Published papers

A new dipping method was studied for the measurement of radioactive solution using plastic scintillator sheets and pellets (PSs) and a liquid scintillation counter. The method consists of analyzing the PSs dipped into test solution composed of nine compounds with five different radionuclides, and measuring them by using the ‘in solution’ and ‘without solution’ method. A qualitative analysis based on the obtained spectra and a quantitative analysis by using the empirical linear relationships between radioactivity and count rate were possible. Minimum detectable activities of this method were calculated and compared with World Health Organization guidelines for drinking water.

Neurodegeneration caused with retinal ischemia or high intraocular pressure is irreversible in general. We have focused on the role of hypoxia-inducible factor (HIF) in retinal homeostasis and revealed that HIF inhibition may be effective against retinal neovascular and neurodegeneration. In this study, we performed in vitro screening of natural products and found halofuginone, which is a derivative of febrifugine extracted from hydrangea, as a novel HIF inhibitor. Administration of halofuginone showed a significant neuroprotective effect by inhibiting HIF-1α expression in a murine retinal ischemia-reperfusion model histologically and functionally. These results indicate that halofuginone can be a neuroprotective agent in ischemic retinal degenerative diseases.

Caffeic acid β-phenethyl ester (CAPE), an antioxidative bioactive catechol isolated from propolis, was semisynthesized from chlorogenic acid and related compounds in an extract of raw (unroasted) Robusta coffee (Coffea canephora) beans in 5 steps and a total yield of 31%. Oxidative degradation of the intermediates and target molecule was prevented by alkaline hydrolysis of the chlorogenic acids in the presence of sodium dithionite (Na2S2O4) and deprotection of the catecholic diacetate precursor by Candida antarctica lipase B-mediated transesterification as the final step.

The low turnover rate of thyroid follicular cells and the lack of a long-term thyroid cell culture system have hampered studies of thyroid carcinogenesis. We have now established a thyroid organoid culture system that supports thyroid cell proliferation in vitro. The established mouse thyroid organoids performed thyroid functions including thyroglobulin synthesis, iodide uptake, and the production and release of thyroid hormone. Furthermore, transplantation of the organoids into recipient mice resulted in the formation of normal thyroid–like tissue capable of iodide uptake and thyroglobulin production in vivo. Finally, forced expression of oncogenic NRAS (NRAS ) in thyroid organoids established from p53 knockout mice and transplantation of the manipulated organoids into mouse recipients generated a model of poorly differentiated thyroid cancer. Our findings suggest that this newly developed thyroid organoid culture system is a potential research tool for the study of thyroid physiology and pathology including thyroid cancer. Q61R

An advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis plays a central role in the pathogenesis of diabetic vascular remodeling. This study was conducted to clarify the role of RAGE in nondiabetic atherosclerosis. We used the aortic and coronary atherosclerotic lesions of Watanabe heritable hyperlipidemic (WHHL) rabbits prone to myocardial infarction (WHHLMI) at 1 to 14 months. Immunohistochemistry demonstrated the significant expression of RAGE as early as at 1 month with the stronger expression at 3 and 7 months, which was remarkably diminished at 14 months. RAGE expression was concordant with AGE accumulation. The major original sources of RAGE expression were macrophages and smooth muscle cells in addition to endothelial cells, and RAGE expression was distributed in the areas of phospholipid products, a component of oxidized LDL and nitrotyrosine. The concentrations of serum AGE did not alter significantly with aging. These findings suggested the expression of RAGE was induced by hyperlipidemia and oxidative stress independent of diabetes in WHHLMI rabbits. Additionally, our in vitro study showed that silencing of RAGE tended to attenuate oxidized-LDL-triggered PAI-1 expression in human cultured macrophages, as well as oxidized-LDL-induced tissue factor expression in peritoneal macrophages, suggesting a possible role of RAGE in prothrombogenic molecular regulation. In conclusion, the present study provides in vivo evidence that RAGE plays an integral role in the initiation and progression of nondiabetic atherosclerosis, suggesting that RAGE may be a novel target for treating not only diabetic but also nondiabetic vascular complications.

Commercially available “Chiralscreen® OH” starter kit containing five types of carbonyl reductases (E001, E007, E031, E039, and E078) was used for the reduction of several aromatic and aliphatic ketones to obtain enantiomerically enriched drug precursors and an insect pheromone. Almost stereochemically pure secondary alcohols, used in the synthesis of drugs such as (R)-rasagiline mesylate, (S)-rivastigmine, (R)-chlorphenesin carbamate, and (R)-mexiletine, and the insect pheromone (4S,5R)-sitophilure, were conveniently obtained. The enzymes worked well with ketones containing at least one non-bulky substituent at the carbonyl group. The diverse stereochemical preference of the above five carbonyl reductases was clarified.

健常成人男女を対象に、バナナを4週間連続摂取したときの腸内フローラ、ビタミンB6の変化、血液中の脂質、電解質、糖代謝マーカー、微量栄養素の変化を調べた。試験参加者の体組成についてバナナ摂取群と非摂取群いずれも有意な変化はみられなかったものの、バナナ摂取群のうちBMI上位(BMI≧24)者において統計学的に有意にBMIが減少した。ビタミンB6は、バナナ摂取群、非摂取群いずれにおいても有意な変化はみられなかった。収縮期血圧では、バナナ摂取群と非摂取群の群間差で4週間の摂取介入後に、バナナ摂取群が有意に減少していた。最終糖化産物は両群いずれにおいても有意な変化はみられなかった。腸内細菌叢を次世代シークエンサー法で調べた結果、バナナ摂取群でいくつかの有用な細菌叢の増加、望ましくないと考えられている細菌叢の減少がみられた。安全性評価のための血液検査の結果では、バナナ摂取群でクレアチニンが有意に上昇し、介入後の群間比較でもバナナ群のクレアチニンが上昇していた。またバナナ群において尿酸が有意に上昇していた。HbA1cがバナナ群も非摂取群も両方の群において上昇していた。塩素が介入前の時点でバナナ摂取群のほうが非摂取群よりも有意に高かったものの、4週間の試験期間後に非摂取群で有意に上昇していた。さらに、マグネシウムがバナナ摂取群で有意に上昇していた。

ヨーグルトとすりごまの4週間摂取がアレルギー性鼻炎・アレルギー性結膜炎症状に及ぼす変化を評価した。30歳以上60歳未満の健常者43名を、1日にヨーグルト200gとすりごま大さじ2杯(約16g)を合わせて摂取する群、ヨーグルト200g摂取群、非摂取群に割り付け、介入前後の症状、血中アレルギー項目、腸内フローラの変化を調査した。その結果、ヨーグルトとすりごまを摂取した群ではアレルギー性鼻炎・アレルギー性結膜炎の自覚的症状が有意に改善し、腸内フローラの組成が変化していくつか有益な細菌叢が増加しており、特異的IgEのカバ(樺)への反応が有意に低下していた。また、CD陽性のヘルパーT細胞1とヘルパーT細胞2の比率はすべての群で有意に低下しており、ヨーグルトやすりごま摂取に起因する有害事象は認めなかった。