Hokkaido Pharmaceutical University School of Pharmacy

www.hokuyakudai.ac.jp
Otaru, Japan
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Kaneda K.,Hokkaido Pharmaceutical University School of Pharmacy | Naruse R.,Hokkaido Pharmaceutical University School of Pharmacy | Yamamoto S.,Hokkaido Pharmaceutical University School of Pharmacy
Organic Letters | Year: 2017

The synthesis of 2-aminobenzenesulfonamide-containing cyclononyne (ABSACN), starting from 2-nitrobenzenesulfonamide and but-2-yne-1,4-diol via Mitsunobu and Nicholas reactions, is described for the development of an adjustable alkyne reagent in click reactions. In a strain-promoted azide-alkyne cycloaddition (SPAAC) reaction, the reactivity of the alkyne is controlled by introducing various N-functionalities. The structure-reactivity relationship is found to be influenced by a transannular hydrogen bond between amino and sulfonyl groups. © 2017 American Chemical Society.


Norose T.,Hokkaido Pharmaceutical University School of Pharmacy
Yakugaku Zasshi | Year: 2013

In Hokkaido Pharmaceutical University, problem-based learning (PBL) has been introduced as a part of the laboratory and practice curriculum for all school years to promote active learning skills and enhance students' problem-solving ability. The PBL program at our school has been developed using a tutorial study based on scenarios and learning strategies, such as experiments and/or standardized patients (SPs) and role-playing, according to students' developmental stage and learning objectives. The course "Practice VIII/Principles of Clinical Communication" for the fifth-grade students is an example of the new PBL program to improve students' clinical communication skills and ability to design a care plan for patients. We divided 196 students into 49 groups (each group had 4 members). We used the large-class PBL model, in which the students had discussions with several facilitators. The students were presented with a patient-case scenario, in which they were first provided with a brief background of the patient. Afterward, students interviewed SPs to obtain detailed information, based on which a care plan was designed for each patient. Students role-played with SPs as a part of patient support, consulted using the patient care plan, and made Subjective information, Objective information, Assessment, and Plan (SOAP) notes at the end. Some students commented that the PBL program was very helpful in understanding how to design a patient care plan and that they understood the importance of communication in obtaining information for designing a patient care plan. © 2013 The Pharmaceutical Society of Japan.


Miura T.,Hokkaido Pharmaceutical University School of Pharmacy
Yakugaku Zasshi | Year: 2013

The pharmaceutical effects of non-steroidal anti-inflammatory drugs (NSAIDs) occur through the inhibition of prostaglandin H synthase (PGHS). Prostaglandin H2 is produced from arachidonic acid via peroxidase and cyclooxygenase cycles in PGHS. NSAIDs exhibit different levels of reactivity in these reaction cycles. To prevent the development of side effect while maintaining the beneficial effects of drugs, a therapeutic strategy should be used. A new classification of NSAIDs has been proposed based on reactivity to peroxidase. Class 1 includes the majority of NSAIDs, which react with horseradish peroxidase (HRP) compounds I and II. Also, their drugs exhibit spectral changes induced by PGHS peroxidase and diminished ESR signals of the tyrosyl radical of metmyoglobin. They reduce compounds I and II of HRP and scavenge tyrosyl radicals. The branched chain mechanism by which the porphyrin radical is transferred to the tyrosine residue of the protein might be blocked by these NSAIDs. Class 2 includes salicylic acid derivatives that react only with the porphyrin radical and do not react with HRP compound II (oxoferryl species). Class 3 includes aspirin, nimesulide, tolmetin, and arylpropionic acid derivatives, including ibuprofen and the coxibs such as celecoxib and rofecoxib, which are not substrates for HRP or PGHS peroxidase. It seems that the selectivity of NSAIDs to PGHS1 and PGHS2 depends on their reactivity with cyclooxygenase rather than with the peroxidase of PGHS. The best drug for each inflammatory disease should therefore be selected for therapy. © 2013 The Pharmaceutical Society of Japan.


Oyama K.,Hokkaido Pharmaceutical University School of Pharmacy | Takahashi K.,Hokkaido Pharmaceutical University School of Pharmacy | Sakurai K.,Hokkaido Pharmaceutical University School of Pharmacy
Biological and Pharmaceutical Bulletin | Year: 2011

Cell cycle arrest is associated with differentiation, senescence and apoptosis. We investigated alterations in the cell cycle during the development of hypertrophy induced by hydrogen peroxide (H 2O 2) in the H9c2 clonal myoblastic cell line. H 2O 2 induced hypertrophy in H9c2 cells that was indicated by an increase in atrial natriuretic peptide (ANP) gene expression, a marker of cardiomyocyte hypertrophy, and a larger cell size. On induction of hypertrophy by H 2O 2 in H9c2 cells, cell proliferation was arrested, indicated by the number of cells remaining constant during a 72-h incubation period. The cell cycle was arrested at the G1 and G2/M phases with an increase in p21 expression, a negative cell cycle regulator. Cell cycle arrest and increase in p21 expression were significantly inhibited by 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra (acetoxymethyl) ester (BAPTA-AM), an intracellular calcium chelator. Although ANP gene expression was induced significantly, H 2O 2 failed to induce hypertrophy in the presence of BAPTA-AM, and the cell cycle progressed. We concluded that H 2O 2 induced cell cycle arrest in H9c2 cells, which was related to cellular hypertrophy. © 2011 Pharmaceutical Society of Japan.


Miura T.,Hokkaido Pharmaceutical University School of Pharmacy
Journal of Pharmacy and Pharmacology | Year: 2012

Objectives To improve understanding of the essential effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on prostaglandin H synthase (PGHS), the reactivity of NSAIDs with peroxidases and the tyrosyl radical derived from myoglobin was examined. Methods Horseradish peroxidase and myoglobin were used as models of peroxidase and cyclooxygenase of PGHS, respectively. Key findings From the results, a new classification of NSAIDs has been proposed. Class 1 includes the majority of NSAIDs, which reacted with horseradish peroxidase compound I, thus causing a spectral change by PGHS peroxidase and also including diminished electron spin resonance signals of the tyrosyl radical of myoglobin. They reduced compound I of horseradish peroxidase and scavenged the tyrosyl radical. The branched-chain mechanism by which the porphyrin radical is transferred to the tyrosine residue of the protein might be blocked by these NSAIDs. Class 2 includes salicylic acid derivatives that reacted only with the porphyrin radical and not with horseradish peroxidase compound II (oxoferryl species). Class 3 includes aspirin, nimesulide, tolmetin, and arylpropionic acid derivatives, including ibuprofen and the coxibs of celecoxib and rofecoxib, which are not substrates for horseradish peroxidase or PGHS peroxidase. Conclusions Understanding the essential mode of action of NSAIDs is particularly important for designing an effective therapeutic strategy against inflammatory diseases. © 2012 The Author. JPP © 2012 Royal Pharmaceutical Society.


Oshiumi H.,Hokkaido University | Miyashita M.,Hokkaido University | Miyashita M.,Hokkaido Pharmaceutical University School of Pharmacy | Matsumoto M.,Hokkaido University | Seya T.,Hokkaido University
PLoS Pathogens | Year: 2013

The innate immune system is essential for controlling viral infections, but several viruses have evolved strategies to escape innate immunity. RIG-I is a cytoplasmic viral RNA sensor that triggers the signal to induce type I interferon production in response to viral infection. RIG-I activation is regulated by the K63-linked polyubiquitin chain mediated by Riplet and TRIM25 ubiquitin ligases. TRIM25 is required for RIG-I oligomerization and interaction with the IPS-1 adaptor molecule. A knockout study revealed that Riplet was essential for RIG-I activation. However the molecular mechanism underlying RIG-I activation by Riplet remains unclear, and the functional differences between Riplet and TRIM25 are also unknown. A genetic study and a pull-down assay indicated that Riplet was dispensable for RIG-I RNA binding activity but required for TRIM25 to activate RIG-I. Mutational analysis demonstrated that Lys-788 within the RIG-I repressor domain was critical for Riplet-mediated K63-linked polyubiquitination and that Riplet was required for the release of RIG-I autorepression of its N-terminal CARDs, which leads to the association of RIG-I with TRIM25 ubiquitin ligase and TBK1 protein kinase. Our data indicate that Riplet is a prerequisite for TRIM25 to activate RIG-I signaling. We investigated the biological importance of this mechanism in human cells and found that hepatitis C virus (HCV) abrogated this mechanism. Interestingly, HCV NS3-4A proteases targeted the Riplet protein and abrogated endogenous RIG-I polyubiquitination and association with TRIM25 and TBK1, emphasizing the biological importance of this mechanism in human antiviral innate immunity. In conclusion, our results establish that Riplet-mediated K63-linked polyubiquitination released RIG-I RD autorepression, which allowed the access of positive factors to the RIG-I protein. © 2013 Oshiumi et al.


Miura T.,Hokkaido Pharmaceutical University School of Pharmacy
Chemico-Biological Interactions | Year: 2015

To investigate the mechanisms of cardiotoxicity induced by adriamycin (ADM), the enzymatic activities of ADM-Fe3+, including the peroxidase and lipoxygenase (LOX) activity, and participation of active oxygen species in the damage to biological components were examined. ADM-Fe3+, but not ADM, steadily oxidized tetramethyl-p-phenylenediamine in the presence of peroxides, indicating that ADM-Fe3+ acts as a peroxidase. However, the activity of ADM-Fe3+ as peroxidase was very low compared with that of heme peroxidase, but was similar to that of LOX, which has a known peroxidase activity. Conversely, the activity of ADM-Fe3+ as a LOX was also very low compared with that of LOX itself. However, the lipid hydroperoxides (LOOH) produced by ADM-Fe3+ were the substrate for ADM-Fe3+ as a peroxidase. These findings indicate that lipid peroxidation cooperates with the peroxidase activity of ADM-Fe3+. Hydroxyl radicals (HO) were generated when ADM-Fe3+ was incubated with H2O2, but not with LOOH. Alcohol dehydrogenase was inactivated by LOOH. Conversely, DNA was mainly damaged by ADM-Fe3+ with H2O2. A small amount of DNA remained at the starting point on agarose gels during incubation with ADM-Fe3+ with LOOH and ADM-Fe3+ with H2O2. It seems that HO and compound I-like species participate in the strand breaks and the aggregation of DNA, respectively. ©2015 Published by Elsevier Ireland Ltd.


Miura T.,Hokkaido Pharmaceutical University School of Pharmacy
Journal of Biochemistry | Year: 2015

In this study, bleomycin-Fe3+ steadily oxidized tetramethylbenzidine (TMB) in the presence of peroxides. However, the ability of bleomycin-Fe3+ to function as a peroxidase was extremely low compared with that of other peroxidases. A characteristic property of bleomycin-Fe3+ different from that observed for other peroxidases is its ability to oxidize TMB at the similar rate at both a pH 5 and 8 in the presence of lipid hydroperoxide (LOOH). In the present experiments, hydroxyl radicals (HO•) were generated only when bleomycin-Fe3+ was incubated with H2O2 at a pH of 5. No generation of HO• was observed during the incubation of bleomycin-Fe3+ with LOOH. Meanwhile, bleomycin-Fe3+ induced the formation of LOOH from linoleic acid and alcohol dehydrogenase was inactivated by bleomycin-Fe3+ with peroxides. Thiobarbituric acid reactive substances were formed from DNA by bleomycin-Fe3+ with H2O2, and strand breaks were caused by bleomycin-Fe3+ with LOOH. The oxidative substrates for bleomycin-Fe3+ blocked the damage to biological components induced by bleomycin-Fe3+. These results suggest that compound I-like species contribute to the process of damage to biological components induced by bleomycin-Fe3+. © 2014 The Authors 2014. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.


Miura T.,Hokkaido Pharmaceutical University School of Pharmacy
Journal of Biochemistry | Year: 2012

During the oxidation of NADH by horseradish peroxidase (HRP-Fe 3+), superoxide (O- 2) is produced, and HRP-Fe3+ is converted to compound III. Superoxide dismutase inhibited both the generation of O- 2 and the formation of compound III. In contrast, catalase inhibited only the generation of O- 2. Under anaerobic conditions, the formation of compound III did not occur in the presence of NADH, thus indicating that compound III is produced via formation of a ternary complex consisting of HRP-Fe3+, NADH and oxygen. The generation of hydroxyl radicals was dependent upon O - 2 and H2O2 produced by HRP-Fe 3+-NADH. The reaction of compound III with H2O2 caused the formation of compound II without generation of hydroxyl radicals. Only HRP-Fe3+-NADH (but not K+O- 2 and xanthine oxidase-hypoxanthine) was able to induce the conversion of metmyoglobin to oxymyoglobin, thus suggesting the participation of a ternary complex made up of HRP-Fe2+..O2 ..NAD . (but not free O- 2 or H2O 2) in the conversion of metmyoglobin to oxymyoglobin. It appears that a cyclic pathway is formed between HRP-Fe3+, compound III and compound II in the presence of NADH under aerobic conditions, and a ternary complex plays the central roles in the generation of O- 2 and hydroxyl radicals. © 2012 The Authors.


Oshiumi H.,Hokkaido University | Miyashita M.,Hokkaido University | Miyashita M.,Hokkaido Pharmaceutical University School of Pharmacy | Okamoto M.,Hokkaido University | And 4 more authors.
Cell Reports | Year: 2015

RIG-I-mediated type I interferon (IFN) production and nuclease-mediated viral RNA degradation are essential for antiviral innate immune responses. DDX60 is an IFN-inducible cytoplasmic helicase. Here, we report that DDX60 is a sentinel for both RIG-I activation and viral RNA degradation. We show that DDX60is an upstream factor of RIG-I that activates RIG-Isignaling in a ligand-specific manner. DDX60 knockout attenuates RIG-I signaling and significantly reduces virus-induced type I IFN production invivo. In addition, we show that DDX60 is involved in RIG-I-independent viral RNA degradation. DDX60 and RIG-I adaptor MAVS double-knockout mice reveal arole for DDX60-dependent RNA degradation in antiviral responses. Several viruses induced DDX60 phosphorylation via epidermal growth factor receptor (EGFR), leading to attenuation of the DDX60 antiviral activities. Our results define DDX60 as a sentinel for cytoplasmic antiviral response, which is counteracted by virus-mediated EGF receptor activation. © 2015 The Authors.

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