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Maeda T.,Kasugai Municipal Hospital | Hayakawa T.,Hokkaido Pharmaceutical University School of Pharmacy
Progress in Palliative Care | Year: 2017

Dyspnea negatively affects the survival and quality of life of patients with terminal cancer. Although corticosteroids are currently used to treat dyspnea, the association between corticosteroid dosage and survival remains unclear. This retrospective study was conducted to determine the relationship betweencorticosteroid doses, administered to hospitalized patients with terminal cancer for dyspnea alleviation, and survival. Subsequently, we investigated the associations between corticosteroid doses, which were classified into three categories, and the length of survival in days after stratifying 52 patients treated between January 2012 and December 2015 into corticosteroid responders and non-responders. The mean daily corticosteroid doses were 28.68 ± 14.4 mg for responders and 29.13 ± 18.5 mg for non-responders. The mean corticosteroid doses on the first day were 27.86 ± 14.9 mg for responders and 27.73 ± 19.5 mg for non-responders. The mean total corticosteroid doses administered during the first 2 days of treatment were 56.84 ± 29.2 mg for responders and 57.16 ± 38.5 mg for non-responders. The mean survival was 11.33 ± 7.5 days and 5.27 ± 3.35 days among responders and non-responders, respectively. In conclusion, the administration of corticosteroid for dyspnea alleviation did not correlate with survival. However, reactivity to corticosteroids increased the duration of corticosteroid use, which may have contributed to survival. © 2017 Informa UK Limited, trading as Taylor & Francis Group.


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.


Baba A.,Hokkaido Pharmaceutical University School of Pharmacy | Yoshioka T.,Hokkaido Pharmaceutical University School of Pharmacy
Journal of Molecular Catalysis B: Enzymatic | Year: 2011

Methyl acetyl derivatives of 1-β-O-(o-, m-, or p-phenyl)benzoyl glucuronides 2a-c are fully deprotected by a one-pot consecutive enzyme-catalyzed hydrolytic reaction to afford 4a-c, without isolation of the O-deacetylated derivatives 3a-c. A lipase AS Amano from Aspergillus niger (LAS) and a carboxylesterase from Streptomyces rochei (CSR) showed high chemoselectivity toward the O-deacetylation of the o- and m-isomers, respectively. Chemoselective O-deacetylation of the p-isomer was promoted only in the presence of both enzymes. A lipase type B from Candida antarctica (CALB) was effective for the subsequent enzymatic hydrolysis of the methyl esters of 3a-c. LAS exhibited also regioselective 3-O-deacetylation activity to afford the corresponding 2,4-di-O-acetyl intermediates 5a-c, for which CSR showed higher O-deacetylation activity than that for 2a-c. In kinetic studies using p-nitrophenyl ester substrates, LAS exhibited a broader acyl preference, the octanoyl ester being most effectively hydrolysed, whereas CSR exhibited the highest hydrolytic activity toward the acetyl ester. LAS and CSR play complementary as well as synergistic roles in the O-deacetylation of 2 bearing R groups of different steric bulkiness. © 2011 Elsevier B.V.


Togami K.,Hokkaido Pharmaceutical University School of Pharmacy | Kanehira Y.,Hokkaido Pharmaceutical University School of Pharmacy | Tada H.,Hokkaido Pharmaceutical University School of Pharmacy
Biopharmaceutics & drug disposition | Year: 2015

Pirfenidone is the first and only clinically used anti-fibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). It was reported previously that pirfenidone metabolites (5-hydroxypirfenidone and 5-carboxypirfenidone) also have anti-fibrotic effects. The present study evaluated the distribution of pirfenidone and its metabolites in the lung, liver and kidney tissues in rats. The time course for the different concentrations of pirfenidone, 5-hydroxypirfenidone and 5-carboxypirfenidone in the lung tissue following oral administration (30 mg/kg) to rats was lower than that in plasma, and the area under the drug concentration-time curve (AUC) ratios of lung/plasma for pirfenidone, 5-hydroxypirfenidone and 5-carboxypirfenidone were 0.52, 0.40 and 0.61, respectively. In in vitro transport experiments, the basolateral-to-apical transport of pirfenidone and its metabolites through the model of lung epithelial cell (Calu-3) monolayers was not significantly different from their apical-to-basolateral transport. In binding experiments, the binding rate of these drugs to the lung tissue was lower than that to the plasma protein. These findings suggest that the low distribution of pirfenidone and its metabolites in the lungs was based on their low affinities with lung tissue and not the transport characteristics of lung epithelial cells. On the other hand, the AUC ratios of liver/plasma for pirfenidone and 5-carboxypirfenidone were 2.3 and 6.5 and the AUC ratios of kidney/plasma were 1.5 and 20, respectively. The binding rates to the liver and kidney tissues were higher than those to the plasma protein. These results suggest that high concentrations of these drugs were found in the liver and kidney tissues. Copyright © 2014 John Wiley & Sons, Ltd.


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.


Satoh T.,Hokkaido Pharmaceutical University School of Pharmacy | Igarashi M.,Hokkaido Pharmaceutical University School of Pharmacy | Yamada S.,Hokkaido Pharmaceutical University School of Pharmacy | Takahashi N.,Hokkaido Pharmaceutical University School of Pharmacy | Watanabe K.,Hokkaido Pharmaceutical University School of Pharmacy
Journal of Ethnopharmacology | Year: 2015

Ethnopharmacological relevance It is said that black tea is effective against type 2 diabetes mellitus because it can help modulate postprandial hyperglycemia. However, the mechanism underlying its therapeutic and preventive effects on type 2 diabetes mellitus is unclear. In this study, we focused on the effect of black tea on the carbohydrate digestion and absorption process in the gastrointestinal tract. We examined whether black tea can modulate postprandial hyperglycemia. Materials and methods The freeze-dried powder of the aqueous extract of black tea leaves (JAT) was used for in vitro studies of α-amylase activity, α-glucosidase activity, and glucose uptake by glucose transporters in Caco-2 cells; ex vivo studies of small intestinal α-glucosidase activity; and in vivo studies of oral sugar tolerance in GK rats, an animal model of nonobese type 2 diabetes mellitus. Results Half maximal inhibitory concentration values indicated that JAT significantly reduced α-glucosidase activity, but weakly reduced α-amylase activity. Kinetic studies of rat small intestinal α-glucosidase activity revealed that the combination of JAT and the α-glucosidase inhibitor, acarbose, showed a mixed-type inhibition. JAT had no effect on the uptake of 2′-deoxy-d-glucose by glucose transporter 2 (GLUT2) and the uptake of α-methyl-d-glucose by sodium-dependent glucose transporter 1 (SGLT1). In the oral sucrose tolerance test in GK rats, JAT reduced plasma glucose levels in a dose-dependent manner compared with the control group. The hypoglycemic action of JAT was also confirmed: JAT, in combination with acarbose, produced a synergistic inhibitory effect on plasma glucose levels in vivo. In contrast to the oral sucrose tolerance test, JAT showed no effect in the oral glucose tolerance test. Conclusions JAT was demonstrated to inhibit the degradation of disaccharides into monosaccharides by α-glucosidase in the small intestine. Thereby indirectly preventing the absorption of the dietary source of glucose mediated by SGLT1 and GLUT2 transporters localized at the apical side of enterocytes in the small intestine. The results indicate that black tea could be useful as a functional food in the dietary therapy for borderline type 2 diabetes mellitus that could modulate postprandial hyperglycemia. © 2014 Elsevier Ireland Ltd. All rights reserved.


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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