Nagase and Co.

Nishi-Tokyo-shi, Japan

Nagase and Co.

Nishi-Tokyo-shi, Japan

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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).


Meng P.,Hirosaki University | Yoshida H.,Hirosaki University | Tanji K.,Hirosaki University | Matsumiya T.,Hirosaki University | And 11 more authors.
Neuroscience Research | Year: 2015

Amyloid-beta (Aβ) peptides, Aβ 1-42 (Aβ42) and Aβ43 in particular, cause neurotoxicity and cell death in the brain of Alzheimer's disease (AD) at higher concentrations. Carnosic acid (CA), a phenolic diterpene compound in the labiate herbs rosemary and sage, serves as an activator for neuroprotective and neurotrophic functions in brain cells. We investigated the effect of CA on apoptosis induced by Aβ42 or Aβ43 in cultured SH-SY5Y human neuroblastoma cells. Treatment of the cells with Aβ42 or Aβ43 (monomer, 10. μM each) induced apoptosis, which was confirmed by the cleavage of poly-(ADP-ribose) polymerase (PARP) and apoptosis-inducing factor (AIF). Concurrently, the Aβ treatment induced the activation of caspase (Casp) cascades including an effector Casp (Casp3) and initiator Casps (Casp4, Casp8 and Casp9). Pretreatment of the cells with CA (10. μM) partially attenuated the apoptosis induced by Aβ42 or Aβ43. CA pretreatment also reduced the cellular oligomers of Aβ42 and Aβ43. These results suggest that CA suppressed the activation of Casp cascades by reducing the intracellular oligomerization of exogenous Aβ42/43 monomer. The ingestion of an adequate amount of CA may have a potential in the prevention of Aβ-mediated diseases, particularly AD. © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society.


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.


Rezaie T.,Sanford Burnham Institute for Medical Research | McKercher S.R.,Sanford Burnham Institute for Medical Research | Kosaka K.,Nagase and Co. | Seki M.,Sanford Burnham Institute for Medical Research | And 10 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

Purpose. The herb rosemary has been reported to have antioxidant and anti-inflammatory activity. We have previously shown that carnosic acid (CA), present in rosemary extract, crosses the blood-brain barrier to exert neuroprotective effects by upregulating endogenous antioxidant enzymes via the Nrf2 transcriptional pathway. Here we investigated the antioxidant and neuroprotective activity of CA in retinal cell lines exposed to oxidative stress and in a rat model of light-induced retinal degeneration (LIRD). Methods. Retina-derived cell lines ARPE-19 and 661W treated with hydrogen peroxide were used as in vitro models for testing the protective activity of CA. For in vivo testing, dark-adapted rats were given intraperitoneal injections of CA prior to exposure to white light to assess protection of the photoreceptor cells. Retinal damage was assessed by measuring outer nuclear layer thickness and by electroretinogram (ERG). Results. In vitro, CA significantly protected retina-derived cell lines (ARPE-19 and 661W) against H2O2-induced toxicity. CA induced antioxidant phase 2 enzymes and reduced formation of hyperoxidized peroxiredoxin (Prx)2. Similarly, we found that CA protected retinas in vivo from LIRD, producing significant improvement in outer nuclear layer thickness and ERG activity. Conclusions. These findings suggest that CA may potentially have clinical application to diseases affecting the outer retina, including age-related macular degeneration and retinitis pigmentosa, in which oxidative stress is thought to contribute to disease progression. © 2012 The Association for Research in Vision and Ophthalmology, Inc.


Xu H.-L.,Meiji Pharmaceutical University | Kitajima C.,Nagase and Co. | Ito H.,Nagase and Co. | Miyazaki T.,Nagase and Co. | And 3 more authors.
Pharmaceutical Biology | Year: 2012

Context: Prevalence of diabetes mellitus type 2 (DM-II) is increasing in Japan. Brown alga Ecklonia kurome Okamura (Laminariaceae) (kurome in Japanese) is rich in phlorotannins, a kind of polyphenol. Phlorotannins have been reported to possess various bioactivities; however, few studies have reported its effect on DM-II. Objective: The present study was conducted to investigate the antidiabetic effect of polyphenols from E. kurome (KPP) on KK-A y mice, the animal model for human DM-II. Materials and methods: Inhibitory activities of KPP against α-amylase and α-glucosidase in vitro, and effects on oral carbohydrate tolerance test in vivo were investigated. KK-A y mice were fed with 0.1% KPP containing water for 5 weeks. A glucose tolerance test was conducted at week 4 of the 5-week period. At the end of experiment, blood biochemical parameters, including blood glucose, insulin, glycoalbumin, and fructosamine were determined. Furthermore, the kidneys and pancreatic islets were histologically examined. Results: KPP showed inhibitory activities on carbohydrate-hydrolyzing enzymes and decreased postprandial blood glucose levels. The body weight gain and blood glucose levels in the KPP group were lower than the control group during the experimental period. KPP improved glucose tolerance and decreased the fasting blood glucose and insulin levels, fructosamine and glycoalbumin levels compared with the control group. Furthermore, KPP contracted the pancreatic islet size and decreased renal mesangial matrix in KK-A y mice. Discussion and conclusion: These results suggest that KPP is effective against DM-II and might provide a source of therapeutic agents for DM-II. © 2012 Informa Healthcare USA, Inc.


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.


Uraji M.,Research Institute for Biological science RIBS | Kimura M.,Research Institute for Biological science RIBS | Inoue Y.,Satake Corporation | Kawakami K.,Research Institute for Biological science RIBS | And 3 more authors.
Applied Biochemistry and Biotechnology | Year: 2013

Ferulic acid (FA), which is present in the cell walls of some plants, is best known for its antioxidant property. By combining a commercial enzyme that shows FA esterase activity with several Streptomyces carbohydrate-hydrolyzing enzymes, we succeeded in enhancing the enzymatic production of FA from defatted rice bran. In particular, the combination of three xylanases, an α-l-arabinofuranosidase, and an acetyl xylan esterase from Streptomyces spp. produced the highest increase in the amount of released FAs among all the enzymes in the Streptomyces enzymes library. This enzyme combination also had an effect on FA production from other biomasses, such as raw rice bran, wheat bran, and corncob. © 2013 Springer Science+Business Media New York.


Igami K.,Nagase and CO. | Shimojo Y.,Nagase and CO. | Ito H.,Nagase and CO. | Miyazaki T.,Nagase and CO. | Kashiwada Y.,Tokushima University
Journal of Pharmacy and Pharmacology | Year: 2015

Objectives This work aimed at evaluating the effect of fermented ginseng (FG) and fermented red ginseng (FRG) against rat liver injury caused by paracetamol (acetaminophen (APAP)). Methods Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum and histopathological changes in the liver were analysed to determine the degree of liver injury. Deoxyribonucleic acid (DNA) microarray analysis was performed to compare gene expression levels altered in the rat livers. Phosphorylated Jun-N-terminal kinase (JNK) in human hepatocellular carcinoma (HepG2) cells were detected using western blot analysis to investigate the anti-inflammatory activity of compound K. Key findings Pretreatment with FG, containing compound K at high concentration, attenuated AST as well as ALT levels in rats, while no obvious effect was observed in the group that received FRG, whose content of compound K was lower than that of FG. In addition, the results of our histopathological analysis were consistent with changes in the serum biochemical analysis. DNA microarray analysis indicated that JNK- and glutathione S-transferase (GST)-related genes were involved in the hepatotoxicity. Notably, compound K, a major ginsenoside in FG, inhibited the phosphorylation of JNK in HepG2 cells. Conclusions FG was shown to possess hepatoprotective activity against paracetamol (APAP)-induced liver injury better than FRG. Compound K might play an important role for an anti-inflammatory activity of FG by inhibiting JNK signalling in the liver. © 2014 Royal Pharmaceutical Society.

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