Kobe Gakuin University

Kobe, Japan

Kobe Gakuin University is a private, co-educational university located on the western edge of the city of Kobe, in Hyōgo Prefecture in Japan. It was founded in 1966 and overlooks the city of Akashi, the Akashi Straits and the Akashi Kaikyo Bridge - the longest suspension bridge in the world. The university has three campuses in Kobe. These are located near Akashi, near Nagata and on Port Island. Wikipedia.

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This review discusses the importance of quantum chemical interactions in biomolecules for medicinal science and their relevance to the author's β-secretase (BACE1) inhibitor drug discovery research. Although molecular mechanics/ dynamics (MM/MD) methods are available in many in silico design tools used for drug discovery, they cannot accurately evaluate quantum effects between biomolecules and drugs. The key roles of biomolecular quantum chemical interactions in drug discovery are discussed using the arginine side chain as an example. Arginine is recognized as a charged amino acid in commonly used drug design software, unlike other amino acids with π-electron orbitals, such as phenylalanine, tyrosine, and tryptophan. Quantum chemical interactions via the arginine side chain are crucial for molecular recognition, and are found in many X-ray crystal structures, such as protein-protein, protein homodimer, RNA aptamer-protein, and enzyme-inhibitor complexes. This review describes the essential role of quantum chemical interactions via the arginine side chain in the mechanism of BACE1 inhibition, and proposes an "electron donor/acceptor bioisostere" concept for medicinal science based on quantum chemical interactions. Several potent BACE1 inhibitors, as well as the first peptides with BACE1 inhibiting activity were designed and synthesized based on studies of quantum chemical interactions via arginine side chain and the "electron donor bioisostere" concept. © 2013 The Pharmaceutical Society of Japan.

Tokuyama S.,Kobe Gakuin University | Nakamoto K.,Kobe Gakuin University
Biological and Pharmaceutical Bulletin | Year: 2011

Fatty acids, which are the essential nutrients for humans, are an important source of energy and an essential component of cell membranes. They also function as signal transduction molecules in a range of biological phenomena. Recently, an increasing number of physiologic and pharmacologic reports on fatty acids have improved our understanding of the association of fatty acids with certain diseases. It has also become apparent that functional properties of fatty acids are modulated by factors such as the amount of individual fatty acid intake and their distribution among organs. Recently, the functional relationship between polyunsaturated fatty acids and pain has been the focus of many studies. Both basic and clinical studies have shown that a dietary intake of n-3 series polyunsaturated fatty acids results in a reduction in the pain associated with rheumatoid arthritis, dysmenorrhea, inflammatory bowl disease, and neuropathy. In addition, levels of n-6 series polyunsaturated fatty acids are high in patients with chronic pain. These results indicate that polyunsaturated fatty acids play a vital role in pain regulation. In this review, we summarize a number of basic and clinical studies on polyunsaturated fatty acids and their association with pain. © 2011 Pharmaceutical Society of Japan.

Fujita-Hamabe W.,Kobe Gakuin University | Tokuyama S.,Kobe Gakuin University
Biological and Pharmaceutical Bulletin | Year: 2012

Neural cell adhesion molecule (NCAM) is a member of the immunoglobulin superfamily with an important function in the central nervous system, particularly in synapse stabilization and neurite outgrowth. Our recent study clearly demonstrated that cleavage of NCAM-180 by matrix metalloproteinase-9 (MMP-9) exacerbated the neuronal damage induced by in vivo ischemic stress. In the present study, we investigated the effect of oxidative stress on the expression levels of full-length NCAM-180 and NCAM-cleavage product (65 kDa) and the relationship between NCAM-180 and MMP-9 in cultured cortical neurons. Primary cultured cortical neurons were exposed to oxidative stress by administration of hydrogen peroxide into the culture medium. After exposure to oxidative stress, cell death of cultured cortical neurons was gradually increased in a time-dependent manner. In parallel to the cell death, levels of full-length NCAM-180 and its cleavage product (65 kDa) were gradually and significantly decreased and increased, respectively, in a time-dependent manner. These changes completely disappeared following addition of an MMP-9 inhibitor, while MMP-9 protein levels were increased only in the early phase of oxidative stress. We conclude that oxidative stress can induce cleavage of NCAM-180 through up-regulation of MMP-9 during the early phase of oxidative stress. These changes might be related to the neuronal death observed under oxidative stress conditions. © 2012 The Pharmaceutical Society of Japan.

Yamazaki Y.,Kobe Gakuin University | Ogihara S.,Kobe Gakuin University | Harada S.,Kobe Gakuin University | Tokuyama S.,Kobe Gakuin University
Neuroscience | Year: 2015

The regulation of post-ischemic hyperglycemia plays an important role in suppressing neuronal damage in therapeutic strategies for cerebral ischemia. We previously reported that the cerebral sodium-glucose transporter (SGLT) was involved in the post-ischemic hyperglycemia-induced exacerbation of cerebral ischemic neuronal damage. Cortical SGLT-1, one of the cerebral SGLT isoforms, is dramatically increased by focal cerebral ischemia. In this study, we focused on the involvement of cerebral SGLT-1 in the development of cerebral ischemic neuronal damage. It was previously reported that activation of 5'-adenosine monophosphate-activated protein kinase (AMPK) increases SGLT-1 expression. Moreover, ischemic stress-induced activation of AMPK exacerbates cerebral ischemic neuronal damage. Therefore, we directly confirmed the relationship between cerebral SGLT-1 and cerebral AMPK activation using in vitro primary culture of mouse cortical neurons. An in vivo mouse model of focal cerebral ischemia was generated using a middle cerebral artery occlusion (MCAO). The development of infarct volume and behavioral abnormalities on day 3 after MCAO were ameliorated in cerebral SGLT-1 knock down mice. Cortical and striatal SGLT-1 expression levels were significantly increased at 12 h after MCAO. Immunofluorescence revealed that SGLT-1 and the neuronal nuclear antigen (NeuN) were co-localized in the cortex and striatum of MCAO mice. In the in vitro study, primary cortical neurons were cultured for five days before each treatment with reagents. Concomitant treatment with hydrogen peroxide and glucose induced the elevation of SGLT-1 and phosphorylated AMPK/AMPK ratio, and this elevation was suppressed by compound C, an AMPK inhibitor in primary cortical neurons. Moreover, compound C suppressed neuronal cell death induced by concomitant hydrogen peroxide/glucose treatment in primary cortical neurons. Therefore, we concluded that enhanced cerebral SGLT-1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage. One of the mechanisms of cerebral SGLT-1 up-regulation may be involved in the AMPK activation after cerebral ischemia. © 2015 IBRO.

Kamiya K.,Kobe Gakuin University | Satake T.,Kobe Gakuin University
Fitoterapia | Year: 2010

Oxidative modification of LDL plays an important role in the genesis of arteriosclerosis. This study focused on the effects of the leaves of Baeckea frutescens in the prevention of arteriosclerosis. The leaves of B. frutescens have afforded, besides known flavonoid and chromone glycosides, a novel biflavonoid glycoside, characterized as 3-O-α-l-rhamnopyranosylmyricetinyl-(I-2″,II-2″)-3-O-α-l-rhamnopyranosylmyricetin on the basis of chemical and spectral evidence. This compound exhibited marked inhibition of copper-induced LDL oxidation. © 2009 Elsevier B.V. All rights reserved.

Lazarus L.H.,National Health Research Institute | Okada Y.,Kobe Gakuin University
Expert Opinion on Therapeutic Patents | Year: 2012

Although endomorphins-1 (EM-1; H-Tyr-Pro-Phe-Trp-NH 2) and -2 (EM-2; H-Tyr-Pro-Phe-Phe-NH 2) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties, suitable for application to health-related topics. While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimentally delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability; formation of MOR antagonists or mixed and dual μ/δ-acting ligands could find considerable therapeutic potential. Areas covered: This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand. Expert opinion: Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high-caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction. © 2012 Informa UK, Ltd.

Kunishima M.,Kanazawa University | Kunishima M.,Kobe Gakuin University | Kikuchi K.,Kobe Gakuin University | Kawai Y.,Kobe Gakuin University | Hioki K.,Kobe Gakuin University
Angewandte Chemie - International Edition | Year: 2012

Scratch the surface: Dehydrocondensations between carboxylates and amines by using an amphiphilic 1,3,5-triazinylammonium-based coupling agent were accelerated by the interfacial effect of micelles and emulsions of common surfactants (see figure). The reaction of carboxylates was promoted by both anionic and nonionic surfactants, and that of amines was promoted by only a nonionic surfactant. High selectivities for more lipophilic substrates were observed in micelles or emulsions. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Takano M.,Kobe Gakuin University | Matsuyama S.,Himeji Dokkyo University
European Journal of Pharmacology | Year: 2014

Bradykinin is a vasoactive peptide that participates in numerous inflammatory processes, vasodilation, and cell growth/survival; it mainly acts through two receptor subtypes, bradykinin B1 and bradykinin B 2 receptors, which are G protein-coupled receptor (GPCR) family members. Details on ubiquitin-dependent degradation via the lysosome and/or proteasome, and the recycling process that directs bradykinin B2 receptor to the cell surface after agonist-induced endocytosis remain unclear; nevertheless, intracellular localization and internalization of GPCRs following stimulation by ligands are well known. Evidence concerning the nuclear localization and functions of GPCRs has been accumulating. The bradykinin B 2 receptor has been shown to localize in the nucleus and suggested to function as a transcriptional regulator of specific genes. The transfer of membrane GPCRs (regardless of liganding), including the bradykinin B2 receptor to the nucleus can be attributed to the presence of a peptide sequence referred to as the nuclear localization signal (NLS). More recently, we found that nuclear bradykinin B2 receptors form heterodimers with the nuclear lamina protein, lamin C. The function of heterodimerization of the bradykinin B2 receptor with lamin C is still unclear. However, nuclear proteins lamin A/C are involved in a variety of diseases. Although further studies are required to elucidate the precise functions and mechanisms of intracellular and nuclear bradykinin B2 receptors, here we discuss the role of lamin A/C in laminopathies and examine the clinical significance of the bradykinin B2 receptor heterodimer. © 2014 Elsevier B.V.

Harada S.,Kobe Gakuin University | Yamazaki Y.,Kobe Gakuin University | Tokuyama S.,Kobe Gakuin University
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N′-1,5- naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Kamei N.,Kobe Gakuin University | Takeda-Morishita M.,Kobe Gakuin University
Journal of Controlled Release | Year: 2015

Intranasal administration is considered as an alternative route to enable effective drug delivery to the central nervous system (CNS) by bypassing the blood-brain barrier. Several reports have proved that macromolecules can be transferred directly from the nasal cavity to the brain. However, strategies to enhance the delivery of macromolecules from the nasal cavity to CNS are needed because of their low delivery efficiencies via this route in general. We hypothesized that the delivery of biopharmaceuticals to the brain parenchyma can be facilitated by increasing the uptake of drugs by the nasal epithelium including supporting and neuronal cells to maximize the potentiality of the intranasal pathway. To test this hypothesis, the CNS-related model peptide insulin was intranasally coadministered with the cell-penetrating peptide (CPP) penetratin to mice. As a result, insulin coadministered with l- or d-penetratin reached the distal regions of the brain from the nasal cavity, including the cerebral cortex, cerebellum, and brain stem. In particular, d-penetratin could intranasally deliver insulin to the brain with a reduced risk of systemic insulin exposure. Thus, the results obtained in this study suggested that CPPs are potential tools for the brain delivery of peptide- and protein-based pharmaceuticals via intranasal administration. © 2014 Elsevier B.V. All rights reserved.

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