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球状疎水性ファーマコフォアを有する非セコステロイド型VDRリガンドの創製研究

藤井晋也, 棚谷綾, 平野智也, 影近弘之

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2014 年 88 巻 8 号 p. 389-395
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_389

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Vitamin D receptor (VDR) is a nuclear receptor for 1α,25-dihydroxyvitamin D_3 (1α,25(OH)_2D_3), and is an attractive target for multiple clinical applications. We have developed two series of novel VDR agonists with different spherical hydrophobic cores, that is, p-carborane (1,12-dicarba-closo-dodecaborane, an icosahedral carbon-containing boron cluster having remarkable thermal and chemical stability) derivatives and bicyclo[2.2.2]octane derivatives. The carborane-based VDR ligands exhibited significant vitamin D activity, comparable to that of the natural hormone, despite its simple structure with flexible skeletal chains. On the other hand, bicyclo[2.2.2]octane derivatives exhibited quite low activity in comparison to the corresponding carborane derivatives. X-ray crystal structure analysis revealed that the binding of the carborane cage to the hydrophobic surface of the ligand-binding pocket of the receptor could promote transition to the active conformation of VDR. These results also suggested that carborane could function efficiently as a hydrophobic anchor in binding to the receptor surface, thereby allowing induced fitting of the three essential hydroxyl groups, despite the entropic disadvantage of the flexible structure. Such a characteristic structure-activity relationship (SAR) of novel non-secosteroidal VDR ligands based on spherical hydrophobic core and information on SAR are thought to contribute to further development of novel VDR ligands which can be applied to medicines.

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マウス骨芽細胞MC3T3-E1の石灰化能に与えるPQQの影響

比嘉由美子, 橘信二郎

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2014 年 88 巻 8 号 p. 396-404
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_396

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Pyrroloquinoline quinone (PQQ), a redox cofactor in several bacteria, has recently attracted attention as a vitamin-like biofactor with various bioactivities reported in mammals. However, there is little information regarding the effects of PQQ on bone metabolism. Thus, we examined the effects of PQQ on mineralization using murine osteoblastic MC3T3-E1 cells to predict its possible actions on bone formation in vivo. In undifferentiated cells, PQQ (10^<-4> M) markedly decreased cell viability and proliferation rate, but these cytotoxic effects were moderately altered in differentiated cells. In differentiated cells cultured for 14 days, PQQ reduced mineralization in a concentration-dependent manner. Alkaline phosphatase (ALP) activity was enhanced in differentiated osteoblastic cells treated with low concentrations of PQQ (10^<-10> and 10^<-6> M), but the expression level of ALP mRNA in the PQQ-treated osteoblastic cells was similar to or lower than that in the control. The mRNA expression of osteocalcin, bone matrix noncollagenous protein, tended to decrease with an increase of PQQ concentrations, even though the COL1A1 mRNA expression levels showed no significant differences between control and PQQ-treated cells. Our findings demonstrate a negative role of PQQ on mineralization during osteoblast differentiation in vitro which is independent of ALP activity.

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疾病罹患時の小児における血液,尿中ビタミンB_1および入院中の変動

東川幸嗣, 美濃眞, 久保敏美, 村知えり, 玉井浩, 大野友彰, 柴田克己

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2014 年 88 巻 8 号 p. 405-411
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_405

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Vitamin B_1 (B_1) deficiency, such as Wernicke's encephalopathy, has been observed occasionally among inpatients prescribed continuous drip infusions including glucose. We examined the blood and urine B_1 levels before and after the treatments, and calculated the calorie and B_1 intake during the period. On admission, B_1 levels in the blood and urine had already declined to that of deficiency. The amount of B_1 from dietary intake in the hospital was thought to be insufficient compared to calorie intake. At the time of discharge from hospital, both of the B_1 levels decreased. Consequently, we should take note of the possibility that many children suffering from disease cannot get enough nutrition. Moreover, their B_1 level was lower than its optimum level and decreased during hospitalization.

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はじめに(<特集>ビタミンB研究委員会平成25年度シンポジウム「ビタミンB群が担う脳内アミノ酸代謝と疾患をターゲットにした次世代学術研究-ビタミン研究が切り拓く疾患生命科学のフロンティア」)

福井清

原稿種別: 本文
2014 年 88 巻 8 号 p. 412-
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_412

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メンデル無作為化解析を用いた統合失調症と血中ホモシステイン濃度との関連の検討(<特集>ビタミンB研究委員会平成25年度シンポジウム「ビタミンB群が担う脳内アミノ酸代謝と疾患をターゲットにした次世代学術研究-ビタミン研究が切り拓く疾患生命科学のフロンティア」)

沼田周助

原稿種別: 本文
2014 年 88 巻 8 号 p. 413-418
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_413

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Previous meta-analyses of studies on the association between blood homocysteine concentration and schizophrenia suggest that elevated blood homocysteine concentration is a risk factor for schizophrenia. However, observational studies on this association have potential problems such as confounding and reverse causation. Mendelian randomization analysis is a method to analyze instrumental variables using genetic variants and can be used for assessing causal relationships. Therefore, we used this Mendelian randomization analysis to investigate the association between blood homocysteine concentration and schizophrenia. As a result, we demonstrated that increased blood homocysteine concentration might be associated with an increased risk of schizophrenia in the Japanese population. This result will offer important insight into the pathophysiology and treatments of schizophrenia.

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D-アスパラギン酸が惹起するタンパク質の異常凝集と加齢性疾患(<特集>ビタミンB研究委員会平成25年度シンポジウム「ビタミンB群が担う脳内アミノ酸代謝と疾患をターゲットにした次世代学術研究-ビタミン研究が切り拓く疾患生命科学のフロンティア」)

藤井紀子

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2014 年 88 巻 8 号 p. 419-424
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_419

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Proteins have been thought to be composed of exclusively L-amino acids. Recently, however, D-aspartate (Asp) residues have been detected in various tissues of elderly humans such as the lens, brain, and skin. The appearance of the D-Asp residues in proteins is responsible for the change in the higher order structure of the proteins leading to the loss of function of the proteins. Therefore, the detection of the optical isomers of individual Asp residues formed in proteins is very important. However, detection of the Asp isomers formed in proteins was difficult because optical resolution is achieved only by use of complex methodology. Therefore, there has been little study of the presence of D-amino acids in proteins. Recently, we developed a new method for rapid and comprehensive analysis of Asp isomerization in proteins using LC-MS. This makes it possible to screen Asp isomers in proteins precisely and quickly. This review focuses on the mechanism of D-amino acid formation in proteins which leads to aggregation of the proteins, and a new method for the detection of individual D-amino acid residues in proteins.

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真核細胞型セリンラセマーゼの反応機構

吉村徹, 伊藤智和

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2014 年 88 巻 8 号 p. 425-428
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_425

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マクロファージにおけるフラボノイド抱合体の活性発現機構

河合慶親, 石坂朱里, 寺尾純二

原稿種別: 本文
2014 年 88 巻 8 号 p. 429-431
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_429

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消化管内で生成する短鎖脂肪酸による糖代謝調節

青山薫英, 白川仁, 駒井三千夫

原稿種別: 本文
2014 年 88 巻 8 号 p. 432-434
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_432

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掲載論文要旨 JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY Vol 60, No 3 (June, 2014)

原稿種別: 文献目録等
2014 年 88 巻 8 号 p. 435-439
発行日: 2014/08/25
公開日: 2017/08/10

DOIhttps://doi.org/10.20632/vso.88.8_435

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