YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
138 巻 , 1 号
選択された号の論文の18件中1~18を表示しています
受賞総説
  • 齊藤 和季
    2018 年 138 巻 1 号 p. 1-18
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     A variety of chemicals produced by plants, often referred to as ‘phytochemicals’, have been used as medicines, food, fuels and industrial raw materials. Recent advances in the study of genomics and metabolomics in plant science have accelerated our understanding of the mechanisms, regulation and evolution of the biosynthesis of specialized plant products. We can now address such questions as how the metabolomic diversity of plants is originated at the levels of genome, and how we should apply this knowledge to drug discovery, industry and agriculture. Our research group has focused on metabolomics-based functional genomics over the last 15 years and we have developed a new research area called ‘Phytochemical Genomics’. In this review, the development of a research platform for plant metabolomics is discussed first, to provide a better understanding of the chemical diversity of plants. Then, representative applications of metabolomics to functional genomics in a model plant, Arabidopsis thaliana, are described. The extension of integrated multi-omics analyses to non-model specialized plants, e.g., medicinal plants, is presented, including the identification of novel genes, metabolites and networks for the biosynthesis of flavonoids, alkaloids, sulfur-containing metabolites and terpenoids. Further, functional genomics studies on a variety of medicinal plants is presented. I also discuss future trends in pharmacognosy and related sciences.
  • 南部 寿則
    2018 年 138 巻 1 号 p. 19-25
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     This review describes our recent efforts to develop efficient methods for the synthesis of heterocyclic compounds, such as indoles and benzofurans, employing ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes, which were prepared by the reaction of 1,3-cyclohexanediones with sulfonium salts. Ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with primary amines proceeded at room temperature to provide 2-substituted tetrahydroindol-4(5H)-ones in good to excellent yield. The obtained product was readily converted into a 2-substituted 4-hydroxyindole derivative. Furthermore, acid-catalyzed ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes proceeded smoothly at room temperature to provide 2-substituted tetrahydrobenzofuran-4(2H)-ones in excellent yield. The obtained product was converted into a 2-substituted 4-hydroxybenzofuran derivative. The synthetic utility of this catalytic protocol was demonstrated by the total synthesis of cuspidan B.
  • 高木 晃
    2018 年 138 巻 1 号 p. 27-35
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     2-[(Neopentyl glycolato)boryl]phenyl triflates, readily synthesized from 2-iodophenol derivatives via halogen-magnesium exchange or Miyaura borylation, were developed as new benzyne precursors. Benzynes were generated under fluoride-ion-mediated conditions and reacted immediately with various arynophiles. Herein, we describe the generation of benzynes having reactive functional groups, such as methoxycarbonyl, acetyl, bromo, and amino groups, as well as their [4+2], (3+2), and [2+2] cycloaddition reactions which produce corresponding benzo-fused compounds.
誌上シンポジウム
  • 猪熊 翼, 佐藤 伸一
    2018 年 138 巻 1 号 p. 37-38
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
  • 佐藤 伸一, 對馬 理彦, 中村 公亮, 中村 浩之
    2018 年 138 巻 1 号 p. 39-46
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     The chemical labeling of proteins with synthetic probes is a key technique used in chemical biology, protein-based therapy, and material science. Much of the chemical labeling of native proteins, however, depends on the labeling of lysine and cysteine residues. While those methods have significantly contributed to native protein labeling, alternative methods that can modify different amino acid residues are still required. Herein we report the development of a novel methodology of tyrosine labeling, inspired by the luminol chemiluminescence reaction. Tyrosine residues are often exposed on a protein's surface and are thus expected to be good targets for protein functionalization. In our studies so far, we have found that 1) hemin oxidatively activates luminol derivatives as a catalyst, 2) N-methyl luminol derivative specifically forms a covalent bond with a tyrosine residue among the 20 kinds of natural amino acid residues, and 3) the efficiency of tyrosine labeling with N-methyl luminol derivative is markedly improved by using horseradish peroxidase (HRP) as a catalyst. We were able to use molecular oxygen as an oxidant under HRP/NADH conditions. By using these methods, the functionalization of purified proteins was carried out. Because N-methyl luminol derivative is an excellent protein labeling reagent that responds to the activation of peroxidase, this new method is expected to open doors to such biological applications as the signal amplification of HRP-conjugated antibodies and the detection of protein association in combination with peroxidase-tag technology.
  • 谷口 敦彦
    2018 年 138 巻 1 号 p. 47-53
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     Amyloid proteins and peptides form aggregates which lead to amyloid diseases. For example, Alzheimer's disease-related amyloid β (Aβ) forms oligomers, protofibrils, and amyloid fibrils, which exhibit neurotoxicity. Controlling the aggregation and toxicity of Aβ would be a therapeutic strategy for the treatment of Alzheimer's disease. Recently, we have investigated an artificial oxygenative modification (chemical introduction of oxygen atoms) of amyloid proteins using a photocatalyst, which attenuated the aggregation potency and toxicity of these proteins. The oxygenation of Aβ1-42 was efficiently induced using a riboflavin catalyst (1). The oxygenated Aβ was less aggregative and cytotoxic than native Aβ. The oxygenated Aβ also showed inhibitory activity against aggregation and the onset of toxicity of native Aβ. Flavin catalyst 2, bearing an Aβ-binding peptide, allowed the selective oxygenation of Aβ even in the presence of living cells, due to its Aβ-affinity. Furthermore, “On/Off” switchable photooxygenation catalysts 3 and 4, which can sense a higher-order amyloid structure (i.e., cross-β-sheet structure), were developed based on the amyloid fluorescence probe thioflavin-T. The photo-excited catalysts generated singlet oxygens to induce oxygenation when binding to the amyloid structure (“On”). In contrast, the free catalysts, without binding to the amyloid structure, produced no singlet oxygen, even if photo-excited (“Off”). This “On/Off” switchable function enabled highly Aβ-selective oxygenation. Catalyst 3 was successfully used for the selective oxygenation of other amyloid proteins and peptides. These findings suggest that amyloid-selective oxygenation could provide a versatile system in developing effective new treatments for amyloid diseases.
  • 後藤 佑樹
    2018 年 138 巻 1 号 p. 55-61
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     Peptidic natural products often consist of not only proteinogenic building blocks but also unique non-proteinogenic structures such as macrocyclic scaffolds and N-methylated backbones. Since such non-proteinogenic structures are important structural motifs that contribute to diverse bioactivity, we have proposed that peptides with non-proteinogenic structures should be attractive candidates as artificial bioactive peptides mimicking natural products, or so-called pseudo-natural products. We previously devised an engineered translation system for pseudo-natural peptides, referred to as the flexible in vitro translation (FIT) system. This system enabled “one-pot” synthesis of highly diverse pseudo-natural peptide libraries, which can be rapidly screened by mRNA display technology for the discovery of pseudo-natural peptides with diverse bioactivities.
一般論文
  • 漆原 尚巳, 村上 結香, 松井 健志, 田代 志門
    2018 年 138 巻 1 号 p. 63-71
    発行日: 2018/01/01
    公開日: 2018/01/01
    [早期公開] 公開日: 2017/09/25
    ジャーナル フリー
     Under the Japanese drug regulatory system, post-marketing studies (PMS) must be in compliance with Good Post-marketing Study Practice (GPSP). The GPSP Ordinance lacks standards for the ethical conduct of PMSs; although only post-marketing clinical trials are subject to Good Clinical Practice. We conducted a web-based questionnaire survey on the ethical conduct of PMSs in collaboration with the Japanese Society of Hospital Pharmacists and pharmacists belonging to the Society. 1819 hospitals around Japan answered the questionnaire, of which 503 hospitals had conducted company-sponsored PMSs in 2015. 40.2% of the hospitals had obtained informed consent from participating patients in at least one PMS conducted in 2015, the majority of which was in written form. The first and second most frequent reasons for seeking informed consent in PMSs were to meet protocol requirements, followed by the requirement to meet institutional standard operational procedures and the request of the ethical review board of the hospital. Ethical review of PMSs was conducted in 251 hospitals. Despite a lack of standards for informed consent and ethical review in PMSs, a considerable number of study sites employed informed consent and ethical review for PMSs. While company policies and protocols are likely to be major determinants of the ethical conduct of PMSs, the governmental regulatory agency should also play a significant role in implementing a standardized ethical code for the conduct of PMSs.
  • 藤居 賢, 村岡 早苗, 宮本 篤, 桜井 光一
    2018 年 138 巻 1 号 p. 73-81
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     Cytopenia is a major adverse event associated with linezolid therapy. The objective of this study was to examine whether the cytotoxicity of linezolid to eukaryotic cells was associated with mitochondrial dysfunction and apoptosis-like cell death in human leukemic monocyte lymphoma cell line U937. Apoptosis-like cell death was clearly observed when cells were incubated with linezolid, depending on the duration and linezolid concentration. Mitochondrial membrane potential of cells treated with linezolid collapsed in a short period of time, but the number of mitochondria did not decrease. Cytotoxicity of linezolid was relieved by the knockdown of superoxide dismutase-1 in U937 cells. On the other hand, no autophagy was observed in cells treated with linezolid. These results suggest that mitochondrial damages would be linked to the induction of apoptosis in U937 cells treated with linezolid and that its mechanism does not involve autophagy.
  • 志田 敏宏, 遠藤 裕司, 白石 正, 吉岡 孝志, 鈴木 薫, 小林 由佳, 小野 裕紀, 伊藤 頼位, 井上 忠夫
    2018 年 138 巻 1 号 p. 83-90
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     We evaluated four representative chemotherapy regimens for unresectable advanced or recurrent KRAS-wild type colorectal cancer: mFOLFOX6, mFOLFOX6+bevacizumab (Bmab), cetuximab (Cmab), or panitumumab (Pmab). We employed a decision analysis method in combination with clinical and economic evidence. The health outcomes of the regimens were analyzed on the basis of overall and progression-free survival. The data were drawn from the literature on randomized controlled clinical trials of the above-mentioned drugs. The total costs of the regimens were calculated on the basis of direct costs obtained from the medical records of patients diagnosed with unresectable advanced or recurrent colorectal cancer at Yamagata University Hospital and Yamagata Prefecture Central Hospital. Cost effectiveness was analyzed using a Markov chain Monte Carlo (MCMC) method. The study was designed from the viewpoint of public medical care. The MCMC analysis revealed that expected life months and expected cost were 20 months/3,527,119 yen for mFOLFOX6, 27 months/8,270,625 yen for mFOLFOX6+Bmab, 29 months/13,174,6297 yen for mFOLFOX6+Cmab, and 6 months/12,613,445 yen for mFOLFOX6+Pmab. Incremental costs per effectiveness ratios per life month against mFOLFOX6 were 637,592 yen for mFOLFOX6+Bmab, 1,075,162 yen for mFOLFOX6+Cmab, and 587,455 yen for mFOLFOX6+Pmab. Compared to the conventional mFOLFOX6 regimen, molecular-targeted drug regimens provide better health outcomes, but the cost increases accordingly. mFOLFOX 6+Pmab is the most cost-effective regimen among those surveyed in this study.
  • 高井 靖, 平本 恵一, 西村 善幸, 大井 一弥
    2018 年 138 巻 1 号 p. 91-96
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     This study investigated the sex differences of the inflammatory mediator level at the time of itch onset in patients with chronic venous disease (CVD). Twenty-seven CVD patients (nineteen women, eight men) and nine healthy controls (five women, four men) participated. CVD-associated itching was observed in both men and women. Before sclerotherapy, both sexes had elevations in several itch-related mediators. Among these, women had significantly higher tryptase, whereas men had significantly higher β-endorphin and adrenocorticotropic hormone. After sclerotherapy, all levels normalized in both sexes. In this study, itching was increased tryptase in women and increased adrenocorticotropic hormone and β-endorphin in men.
    Editor’s picks

    This study investigated the sex differences of the inflammatory mediator level at the time of itch onset in patients with chronic venous disease (CVD). CVD-associated itching was observed in both men and women. In this study, itching was related to increased tryptase in women and increased adrenocorticotropic hormone and β-endorphin in men. Our findings could be helpful in the treatment of patients with CVD.



  • 宮越 順二, 松原 恵理, 成田 英二郎, 小山 眞, 清水 陽子, 川井 秀一
    2018 年 138 巻 1 号 p. 97-106
    発行日: 2018/01/01
    公開日: 2018/01/01
    [早期公開] 公開日: 2017/09/20
    ジャーナル フリー
     In recent years, highly antimicrobial properties of cedar heartwood essential oil against the wood-rotting fungi and pathogenic fungi have been reported in several papers. Antimicrobial properties against oral bacteria by hinokitiol contained in Thujopsis have been also extensively studied. The relation of naturally derived components and human immune system has been studied in some previous papers. In the present study, we focused on Japanese cedar, which has the widest artificial afforestation site in the country among various tree species. Extract oil was obtained from mixture of sapwood and heartwood of about 40-year cedar grown in Oguni, Kumamoto, Japan. We examined the influence of extract components from Japanese cedar woods on the expression of heat shock protein 70 (Hsp70) during heating, and on the micronucleus formation induced by the treatment of bleomycin as a DNA damaging agent. Cell lines used in this study were human fetal glial cells (SVGp12) and human glioma cells (MO54). Remarkable suppression of the Hsp70 expression induced by heating at 43°C was detected by the treatment of cedar extract in both SVGp12 and MO54 cells. We also found that cedar extract had an inhibitory tendency to reduce the micronucleus formation induced by bleomycin. From these results, the extract components from Japanese cedar woods would have an inhibitory effect of the stress response as a suppression of the heat-induced Hsp70 expression, and might have a reductive effect on carcinogenicity.
ノート
  • 中川 博雄, 松丸 由美, 能勢 誠一, 佐々木 均, 北原 隆志
    2018 年 138 巻 1 号 p. 107-110
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     The concentration of ganciclovir eye drops for hospital preparation was changed from 0.5% to 2.0% at the Nagasaki University Hospital from March 2015. We investigated the incidence of side effects in 12 patients using 2.0% ganciclovir eye drops and evaluated the cytotoxicity of 2.0% ganciclovir eye drops using cultured rabbit corneal cells in vitro. As a side effect of 2.0% ganciclovir eye drops, three patients exhibited an early feeling of transient stimulation. The 2.0% ganciclovir eye drops did not demonstrate cell cytotoxicity for cultured corneal cells after 5 min, but did after 10 min. These findings suggested that the 2.0% ganciclovir eye drops can be used without corneal epithelium disorder in clinical settings.
  • 内山 将伸, 上野 美穂, 高松 泰, 松尾 宏一, 今給黎 修, 神村 英利
    2018 年 138 巻 1 号 p. 111-115
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     In general, the intraventricular administration of cytotoxic antitumor drugs provides a high drug concentration in the cerebrospinal fluid with a reduced risk of systemic adverse reactions. Methotrexate (MTX) high-dose therapy requires close monitoring when performed in combination with trimethoprim-sulfamethoxazole (ST) therapy and proton pump inhibitor (PPI) and nonsteroidal anti-inflammatory drug administration for excretion delay and toxicity enhancement. While the frequency of systemic side effects is thought to be low with intrathecal administration, such effects do rarely but occasionally occur. We must consider drug interactions with combination therapy as a potential factor inducing such effects. We examined the patients who received MTX intrathecal administration at Fukuoka University Hospital from January 2013 to December 2014 with respect to the onset of side effects and combination therapy. MTX intrathecal administration was performed a total of 79 times in 27 patients. In five of these 27 patients, MTX intrathecal administration was performed twice a week, and hematotoxicity and non-hematotoxicity developed in two patients in whom ST was also administered. On the other hand, even if ST and/or PPI was administered, no side effects were observed in the patients administered levofolinate.
  • 見坂 武彦, 片岡 憲司, 藤光 隆司, 谷 佳津治
    2018 年 138 巻 1 号 p. 117-122
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     Migratory birds are considered as vectors of infectious diseases, owing to their potential for transmitting pathogens over large distances. The populations of barn swallow (Hirundo rustica) migrate from Southeast Asia to the Japanese mainland during spring and migrate back to Southeast Asia during autumn. This migratory population is estimated to comprise approximately hundreds to thousands of individuals per year. However, to date, not much is known about the gastrointestinal microbiota of the barn swallow. In this study, we characterized the fecal bacterial community in barn swallow. Using 16S rRNA gene metagenomic sequencing analysis, we examined the presence and composition of potentially pathogenic bacteria in the fecal samples, which were collected during spring season from Osaka. The number (±S.D.) of total bacteria was approximately 2.1(±3.4)×108 per gram of feces. In most samples, the bacterial community composition was dominated by families, such as Enterobacteriaceae, Pseudomonadaceae, Mycoplasmataceae, Enterococcaceae, Streptococcaceae, and Alcaligenaceae. However, no relationship was found between the bacterial community composition and geographical area in the fecal samples. Potentially pathogenic bacteria were detected at the rate of >0.1%, which included Pseudomonas spp., Escherichia/Shigella spp., Enterobacter spp., Yersinia spp., Mycoplasma spp., Enterococcus spp., Achromobacter spp., and Serratia spp. Our results suggested that barn swallow is instrumental in the transmission of these genera over large distances.
  • 笹岡 沙也加, 畠平 春奈, 長谷川 栞, 元岡 佑美, 福田 昌穂, 長沼 美紗, 梅津 亮冴, 中尾 智史, 島内 あかり, 上田 夏実 ...
    2018 年 138 巻 1 号 p. 123-134
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     OTC combination cold remedies are widely used in Japan. In the present study, we aimed to evaluate the adverse event profiles of OTC combination cold remedy based on the components using the Japanese Adverse Drug Event Report (JADER) database. The JADER database contained 430587 reports between April 2004 and November 2016. 1084 adverse events associated with the use of OTC combination cold remedy were reported. Reporting odds ratio (ROR) was used to detect safety signals. The ROR values for “skin and subcutaneous tissue disorders”, “hepatobiliary disorders”, and “immune system disorders” stratified by system organ class of the Medical Dictionary for Regulatory Activities (MedDRA) were 9.82 (8.71-11.06), 2.63 (2.25-3.07), and 3.13 (2.63-3.74), respectively. OTC combination cold remedy containing acetaminophen exhibited a significantly higher reporting ratio for “hepatobiliary disorders” than OTC combination cold remedy without acetaminophen. We demonstrated the potential risk of OTC combination cold remedy in a real-life setting. Our results suggested that the monitoring of individuals using OTC combination cold remedy is important.
ケースレポート
  • 三星 知, 山田 仁志, 長井 一彦, 岡島 英雄
    2018 年 138 巻 1 号 p. 135-139
    発行日: 2018/01/01
    公開日: 2018/01/01
    ジャーナル フリー
     This prospective observational study was conducted to evaluate the continuity, efficacy, and tolerability of sucroferric oxyhydroxide (SO) among hemodialysis (HD) patients who switched to SO from sevelamer hydrochloride (SH) or bixalomer (BX). Participants were 9 HD patients in Kaetsu Hospital who had been receiving more than 9 tablets/d of SH or BX and were switched to SO 750 mg/d. All the participants were men. Over a 6-month observational period, 6 of the 9 patients (67%) discontinued SO because of adverse events, including diarrhea, atheroma, and polycythemia. Although the diarrhea and atheroma were mild, the affected patients did not wish to restart SO. On the other hand, 3 of the 9 patients (33%) continued taking SO throughout the observation period. These patients tended to have increased levels of serum calcium, hematocrit, and serum ferritin; a decreased number of phosphate binder tablets (from 21 tablets/d to 8 tablets/d); and a decreased dosage of erythropoiesis-stimulating agents. Serum phosphate levels tended to decrease in continuers, but tended to increase in discontinuers. It may be preferable to increase the SO dosage gradually rather than switching from SH or BX all at once, and patients who switch to SO should be carefully monitored.
正誤表
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