論文 - 美谷島 克宏
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OKI Chika, UNO Kinuko, SASASE Tomohiko, TSUTSUI Takahiro, SEKIGUCHI Keita, YAMAGUCHI Ayane, MANDAI Kouhei, SHINOHARA Masami, SUGIMOTO Miki, MAEKAWA Tatsuya, MIYAJIMA Katsuhiro, OHTA Takeshi
Journal of Veterinary Medical Science 87 ( 2 ) 138 - 146 2025年
記述言語：英語 出版者・発行元：JAPANESE SOCIETY OF VETERINARY SCIENCE
<p>Many genetic and environmental factors are involved in the development and progression of diabetic kidney disease (DKD), and its pathology shows various characteristics. Animal models of DKD play an important role in elucidating its pathogenesis and developing new therapies. In this study, we investigated the pathophysiological features of two DKD animal models: <i>db/db</i> mice (background of hyperglycemia) and KK-Ay mice (background of hyperinsulinemia). Male and female mice were fed a high-fat/high-sucrose (HFS) diet for eight weeks. Two mouse models fed the HFS diet showed increases in urinary protein, kidney weight, and glomerular size, but these changes were pronounced in KK-Ay mice. Pathological examination revealed tubulointerstitial fibrosis in KK-Ay mice fed the HFS diet, but not in <i>db/db</i> mice. In addition, fat accumulation was observed in the macula densa of <i>db/db</i> mice and in the glomeruli of KK-Ay mice fed with the HFS diet. In conclusion, an HFS diet exacerbates renal lesions with tubulointerstitial fibrosis in KK-Ay mice, and KK-Ay mice fed an HFS diet are expected to be useful as a DKD model.</p>
DOI： 10.1292/jvms.24-0313
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Ryoke Katsunori, Ishizuka Kana, Yasui Yuzo, Kondo Kazuma, Suzuki-Kemuriyama Noriko, Maekawa Tatsuya, Miyajima Katsuhiro
Fundamental Toxicological Sciences 11 ( 4 ) 159 - 168 2024年
記述言語：英語 出版者・発行元：The Japanese Society of Toxicology
<p>Titin is a giant protein that is specifically expressed in striated muscle and essential for the maintenance of sarcomere structure and function. Recently, the N-terminal fragment of the Titin (N-titin) has been reported to show high levels in human urine in patients with muscular diseases and is expected to serve as a diagnostic biomarker for these diseases. In this study, we examined the utility of N-titin as a biomarker to detect muscle atrophy in mice. Male BALB/c mice (6 weeks of age, n=5 per group) were given 10 mg/L dexamethasone (DEX) dissolved in drinking water for 4 weeks. The gastrocnemius muscle (GAS) weight was significantly decreased and mRNA levels of muscle atrophy-related genes (Atrogin-1 and MuRF-1) were increased in the GAS after 4 weeks of DEX treatment. Although there were no degenerative/necrotic changes in the histopathological examination, the muscle fiber cross-sectional area significantly decreased in the GAS. On the other hand, there were no DEX treatment-related changes in the muscle weights and the muscle fiber cross-sectional area in the soleus muscle. These results suggest that 4-week of DEX treatment preferentially caused atrophy of fast-dominant muscle. Under the condition of this study, urinary N-titin/CRN ratio markedly increased from Week 2 of the DEX treatment. From the above results, the urinary N-titin/CRN ratio could be a biomarker for monitoring skeletal muscle atrophy in mice.</p>
DOI： 10.2131/fts.11.159
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Sano Ryuhei, Ryu Kanjiro, Sasase Tomohiko, Shinozaki Yuichi, Teoh Soon Hui, Yamaguchi Ayane, Uno Kinuko, Maekawa Tatsuya, Ohta Takeshi, Miyajima Katsuhiro
The Journal of Toxicological Sciences 48 ( 11 ) 597 - 606 2023年
記述言語：英語 出版者・発行元：The Japanese Society of Toxicology
<p>Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD). Although current therapeutic strategies for DKD, including sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists, have shown some degree of efficacy, they have failed to completely halt the progression of DKD to ESRD owing to the complexity of DKD pathogenesis. Elucidating the pathophysiological mechanism of DKD is essential for the development of novel therapeutic strategies. In this study, we investigated the pathophysiological characteristics of uninephrectomized (UNx) KK-Ay mice and examined the effects of salt supplementation on the acceleration of renal injury in these mice. UNx KK-Ay mice exhibited pathophysiological renal abnormalities with glomerular and tubulointerstitial fibrosis. Additionally, salt supplementation exacerbated renal injury, particularly tubular injury. These results suggest that UNx KK-Ay mice are useful models for advanced DKD and that salt exacerbates tubular damage in DKD.</p>
DOI： 10.2131/jts.48.597
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Ｊｏｕｒｎａｌ ｏｆ Ｔｏｘｉｃｏｌｏｇｉｃ Ｐａｔｈｏｌｏｇｙ 36 ( 1 ) 1 - 10 2023年
記述言語：英語 出版者・発行元：日本毒性病理学会
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げっ歯類を用いた農薬の発がん性試験結果を解釈する上で留意すべき点について
佐藤 洋, 町野 諭, 藤井 達也, 吉田 緑, 浅野 哲, 横山 央子, 美谷島 克宏
食品衛生学雑誌 63 ( 1 ) 34 - 42 2022年02月
記述言語：日本語 出版者・発行元：公益社団法人 日本食品衛生学会
<p>残留農薬のリスク評価において，発がん性の評価は人への健康にとって最重要課題の一つである．透明かつ一貫性のある評価のためには評価手法の公表は必要不可欠である．本稿は，残留農薬の海外のリスク評価機関や食品安全委員会の農薬評価書など，公表された評価手法を参考に，リスクアナリシスの原則に則り，農薬の発がん性試験評価の考え方と，評価にあたり留意すべき点を提言するものである．本稿ではげっ歯類を用いた発がん性試験の評価で考慮すべき点を，毒性評価のステップごとにまとめた．構成は，げっ歯類を用いた発がん性試験を評価する目的やこれらの試験の有用性に始まり，発がん性を示唆する根拠や影響を与える因子，げっ歯類の発がん性を評価する際に留意すべき点を挙げた．毒性評価のステップであるハザードの特性評価として，これらの知見を総合し判断すべきげっ歯類の発がん性と人への外挿性の考え方を記載した．さらに次のステップとして用量反応関係から判断すべき発がん性についてまとめた．本稿は毒性評価に主眼をおいたものであるが，発がん性評価の今後の展望と課題についても言及した．</p>
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Uno Kinuko, Miyajima Katsuhiro, Toma Marika, Suzuki-Kemuriyama Noriko, Nakae Dai
Journal of Toxicologic Pathology 35 ( 2 ) 149 - 157 2022年
記述言語：英語 出版者・発行元：JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY
<p> Nonalcoholic steatohepatitis is a lifestyle-related disease and an increasing threat worldwide. Hepatic fibrosis, which results from chronic hepatic diseases including nonalcoholic steatohepatitis, is closely correlated with mortality among hepatic lesions, such as steatosis and inflammation. Thus, it is important to identify factors that can serve as diagnostic and therapeutic targets for hepatic fibrosis. In this study, we examined the function of CD44 in the development of hepatic fibrosis in choline-deficient, methionine-lowered, L-amino-acid diet-fed rats, especially with respect to the proliferation of bile duct epithelium. Male Fischer 344 rats were fed a choline-deficient, methionine-lowered, L-amino-acid diet for 2, 4, 13, or 26 weeks. This diet decreased the body weight; increased the levels of serum parameters indicating liver injury, such as aspartate and alanine aminotransferase; upregulated inflammation- and fibrosis-related gene expression in the liver; and resulted in the development of hepatic lesions, including fatty changes in hepatocytes, inflammatory cell infiltration, and fibrosis. Hepatic hyaluronan was synthesized and deposited in the liver tissue. The expression of both CD44 mRNA and protein was significantly increased throughout the experimental period. CD44 protein was observed in some of the bile duct epithelium, around which hyaluronic acid was deposited, and these bile duct lesions were concordant with the area of hepatic fibrosis. Thus, CD44 expressed in the bile duct epithelium may be a target for controlling nonalcoholic steatohepatitis-related hepatic fibrosis.</p>
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A case of spontaneous Zymbal’s gland carcinoma with lung metastasis in an aged Fischer 344 rat
Maeno Ai, Sakamoto Yoshimitsu, Hojo Motoki, Tada Yukie, Suzuki Jin, Inomata Akiko, Moriyasu Takako, Hirose Akihiko, Kemuriyama Noriko, Miyajima Katsuhiro, Nakae Dai
Journal of Toxicologic Pathology 34 ( 4 ) 353 - 358 2021年
記述言語：英語 出版者・発行元：JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY
<p> Zymbal’s gland neoplasms are induced in rats through the administration of various carcinogens, but spontaneous neoplasia is rare. This report describes a spontaneous Zymbal’s gland carcinoma with lung metastasis found in an aged male Fischer 344 rat. Macroscopically, the dome-like tumor nodule, approximately 30 mm in diameter with ulceration, was located near the ear canal of the rat. No healthy tissue or structure of Zymbal’s gland was identified on the corresponding side, while the normal salivary glands and a lacrimal gland were observed. Histologically, a large part of the tumor mass was occupied by poorly differentiated neoplastic cells, the shapes of which were oval to polygonal or fusiform. Additionally, clusters of sebaceous-like foamy cells and squamous metaplasia with prominent keratinization were observed. Tumor cells were found to metastasize to the lung; these cells displayed histological similarities, including a sebaceous gland-like pattern, to those in the primary site. The tumor cells were immunohistochemically positive for cytokeratin AE1/AE3 or vimentin but negative for CD68, S100, α-smooth muscle actin, von Willebrand factor, and desmin. Our results indicate that the tumor was a poorly differentiated Zymbal’s gland carcinoma with lung metastasis.</p>
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Uno Kinuko, Miyajima Katsuhiro, Matsumoto Marika, Toma Marika, Suzuki-Kemuriyama Noriko, Nakae Dai
Fundamental Toxicological Sciences 8 ( 7 ) 221 - 228 2021年
記述言語：英語 出版者・発行元：The Japanese Society of Toxicology
<p><i>Trans</i> fatty acids (TFAs) are risk factors for cardiovascular diseases and have been suggested to play roles in various metabolic diseases, including non-alcoholic steatohepatitis (NASH). The present study aimed to assess the influence of TFAs on the development of NASH lesions. Male Harlan Sprague Dawley rats were fed a choline-deficient, methionine-lowered, L-amino acid-defined (CDAA) diet with or without TFAs for two, four, and 13 weeks. The CDAA diet caused hepatic steatosis, macrophage infiltration, and fibrosis. Further, it increased serum activities of aspartate and alanine aminotransferase, and upregulated inflammation- and fibrosis-related genes in the liver. TFAs enhanced or tended to enhance the serum ALT activity but did not affect other outcomes. In the present study using the CDAA rat model, NASH lesions were clearly induced; however, the effect of TFAs was minimal. In conclusion, TFAs may be a risk factor for NASH by enhancing hepatocellular injury. With the composition and amount used in the present study, TFAs did not affect hepatic steatosis, chronic inflammation, or fibrosis in rats fed with the CDAA diet. To assess the risk of TFAs for NASH, more comprehensive studies are warranted, using other compositions and/or amounts of TFAs.</p>
DOI： 10.2131/fts.8.221
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Teoh Soon Hui, Miyajima Katsuhiro, Shinozaki Yuichi, Shinohara Masami, Ohata Keiichi, Briand François, Morimoto Rika, Nakamura Yuka, Uno Kinuko, Kemuriyama Noriko, Nakae Dai, Ohta Takeshi, Maekawa Tatsuya
The Journal of Toxicological Sciences 46 ( 12 ) 589 - 599 2021年
記述言語：英語 出版者・発行元：The Japanese Society of Toxicology
<p>Type 2 diabetes mellitus represents an international health concern with its growing number of patients worldwide. At the same time, excessive salt consumption is also seen as a major cause of diseases such as hypertension and may expedite renal complications in diabetic patients. In this study, we investigated the effects of excessive sodium chloride supplementation on the kidney of the Spontaneously Diabetic Torii-<i>Lepr<sup>fa</sup></i> (SDT fatty) rat, an obese type 2 diabetes model. Male and female SDT fatty rats and normal Sprague-Dawley (SD) rats at 5 weeks of age were loaded with 0.3% sodium chloride (NaCl) in drinking water for 13 weeks. Blood serum and urinary parameters were observed throughout the experiment and kidney samples were examined in histopathological and genetical analyses. Significant changes on the body weight, blood pressure, urine volume, creatinine clearance, blood urea nitrogen (BUN), relative gene expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and transforming growth factor-β (TGF-β) were observed in the salt-loaded male SDT fatty rats. Urinary L-type fatty acid-binding protein (L-FABP) and albumin levels were higher observed in the salt-loaded male SDT fatty rats throughout the period, but urinary albumin levels in the female SDT fatty rats remain unchanged. In the kidney, slight Armani-Ebstein changes, tubular degeneration, hyaline cast, and inflammatory cell infiltration were observed in female SDT fatty rats while the levels of some changes were higher in the salt-loaded group. The kidney of the salt-loaded male SDT fatty rats demonstrated a higher degree of lesions compared to the female group and the male unloaded group. Histopathological changes in salt-loaded SDT fatty rats show that excessive salt consumption may act as a diabetic pathology exacerbation factor, but the pathology may be influenced by gender difference. Urinary L-FABP levels may act as a useful biomarker to detect slight tubular damages in the kidney. Excessive salt loading was shown to exacerbate the renal injury in SDT fatty rats.</p>
DOI： 10.2131/jts.46.589
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Suzuki-Kemuriyama Noriko, Abe Akari, Nakane Sae, Uno Kinuko, Ogawa Shuji, Watanabe Atsushi, Sano Ryuhei, Yuki Megumi, Miyajima Katsuhiro, Nakae Dai
Fundamental Toxicological Sciences 8 ( 5 ) 135 - 145 2021年
記述言語：英語 出版者・発行元：The Japanese Society of Toxicology
<p>Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease that presents with steatosis, inflammation, and fibrosis and can progress to cirrhosis and cancer. Thus, methods for controlling this lifestyle-related disease are urgently needed. An extract of <i>Siraitia grosvenorii</i> (Luo-Han-Guo) (luohanguo extract (LE)) is widely used as a sweetener; its major bioactive constituents, mogrosides, have shown anti-oxidative and anti-inflammatory properties, exerting multiple pharmacological effects in various disorders. In the present study, we investigated the effects of LE on NASH induced in mice fed a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet without <i>trans</i> fatty acids (CDAA-HF- T(−)). Mice were fed with CDAA-HF- T(−) and drinking water containing LE at concentrations of 0%, 0.2%, 0.6%, and 2% for 28 weeks. Our results showed that LE was not toxic under the experimental conditions evaluated. In the liver of mice fed CDAA-HF- T(−), LE did not affect steatosis or early phase events from macrophage recruitment to hepatocyte death but inhibited late phase events, the progression of inflammation, and fibrosis (mechanisms independent of transforming growth factor-β signaling). Sweeteners with beneficial biological functions, such as LE, may be useful for controlling lifestyle-related diseases, such as NASH, and promoting human health.</p>
DOI： 10.2131/fts.8.135
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Hojo Motoki, Sakamoto Yoshimitsu, Maeno Ai, Tayama Kuniaki, Tada Yukie, Yuzawa Katsuhiro, Ando Hiroshi, Kubo Yoshikazu, Nagasawa Akemichi, Tanaka Kazuyoshi, Yano Norio, Kaihoko Fujifumi, Hasegawa Yuko, Suzuki Toshinari, Inomata Akiko, Moriyasu Takako, Miyajima Katsuhiro, Nakae Dai
Journal of Toxicologic Pathology 33 ( 1 ) 47 - 55 2020年
記述言語：英語 出版者・発行元：JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY
<p> Histopathological information about spontaneous lesions in aged Hannover Wistar rats is limited. In this study, we describe spontaneous lesions found in 39 male RccHan:WIST rats used as a control in a carcinogenicity study. Neoplastic lesions were frequently seen in the endocrine system, such as pituitary adenomas in the pars distalis. This strain exhibited a high incidence of thymoma (10.3%), compared to other strains. We encountered an oligodendroglioma, a pituitary adenoma of the pars intermedia, and a prostate adenocarcinoma, which are comparatively rare in rats. While the variety and incidence of non-neoplastic lesions were similar to those in other strains, several interesting lesions occurred with relatively high incidence, including “harderianization” of the extraorbital lacrimal gland, common bile duct ectasia, and hyperplasia of pulmonary endocrine cells in the lung. Furthermore, comparative analyses demonstrated that the severity of chronic progressive nephropathy and murine progressive cardiomyopathy in RccHan:WIST rats was less than that in F344 rats.</p>
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Watanabe Atsushi, Koizumi Toshinori, Horikawa Takumi, Sano Yusuke, Uki Haruka, Miyajima Katsuhiro, Kemuriyama Noriko, Anzai Reo, Iwata Hijiri, Anzai Takayuki, Nakagawa Kenshi, Nakae Dai
Journal of Toxicologic Pathology 33 ( 2 ) 77 - 86 2020年
記述言語：英語 出版者・発行元：JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY
<p> This study aimed to establish a rat chronic kidney disease (CKD) model by studying the effects of a high-phosphorus diet in rats that had undergone partial ligation of the renal arteries (RL). Separate groups of 10-week-old male Slc:Sprague-Dawley rats underwent RL and were fed diets with varying phosphorous levels for a period of 48 days. A marked suppression of body weight gain necessitating humane euthanization occurred on day 28 in rats that had undergone RL and were given high-phosphorus feed. By contrast, the group of intact animals on a high-phosphorus feed exhibited a slightly decreased body weight gain from day 21 and survived until scheduled euthanization. In rats with RL, hematological, blood biochemical, and histopathological analyses demonstrated the presence of CKD-like conditions, particularly in the group that were fed a high-phosphorus diet. Hyperphosphatemia and hypocalcemia were induced by a high-phosphorus diet in both the RL and intact groups, both of which had high levels of FGF23 and parathyroid hormone in the blood. Rats with RL on a high-phosphorus diet showed decreased hematopoiesis by the hematopoietic cell area being narrower in the medullary cavity, proliferation of mesenchymal cells and osteoblasts/osteoclasts, and expansion of the osteoid area, a furthermore generalized vascular lesions, such as calcification, were observed. These findings demonstrate that the partial ligation of the renal arteries combined with a calcium–phosphorus imbalance induced by a high-phosphorus diet serves as an animal model for CKD-like conditions accompanied by bone lesions, helping to elucidate this clinical condition and its underlying molecular mechanisms.</p>
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Maternal high-fat diet promotes onset of diabetes in rat offspring 査読あり
T. Ohta, Y. Toriniwa, N. Ryumon, N. Inaba, T. Hirao, S. Yamanaka, T. Maeno, W. Sakakibara, M. Sumikawa, K. Chiba, A. Nakamura, K. Miyajima, F. Fatchiyah, T. Yamada
Animal Science Journal 10 ( 1111 ) 12606 2016年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
高脂肪食で飼育した際のSDT fattyラットの糖尿病発症に関して検討した。
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Pathophysiological Changes With Aging in a Novel Obese Diabetic Rat 査読あり
Ohta T, Shinohara M, Gotoh T Yamada T, Miyajima K
Mathews Journal of Nutrition & Dietetics 1 ( 4 ) 1 - 5 2016年05月
記述言語：英語 掲載種別：研究論文（学術雑誌）
高週齢のSDT fattyラットの病態を病理学的に明らかにして動物モデルとしての加齢性病変の特徴をまとめ報告した。
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JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, ameliorates lipid metabolism and attenuates atherosclerosis in hyperlipidemic animal models 査読あり
Y. Mera, T. Kawai, N.Ogawa, N. Odani, T. Sasase, K. Miyajima, T. Ohta, M. Kakutani
Journal of Pharmacological Sciences 129 169 - 176 2015年10月
記述言語：英語 掲載種別：研究論文（学術雑誌）
新規トリグルセライド低下剤であるJTT-130について肝臓の脂質代謝、動脈硬化に対する薬理作用に関して取りまとめた。
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Female spontaneously diabetic Torii fatty rats develop nonalcoholic steatohepatitis-like hepatic lesions
Yukihito Ishii, Yu Motohashi, Makoto Muramatsu, Yoshiaki Katsuda, Katsuhiro Miyajima, Tomohiko Sasase,Takahisa Yamada, Tohru Matsui, Shinichi Kume, Takeshi Ohta
World J Gastroenterol 21 ( 30 ) 2015年08月
記述言語：英語 掲載種別：研究論文（学術雑誌）
雌SDT fattyラットがヒトの非アルコール性脂肪性肝炎（NASH）様病態を呈することを見出し生化学，病理学的にその特徴をまとめ報告した。
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Investigation of Gender Difference of Physiological Response in Gonadectomy in Sprague-Dawley (SD) Rats
K. Miyajima, Y. Toriniwa, Y. Motohashi, Y. Ishii, M. Shinohara, H. Yamashiro, T. Yamada, T. Ohta
British Journal of Medicine & Medical Research 9 ( 6 ) 2015年07月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
雌雄ラットに性腺除去術を施し，全身状態及び脂質代謝に及ぼす影響を検討し，性ホルモンの代謝系に対する関与を発見した。
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Pathophysiological Changes by Short-term Food Restriction in Obese Diabetic Rats
K. Miyajima, Y. Toriniwa, Y. Motohashi, Y. Ishii, M. Shinohara, H. Yamashiro, T. Yamada, T. Ohta
British Journal of Medicine & Medical Research 9 ( 6 ) 2015年06月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
糖尿病モデルラットに短期間の制限摂餌を施し，膵臓保護作用を示唆する変化を確認し報告した。
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Effect of Isolation Stress on Glucose/Lipid Metabolism in Spontaneously Diabetic Torii (SDT) Fatty Rats
K. Miyajima, Y. Toriniwa, Y. Motohashi, Y. Ishii, M. Shinohara, H. Yamashiro, T. Yamada, T. Ohta
British Journal of Medicine & Medical Research 8 ( 7 ) 2015年05月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
肥満を伴う2型糖尿病モデル動物であるSDT fattyラットを群飼育及び個別飼育し各種パラメータの推移について比較した。雌動物では糖尿病病態が進行し，飼育環境が重要な要因の一つであることを確認した。
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Spontaneously Diabetic Torii（SDT）rat における片腎摘出術の有用性の検討
前野孝之，榊原和佳子，住川守男，平尾直啓，山中沙織，千葉薫，勝田佳朋，槇美実，剣持佑介，TongBin，山田宜永，太田毅，美谷島 克宏
実験動物技術 50 ( 1 ) 2015年05月
担当区分：筆頭著者 記述言語：日本語 掲載種別：研究論文（学術雑誌）
糖尿病モデルであるSDTラットに片側腎摘出術を施し病態進行が促進され顕著となることを見出した。