Kobe Pharmaceutical University

Kobe, Japan

Kobe Pharmaceutical University is a private university in Higashinada, Kobe, Hyōgo, Japan. The predecessor of the school was founded in 1930, and it was chartered as a women's college in 1949. In 1994 the school became coeducational, adopting the present name. Wikipedia.

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News Article | December 14, 2016
Site: www.eurekalert.org

A Japanese research team has become the first in the world to discover that 2-aminobutyric acid (2-AB) is closely involved in the metabolic regulation of the antioxidant glutathione, and that it can effectively raise levels of glutathione in the body when ingested. The findings were published in the online version of Scientific Reports on November 9. Glutathione, an antioxidant with antidotal properties, plays an important role in keeping us healthy. This finding could contribute to the development of new ways to prevent, diagnose and treat various oxidative stress-related conditions including Alzheimer's, aging, cancer, lifestyle-related diseases, hardened arteries, and organ damage caused by medicines and toxins. The team was led by Kobe University Graduate School of Medicine, Division of Evidence-Based Laboratory Medicine Assistant Professor IRINO Yasuhiro and Associate Professor TOH Ryuji, in collaboration with Professor HIRATA Ken-ichi (Kobe University, Division of Cardiovascular Medicine) and Professor MIYATA Okiko (Kobe Pharmaceutical University, Medicinal Chemistry Laboratory) Glutathione is a major antioxidant component within cells, and keeps our bodies healthy by contributing to the detoxification of foreign substances. Monitoring glutathione metabolism in the body can help with early diagnosis of illness, as glutathione is consumed when bodies experience oxidative stress. However, glutathione concentration in the blood is 100- to 1000-fold lower than levels within cells, making it hard to accurately measure. Our bodies also compensate for the depletion of glutathione under stress, so circulating levels will not necessarily decrease during illness. This makes it difficult to accurately monitor the metabolism of glutathione just by measuring its levels in the blood. Increasing levels of glutathione in the body could help to prevent and treat a variety of conditions which involve oxidative stress and organ damage caused by toxins. However, simply ingesting glutathione does not efficiently increase glutathione levels in the body. 2-aminobutyric acid (2-AB) has been reported as a basic component of ophthalmic acid, which is produced when glutathione is synthesized. Until now, the metabolism and physiological effects of 2-AB itself were unknown. The group investigated whether 2-AB could be a marker for glutathione dynamics, and whether it could be used to modulate glutathione homeostasis. Searching for leads to develop new diagnoses and treatment to combat heart failure, the group started by comprehensively analyzing metabolites in the bloodstreams of atrial septal defect patients using a gas chromatography mass spectrometer. Results showed that levels of 2-AB were higher in these patients than in healthy subjects, and 2-AB levels decreased after the closure of atrial septal defect. Then, the group clarified for the first time that 2-AB is a byproduct of cysteine, one of the constituent amino acids of glutathione (figure 1), and revealed that activation of glutathione synthetic pathway under oxidative damage led to 2-AB accumulation. Because blood concentration of 2-AB reflects the metabolism of glutathione within the body, 2-AB could potentially be used as a new biomarker for early detection of oxidative stress. Intriguingly, the group also found that 2-AB promotes glutathione synthesis. The anticancer drug doxorubicin causes heart damage via oxidative stress as an adverse effect. They discovered that when taken orally, 2-AB increases the concentration of glutathione in the bloodstream and the heart, lessening the heart damage caused by doxorubicin (figure 2). This research found that as well as being a biomarker, 2-AB itself is an antioxidant that can be used to effectively increase glutathione in the body (patent pending). 2-AB is a naturally-occurring amino acid that can be found in everyday food products. Future research will examine which foods contain high levels of 2-AB, the recommended level to ingest, whether it can be used as an antioxidant for other organs, and the development of medicines and functional food for clinical use.

Shitan N.,Kobe Pharmaceutical University | Yazaki K.,Kyoto University
International Review of Cell and Molecular Biology | Year: 2013

The vacuole is the largest compartment in plant cells, often occupying more than 80% of the total cell volume. This organelle accumulates a large variety of endogenous ions, metabolites, and xenobiotics. The compartmentation of divergent substances is relevant for a wide range of biological processes, such as the regulation of stomata movement, defense mechanisms against herbivores, flower coloration, etc. Progress in molecular and cellular biology has revealed that a large number of transporters and channels exist at the tonoplast. In recent years, various biochemical and physiological functions of these proteins have been characterized in detail. Some are involved in maintaining the homeostasis of ions and metabolites, whereas others are related to defense mechanisms against biotic and abiotic stresses. In this review, we provide an updated inventory of vacuolar transport mechanisms and a comprehensive summary of their physiological functions. © 2013 Elsevier Inc.

Ueda M.,Kobe Pharmaceutical University
Chemical and Pharmaceutical Bulletin | Year: 2014

The application of conjugated oxime ethers to the synthesis of complex chemical scaffolds using domino radical reactions has been described in detail. The triethylborane-mediated hydroxysulfenylation reaction allows for the regioselective construction of a carbon-sulfur bond and a carbon-oxygen bond in a single operation for the formation of β-hydroxy sulfides. This reaction proceeds via a radical pathway involving regioselective thiyl addition and the subsequent trapping of the resulting α-imino radical with O2, where the imino group enhances the stability of the intermediate radical. Hydroxyalkylation reactions that occur via a carbon radical addition reaction followed by the hydroxylation of the resulting N-borylenamine with O2have also been developed. We investigated sequential radical addition aldol-type reactions in detail to explore the novel domino reactions that occur via the generation of N-borylenamine. The radical reaction of a conjugated oxime ether with triethylborane in the presence of an aldehyde affords γ-butyrolactone via sequential processes including ethyl radical addition, the generation of N-borylenamine, an aldol-type reaction with an aldehyde, and a lactonization reaction. A novel domino reaction has also been developed involving the [3,3]-sigmatropic rearrangement of N-boryl-N-phenoxyenamine. The triethylborane-mediated domino reactions of O-phenyl-conjugated oxime ethers afforded the corresponding benzofuro[2,3-b]pyrrol-2-ones via a radical addition/[3,3]-sigmatropic rearrangement/cyclization/lactamization cascade. © 2014 The Pharmaceutical Society of Japan.

Yamaki K.,Kobe Pharmaceutical University | Yoshino S.,Kobe Pharmaceutical University
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2012

Background: Systemic and oral antigen-induced anaphylaxes are mediated by immunoglobulin (Ig) E and mast cells, but there is no satisfactory treatment for the life-threatening allergic reaction. We investigated the potential of the multitargeted receptor tyrosine kinase inhibitor sunitinib to relieve anaphylactic reactions in food allergy and systemic anaphylaxis. Methods: Efficacy of oral sunitinib on oral and parenteral antigen-induced anaphylaxes in Balb/c mice was evaluated. IgE-dependent degranulation and growth of rat basophilic leukemia RBL2H3 and bone marrow-derived mast cells (BMMCs) in response to sunitinib were investigated. Results: Daily administration of sunitinib throughout antigen challenges prevented oral antigen-induced anaphylaxis including diarrhea, anaphylactic symptoms, and hypothermia. The mouse mast cell protease (MMCP)-1 concentration in serum and mast cell number in intestinal tissue after challenge were also decreased by the treatment. Spleen cells from sunitinib-treated mice contained smaller numbers of antigen-specific IgG-producing cells and secreted lower amounts of both Th1 and Th2 cytokines than those of the control mice, whereas the levels of antigen-specific antibodies in serum were not decreased. The reactions and MMCP-1 release in oral antigen-induced anaphylaxis and passive systemic anaphylaxis were attenuated even by a single predose of sunitinib. Degranulation and growth of RBL2H3 cells and BMMCs were greatly reduced by sunitinib. Conclusion: These results suggested that sunitinib relieves systemic and oral antigen-induced anaphylaxes by the prevention of mast cell activation and hyperplasia in intestinal tissue directly and indirectly through an immunosuppressive effect. Sunitinib and its related kinase inhibitors might be potential drugs for the treatment of food allergy and systemic anaphylaxis. © 2011 John Wiley & Sons A/S.

Kobayashi N.,Kobe Pharmaceutical University | Oyama H.,Kobe Pharmaceutical University
Analyst | Year: 2011

Clinical and environmental analyses often require immunochemical detection and quantification of small molecules (haptens) that are available as biomarkers. However, the affinity ceilings of conventional anti-hapten antibodies, which are produced by immunizing animals, prevent subfemtomole-range determinations with competitive immunoassay formats. "Sandwich-type" noncompetitive (immunometric) assays allow for sensitive determinations of macromolecules (subattomole-range) and the direct relationship between analyte amount and signal intensity provides higher accessibility to modern high-throughput sensing systems. Unfortunately, sandwich-type assays require that analytes have at least two epitopes, and thus are not applicable to haptens. Antibody engineering, i.e., genetic manipulation of antibody molecules, could provide artificially improved reagents that enable us to overcome these limitations. In this review, we summarize recent successful developments and applications of engineered antibodies for sensitive and high-throughput hapten sensing. © The Royal Society of Chemistry 2011.

Kitagawa H.,Kobe Pharmaceutical University
Biological and Pharmaceutical Bulletin | Year: 2014

Chondroitin sulfate (CS) chains constitute a class of glycosaminoglycans (GAGs). CS chains are distributed on the surfaces of virtually all cells and throughout most extracellular matrices; they are covalently attached to serine residues of core proteoglycan proteins. CS proteoglycans have been implicated as regulators of a variety of biological events, including cell-cell and cell-matrix adhesion, cell proliferation, morphogenesis, and neurite outgrowth. The functional diversity of CS proteoglycans is mainly attributed to the structural variability of the GAG chains, specifically the CS chains. Despite their relatively simple polysaccharide backbones, CS chains acquire remarkable structural variability via several types of enzymatic modifications, including sulfation. Moreover, the sulfation status of CS chains, chain length, number of CS chains per core protein, or combinations thereof can be finely tuned via CS biosynthetic machinery to specify the structure and function of CS proteoglycans. The term "sugar remodeling" refers to the experimental or therapeutic structural alteration of CS chains via perturbation of specific CS biosynthetic enzymes in cells or living organisms; sugar remodeling is a promising approach to the study of CS chain function. This review focuses on our recent findings regarding CS function which have resulted from studies involving sugar remodeling. © 2014 The Pharmaceutical Society of Japan.

Yamaki K.,Kobe Pharmaceutical University | Yoshino S.,Kobe Pharmaceutical University
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2012

Background: Because few curative treatments are available for food allergy, we investigated the therapeutic potential of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, on mouse food allergy. Methods: The preventive and therapeutic effects of oral rapamycin on anaphylactic symptoms induced by oral ovalbumin (OVA) challenge in food allergy mice were investigated. Mast cell functions in response to rapamycin were also measured in the passive systemic anaphylaxis model and bone marrow-derived mast cells (BMMCs). Results: Daily rapamycin from the first challenge (preventive protocol) attenuated food allergy symptoms including diarrhea, anaphylactic reactions, and hypothermia in mice. The treatment decreased the challenge-induced increases in mouse mast cell protease-1 in serum and mast cell numbers in the intestine. Notably, the mice that already showed food allergy symptoms by previous challenges recovered from the disease with daily administration of rapamycin (therapeutic protocol). Anti-OVA IgG1 and IgE levels in serum, as well as IFN-γ, IL-4, IL-13, IL-9, IL-10, and IL-17 secretion from splenocytes, were decreased by the treatments. In contrast, a single dose of rapamycin failed to affect passive systemic anaphylaxis. Spontaneous and IL-9-dependent survival and IgE-induced IL-13 secretion, but not degranulation, of BMMCs were reduced by rapamycin. Conclusion: Our data show that mouse food allergy was attenuated by rapamycin through an immunosuppressive effect and inhibition of intestinal mast cell hyperplasia. Inhibition of the IL-9 production-mast cell survival axis is one of the mechanisms of the therapeutic effect of rapamycin. Rapamycin and other mTOR inhibitors might be good candidates for therapeutic drugs for food allergy. © 2012 John Wiley & Sons A/S.

Okitsu T.,Kobe Pharmaceutical University | Sato K.,Kobe Pharmaceutical University | Wada A.,Kobe Pharmaceutical University
Organic Letters | Year: 2010

(Equation Presented). Switchable access to dihydropyrazoles and pyrazoles has been developed from common hydrazides by reagent-controlled iodocyclization. Controlling the oxidative aromatization in iodocyclization for heterocycles is reported for the first time, and this methodology maximally utilizes the dual nature of iodine. © 2010 American Chemical Society.

Izumikawa T.,Kobe Pharmaceutical University | Sato B.,Kobe Pharmaceutical University | Kitagawa H.,Kobe Pharmaceutical University
Scientific Reports | Year: 2014

Chondroitin sulfate (CS) proteoglycans are present on the surfaces of virtually all cells and in the extracellular matrix and are required for cytokinesis at early developmental stages. Studies have shown that heparan sulfate (HS) is essential for maintaining mouse embryonic stem cells (ESCs) that are primed for differentiation, whereas the function of CS has not yet been elucidated. To clarify the role of CS, we generated glucuronyltransferase-I- knockout ESCs lacking CS. We found that CS was required to maintain the pluripotency of ESCs and promoted initial ESC commitment to differentiation compared with HS. In addition, CS-A and CS-E polysaccharides, but not CS-C polysaccharides, bound to E-cadherin and enhanced ESC differentiation. Multiple-lineage differentiation was inhibited in chondroitinase ABC-digested wild-type ESCs. Collectively, these results suggest that CS is a novel determinant in controlling the functional integrity of ESCs via binding to E-cadherin.

Mikami T.,Kobe Pharmaceutical University | Kitagawa H.,Kobe Pharmaceutical University
Biochimica et Biophysica Acta - General Subjects | Year: 2013

Background Chondroitin sulfate proteoglycans (CSPGs) are principal pericellular and extracellular components that form regulatory milieu involving numerous biological and pathophysiological phenomena. Diverse functions of CSPGs can be mainly attributed to structural variability of their polysaccharide moieties, chondroitin sulfate glycosaminoglycans (CS-GAG). Comprehensive understanding of the regulatory mechanisms for CS biosynthesis and its catabolic processes is required in order to understand those functions. Scope of review Here, we focus on recent advances in the study of enzymatic regulatory pathways for CS biosynthesis including successive modification/degradation, distinct CS functions, and disease phenotypes that have been revealed by perturbation of the respective enzymes in vitro and in vivo. Major conclusions Fine-tuned machineries for CS production/degradation are crucial for the functional expression of CS chains in developmental and pathophysiological processes. General significance Control of enzymes responsible for CS biosynthesis/ catabolism is a potential target for therapeutic intervention for the CS-associated disorders. © 2013 Elsevier B.V.

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