Gifu International Institute of Biotechnology

Kakamigahara, Japan

Gifu International Institute of Biotechnology

Kakamigahara, Japan
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Nozawa Y.,Tokai Gakuin University | Nozawa Y.,Gifu International Institute of Biotechnology
Proceedings of the Japan Academy Series B: Physical and Biological Sciences | Year: 2011

The free-living eukaryotic protozoan Tetrahymena is a potentially useful model for the thermoadaptive membrane regulation because of easy growth in the axenic culture, systematic isolation of subcellular organelles, and quick response to temperature stress. Exposure of Tetrahymena cells to the cold temperature induces marked alterations in the lipid composition and the physical properties (fluidity) of various membranes. The increase in fatty acid unsaturation of membrane phospholipids is required to preserve the proper fluidity. In this homeoviscous adaptive response, acyl-CoA desaturase plays a pivotal role and its activity is regulated by induction of the enzyme via transcriptional activation. © 2011 The Japan Academy.


Naoi M.,Gifu International Institute of Biotechnology | Maruyama W.,National Research Center for Geriatrics and Gerontology
Current Pharmaceutical Design | Year: 2010

Alzheimer's and Parkinson's diseases are the most common neurodegenerative disorders among the aged. The etiologies of these diseases remain to be clarified, but the common disease-modifying factors are confirmed: oxidative stress, apoptosis, mitochondrial dysfunction, excitotoxicity, impaired ubiquitine-proteasome system and inflammation. Neuroprotective therapy is proposed to prevent the disease progression by intervening the pathogenic and disease-modifying factors. From the studies on Parkinson's disease, the inhibitors of type B monoamine oxidase, such as selegiline and rasagiline, are the most promising neuroprotective agents to date. These inhibitors protect neuronal cells against cell death induced in cellular and animal models. The neuroprotective functions are ascribed to the stabilization of mitochondria, the prevention of death signaling process and the induction of pro-survival anti-apoptotic Bcl-2 protein family and neurotrophic factors. In cellular models, selegiline and rasagiline increased the different neurotrophic factors classes, neurotrophins (nerve growth factor, brain-derive neurotrophic factor, neurotrophin 3) and ligands of glial cell line-derived neurotrophic factor, respectively. Studies in non-human primates and patients with Parkinson's disease confirmed further the induction of these specified neurotrophic factors. Selegiline and rasagiline are expected to show distinct pharmaceutical activities in selective neuronal systems through induction of distinct neurotrophic factors, and then activation of their own receptors and kinase systems. This review presents the molecular mechanisms behind neuroprotection by monoamine oxidase inhibitors and discusses the possible development of new drugs to prevent, delay and restore the neuronal cell death in Alzheimer's and Parkinson's diseases. © 2010 Bentham Science Publishers Ltd.


Iio A.,Gifu International Institute of Biotechnology | Nakagawa Y.,Aichi University | Hirata I.,Aichi University | Naoe T.,Nagoya University | And 2 more authors.
Molecular Cancer | Year: 2010

In a variety of cancers, altered patterns of microRNA (miRNA) expression are reported and may affect the cell cycle and cell survival. Recent studies suggest that the expression level of miRNAs that act as tumor suppressors is frequently reduced in cancers because of chromosome deletions, epigenetical changes, aberrant transcription and disturbances in miRNA processing. miR-143 and -145, which are located approximately 1.3 kb from each other at chromosome 5q33, are highly expressed in several tissues, but down-regulated in most cancers. However, the mechanism of this down-regulation has not been investigated in detail. Here, we show that both miRNAs were expressed well under the same control program in human tissues, but were down-regulated equally in the most of the cancer cell lines tested. Then we identified the host gene encoding both miRNAs. The transcripts of this gene were approximately 11, 7.5, and 5.5 kb long; and the expression of these transcripts was coordinated with that of its resident miRNAs and down-regulated in the cancer cell lines tested as well as in colorectal cancer tissue samples. These data demonstrate that the host gene can function as a primary miRNA transcript and suggest that the down-regulation of host gene expression caused the low-expression of its encoded microRNAs-143 and -145 in human cancer cell lines and in cancer tissues.© 2010 Iio et al; licensee BioMed Central Ltd.


Naoi M.,Gifu International Institute of Biotechnology | Maruyama W.,National Research Center for Geriatrics and Gerontology | Inaba-Hasegawa K.,Gifu International Institute of Biotechnology | Akao Y.,Gifu University
International Review of Neurobiology | Year: 2011

In Parkinson's disease, type B monoamine oxidase (MAO-B) is proposed to play an important role in the pathogenesis through production of reactive oxygen species and neurotoxins from protoxicants, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In addition, inhibitors of MAO-B protect neurons in the cellular and animal models of Parkinson's and Alzheimer's diseases. However, the role of type A MAO (MAO-A) in neuronal death and neuroprotection by MAO-B inhibitors has been scarcely elucidated. This chapter presents our recent results on the involvement of MAO-A in the activation of mitochondrial death signal pathway and in the induction of prosurvival genes to prevent cell death with MAO-B inhibitors. The roles of MAO-A in the regulation of neuronal survival and death are discussed in concern to find a novel strategy to protect neurons in age-associated neurodegenerative disorders and depression. © 2011 Elsevier Inc.


Akao Y.,Gifu University | Noguchi S.,Gifu University | Iio A.,Gifu International Institute of Biotechnology | Kojima K.,Gifu International Institute of Biotechnology | And 2 more authors.
Cancer Letters | Year: 2011

MiR-34a was identified as one of the down-regulated micro-RNAs (miRs) in human colorectal cancer 5-fluorouracil (5-FU)-resistant DLD-1 cells compared with those in the parental DLD-1 cells. Exposure to 5-FU at 30μM activated phosphoinositide 3-kinase (PI3K)/Akt signaling markedly from 12. h up to 48. h in the 5-FU-resistant cells compared with that in the parental cells and resulted in an overt difference in growth at those times. Furthermore, the expression of miR-34a in the 5-FU-resistant cells was sustained at a low-level, whereas it was up-regulated in the parental cells after the 5-FU treatment. Sirt1, which is one of the target genes for miR-34a and related to drug-resistance, was strikingly up-regulated in the 5-FU-resistant cells. The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth, as in the parental cells, and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3. Moreover, the silencing of Sirt1 significantly canceled the resistance to 5-FU in the 5-FU-resistant cells. These findings suggest that miR-34a targeting the Sirt1 and E2F3 genes could negatively regulate, at least in part, the resistance to 5-FU in human colorectal cancer DLD-1 cells. © 2010 Elsevier Ireland Ltd.


Akao Y.,Gifu University | Iio A.,Gifu International Institute of Biotechnology | Itoh T.,Gifu International Institute of Biotechnology | Noguchi S.,Gifu University | And 3 more authors.
Molecular Therapy | Year: 2011

Microvesicles (MVs) and exosomes, which are shed from cells as a cell-to-cell communication tool, are possible vehicles for navigating RNA molecules to body tissues. It is considered that intravenous injection of such MVs or exosomes from patients would not cause severe not-self and toxic reactions. Previously, we found that macrophages take up liposome-entrapped RNA molecules, some of which remain undegraded in the cells. Here, we demonstrate that transfected RNA molecules in human monocytic leukemia THP-1 cells were shed from THP-1 macrophages as contents in MVs during incubation in serum-free medium, which shedding was shown by biochemical analyses such as quantitative reverse transcription (qRT)-PCR, expression of TSG101 (a membrane-associated exosomal protein), and immunoelectron microscopic study. More chemically modified RNA molecules (miR-143BPs) entrapped by MVs (MV-miR-143BPs) were secreted from THP-1 macrophages after miR-143BP transfection compared with the amount after transfection with nonmodified miR-143 transfection. Furthermore, we show that the THP-1 macrophages, which were transfected with the miR-143BP ex vivo, secreted MV-miR-143BPs in xenografted nude mice after intravenous injection, because miR-143 levels were significantly increased in the serum, tumor, and kidney of the host animals. These data suggest that some of the transfected miR-143BPs were secreted from THP-1 macrophages as MV-RNAs both in vitro and in vivo. © The American Society of Gene & Cell Therapy.


Maruyama W.,National Research Center for Geriatrics and Gerontology | Naoi M.,Gifu International Institute of Biotechnology | Naoi M.,Aichi Gakuin University
Journal of Neural Transmission | Year: 2013

Neuroprotection has been proposed in neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, to delay or halt disease progression or reverse neuronal deterioration. The inhibitors of type B monoamine oxidase (MAO), rasagiline and (-)deprenyl, prevent neuronal loss in cellular and animal models of neurodegenerative disorders by intervening in the death signal pathway in mitochondria. In addition, rasagiline and (-)deprenyl increase the expression of anti-apoptotic Bcl-2 protein family and neurotrophic factors. Neurotrophic factors, especially glial cell line-derived neurotrophic factor (GDNF) and brain-derived derived neurotrophic factor (BDNF), are required not only for growth and maintenance of developing neurons, but also for function and plasticity of distinct population of adult neurons. GDNF and BDNF have been reported to reduce Parkinson and Alzheimer's diseases, respectively. GDNF protects the nigra-striatal dopamine neurons in animal models of Parkinson's disease, and its administration has been tried as a disease-modifying therapy for parkinsonian patients. However, the results of clinical trials have not been fully conclusive and more practical ways to enhance GDNF levels in the targeted neurons are essentially required for future clinical application. Rasagiline and (-)deprenyl induced preferentially GDNF and BDNF in cellular and non-human primate experiments, and (-)deprenyl increased BDNF level in the cerebrospinal fluid of parkinsonian patients. In this paper, we review the induction of GDNF and BDNF by these MAO inhibitors as a strategy of neuroprotective therapy. The induction of prosurvival genes is discussed in relation to a possible disease-modifying therapy with MAO inhibitors in neurodegenerative disorders. © 2012 Springer-Verlag.


Itoh T.,Gifu International Institute of Biotechnology | Takeda S.,Keio University | Akao Y.,Gifu International Institute of Biotechnology | Akao Y.,Gifu University
Journal of Biological Chemistry | Year: 2010

MicroRNAs (miRs) represent a class of endogenous ∼18-25 nucleotide RNAs that regulate gene expression through translational repression by binding to a target mRNA. These miRs regulate several biological functions, such as cell growth, cell differentiation, carcinogenesis, and so on. In a previous report, we have indicated that miR-141 and -200a act as preosteoblast differentiation modulators. In the present study, using microRNA array and in silico analyses, we found that miR-208 is closely involved in preosteoblast differentiation by partially regulating the expression of Ets1 (V-ets erythroblastosis virus E26 oncogene homolog 1), which transactivates osteopontin, runt-related transcription factor 2, parathyroid hormone-related protein, and type I procollagen. Furthermore, the enforced expression of mature miR-208 in murine preosteoblast in MC3T3-E1 cells or primary osteoblast cells remarkably attenuated BMP-2-induced preosteoblast differentiation. In addition, we determined that Ets1 is a target gene of miR-208 by using a sensor luciferase reporter assay. Taken together, these results suggest that the down-regulation of miR-208 in BMP-2-stimulated osteoblast differentiation is an important part of the regulatory machinery involved in early osteogenesis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Naoi M.,Gifu International Institute of Biotechnology | Naoi M.,Aichi Gakuin University | Maruyama W.,National Research Center for Geriatrics and Gerontology | Yi H.,Gifu International Institute of Biotechnology
Journal of Neural Transmission | Year: 2013

Rasagiline protects neuronal cells from cell death caused by various lines of insults. Its neuroprotective function is due to suppression of mitochondrial apoptosis signaling and induction of neuroprotective genes, including Bcl-2 and neurotrophic factors. Rasagiline inhibits the mitochondrial membrane permeabilization, an initial stage in apoptosis, but the mechanism has been elusive. In this paper, it was investigated how rasagiline regulates mitochondrial death cascade in apoptosis induced in SH-SY5Y cells by PK11195, a ligand of the outer membrane translocator protein of 18 kDa. Rasagiline prevented release of cytochrome c (Cyt-c), and the following caspase 3 activation, ATP depletion and apoptosis, but did not inhibit the mitochondrial membrane potential collapse, in contrast to Bcl-2 overexpression. Rasagiline stabilized the mitochondrial contact site and suppressed Cyt-c release into cytoplasm, which should be the critical point for the regulation of apoptosis. Monoamine oxidase was not associated with anti-apoptotic activity of rasagiline in PK11195-induced apoptosis. © 2013 Springer-Verlag Wien.


Inaba-Hasegawa K.,Gifu International Institute of Biotechnology | Akao Y.,Gifu University | Maruyama W.,National Research Center for Geriatrics and Gerontology | Naoi M.,Gifu International Institute of Biotechnology
Journal of Neural Transmission | Year: 2012

Rasagiline and (-)deprenyl (selegiline), irreversible type B monoamine oxidase (MAO-B) inhibitors, protect neuronal cells through gene induction of pro-survival Bcl-2 and neurotrophic factors in the cellular models of neurodegenerative disorders. In this paper, the role of MAO in the up-regulation of neuroprotective Bcl-2 gene by these inhibitors was studied using type A MAO (MAO-A) expressing wild SH-SY5Y cells and the transfectionenforced MAO-B overexpressed cells. Rasagiline and (-)deprenyl, and also befloxatone, a reversible MAO-A inhibitor, increased Bcl-2 mRNA and protein in SH-SY5Y cells. Silencing MAO-A expression with short interfering (si) RNA suppressed Bcl-2 induction by rasagiline, but not by (-)deprenyl. MAO-B overexpression inhibited Bcl-2 induction by rasagiline and befloxatone, but did not affect that by (-)deprenyl, suggesting the different mechanisms behind Bcl-2 gene induction by theseMAO-B inhibitors. The novel role of MAO-A in Bcl-2 induction by rasagiline is discussed with regard to the molecular mechanism underlying neuroprotection by the MAO inhibitors. © Springer-Verlag 2011.

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