout the estrous cycle of MMpigs are similar to those of domestic pigs and other miniature pig strains.

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

Taro Uchida, Yumi Furuno, Akihide Tanimoto, Yumiko Toyohira, Kumiko Arakaki, Mika Kina-Tanada, Haruaki Kubota, Mayuko Sakanashi, Toshihiro Matsuzaki, Katsuhiko Noguchi, Junko Nakasone, Tomonori Igarashi, Susumu Ueno, Masayuki Matsushita, Shogo Ishiuchi, Hiroaki Masuzaki, Yusuke Ohya, Nobuyuki Yanagihara, Hiroaki Shimokawa, Yutaka Otsuji, Masahito Tamura, Masato Tsutsui . Development of an experimentally useful model of acute myocardial infarction: 2/3 nephrectomized triple nitric oxide synthases-deficient mouse . JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY77 29 - 41 2014.12Reviewed International journal

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

We investigated the effect of subtotal nephrectomy on the incidence of acute myocardial infarction (AMI) in mice deficient in all three nitric oxide synthases (NOSs). Two-thirds nephrectomy (NX) was performed on male triple NOSs(-/-) mice. The 2/3NX caused sudden cardiac death due to AMI in the triple NOSs(-/-) mice as early as 4 months after the surgery. The 2/3NX triple NOSs(-/-) mice exhibited electrocardiographic ST-segment elevation, reduced heart rate variability, echocardiographic regional wall motion abnormality, and accelerated coronary arteriosclerotic lesion formation. Cardiovascular risk factors (hypertension, hypercholesterolemia, and hyperglycemia), an increased number of circulating bone marrow-derived vascular smooth muscle cell (VSMC) progenitor cells (a pro-arteriosclerotic factor), and cardiac up-regulation of stromal cell-derived factor (SDF)-1 alpha (a chemotactic factor of the progenitor cells) were noted in the 2/3NX triple NOSs(-/-) mice and were associated with significant increases in plasma angiotensin II levels (a marker of renin-angiotensin system activation) and urinary 8-isoprostane levels (a marker of oxidative stress). Importantly, combined treatment with a clinical dosage of an angiotensin II type 1 receptor blocker, irbesartan, and a calcium channel antagonist, amlodipine, markedly prevented coronary arteriosclerotic lesion formation and the incidence of AMI and improved the prognosis of those mice, along with ameliorating all those pro-arteriosclerotic parameters. The 2/3NX triple NOSs(-/-) mouse is a new experimentally useful model of AMI. Renin-angiotensin system activation, oxidative stress, cardiovascular risk factors, and SDF-1 alpha-induced recruitment of bone marrow-derived VSMC progenitor cells appear to be involved in the pathogenesis of AMI in this model. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.yjmcc.2014.09.021

Naoki Miura, Ken-Ichi Kucho, Michiko Noguchi, Noriaki Miyoshi, Toshiki Uchiumi, Hiroaki Kawaguchi, Akihide Tanimoto . Comparison of the Genomic Sequence of the Microminipig, a Novel Breed of Swine, with the Genomic Database for Conventional Pig . IN VIVO28 ( 6 ) 1107 - 1111 2014.11Reviewed International journal

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

The microminipig, which weighs less than 10 kg at an early stage of maturity, has been reported as a potential experimental model animal. Its extremely small size and other distinct characteristics suggest the possibility of a number of differences between the genome of the microminipig and that of conventional pigs. In this study, we analyzed the genomes of two healthy microminipigs using a next-generation sequencer SOLiD (TM) system. We then compared the obtained genomic sequences with a genomic database for the domestic pig (Sus scrofa). The mapping coverage of sequenced tag from the microminipig to conventional pig genomic sequences was greater than 96% and we detected no clear, substantial genomic variance from these data. The results may indicate that the distinct characteristics of the microminipig derive from small-scale alterations in the genome, such as Single Nucleotide Polymorphisms or translational modifications, rather than large-scale deletion or insertion polymorphisms. Further investigation of the entire genomic sequence of the microminipig with methods enabling deeper coverage is required to elucidate the genetic basis of its distinct phenotypic traits.

Sohsuke Yamada, Tomoyuki Koyama, Hirotsugu Noguchi, Yuki Ueda, Ryo Kitsuyama, Hiroya Shimizu, Akihide Tanimoto, Ke-Yong Wang, Aya Nawata, Toshiyuki Nakayama, Yasuyuki Sasaguri, Takumi Satoh . Marine Hydroquinone Zonarol Prevents Inflammation and Apoptosis in Dextran Sulfate Sodium-Induced Mice Ulcerative Colitis . PLOS ONE9 ( 11 ) e113509 2014.11Reviewed International journal

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background and Aim: We previously identified an anti-inflammatory compound, zonarol, a hydroquinone isolated from the brown algae Dictyopteris undulata as a marine natural product. To ascertain the in vivo functions of zonarol, we examined the pharmacological effects of zonarol administration on dextran sulfate sodium (DSS)-induced inflammation in a mouse model of ulcerative colitis (UC). Our goal is to establish a safe and effective cure for inflammatory bowel disease (IBD) using zonarol.
Methods and Results: We subjected Slc:ICR mice to the administration of 2% DSS in drinking water for 14 days. At the same time, 5-aminosalicylic acid (5-ASA) at a dose of 50 mg/kg (positive control) and zonarol at doses of 10 and 20 mg/kg, were given orally once a day. DSS-treated animals developed symptoms similar to those of human UC, such as severe bloody diarrhea, which were evaluated by the disease activity index (DAI). Treatment with 20 mg/kg of zonarol, as well as 5-ASA, significantly suppressed the DAI score, and also led to a reduced colonic ulcer length and/or mucosal inflammatory infiltration by various immune cells, especially macrophages. Zonarol treatment significantly reduced the expression of pro-inflammatory signaling molecules, and prevented the apoptosis of intestinal epithelial cells. Finally, zonarol protected against in vitro lipopolysaccharide (LPS)-induced activation in the RAW264.7 mouse macrophage cell line.
Conclusions: This is the first report that a marine bioproduct protects against experimental UC via the inhibition of both inflammation and apoptosis, very similar to the standard-of-care sulfasalazine, a well-known prodrug that releases 5-ASA. We believe that the oral administration of zonarol might offer a better treatment for human IBDs than 5-ASA, or may be useful as an alternative/additive therapeutic strategy against UC, without any evidence of side effects.

DOI： 10.1371/journal.pone.0113509

Takehiro Yamaguchi, Takanori Yamazaki, Hiroaki Kawaguchi, Masashi Tawa, Yasuhiro Nakamura, Masayuki Shiota, Mayuko Osada-Oka, Akihide Tanimoto, Tomio Okamura, Katsuyuki Miura, Hiroshi Iwao, Minoru Yoshiyama, Yasukatsu Izumi . A Noninvasive Metabolic Syndrome Model Using an Extremely Small Minipig, the Microminipig . JOURNAL OF PHARMACOLOGICAL SCIENCES126 ( 2 ) 168 - 171 2014.10Reviewed

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

Metabolic syndrome (MetS) induces serious complications; therefore, we developed a noninvasive MetS model using an extremely small minipig, the Microminipig. For 8 weeks, Microminipigs were administrated a high-fat and high-cholesterol diet (HFCD) for atherosclerosis and N-G-nitro-L-arginine methyl ester (L-NAME) for inhibiting nitric oxide synthase. HFCD significantly increased serum low-density lipoprotein levels, L-NAME increased blood pressure and cardiac hypertrophy, and HFCD-induced aortal arteriosclerosis was accelerated by L-NAME administration. Endothelium-dependent relaxation of the coronary artery was remarkably decreased by L-NAME administration. This model may be useful for elucidating the mechanisms of MetS and developing new therapeutic medicines for its treatment.

DOI： 10.1254/jphs.14171SC

Kazuhito Hatanaka, Takako Yoshioka, Takashi Tasaki, Akihide Tanimoto . The Hyaline Vascular Type of Castleman's Disease of the Ovary: A Case Report . INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY22 ( 7 ) 652 - 655 2014.10Reviewed International journal

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE PUBLICATIONS INC

Castleman's disease in the pelvic cavity is rare. We present a 72-year-old woman with hyaline vascular type of Castleman's disease of the right ovary. Right ovarian enlargement was detected in the medical examination. Computed tomography revealed a solid mass, measured 2.5 cm in size, in the right ovary. A bilateral salpingo-oophorectomy was performed. Morphologically, lymphoid follicles with regressed germinal centers (GCs) were surrounded by a broad mantle zone composed of concentric rings of small lymphocytes, and the hyalinized blood vessels with plump endothelial cells penetrated radially into GCs. Proliferation of follicular dendritic cells, which were positive for CD21 and epidermal growth factor receptor, were detected in GCs and mantle zone. No other lesions were found. To the best of our knowledge, this is the first case of hyaline vascular type of Castleman's disease of ovarian primary.

DOI： 10.1177/1066896913517936

Taiji Hamada, Masakazu Souda, Takuya Yoshimura, Shoko Sasaguri, Kazuhito Hatanaka, Takashi Tasaki, Takako Yoshioka, Yasuyo Ohi, Sohsuke Yamada, Masato Tsutsui, Yoshihisa Umekita, Akihide Tanimoto . Anti-apoptotic Effects of PCP4/PEP19 in Human Breast Cancer Cell Lines: A Novel Oncotarget . ONCOTARGET5 ( 15 ) 6076 - 6086 2014.8Reviewed International journal

Language：English Publishing type：Research paper (scientific journal) Publisher：IMPACT JOURNALS LLC

The PCP4/PEP19 is a calmodulin-binding anti-apoptotic peptide in neural cells but its potential role in human cancer has largely been unknown. We investigated the expression of PCP4/PEP19 in human breast cancer cell lines MCF-7, SK-BR-3, and MDA-MB-231 cells, and found that estrogen receptor (ER)-positive MCF-7 and ER-negative SK-BR-3 cells expressed PCP4/PEP19. In the MCF-7 cells, cell proliferation was estrogen-dependent, and PCP4/PEP19 expression was induced by estrogen. In both cell lines, PCP4/PEP19 knockdown induced apoptosis and slightly decreased Akt phosphorylation. Knockdown of calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1), resulting in decreased phospho-Akt(Thr308), enhanced apoptosis in SK-BR-3 but not in MCF-7 cells. CaMKK2 knockdown moderately decreased phospho-Akt(Thr308) and increased apoptosis in MCF-7 cells but not in SK-BR-3 cells. These data indicated that PCP4/PEP19 regulates apoptosis but exact mechanism is still unknown. PCP4/PEP19 can therefore potentially serve as independent oncotarget for therapy of PCP4/PEP19-positive breast cancers irrespective of ER expression.

DOI： 10.18632/oncotarget.2161

Tsubasa Hiraki, Michiyo Higashi, Yuko Goto, Ikumi Kitazono, Seiya Yokoyama, Hiroyuki Iuchi, Hiromi Nagano, Akihide Tanimoto, Suguru Yonezawa . A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1 . CARDIOVASCULAR PATHOLOGY23 ( 4 ) 244 - 247 2014.7Reviewed International journal

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

Neurofibromatosis Type 1 (NF1) is a relatively common autosomal dominant disorder. Vascular involvement is a well-recognized manifestation of NF1, but venous aneurysm associated with NF1 is extremely rare. We present a case of an NF1 patient with a left internal jugular vein aneurysm with massive hemorrhage occurring during surgery. Due to the extreme fragility of both the aneurismal wall and the surrounding tissue, the patient developed severe intraoperative bleeding. Pathological examination confirmed aneurismal wall infiltration of the neurofibromatosis. Physicians should be aware that hemorrhagic complication in NF1 can occur and be fatal. (C) 2014 The Authors. Published by Elsevier Inc.

DOI： 10.1016/j.carpath.2014.02.001

Toshiaki Kakimoto, Akira Otsuka, Hiroaki Kawaguchi, Kenji Ogata, Akihide Tanimoto, Hiroaki Kanouchi . Plasma Homocysteine Concentrations in Novel Microminipigs . IN VIVO28 ( 4 ) 579 - 582 2014.7Reviewed International journal

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

A novel microminipig has been recently developed for use in biomedical research. In the present study, age- and sex-related differences, as well as 24-h fluctuations in plasma total homocysteine concentrations (tHcy), were investigated in these microminipigs. tHcy (mean +/- SD) was 10.2 +/- 3.4 mu M and significantly correlated with age. By contrast, neither the differences in tHcy between sexes nor the 24-h fluctuations in tHcy after feeding were significant. The kinetics of plasma tHcy after intravenous injection of reduced Hcy showed that its levels peaked within 5 min post-injection, as did the levels of tHcy. These results suggested that reduced Hcy is rapidly oxidized or metabolized. The half-lives of reduced Hcy, tHcy, and reduced cysteine in the blood were 47, 71, and 141 min, respectively. In conclusion, there was a significantly positive correlation between age and plasma tHcy in microminipigs. After intravenous injection of reduced Hcy, plasma tHcy quickly returned to pre-injection levels.

Masahiro Yokouchi, Satoshi Nagano, Yuko Kijima, Takako Yoshioka, Akihide Tanimoto, Shoji Natsugoe, Setsuro Komiya . Solitary breast metastasis from myxoid liposarcoma . BMC CANCER14 482 - 482 2014.7Reviewed International journal

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Metastasis to the breast from nonmammary malignancies is rare, and mostly involves patients in a pre-terminal condition with systemic metastases outside the breast. Lymphoma and leukemia, melanoma, and lung carcinoma are the most common primary malignancies to cause breast metastasis; metastasis of soft tissue sarcoma to the breast is very rare. Here, we report a case of primary lower-extremity myxoid liposarcoma with the development of a solitary metastasis to the breast. To the best of our knowledge, no isolated case reports of solitary breast metastasis by myxoid liposarcoma have been previously reported in the English-language literature.
Case presentation: The patient, a 66-year-old woman, had been previously diagnosed with myxoid liposarcoma of the right thigh. At 21 months after complete surgical resection of the primary tumor with negative margins, a palpable tumor was identified in the patient's left breast. Needle biopsy revealed the presence of metastatic liposarcoma; positron emission tomography/computed tomography examination confirmed the metastasis as solitary, and no local recurrence of the primary tumor was identified. The patient underwent lumpectomy with negative margins and did not provide consent for adjuvant chemotherapy. As with the biopsy specimen and the total cleavage specimen, myxoid liposarcoma with metastasis to the breast was diagnosed. No recurrence or new metastases were observed five years after resection of the metastatic breast lesion.
Conclusions: We have presented an extremely rare case of a solitary metastatic breast tumor arising from myxoid liposarcoma of the lower limbs. There is no standard treatment for the management of solitary breast metastasis from myxoid liposarcoma. Therefore, treatment should be guided by consideration of an individual patient's overall condition.

DOI： 10.1186/1471-2407-14-482

Yuichiro Sakamoto, Masahiro Yokouchi, Satoshi Nagano, Hirofumi Shimada, Shunsuke Nakamura, Takao Setoguchi, Ichiro Kawamura, Yasuhiro Ishidou, Akihide Tanimoto, Setsuro Komiya . Metastasis of osteosarcoma to the trapezius muscle: a case report . WORLD JOURNAL OF SURGICAL ONCOLOGY12 176 - 176 2014.6Reviewed International journal

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Metastasis of a primary osteosarcoma to the muscles is extremely rare. As there have been few reported cases, the necessity of surgical treatment for such metastatic lesions remains controversial. We present the case of a primary osteosarcoma with development of a solitary metastasis to the trapezius muscle during chemotherapy for pulmonary metastasis. The patient was a 51-year-old man diagnosed with osteosarcoma of the right tibia. After undergoing chemotherapy and femoral amputation, he developed pulmonary metastasis. Chemotherapy was reinitiated, however, after approximately 1 year a palpable tumor was identified in the patient's right shoulder. This tumor grew and was associated with pain in the right shoulder. It was surgically removed 3 years after the reinitiation of chemotherapy. The pathological diagnosis was osteosarcoma with metastasis to the trapezius muscle. Although the patient died of respiratory failure due to pulmonary metastasis 14 months after resection of the metastatic lesion in the trapezius muscle, no new extrapulmonary metastasis was observed after the resection.

DOI： 10.1186/1477-7819-12-176