YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
139 巻, 7 号
選択された号の論文の13件中1~13を表示しています
受賞総説
  • 平井 みどり
    2019 年 139 巻 7 号 p. 963-968
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    In 2006, four-year pharmacist training courses in Japanese pharmacy schools were extended to a six-year course. Around that time, I participated in a committee related to pharmacy education reform within the Ministry of Education, Culture, Sports, Science and Technology. I also joined the pharmacist division of the medical council of the Ministry of Health, Labour and Welfare, to reform the national pharmacist examination system. In addition, I was part of the Pharmacy Education Council responsible for developing the contents of the new six-year curriculum, especially for clinical training. In the process, I had the opportunity to interact with many pharmacists and pharmacy educators. Following my transfer from the Pharmaceutical University Division to the Hospital Pharmacy Division in 2007, I participated in multidisciplinary collaborative education [inter professional work (IPW)/inter professional education (IPE)] for students in the disciplines of medicine, nursing, clinical laboratory examination, physiotherapy, occupational therapy, and pharmacy. This gave me an opportunity to apply this multidisciplinary experience to pharmacy education. “IPW”, beyond the so-called “team medical care”, is becoming an increasingly important concept in the medical field. Since all pharmacists are members of a team dedicated to patient-centered care, it is necessary to strengthen collaborative education, which will lead to an overall improvement in medical care. I believe that education is fundamental in all fields, and especially so in medical care. Pharmacy education needs radical reforms to increase its potency and to augment the value of pharmacists in the medical field.

  • 原 幸大
    2019 年 139 巻 7 号 p. 969-973
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    Translesion DNA synthesis (TLS) is an emergency system activated to inhibit cell death caused by DNA damage-induced replication arrest. Thus, TLS enables cancer cells to acquire resistance to alkylate anticancer drugs. REV7 functions as the hub protein that interacts with both the inserter DNA polymerase REV1 and the extender DNA polymerase REV3 in TLS. REV7-mediated protein-protein interactions (PPIs) are essential for the activation of TLS, and are therefore attractive targets for anticancer drug development. To clarify the REV7-REV3 and REV7-REV1 PPIs, we determined the structures of REV7-REV3 and REV7-REV3-REV1 complexes. In the structures of REV7-REV3 and REV7-REV3-REV1 complexes, REV7 wraps around the REV3 fragment, and the REV1-binding interface is distinct from the REV3-binding site of REV7. We also identified a novel REV7 binding protein, transcription factor II-I (TFII-I), which is required for TLS. Of note, TFII-I binds the REV7-REV3-REV1 complex, suggesting that REV7-TFII-I PPIs are independent of other REV7-mediated PPIs. Furthermore, we found a small-molecule compound that inhibits TLS by targeting the REV7-REV3 PPIs. Lastly, we determined the structure of REV7 in complex with chromosome alignment maintaining phosphoprotein (CAMP), a known kinetochore-microtubule attachment protein. The overall structure of the REV7-CAMP complex is similar to that of the REV7-REV3 complex, but the REV7-CAMP PPIs are markedly different from the REV7-REV3 PPIs. These findings improve our understanding of multifunctional hub proteins, and are helpful for designing small-molecule compounds for novel anticancer drug development.

  • 神野 伸一郎
    2019 年 139 巻 7 号 p. 975-986
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    We have found that the spiro form of aminobenzopyranoxanthene (ABPX) exhibits dual solvatochromic and nanoaggregate fluorescence in organic solvents by spectrophotometric and theoretical analyses. The dual fluorescence properties of ABPX were adjustable in response to water content, and served as a new detection principal for naked-eye visualization (above 0.5 wt%) and quantification (0.010-0.125 wt%) of water in tetrahydrofuran. In investigating the optical properties of a dicationic form of ABPX, ABPX containing linear n-alkyl chains at amino groups were then synthesized. These ABPX exhibited fluorescence emission in the far-red and NIR wavelength regions, and we noted an increased fluorescence quantum efficiency with increasing n-alkyl chain length. To further improve the fluorescence quantum yields, we have designed and synthesized ABPX with different nitrogen-containing fused rings. It was kinetically demonstrated that the structurally rigid conjugation of the xanthene moiety is an effective molecular design for the drastic enhancement of fluorescence emission efficiency.

誌上シンポジウム
  • 佐野 和憲, 細川 雅人
    2019 年 139 巻 7 号 p. 987
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー
  • 今村 守一, 森 剛志, 高月 英恵, 岩丸 祥史, 新 竜一郎
    2019 年 139 巻 7 号 p. 989-992
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    The molecular basis underlying the conversion of normal prion protein (PrPC) into abnormal prion protein (PrPSc) has not been fully elucidated. The protein-misfolding cyclic amplification (PMCA) technique, which can amplify PrPSc in vitro with the use of intermittent sonication, mimics the process of in vivo PrPSc replication. Accumulating evidence suggests that co-factors other than PrP may play a crucial role in the faithful replication of PrPSc. In conventional PMCA, brain homogenates (BHs) from normal animals are used as the PrPC substrate. Since BHs contain many impurities, it is difficult to identify the co-factors using conventional PMCA. Thus, we developed a modified PMCA system using baculovirus and insect cell-derived recombinant PrP as a substrate (insect cell PMCA; iPMCA). We demonstrated that nucleic acids and glycosaminoglycans (GAGs) such as heparan sulfate (HS) or its analogue heparin (HP) are critical for PrPSc amplification in iPMCA. Of note, the addition of HS or HP restored the conversion efficiency in iPMCA under nucleic acid-depleted conditions. Moreover, the iPMCA products were infectious and preserved the strain properties of the input seed PrPSc. These data suggest that not only nucleic acids but also some GAGs play an important role in facilitating faithful replication of prions, at least in vitro.

  • 石橋 大輔
    2019 年 139 巻 7 号 p. 993-998
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    Prion diseases, including human Creutzfeldt-Jakob disease, are infectious, intractable central neurodegenerative diseases, which are also zoonoses that commonly infect not only higher organisms but also a wide variety of animals. Pathogenic prions induce abnormal prion protein (PrP), which is produced by structural conversion of normal PrP, a beta-sheet-rich structure with high aggregation propensity. Thus, it is believed that the host is immunotolerant against prions because there is no difference in the primary structure of normal and abnormal PrP, and prions do not induce a marked immune response. Recently, using mutated Toll-like receptor (TLR) 4-transgenic mice, a bioassay after prion inoculation has intriguingly found that the TLR4-signaling pathway may have a protective role against prion infection. Meanwhile, we reported that a transcription factor, interferon regulatory factor-3 (IRF-3), located downstream of TLR4 signaling, showed resistance to prions. IRF-3-inducing type I interferon (I-IFN) is a critical factor for the host defense against pathogen invasion. These findings indicate that the TLR-signaling pathway of the innate immune system might regulate prion invasion. However, the details have not been fully determined. In this symposium, we will introduce new findings including the relationship between I-IFN and prions.

  • 佐野 和憲
    2019 年 139 巻 7 号 p. 999-1005
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    Pathological α-synuclein (αSyn) has been shown to retain the ability to propagate as prions in humans and animals. However, the molecular basis underlying the prion-like properties of αSyn remains poorly understood. We examined whether brain tissues from cases of dementia with Lewy bodies (DLB), which contain serine 129 (Ser129)-phosphorylated insoluble aggregates of αSyn, exhibit prion-like seeding activity in vitro using the real-time quaking-induced conversion (RT-QuIC) seeding assay. Brain tissues from cases of diffuse neocortical DLB yielded a 50% seeding dose of 107.3-109.8/g brain. The RT-QuIC assay could discriminate between DLB and other neurological and neurodegenerative disorders, suggesting its potential applicability for differential diagnosis. Insoluble aggregates of αSyn>250 kDa detected only in DLB brain tissues by Western blotting analysis were specifically phosphorylated at Ser129. Therefore, we postulated that Ser129-phosphorylated insoluble aggregates of αSyn have prion-like seeding activity. However, insoluble aggregates of recombinant human αSyn (rSyn) with increased β-sheet structures showed little seeding activity in either the phosphorylated or nonphosphorylated state. In contrast, prefibrillar oligomers of rSyn showed seeding activity both with and without phosphorylation. The findings of the present study suggested that soluble oligomeric αSyn, but not the fully fibrillary form, is a seeding species in vitro.

  • 鈴掛 雅美, 長谷川 成人
    2019 年 139 巻 7 号 p. 1007-1013
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    α-Synuclein (αS) is the major component of the filamentous inclusions that constitute the defining characteristic of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. αS is deposited in a hyperphosphorylated and ubiquitinated form with a β-sheet-rich fibrillar structure in diseased brains. In 2008, some researchers reported that embryonic neurons transplanted into Parkinson's disease brains had Lewy body-like pathologies, suggesting that pathological αS propagates from diseased neurons to young neurons. Subsequently, a growing body of evidence supported the cell-to-cell spread of αS pathologies. Recent studies have revealed that intracerebral injection of insoluble αS into wild-type mice can induce prion-like propagation of phosphorylated αS pathology even 1 month after injection, while injection into αS-knockout mice failed to induce any pathology. We also showed that intracerebral injection of insoluble αS into adult common marmoset brains results in the spreading of abundant αS pathology. These in vivo experiments clearly indicate that insoluble αS has prion-like properties and that it propagates through neural networks. The underlying mechanisms of αS propagation are still poorly understood, but αS propagation model animals could be helpful in elucidating the pathogenetic mechanisms and developing drugs for synucleinopathies.

  • 徳田 栄一, Stefan L. Marklund, 古川 良明
    2019 年 139 巻 7 号 p. 1015-1019
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that is characterized by the loss of motor neurons, which results in progressive muscle atrophy. The pathology spreads from the initial site of onset to contiguous anatomic regions. Mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) have been identified in a dominantly inherited form of ALS (ALS-SOD1). A major hallmark of ALS-SOD1 is the abnormal accumulation of conformationally aberrant SOD1 protein (i.e., misfolded SOD1) within motor neurons. Emerging experimental evidence has suggested that misfolded proteins associated with neurodegenerative diseases exhibit prion-like properties, i.e., misfolded proteins act as conformational templates that convert normal proteins into a pathogenic form. Possibly as a result of this prion-like self-propagation property, misfolded forms of pathological proteins are considered to accumulate in the central nervous system and cause neurodegeneration. In this article, we review recent evidence for the role of prion-like mechanisms in ALS-SOD1. In particular, we discuss the propensity of misfolded SOD1 to act as a pathological seed, spread between cells, and propagate neuroanatomically.

  • 細川 雅人, 長谷川 成人
    2019 年 139 巻 7 号 p. 1021-1025
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    Abnormal proteins such as tau or α-synuclein that accumulate in brains with dementia have been shown to propagate like prion proteins. However, the expression patterns of tau in the mouse brain are different from those in humans, and the pathogenesis in the animal model of abnormal tau propagation remains incompletely understood. To overcome this problem, a novel mouse showing tau expression patterns similar to those of humans was developed using genome editing techniques. We inoculated the brain of this mouse with a sarkosyl-insoluble fraction containing abnormal tau derived from tauopathy patients and examined the accumulation of tau pathologies. We also performed a detailed analysis of the relationship between the inoculation site and the sites where tau accumulates abnormally by histochemical and neuronal circuitry and elucidated the propagation mechanism of the abnormally accumulated protein. This research is expected to lead to the development of novel drugs for the treatment of dementia using the innovative approach of “inhibition of abnormal protein propagation”.

一般論文
  • 佐々木 裕伊, 全 天候, 元雄 良治, 張 秀嬪, 朴 宣柱, 高 成奎, 張 普亨, 黃 德相
    2019 年 139 巻 7 号 p. 1027-1046
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    The application of systematic review (SR) has been increased rapidly in the field of cancer treatment. Complementary and alternative medicine (CAM) for cancer is no exception. The aim of this review is to evaluate and summarize systematic reviews on the CAM use in breast cancer patients. Search sources were Centre for Reviews and Dissemination (CRD), Cochrane Database of Systematic Reviews (CDSR), and PubMed. In addition, we assessed the quality of SR with the Assessing the Methodological Quality of Systematic Reviews (AMSTAR). This review did not consider control groups and outcomes. Thirty-four SRs met a set of criteria. According to interventions, there were twenty SRs which included yoga, acupuncture, and herbal medicines. Meta-analysis of 19 out of 34 reviews showed the followings: (1) acupuncture had a beneficial effect on the frequency of hot flushes, (2) yoga had a beneficial effect on depression and health-related QOL, (3) mindfulness-based stress reduction (MBSR) had a beneficial effect on anxiety and depression, (4) combination of herbal medicine and chemotherapy synergistically improved clinical outcomes, (5) acupuncture did not show significant effect on the severity of hot flushes and cancer-related pain, (6) yoga was unable to be confirmed as having an effect on cancer-related pain and physical well-being. Given the results of AMSTAR, 9 out of 34 reviews were of high quality and 3 reviews were deemed to be of low quality. In conclusion, since most SRs were at moderate or high quality levels, CAM could be helpful for treating specific symptoms related to breast cancer.

    Editor's pick

    We reviewed systematic reviews (SRs) subjected for breast cancer patients who used complementary and alternative medicine (CAM); that is, (1) which CAM was used, (2) how much evidence was contained. Thirty-four SRs met a set of criteria. Among interventions, yoga (9), acupuncture (6), and herbal medicines (5) were mainly used. Evaluation of quality of SRs using AMSTAR revealed that 9 out of 34 reviews were of high quality and 3 reviews were deemed to be of low quality.

ノート
  • 鈴木 理珠, 鈴木 匡, 菊池 千草
    2019 年 139 巻 7 号 p. 1047-1054
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    In 2015, Japan's Ministry of Health, Labour and Welfare released a report on the need for pharmacies to support public health, although the details of such a service was left to each pharmacy. Consequently, pharmacists had to determine the nature of such services. We considered the services that pharmacists could offer to improve people's lifestyles. This study tests such a service at a pharmacy. We prepared a lifestyle self-review test. From September 2015 to February 2016, pharmacists interviewed members of the community using the test, and pharmacists at 50 pharmacies in Aichi prefecture, Japan, set goals for lifestyle improvement. We analyzed 289 tests. The number of people who had a dietary goal concerning snacking was reduced from 19 people who snacked every day to 11. The number of people who had a goal to reduce their drinking was reduced from 7 people who drank every day to 4. The number of people who had an exercise goal was reduced from 17 people who did not exercise every day to 7. The people who had a sleep goal increased the number of days in which they got adequate rest. Those who had specific, tangible goals for walking achieved their goal at a higher rate than did those who had a goal but no tangible elements, such as time spent or number of steps achieved. Overall, the lifestyle self-review at the pharmacy was effective for lifestyle improvement. Pharmacists should help people set goals with tangible elements to improve their lifestyle more effectively.

  • 堤 竹蔵, 今井 俊吾, 山田 勝久, 山田 武宏, 笠師 久美子, 小林 正紀, 井関 健
    2019 年 139 巻 7 号 p. 1055-1061
    発行日: 2019/07/01
    公開日: 2019/07/01
    ジャーナル フリー

    Linezolid (LZD), an antimicrobial agent against methicillin-resistant Staphylococcus aureus, demonstrates good bone and joint penetration, and is used for prosthetic bone and joint infections. Recently, we observed vomiting in several patients administered LZD. However, there are few reports on the incidence rate of, and risk factors for, LZD-induced nausea and vomiting. In this study, we aimed to verify the relationship between LZD administration and vomiting. Patients administered LZD at the Department of Orthopedic Surgery of Hokkaido University Hospital between November 2008 and December 2017 were enrolled in the study. The primary endpoint was the comparison of the vomiting rate between patients administered LZD (LZD group) and those administered other antibiotics (non-LZD group). For the secondary endpoint, to verify the risk factors of vomiting, a univariate logistic regression analysis was performed. In total, 130 patients were included in this study; 77 patients in the LZD group, and 53 in the non-LZD group. Vomiting occurred in 18 patients in the LZD group and 4 patients in the non-LZD group (23.4% and 7.5%, respectively); this was significantly higher in the LZD group. In the univariate logistic regression analysis, LZD administration, gender (female), age ≥65 years, renal impairment (creatinine clearance <60 mL/min) and concomitant use of rifampicin were extracted as potential risk factors of vomiting. The results of this study reveal a possible relationship between LZD administration and vomiting.

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