Nagase and Co.

Nishi-Tokyo-shi, Japan

Nagase and Co.

Nishi-Tokyo-shi, Japan
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Meng P.,Hirosaki University | Yoshida H.,Hirosaki University | Matsumiya T.,Hirosaki University | Imaizumi T.,Hirosaki University | And 10 more authors.
Neuroscience Research | Year: 2013

A hallmark of Alzheimer's disease (AD) is the aggressive appearance of plaques of amyloid beta (Aβ) peptides, which result from the sequential cleavage of amyloid precursor protein (APP) by the β- and γ-secretases. Aβ production is evaded by alternate cleavage of APP by the α- and γ-secretases. Carnosic acid (CA) has been proven to activate the transcription factor Nrf2, a main regulator of the antioxidant response. We investigated the effects of CA on the production of Aβ 1-42 peptide (Aβ42) and on the expressions of the related genes in SH-SY5Y human neuroblastoma cells. The treatment of cells with CA suppressed Aβ42 secretion (61% suppression at 30. μM). CA treatment enhanced the mRNA expressions of an α-secretase TACE (tumor necrosis factor-α-converting enzyme, also called a disintegrin and metalloproteinase-17, ADAM17) significantly and another α-secretase ADAM10 marginally; however, the β-secretase BACE1 (β-site APP-cleaving enzyme-1) was not increased by CA. Knockdown of TACE by siRNA reduced soluble-APPα secretion enhanced by CA and partially recovered the CA-suppressed Aβ42 secretion. These results suggest that CA reduces Aβ42 production by activating TACE without promoting BACE1 in human neuroblastoma cells. The use of CA may have a potential in the prevention of Aβ-mediated diseases, particularly AD. © 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society.


Yoshida H.,Hirosaki University | Meng P.,Hirosaki University | Matsumiya T.,Hirosaki University | Tanji K.,Hirosaki University | And 10 more authors.
Neuroscience Research | Year: 2014

Amyloid beta (Aβ) peptides are key molecules in the pathogenesis of Alzheimer's disease (AD). The sequential cleavage of amyloid precursor protein (APP) by the β- and γ-secretases generates Aβ peptides; however, the alternate cleavage of APP by the α- and γ-secretases decreases Aβ production. We previously reported that carnosic acid (CA), a phenolic diterpene compound found in the labiate herbs rosemary and sage, suppresses Aβ (1-40 and 1-42) production by activating α-secretase in cultured SH-SY5Y human neuroblastoma cells (Neurosci. Res. 2013; 75: 94-102). Here, we investigated the effect of CA on the production of Aβ peptides (1-40, 1-42 and 1-43) in U373MG human astrocytoma cells. The treatment of cells with CA suppressed Aβ40/42/43 release (55-71% decrease at 50. μM). CA treatment enhanced the mRNA expressions of an α-secretase TACE (tumor necrosis factor-α-converting enzyme, also called a disintegrin and metalloproteinase-17, ADAM17); however, the β-secretase BACE1 (β-site APP-cleaving enzyme-1) was not increased by CA. Knockdown of TACE by siRNA reduced soluble-APPα release enhanced by CA and partially recovered the CA-suppressed Aβ40/42/43 release. These results suggest that CA reduces Aβ production, at least partially, by activating TACE in human astroglial cells. The use of CA may have a potential in the prevention of Aβ-mediated diseases. © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society.


Shimojo Y.,Nagase and Co. | Kosaka K.,Nagase and Co. | Noda Y.,Tokyo Metropolitan University | Shimizu T.,Tokyo Metropolitan University | Shirasawa T.,Juntendo University
Journal of Neuroscience Research | Year: 2010

Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disease affecting motor neurons. About 2% of patients with the disease are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). The purpose of this study is to assess the effect of rosemary extract and its major constituents, rosmarinic acid (RA) and carnosic acid (CA), in human SOD1 G93A transgenic mice, which are well-established mouse models for ALS. The present study demonstrates that intraperitoneal administration of rosemary extract or RA from the presymptomatic stage significantly delayed motor dysfunction in paw grip endurance tests, attenuated the degeneration of motor neurons, and extended the life span of ALS model mice. In addition, RA administration significantly improved the clinical score and suppressed body weight loss compared with a vehicle-treated group. In conclusion, this study provides the first report that rosemary extract and, especially, RA have preventive effects in the mouse model of ALS. © 2009 Wiley-Liss, Inc.


Yotsu-Yamashita M.,Tohoku University | Kondo S.,Tohoku University | Segawa S.,Tohoku University | Lin Y.-C.,Tohoku University | And 5 more authors.
Marine Drugs | Year: 2013

Two novel phlorotannins with a molecular weight of 974, temporarily named 974-A and 974-B, were isolated from the polyphenol powder prepared from the edible marine brown alga Ecklonia kurome Okamura, and their chemical structures were determined by spectroscopic method. The isolated yield of the total of 974-A and 974-B was approximately 4% (w/w) from the polyphenol powder. In 974-A, the carbon at the C2' position in the A ring of phlorofucofuroeckol-A forms a C-C bond with the carbon at the C2'' position of the C ring of triphloretol-B, while in 974-B, phlorofucofuroeckol-B and triphloretol-B form a C-C bond in the same manner as in 974-A. These structures were supported by high resolution-MS/MS data. To evaluate the antioxidant activities, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and intracellular radical scavenging assay, using 2',7'-dichlorofluorescin diacetate (DCFH-DA), were performed for 974-A, 974-B, and four known phlorotannins. The results of the DPPH assay showed that the IC50 values of 974-A, 974-B, phlorofucofuroeckol-A, and dieckol were significantly smaller than those of phlorofucofuroeckol-B, phloroglucinol, α-tocopherol, and ascorbic acid. Furthermore, the DCFH-DA assay suggested that 974-A, 974-B, and dieckol reduce intracellular reactive oxygen species most strongly among the tested compounds. © 2013 by the authors.


Shimojo Y.,Nagase and Co. | Kosaka K.,Nagase and Co. | Shirasawa T.,Juntendo University
Phytotherapy Research | Year: 2011

Ganoderma lucidum (G. lucidum), a traditional Chinese medicine, has been used for the treatment of various diseases including cancer and atherosclerosis. In this study, the positive effect of G. lucidum on metabolic syndrome was investigated in more detail by the use of 3T3-L1 pre-adipocyte cells. Treatment of 3T3-L1 cells with G. lucidum extract (GE) significantly promoted adipocyte differentiation and adiponectin production in a dose-dependent manner, as assessed by Oil-Red O staining, quantitative RT-PCR and ELISA. Treatment with GW9662, an inhibitor for peroxisome proliferator-activated receptor-gamma (PPARgamma), significantly attenuated GE-dependent adipocyte differentiation and adiponectin gene expression, suggesting the involvement of PPARgamma. Moreover, a reporter gene assay using GAL4-PPAR fusion proteins revealed that GE enhances GAL4-PPARgamma and GAL4-PPARalpha activities. These results indicate the presence of natural compounds possessing PPARgamma and PPARalpha activating properties in G. lucidum. © 2010 John Wiley & Sons, Ltd.


Mimura J.,Hirosaki University | Kosaka K.,Nagase and Co | Maruyama A.,Hirosaki University | Satoh T.,Iwate University | And 5 more authors.
Journal of Biochemistry | Year: 2011

Nerve growth factor (NGF) is a neurotrophic factor that plays an important role in neuronal cell development and survival. Carnosic acid (CA), a hydrophobic constituent of the herb rosemary, induces NGF production in human T98G glioblastoma cells, but the mechanism through which it works remains unknown. In the present study, we found a redox-sensitive transcription factor, Nrf2, which coordinates the expression of cytoprotective phase 2 genes, also participates in CA-inducible NGF expression. In T98G cells, CA caused NGF gene induction in a dose- and time-dependent manner without altering NGF mRNA stability. Simultaneously, CA increased Nrf2 nuclear accumulation and activated expression of prototypical Nrf2 target genes such as haem oxygenase 1 (HO-1) and thioredoxin reductase 1 (TXNRD1). Knockdown of endogenous Nrf2 by Nrf2-specific siRNA significantly reduced constitutive and CA-inducible NGF gene expression. In addition, NGF gene expression was enhanced by knockdown of Keap1, an Nrf2 inhibitor, in the absence of CA. Furthermore, CA induced NGF expression in normal human astrocytes in an Nrf2-dependent manner. These results highlight a role of Nrf2 in NGF gene expression in astroglial cells. © The Authors 2011.


Kosaka K.,Nagase and Co. | Mimura J.,Hirosaki University | Itoh K.,Hirosaki University | Satoh T.,Iwate University | And 5 more authors.
Journal of Biochemistry | Year: 2010

Neurotrophins such as NGF promote neuronal survival and differentiation via the cell surface TrkA neurotrophin receptor. Compounds with neurotrophic actions that are low in molecular weight and can permeate the blood-brain barrier are promising therapeutic agents against neurodegenerative diseases such as Alzheimer's disease. Carnosic acid (CA), an electrophilic compound in rosemary, activates antioxidant responsive element (ARE)-mediated transcription via activation of Nrf2. In the present study, we discovered that CA strongly promotes neurite outgrowth of PC12h cells. NGF as well as CA activated Nrf2, whereas CA and NGF-mediated neuronal differentiation was suppressed by Nrf2 knockdown. On the other hand, CA activated TrkA-downstream kinase Erk1/2 independently of Nrf2. CA-induced p62/ZIP expression in an Nrf2-dependent manner, while the CA-induced neural differentiation was suppressed by p62/ZIP knockdown. Furthermore, CA-induced ARE activation was attenuated both by p62/ZIP knockdown and a Trk signal inhibitor. These results suggest that the CA induction of p62/ZIP by Nrf2 enhances TrkA signaling which subsequently potentiates Nrf2 pathway. This is the first demonstration that activation of the Nrf2-p62/ZIP pathway by a low-molecular natural electrophilic compound plays important roles in TrkA-mediated neural differentiation and may represent the common molecular mechanism for neurotrophic activities of electrophilic compounds.


Fujiwara T.,Institute of Microbial Chemistry | Fukao A.,Kobe University | Sasano Y.,Nagase and Co. | Matsuzaki H.,Kobe University | And 8 more authors.
Nucleic Acids Research | Year: 2012

The RNA binding protein HuD plays essential roles in neuronal development and plasticity. We have previously shown that HuD stimulates translation. Key for this enhancer function is the linker region and the poly(A) binding domain of HuD that are also critical for its function in neurite outgrowth. Here, we further explored the underlying molecular interactions and found that HuD but not the ubiquitously expressed HuR interacts directly with active Akt1. We identify that the linker region of HuD is required for this interaction. We also show by using chimeric mutants of HuD and HuR, which contain the reciprocal linker between RNA-binding domain 2 (RBD2) and RBD3, respectively, and by overexpressing a dominant negative mutant of Akt1 that the HuD-Akt1 interaction is functionally important, as it is required for the induction of neurite outgrowth in PC12 cells. These results suggest the model whereby RNA-bound HuD functions as an adapter to recruit Akt1 to trigger neurite outgrowth. These data might also help to explain how HuD enhances translation of mRNAs that encode proteins involved in neuronal development. © 2011 The Author(s).


Ichinose H.,Japan National Food Research Institute | Araki Y.,Mie University | Michikawa M.,Japan National Food Research Institute | Harazono K.,Nagase and Company Ltd | And 3 more authors.
Applied and Environmental Microbiology | Year: 2012

We cloned two glycoside hydrolase family 74 genes, the sav_1856 gene and the sav_2574 gene, from streptomyces avermitilis nbrc14893 and characterized the resultant recombinant proteins. The sav_1856 gene product (saGH74a) consisted of a catalytic domain and a family 2 carbohydrate-binding module at the c terminus, while the sav_2574 gene product (sagh74b) consisted of only a catalytic domain. Sagh74a and sagh74b were expressed successfully and had molecular masses of 92 and 78 kda, respectively. Both recombinant proteins were xyloglucanases. SaGH74a had optimal activity at 60°c and ph 5.5, while sagh74b had optimal activity at 55°c and ph 6.0. SaGH74a was stable over a broad ph range (pH 4.5 to 9.0), whereas sagh74b was stable over a relatively narrow ph range (pH 6.0 to 6.5). Analysis of the hydrolysis products of tamarind xyloglucan and xyloglucan-derived oligosaccharides indicated that sagh74a was endo-processive, while sagh74b was a typical endo-enzyme. The c terminus of sagh74a, which was annotated as a carbohydrate-binding module, bound to β-1,4-linked glucan-containing soluble polysaccharides such as hydroxyethyl cellulose, barley glucan, and xyloglucan. © 2012, American Society for Microbiology.


Sota M.,University of Idaho | Sota M.,NAGASE Co. and Ltd. | Yano H.,University of Idaho | M Hughes J.,University of Idaho | And 5 more authors.
ISME Journal | Year: 2010

The ability of bacterial plasmids to adapt to novel hosts and thereby shift their host range is key to their long-term persistence in bacterial communities. Promiscuous plasmids of the incompatibility group P (IncP)-1 can colonize a wide range of hosts, but it is not known if and how they can contract, shift or further expand their host range. To understand the evolutionary mechanisms of host range shifts of IncP-1β plasmids, an IncP-1Β mini-replicon was experimentally evolved in four hosts in which it was initially unstable. After 1000 generations in serial batch cultures under antibiotic selection for plasmid maintenance (kanamycin resistance), the stability of the mini-plasmid dramatically improved in all coevolved hosts. However, only plasmids evolved in Shewanella oneidensis showed improved stability in the ancestor, indicating that adaptive mutations had occurred in the plasmid itself. Complete genome sequence analysis of nine independently evolved plasmids showed seven unique plasmid genotypes that had various kinds of single mutations at one locus, namely, the N-terminal region of the replication initiation protein TrfA. Such parallel evolution indicates that this region was under strong selection. In five of the seven evolved plasmids, these trfA mutations resulted in a significantly higher plasmid copy number. Evolved plasmids were found to be stable in four other naive hosts, but could no longer replicate in Pseudomonas aeruginosa. This study shows that plasmids can specialize to a novel host through trade-offs between improved stability in the new host and the ability to replicate in a previously permissive host. © 2010 International Society for Microbial Ecology All rights reserved.

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