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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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.

Harada S.,Kobe Gakuin University | Fujita-Hamabe W.,Kobe Gakuin University | Tokuyama S.,Kobe Gakuin University
Journal of Pharmacological Sciences | Year: 2011

Orexin-A is a newly identified neuropeptide expressed in the lateral areas of the hypothalamus that plays a role in various physiological functions, including regulation of glucose metabolism. We have previously reported that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage. Therefore, the aim of this study was to determine the effects of orexin-A on the development of post-ischemic glucose intolerance and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Neuronal damage was estimated by histological and behavioral analysis after MCAO. Intracerebroventricular administration of orexin-A (2.5, 25, or 250 pmol/mouse) significantly and dose-dependently suppressed the development of post-ischemic glucose intolerance on day 1 after MCAO and neuronal damage on day 3 after MCAO. In the liver and skeletal muscle, the expression levels of insulin receptor were decreased, whereas those of gluconeogenic enzymes were increased on day 1 after MCAO. Furthermore, these expressions were completely recovered to normal levels by orexin-A and were reversed by the administration of SB334867, a specific orexin-1 receptor antagonist. These results suggest that regulation of post-ischemic glucose intolerance by orexin-A suppressed cerebral ischemic neuronal damage. © The Japanese Pharmacological Society.

Fukumoto Y.,Kobe Gakuin University
American Journal of Physical Medicine and Rehabilitation | Year: 2016

OBJECTIVE: The aim of this study was to investigate the effects of high-velocity (HV) and low-velocity (LV) resistance training on gait kinematics and kinetics in patients with hip osteoarthritis. DESIGN: This was a single-blind, randomized controlled trial. Forty-six women with hip osteoarthritis were randomly allocated to the HV (n = 23) or LV (n = 23) training group. The participants underwent an 8-week home-based the HV or LV resistance-training program, involving the hip and knee muscles. Outcome measures included gait kinematics and kinetics using 3-dimensional analyses, muscle strength and power, the Harris Hip Score, and hip pain using the visual analog scale. RESULTS: There was no significant difference in changes for any of the outcome measures between groups. After the training session, muscle power, walking speed, and cadence significantly increased only in the HV group, whereas stride length and the peak hip extension angle during gait significantly increased, and pain on the visual analog scale and the peak ankle dorsiflexion moment during gait significantly decreased only in the LV group. Muscle strength and Harris Hip Score significantly increased in both groups. CONCLUSIONS: The results of this study may indicate that the potential effect of resistance training on abnormal gait pattern depends on movement velocities during training. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Harada S.,Kobe Gakuin University | Fujita-Hamabe W.,Kobe Gakuin University | Tokuyama S.,Kobe Gakuin University
Journal of Pharmacological Sciences | Year: 2012

Stroke is one of the leading causes of death and disability worldwide. It is well known that hyperglycemia and/or diabetes potentially exacerbate the neuronal damage observed following ischemic stroke. Recent reports have shown that hyperglycemia/glucose intolerance may be induced by cerebral ischemic stress, and that normalization of blood glucose levels during the first 48 h of hospitalization appears to confer greater survival outcomes in stroke patients. However, the mechanisms underlying post-ischemic glucose intolerance remain unclear. Here, we review research to date on the mechanisms through which ischemic neuronal damage develops and on the role of post-ischemic glucose intolerance focusing on insulin and adiponectin signaling and communication between the brain and peripheral tissues. The relationship between ischemic neuronal damage and post-ischemic glucose intolerance is also discussed. With respect to therapeutic options, in addition to traditional post-stroke therapies, we also discuss the effect of anti-diabetic drugs and glucose-sensing neuropeptides on the development of the post-ischemic glucose intolerance and neuronal damage. In conclusion, we support the idea for focusing research on the development of post-ischemic glucose intolerance as a new therapeutic target for the stroke patients. © The Japanese Pharmacological Society.

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.

Yamazaki Y.,Kobe Gakuin University | Harada S.,Kobe Gakuin University | Tokuyama S.,Kobe Gakuin University
Neuroscience | Year: 2014

Cerebral ischemia can be exacerbated by post-ischemic hyperglycemia, which may involve the cerebral sodium-glucose transporter (SGLT). However, the contribution of each SGLT isoform in cerebral ischemia is still unclear. SGLT-1, -3, -4, and -6 have been reported to be expressed in various brain regions. Among these isoforms, only SGLT-3 does not transport glucose, but depolarizes the plasma membrane when glucose is bound, suggesting that SGLT-3 is a glucose sensor. Therefore, in this study, we investigated the involvement of cerebral SGLT-3 in the development of ischemia. The mouse model of focal ischemia was generated by middle cerebral artery occlusion (MCAO). Neuronal damage was assessed by histological and behavioral analyses. Fasting blood glucose levels on day 1 after MCAO were not affected in SGLT-3 siRNA-mediated knockdown of SGLT-3. The development of infarct volume and behavioral abnormalities on day 1 after MCAO were exacerbated in SGLT-3 knockdown mice (control group: n=7, 94.2±21.8mm3, 2 (1.6-2.4), SGLT-3 knockdown group: n=6, 1414.8±492.4mm3, 6 (5.8-6.3), P<0.05). Moreover, SGLT-3 expression levels were significantly decreased in the striatum (65.0±8.1%, P<0.05) on day 1, and in the hippocampus (67.6±7.2%, P<0.05) and hypothalamus (47.5±5.1%, P<0.01) on day 3 after MCAO (n=12-13). These effects were significantly inhibited by donepezil (DPZ) treatment (SGLT-3 knockdown group: n=6, 1419.0±181.5mm3, 3.6 (3.4-3.7), SGLT-3 knockdown and 3mg/kg DPZ-treated group: n=5, 611.3±205.3mm3, 1.5 (1.4-1.8), P<0.05). Immunofluorescence revealed that SGLT-3 and choline acetyltransferase were co-localized in the cortex. Our results indicated that cerebral SGLT-3 suppressed neuronal damage by the activation of cholinergic neurons, which are neuroprotective. In contrast, other cerebral SGLT isoforms may be involved in the development of ischemia. © 2014 IBRO.

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 | Nakamoto K.,Kobe Gakuin University | Tokuyama S.,Kobe Gakuin University
Life Sciences | Year: 2013

Aims Systemic administration of opiate analgesics such as morphine remains the most effective treatment for alleviating severe pain across a range of conditions including acute pain. However, chronic or repeated administration of opiate analgesics results in the development of analgesic tolerance. Glial cells such as microglia and astrocytes are known to release various inflammatory cytokines and neurotrophic factors leading to regulation of neuronal function. Recently, glial cells were reported to play important roles in the development of analgesic tolerance to morphine. Here, we focused on the involvement of midbrain glial cells, particularly astrocytes, in the development of analgesic tolerance to morphine. Main methods Mice were treated with morphine (10 mg/kg, s.c.) or vehicle once a day for 5 days. Pentoxifylline (an inhibitor of glial activation; 20 mg/kg, i.p. or 50 and 100 μg/mouse, i.c.v.) was administered 30 min before morphine treatment. Flavopiridol (a cyclin-dependent kinase inhibitor; 5 nmol/mouse, i.c.v.) was administered 10 min before and 10 h after morphine treatment. The analgesic effect of morphine was measured using the tail flick method. Key findings The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine for 5 days in mice. On days 1 and 3 after repeated morphine treatment, astrocyte marker glial fibrillary acidic protein expression levels were significantly increased, as determined by western blot analyses. These phenomena were significantly inhibited following pre-treatment with pentoxifylline or flavopiridol. Significance We demonstrated that midbrain astrocytes play an important role in the development of analgesic tolerance to morphine. © 2013 Elsevier Inc.

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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