YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
132 巻 , 9 号
選択された号の論文の18件中1~18を表示しています
総説
  • 松岡 茂
    2012 年 132 巻 9 号 p. 969-978
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Many small molecule drugs have molecular targets that are non-crystalline and insoluble biological matrices, such as proteins embedded in lipid membrane, cell membranes, and cell walls. To understand the action mechanisms, it is essential to determine the binding structure with atomic-level resolution. Although solution nuclear magnetic resonance (NMR) and X-ray crystallography have been used to determine molecular structures of cell membrane and membrane proteins, these methods are unable to reproduce the complexity of biological systems because either solubilization or crystallization of target molecules is requisite. For structural studies of insoluble non-crystalline biological samples, so-called “biological solids”, high resolution distance measurements using solid-state NMR are indispensable techniques, of which rotational-echo double-resonance (REDOR) is one of the most widely used methods. In this paper, a brief introduction to REDOR NMR and its applications to structural studies on the antifungal amphotericin B-membrane phospholipid complex and a structural elucidation of photorespiration metabolites in plant cells without extraction or isolation is provided.
  • 室本 竜太
    2012 年 132 巻 9 号 p. 979-984
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Death domain-associated protein (DAXX) is a multifunctional protein that modulates both cell death and transcription. DAXX predominantly localizes in the nucleus and regulates the transcription of genes. Several studies have indicated that DAXX is a mediator of lymphocyte death and/or growth suppression, although it is still unclear whether DAXX pro-cell death function is dependent on its transcriptional functions. We found that DAXX suppresses the gp130/STAT3-dependent cell growth and that DAXX interacts with STAT3 and inhibits its DNA-binding activity. Here we will discuss recent developments in our understanding of the nuclear functions of DAXX.
  • 小谷 明
    2012 年 132 巻 9 号 p. 985-991
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      HPLC with electrochemical detection (HPLC-ECD) is an attractive method with sensitivity and selectivity for the determination of redox compounds. However, an improper system makeup or operation is apt not to show such the intrinsic characteristics of the analytical results by HPLC-ECD in regards to biological sample assays. In this review, HPLC-ECD enabling high-sensitive and precise analysis of compounds of biological importance was developed using the following chemometric strategies: spectrum analysis of chromatographic baseline noise, standard deviation (S.D.) of area measurements in baseline noise from stochastic aspects, and optimization of HPLC conditions and method validations in HPLC-ECD using the prediction of precision based on the FUMI (Function of Mutual Information) theory. When HPLC-ECD was established using a capillary column (0.2 mm i.d.), catechins were determined at attomole levels and the present HPLC-ECD was applied to the determination of concentration profiles of catechins in human plasma after green tea ingestion. Moreover, two HPLC-ECD systems for determining acids and bases were developed by the means of the voltammetric reduction of quinone and the oxidation of trolox, respectively. Thus, the application of HPLC-ECD methods has been remarkably expanded through the development of novel ECD for the determination of acids and bases which are less active electrochemically. The present methods for determining acids and bases were applied to the pharmacokinetic studies of free fatty acids and theophylline, respectively. In conclusion, it was shown the present HPLC-ECD methods have been successfully applied to biomedical and pharmaceutical analyses.
  • 中田 健也
    2012 年 132 巻 9 号 p. 993-1000
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      A novel and efficient method for preparing chiral 2-arylalkanoic acid derivatives, including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, ketoprofen, fenoprofen, flurbiprofen, and naproxen, and their esters by asymmetric esterification is presented in this paper. A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic 2-arylalkanoic acids with achiral alcohols, using carboxylic anhydrides in the presence of chiral acyl-transfer catalysts. It was found that the combination of the modified benzotetramisole-type catalyst, (S)-β-Np-BTM, and a newly designed nucleophile, di(α-naphthyl)methanol, in the presence of a carboxylic anhydride, p-methoxybenzoic anhydride (PMBA) or pivalic anhydride (Piv2O), is most suitable for producing the corresponding chiral esters from 2-arylpropionic acid derivatives, with high enantiomeric excess under very mild reaction conditions. Using this new chiral acylation system, fairly broad substrate scope could be realized despite the multi-functional groups on the aromatic ring of the substrate. It was also revealed that ortho-substituted aromatic compounds, especially, 2,5-disubstituted aromatic ones were the most suitable compounds for providing a high selectivity.
  • 廣瀬 友靖
    2012 年 132 巻 9 号 p. 1001-1010
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Chitin, the second most abundant polysaccharide in nature, is a constituent of fungal cell walls, the exoskeletons of crustaceans and insects and the microfilarial sheaths of parasitic nematodes. Chitin has, so far, not been found in mammals. Accumulation of chitin by organisms is modulated by chitin synthase-mediated biosynthesis and by chitinase-mediated hydrolytic degradation. Thus, chitinases are expected to be specific targets for antifungal, insecticidal and antiparasitic agents. Paradoxically, while chitin does not exist in mammals, human chitinase family members, such as acidic mammalian chitinase, have recently been described, and offer significant potential for the treatment of asthma and other related diseases in humans. This review covers the development of two chitinase inhibitors of natural origin, Argifin and Argadin, isolated from the cultured broth of microorganisms in our laboratory. In particular, the practical total synthesis of these natural products and discovery methods that generate only highly-active compounds using a kinetic target (chitinase)-guided synthesis approach (termed in situ click chemistry) are described.
  • 村木 優一
    2012 年 132 巻 9 号 p. 1011-1017
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Fifty-five thousand organ transplants are performed each year around the world. It is now estimated that over 300000 organ transplant recipients are alive worldwide. Most of these transplant recipients will remain on immunosuppressive drugs for the remainder of their lives to prevent rejection episodes. Doses of these medications must be judiciously managed to optimize patient outcomes. Subtherapeutic drug concentrations may lead to graft rejection and subsequent graft loss. Supratherapeutic drug concentrations increase the likelihood of drug toxicities and increase the likelihood of opportunistic infections. In this review, the latest reports concerning the factors affecting the pharmacokinetics of tacrolimus and micafungin after living donor liver transplant (LDLT) are summarized. Our experimental results demonstrate that preoperative assessment of cytochrome P450 3A5 (CYP3A5) genotypes in both recipients and donors and an immune cell function assay would be useful not only for predicting tacrolimus pharmacokinetics but also for defining groups at high-risk of infectious complications after LDLT. Finally, monitoring plasma trough micafungin concentrations allows safe and effective dose titration of micafungin in LDLT-recipients with total bilirubin concentrations greater than 5 mg/dL.
  • 鈴木 康裕
    2012 年 132 巻 9 号 p. 1019-1024
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      To investigate cerebral infarction and intracranial hemorrhage (ICH) in relation to antithrombotic agents, we established an animal stroke model induced by using a combination of a photosensitive dye and local green photoillumination. Microplasmin (μPli), a derivative of plasmin lacking the five “kringle” domains, was administered in this model, and its effect was studied using magnetic resonance imaging. μPli treatment reduced cerebral damage 24 h after middle cerebral artery occlusion; it also reduced the expansion of the positive area on perfusion-weighted images between 1 and 24 h and the degree of neurological deficits. Tissue-type plasminogen activator (t-PA), a serine proteinase that converts plasminogen to plasmin, has been approved for treating acute ischemic stroke, but delayed treatment is associated with increased risk of ICH. Plasmin participates in the degradation of fibrin, causing clot lysis, and of various extracellular matrix proteins, either directly or via the activation of matrix metalloproteinases (MMPs). In this study, we observed that MMP-3 is relatively important in the enhanced risk of ICH induced by delayed t-PA treatment for ischemic stroke. In particular, the binding of t-PA with low-density lipoprotein receptor-related protein (LRP) results in the release of MMP-3 by endothelial cells. LRP production is upregulated in endothelial cells exposed to ischemia, and elevated LRP levels have been implicated in the increased ICH risk associated with delayed t-PA treatment. This implies that the t-PA/LRP/MMP-3 pathway may be a suitable target for developing strategies to improve the therapeutic efficacy of t-PA in acute ischemic stroke.
  • 井口 和弘
    2012 年 132 巻 9 号 p. 1025-1030
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Bisphosphonates are widely used to treat for osteoporosis and have recently been suggested to be effective in preventing tumor metastasis to the bone. One of the mechanisms underlying metastasis inhibition by bisphosphonates has been explained on the basis of the direct effects of these drugs on cancer cells in the bone microenvironment. Here we have focused on the effect of bisphosphonates on anticancer activity in prostate cancer cells because these cancer cells frequently metastasize to the bone. We found that nitrogen-containing bisphosphonates induced apoptosis and inhibited invasion in prostate cancer PC-3 cells. Bisphosphonate pretreatment was found to enhance cell death induced by anticancer drugs. The expression of the apoptosis- or invasion- related factors, bcl-2, protein kinase C (PKC), aminopeptidase-N (AP-N), and urokinase-type plasminogen activator (uPA) decreased on treatment with nitrogen-containing bisphosphonates. The molecular mechanisms underlying the decrease in bcl-2, AP-N, and uPA expression involved suppression of protein prenylation through inhibition of the mevalonate pathway. These findings have implications with respect to understanding the mechanisms underlying the suppressive effect of bisphosphonates on bone metastasis of prostate cancer.
  • 山本 佐知雄
    2012 年 132 巻 9 号 p. 1031-1035
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Microchip electrophoresis is widely used for microfluidics and has been studied extensively over the past decade. Translation of capillary electrophoresis methods from traditional capillary systems to a microchip platform provides rapid separation and easy quantitation of sample components. However, most microfluidic systems suffer from critical scaling problems. One promising solution to this problem is online sample preconcentration of all analytes in a sample reservoir before the separation channel. Herein, the following three techniques for online preconcentration during microchip electrophoresis are proposed: (1) in situ fabrication of an ionic polyacrylamide-based preconcentrator on a simple poly(methyl methacrylate) microfluidic chip for perm-selective preconcentration and capillary electrophoretic separation of anionic compounds, (2) simultaneous concentration enrichment and electrophoretic separation of weak acids on a microchip using an in situ photopolymerized carboxylate-type polyacrylamide gels as the perm-selective preconcentrator, and (3) microchip electrophoresis of oligosaccharides using lectin-immobilized preconcentrator gels fabricated by in situ photopolymerization. These techniques are expected to be powerful tools for clinical and pharmaceutical studies with on-line preconcentration during microchip electrophoresis.
  • 山崎 大樹
    2012 年 132 巻 9 号 p. 1037-1043
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      TRIC (trimeric intracellular cation) channel subtypes, namely TRIC-A and TRIC-B, are intracellular monovalent cation channels postulated to mediate counter-ion movements facilitating physiological Ca2+ release from intracellular stores. Tric-a-knockout mice developed hypertension during the daytime due to enhanced myogenic tone in resistance arteries. There are two Ca2+ release mechanisms in vascular smooth muscle cells (VSMCs); incidental opening of ryanodine receptors (RyRs) generates local Ca2+ sparks to induce hyperpolarization, while agonist-induced activation of inositol trisphosphate receptors (IP3Rs) evokes global Ca2+ transients causing contraction. Tric-a gene ablation inhibited RyR-mediated hyperpolarization signaling to stimulate voltage-dependent Ca2+ influx, and adversely enhanced IP3R-mediated Ca2+ transients by overloading Ca2+ stores in VSMCs. Therefore, TRIC-A channels contribute to maintaining blood pressure in vascular smooth muscles.
  • 岡田 欣晃
    2012 年 132 巻 9 号 p. 1045-1049
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Roundabout4 (Robo4) is a transmembrane receptor that belongs to the Robo family of neural cell adhesion molecules. Robo4 has been shown to play a role in endothelial cell (EC) migration, proliferation, angiogenesis, and stabilizing the vasculature. Robo4 is expressed specifically in ECs in the developing embryo, placenta, tumors, and normal tissues. The goal of our study is to understand the mechanism for Robo4 gene expression. In the previous study we demonstrated that EC-specific Robo4 gene expression was regulated by the 3-kb Robo4 promoter in the 5′-flanking region of the human Robo4 gene. In vitro studies demonstrated that the Robo4 promoter is activated by the transcription factors GA-binding protein (GABP) and SP1 through the ETS binding site at −119 and the 2 SP1 binding sites at −42 and −153, respectively. The functional relevance of these sites was confirmed by in vivo reporter gene assays using Hprt locus knock in mice. In addition to the regulation mechanism by transcription factors, our recent study implicated that epigenetic modification of the promoter contributes to the Robo4 gene expression. Here I will discuss the regulation mechanism of Robo4 gene expression by transcription factors and epigenetic control.
  • 吉川 豊
    2012 年 132 巻 9 号 p. 1051-1055
    発行日: 2012年
    公開日: 2012/09/01
    ジャーナル フリー
      The number of patients suffering from diabetes mellitus in 2007 was reported to be approximately 200 million people worldwide. Since the finding of insulinomimetic activity of Zn ion, several insulinomimetic Zn complexes have been reported. Zn complexes are expected to be useful in the treatment of diabetes mellitus. We reported that Zn complexes with coordinating sulfur atom exhibit higher insulin-mimetic activity. In this study, we investigated the pharmacological and pharmacokinetic differences between Zn(O4) and Zn(S2O2) coordination environments of tropolonate-Zn complexes with antidiabetic effect. Among the tropolonate-Zn complexes with various coordination environments, di(2-mercaptotropolonato)Zn with the Zn(S2O2) coordination environments was found to exhibit the highest in vitro insulinomimetic activity with respect to glucose uptake in isolated rat adipocytes treated with adrenaline. In vivo experiments, di(2-mercaptotropolonato)Zn was found to exhibit potent hypoglycemic activity and improve insulin resistance in type 2 diabetic KKAy mice at a low orally administered daily dose. On the other hand, di(tropolonato)Zn, which has the Zn(O4) coordination mode, had a lesser effect at the same dose. In a pharmacokinetic analysis based on the tracer method, di(2-mercaptotropolonato)Zn was found to be absorbed at a significantly slower rate with a longer half-life than di(tropolonato)Zn. These results suggest that the potent hypoglycemic activity of di(2-mercaptotropolonato)Zn with Zn(S2O2) coordination environments might be attributed to its long half-life.
  • 高橋 有己
    2012 年 132 巻 9 号 p. 1057-1061
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Interferon-γ (IFN-γ) is a type II IFN that possesses various biological activities including antivirus effect and antitumor effect. Because of its potent biological activities, IFN-γ has been used as a therapeutic treatment for cancer patients and is expected to be a therapeutic for other diseases. As the half-life of IFN-γ in blood circulation is very short, IFN-γ gene therapy, in which IFN-γ gene is used to continuously supply IFN-γ protein, is a promising approach because it can continuously supply IFN-γ. To improve therapeutic effect of IFN-γ-based gene therapy, it is important to control the spatiotemporal distribution of IFN-γ expressed from the plasmid DNA vector encoding IFN-γ. We developed a method to regulate the time profile of IFN-γ expressed from plasmid DNA by modifying vector backbone. In addition, we developed a method that can increase retention time of IFN-γ in blood circulation by designing IFN-γ encoded in plasmid vector as a fusion protein with mouse serum albumin (MSA). Regulation of time profile of IFN-γ expression was highly effective in avoiding unwanted effect of IFN-γ without decreasing therapeutic effect. In addition, gene delivery of MSA-IFN-γ fusion protein increased retention time of IFN-γ in blood circulation than native IFN-γ gene delivery did. Thus, designing both plasmid vector and therapeutic protein encoded by the vector is a promising approach to controlling the spatiotemporal distribution of proteins which can increase the therapeutic potency of IFN-γ-based gene therapy as well as safety of in vivo IFN-γ gene therapy.
  • 中村 誠宏
    2012 年 132 巻 9 号 p. 1063-1067
    発行日: 2012年
    公開日: 2012/09/01
    ジャーナル フリー
      Many foods are known to have not only nutritive and taste values but also medicinal effects. In Egypt, many medicinal foods have been used for the prevention and treatment of various diseases since ancient. However, in most cases, their effective constituents as well as the mechanism of action remained uncharacterized. In the course of our characterization studies on Egyptian medicinal foods and plants, cucurbitane-type triterpene and related compounds such as cucurbitacin E from the fruit of Citrullus colocynthis and the roots of Bryonia cretica were found to show anti-proliferation effects. We therefore synthesized a biotin-linked cucurbitacin E to isolate target proteins based on affinity for the molecule. As a result, cofilin, which regulates the depolymerization of actin, was isolated and suggested to be a target.
  • 土屋 創健
    2012 年 132 巻 9 号 p. 1069-1073
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      In this review, we summarize our findings on microRNA-210 (miR-210) and the target gene, and discuss their significance in human esophageal squamous cell carcinoma (ESCC). MicroRNAs are evolutionarily conserved small noncoding RNAs (20-23 nucleotides) that bind to complementary sequences in the 3′ UTR of target mRNAs and regulate gene expression by the cleavage of target mRNAs and/or translational inhibition. MicroRNAs play important roles in the initiation and progression of cancer, and it has been shown that the expression of some microRNAs is altered in malignancies. Carcinomas are derived from epithelial cells, and poor prognosis in patients with carcinoma is associated with the disruption of characteristics of differentiated epithelial cells, such as cell junctions and polarity. Here, we identified miR-210 as one of the microRNAs that is markedly differentially expressed during the process of epithelial differentiation, though the clinical roles of miR-210 in carcinomas remained unknown. We show that the expression of miR-210 is downregulated in ESCC and derived cell lines. Marked decreases in the level of miR-210 were observed especially in poorly differentiated carcinomas. Moreover, we found that miR-210 inhibits cancer cell survival and proliferation. Finally, we identified fibroblast growth factor receptor-like 1 (FGFRL1) as a target gene of miR-210 in ESCC, and demonstrated that FGFRL1 accelerates cancer cell proliferation. Taken together, our findings show an important role for miR-210 as a tumor suppressive microRNA with effects on cancer cell proliferation.
  • 重永 章
    2012 年 132 巻 9 号 p. 1075-1082
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      An understanding of the physiological significance of peptides and proteins is indispensable in the fields of life sciences and drug development. Recently, methods for controlling peptide and protein activities using stimuli such as UV irradiation have been attracting much attention because of their potential for clarifying the physiological roles of the peptides/proteins. In this context, we have developed a stimulus-responsive amino acid that induces peptide-bond cleavage after exposure to a stimulus. Although it has previously been reported that stimulus-responsive units can respond to a specific stimulus, our stimulus-responsive amino acid is potentially applicable to any stimulus simply by changing the protective group. In this review, the design and synthesis of stimulus-responsive amino acids are described. Their applications in chemical biology, including their use for spatiotemporal control of the activity of peptides in living cells, are also reported.
ノート
  • 奥貞 佳奈子, 奥貞 智, 北田 徳昭, 田中 詳二, 橋田 亨
    2012 年 132 巻 9 号 p. 1083-1088
    発行日: 2012/09/01
    公開日: 2012/09/01
    ジャーナル フリー
      Long-term clinical training programs started as part of a 6-year pharmacy course in May 2010. In order to provide training approaches more appropriately and efficiently, it is necessary for teaching facilities to develop effective training systems and curriculums. In Kobe City Medical Center General Hospital, a pharmacy residency system was instituted in 2009, and, based on this, a preceptorship program for clinical training was adopted. In this study, the influence of pharmacy residents as preceptors on clinical training was evaluated based on training reports submitted by 26 students, consisting of a total of 1238 pages; residents' comments were observed in 31.3% of them. Changes in students' awareness were also noted; in the course of training, they became more aware of the responsibility and role of pharmacists, and such awareness appeared to provide a basis for their future goals. Further, although most of the residents' comments were initially made for encouragement, concrete advice gradually increased with time. Residents' commitment to clinical training as preceptors may have facilitated students' understanding of the significance of training, while promoting their own development.
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