Tanaka N

References (38)

Title : Biochemical Evaluation of Laparoscopic Portoenterostomy for Treating Biliary Atresia and Redo for Failed Portoenterostomy - Tsukui_2022_J.Laparoendosc.Adv.Surg.Tech.A__
Author(s) : Tsukui T , Koga H , Cazares J , Yamada S , Murakami H , Shibuya S , Nakamura H , Ochi T , Tsuboi K , Lane G , Tanaka N , Miyano G , Okazaki T , Urao M , Yamataka A
Ref : J Laparoendosc Adv Surg Tech A , : , 2022
Abstract : Background: Postoperative outcomes of portoenterostomy (PE) and redo-PE were evaluated using selected biochemical markers (SBM) and biochemical status categories (BSC). Methods: Subjects were 70 consecutive PE performed for biliary atresia. SBM were aspartate aminotransferase (AST)/alanine aminotransferase (ALT), cholinesterase (ChE), and platelet count (PLT) assessed at 1, 2, 3, 6, and 12 months, and thence, annually for a maximum of 10 years. BSC were as follows: all SBM normal (N-SBM), normal AST/ALT (N-SLT), normal ChE (N-ChE), normal PC (N-PLT), all abnormal (A-SBM), abnormal AST/ALT (A-SLT), abnormal ChE (A-ChE), and abnormal PC (A-PLT). Subjects achieving jaundice clearance (JC) and surviving with native livers (SNL) also had gamma glutamyl transpeptidase assessed. Redo-PE indicated for failed PE was assessed postoperatively using the same SBM/BSC protocol. Results: PE were laparoscopic (LPE; n = 40) or open (OPE; n = 30). Mean age/weight at PE and duration of follow-up were similar. For JC, LPE = 34/40 (85.0%) and OPE = 22/30 (73.3%); P = .23. For SNL, LPE = 29/40 (72.5%) and OPE = 16/30 (53.3%); P = .10. LPE and OPE were similar for SBM/BSC, except for a single significant increase in ALT in OPE at 6 months. Redo-PE was performed 17-180 days (mean 67.1 days) after primary PE. AST was significantly increased at the last preredo assessment 3 months after primary PE; P < .05. After redo, AST decreased and SBM/BSC results were equivalent to nonredo subjects. Conclusion: Postoperative biochemical data for all PE cases were comparable; redo-PE would appear to be viable for restoring SBM, and AST could be valuable as a single marker of deterioration in redo cases.
ESTHER : Tsukui_2022_J.Laparoendosc.Adv.Surg.Tech.A__
PubMedSearch : Tsukui_2022_J.Laparoendosc.Adv.Surg.Tech.A__
PubMedID: 35939285

Title : Crystal structures of a bacterial dipeptidyl peptidase IV reveal a novel substrate recognition mechanism distinct from that of mammalian orthologues - Roppongi_2018_Sci.Rep_8_2714
Author(s) : Roppongi S , Suzuki Y , Tateoka C , Fujimoto M , Morisawa S , Iizuka I , Nakamura A , Honma N , Shida Y , Ogasawara W , Tanaka N , Sakamoto Y , Nonaka T
Ref : Sci Rep , 8 :2714 , 2018
Abstract : Dipeptidyl peptidase IV (DPP IV, DPP4, or DAP IV) preferentially cleaves substrate peptides with Pro or Ala at the P1 position. The substrate recognition mechanism has been fully elucidated for mammalian DPP IV by crystal structure analyses but not for bacterial orthologues. Here, we report the crystal structures of a bacterial DPP IV (PmDAP IV) in its free form and in complexes with two kinds of dipeptides as well as with a non-peptidyl inhibitor at 1.90 to 2.47 A resolution. Acyl-enzyme intermediates were observed for the dipeptide complexes of PmDAP IV, whereas tetrahedral intermediates were reported for the oligopeptide complexes of mammalian DPP IVs. This variation reflects the different structural environments of the active site Arg residues, which are involved in the recognition of a substrate carbonyl group, of mammalian and bacterial enzymes. A phylogenetic analysis revealed that PmDAP IV is a closer relative of dipeptidyl peptidases 8 and 9 (DPP8 and DPP9, DPP IV-family enzymes) than DPP IV. These results provide new insights into the substrate recognition mechanism of bacterial DAP IVs and may assist in the development of selective inhibitors for DAP IVs from pathogenic asaccharolytic bacteria, which utilise proteins or peptides as an energy source.
ESTHER : Roppongi_2018_Sci.Rep_8_2714
PubMedSearch : Roppongi_2018_Sci.Rep_8_2714
PubMedID: 29426867
Gene_locus related to this paper: 9psed-q6f3i7

Title : Voxel-Based Acetylcholinesterase PET Study in Early and Late Onset Alzheimer's Disease - Hirano_2018_J.Alzheimers.Dis_62_1539
Author(s) : Hirano S , Shinotoh H , Shimada H , Ota T , Sato K , Tanaka N , Zhang MR , Higuchi M , Fukushi K , Irie T , Kuwabara S , Suhara T
Ref : J Alzheimers Dis , 62 :1539 , 2018
Abstract : BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. OBJECTIVE: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. METHODS: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value <0.05 on cluster-level and cluster extent over 30 voxels. RESULTS: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. CONCLUSION: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.
ESTHER : Hirano_2018_J.Alzheimers.Dis_62_1539
PubMedSearch : Hirano_2018_J.Alzheimers.Dis_62_1539
PubMedID: 29562505

Title : Periplasmic form of dipeptidyl aminopeptidase IV from Pseudoxanthomonas mexicana WO24: purification, kinetic characterization, crystallization and X-ray crystallographic analysis - Roppongi_2017_Acta.Crystallogr.F.Struct.Biol.Commun_73_601
Author(s) : Roppongi S , Tateoka C , Fujimoto M , Iizuka I , Morisawa S , Nakamura A , Honma N , Suzuki Y , Shida Y , Ogasawara W , Tanaka N , Sakamoto Y , Nonaka T
Ref : Acta Crystallographica F Struct Biol Commun , 73 :601 , 2017
Abstract : Dipeptidyl aminopeptidase IV (DAP IV or DPP IV) from Pseudoxanthomonas mexicana WO24 (PmDAP IV) preferentially cleaves substrate peptides with Pro or Ala at the P1 position [NH2-P2-P1(Pro/Ala)-P1'-P2'...]. For crystallographic studies, the periplasmic form of PmDAP IV was overproduced in Escherichia coli, purified and crystallized in complex with the tripeptide Lys-Pro-Tyr using the hanging-drop vapour-diffusion method. Kinetic parameters of the purified enzyme against a synthetic substrate were also determined. X-ray diffraction data to 1.90 A resolution were collected from a triclinic crystal form belonging to space group P1, with unit-cell parameters a = 88.66, b = 104.49, c = 112.84 A, alpha = 67.42, beta = 68.83, gamma = 65.46 degrees . Initial phases were determined by the molecular-replacement method using Stenotrophomonas maltophilia DPP IV (PDB entry 2ecf) as a template and refinement of the structure is in progress.
ESTHER : Roppongi_2017_Acta.Crystallogr.F.Struct.Biol.Commun_73_601
PubMedSearch : Roppongi_2017_Acta.Crystallogr.F.Struct.Biol.Commun_73_601
PubMedID: 29095153
Gene_locus related to this paper: 9psed-q6f3i7

Title : Discrimination of a nerve fiber that is the origin of a cauda equina tumor using acetylcholinesterase staining - Kamei_2017_Neuropathology_37_415
Author(s) : Kamei N , Tanaka N , Arihiro K , Nakanishi K , Kotaka S , Adachi N , Ochi M
Ref : Neuropathology , 37 :415 , 2017
Abstract : Spinal nerve sheath tumors are well known to typically originate from dorsal sensory nerve roots. However, it is difficult to anatomically identify the origin in the case of cauda equina tumors. In this study, we aimed to ascertain whether a cauda equina nerve root removed with a nerve sheath tumor was a motor nerve using acetylcholinesterase (AchE) staining. Nerve rootlet sections removed with tumors were stained for AchE using the AchE Rapid Staining Kit. Additionally, we performed intraoperative motor-evoked potential (MEP) monitoring following either transcranial electrical stimulation (TES) or electrical stimulation of nerve rootlets. The muscular strength of the lower extremities was assessed bilaterally before and after surgery using manual muscle testing. An AchE-positive motor nerve rootlet that was the origin of a cauda equina tumor was observed in one of the 12 patients. In this patient, a MEP in the right quadriceps evoked by electrical stimulation of this rootlet was detected. TES-MEP showed a 30% decrease in the amplitude in the right quadriceps evoked after tumor resection with this nerve rootlet. However, the motor strength in both lower extremities did not change after surgery. AchE staining and intraoperative MEP monitoring could detect the motor nerve rootlet that was the origin of a cauda equina tumor. Nerve sheath tumors originating from the motor nerve might be rare even in cauda equina.
ESTHER : Kamei_2017_Neuropathology_37_415
PubMedSearch : Kamei_2017_Neuropathology_37_415
PubMedID: 28493390

Title : Comparison of genetic structures and biochemical properties of tandem cutinase-type polyesterases from Thermobifida alba AHK119 - Thumarat_2015_J.Biosci.Bioeng_120_491
Author(s) : Thumarat U , Kawabata T , Nakajima M , Nakajima H , Sugiyama A , Yazaki K , Tada T , Waku T , Tanaka N , Kawai F
Ref : J Biosci Bioeng , 120 :491 , 2015
Abstract : This study described the genetic map of tandem genes (est1 and est119) encoding cutinase-type polyesterases in Thermobifida alba AHK119 and comparison of wild type and mutant enzymes of Est1 and Est119. Two genes were independently and constitutively expressed. The activity of Est1 was higher by approximately 1.6-1.7-fold than that of Est119 towards p-nitrophenyl butyrate, although both enzymes shared 95% sequence identity and 98% similarity and possessed similar 3D structures except that several amino acids in the probable substrate-docking loops were different from each other. Calcium ion enhanced the activity and the thermostability of both enzymes. Based on conserved sequences among Thermobifida cutinases, valine, proline and lysine were introduced into Est1 at Ala68, Thr253 and Met256, respectively. Among wild and mutant enzymes of Est119 and Est1, Est1 (A68V/T253P) possessed three prolines in the substrate-docking loops and displayed the highest thermostability that spotlighted the important effect of proline numbers in the loops. Est1 (A68V/T253P) was stable for 1 h below 60 degrees C and even at 65 degrees C, more than 70% and 50% activities were maintained after 30 and 60 min, respectively. Est1 (A68V/T253P) degraded various aliphatic and aliphatic-co-aromatic polyesters and hydrophilized an amorphous PET film. The enzyme hydrolyzed a PET trimer model compound, indicating its specificity towards an ester bond between terephthalic acid and ethylene glycol.
ESTHER : Thumarat_2015_J.Biosci.Bioeng_120_491
PubMedSearch : Thumarat_2015_J.Biosci.Bioeng_120_491
PubMedID: 25910960
Gene_locus related to this paper: 9acto-d4q9n1 , 9acto-f7ix06

Title : Comparative genomics of Fructobacillus spp. and Leuconostoc spp. reveals niche-specific evolution of Fructobacillus spp - Endo_2015_BMC.Genomics_16_1117
Author(s) : Endo A , Tanizawa Y , Tanaka N , Maeno S , Kumar H , Shiwa Y , Okada S , Yoshikawa H , Dicks L , Nakagawa J , Arita M
Ref : BMC Genomics , 16 :1117 , 2015
Abstract : BACKGROUND: Fructobacillus spp. in fructose-rich niches belong to the family Leuconostocaceae. They were originally classified as Leuconostoc spp., but were later grouped into a novel genus, Fructobacillus, based on their phylogenetic position, morphology and specific biochemical characteristics. The unique characters, so called fructophilic characteristics, had not been reported in the group of lactic acid bacteria, suggesting unique evolution at the genome level. Here we studied four draft genome sequences of Fructobacillus spp. and compared their metabolic properties against those of Leuconostoc spp.
RESULTS: Fructobacillus species possess significantly less protein coding sequences in their small genomes. The number of genes was significantly smaller in carbohydrate transport and metabolism. Several other metabolic pathways, including TCA cycle, ubiquinone and other terpenoid-quinone biosynthesis and phosphotransferase systems, were characterized as discriminative pathways between the two genera. The adhE gene for bifunctional acetaldehyde/alcohol dehydrogenase, and genes for subunits of the pyruvate dehydrogenase complex were absent in Fructobacillus spp. The two genera also show different levels of GC contents, which are mainly due to the different GC contents at the third codon position. CONCLUSION: The present genome characteristics in Fructobacillus spp. suggest reductive evolution that took place to adapt to specific niches.
ESTHER : Endo_2015_BMC.Genomics_16_1117
PubMedSearch : Endo_2015_BMC.Genomics_16_1117
PubMedID: 26715526
Gene_locus related to this paper: 9lact-a0a0k8mi40 , 9lact-a0a0k8ms25 , 9lact-a0a0k8msc5

Title : Dementia with Lewy bodies can be well-differentiated from Alzheimer's disease by measurement of brain acetylcholinesterase activity-a [(11) C]MP4A PET study - Shimada_2015_Int.J.Geriatr.Psychiatry_30_1105
Author(s) : Shimada H , Hirano S , Sinotoh H , Ota T , Tanaka N , Sato K , Yamada M , Fukushi K , Irie T , Zhang MR , Higuchi M , Kuwabara S , Suhara T
Ref : Int J Geriatr Psychiatry , 30 :1105 , 2015
Abstract : OBJECTIVE: To investigate the diagnostic performance of brain acetylcholinesterase (AChE) activity measurement using N-[(11) C]-methyl-4-piperidyl acetate (MP4A) and PET in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).
METHODS: Participants were 14 DLB patients, 25 AD patients and 18 age-matched healthy controls (HC). All subjects underwent PET scans and MP4A to measure regional brain AChE activity. We performed anatomical standardization of each brain image, and k3 values, an index of AChE activity, in each voxel were estimated by nonlinear least squares analysis. Volumes of interest (VOIs) were identified on parametric k3 images in frontal, temporal, parietal and occipital cortices, and in anterior and posterior cingulate gyri (ACG and PCG). In each VOI, the differential diagnostic performance between AD and DLB of k3 values was assessed by area under the curve (AUC) of the receiver-operating characteristic. Voxel-based statistical analyses were also performed.
RESULTS: Mean cortical AChE activities in AD patients (-8.2% compared with normal mean) and DLB patients (-27.8%) were lower than HCs (p < 0.05, p < 0.001, respectively). There was a significant difference in mean cortical AChE activities between AD and DLB patients (p < 0.001). All regional brain AChE activities of defined VOIs except ACG were able to well discriminate DLB from AD, and notably performance was the most significant in PCG (AUC = 0.989, 95% CI: 0.965-1.000).
CONCLUSIONS: Brain cholinergic deficit is consistently prominent in DLB compared with AD. PET measurement of brain AChE activity may be useful for the differential diagnosis between DLB and AD. Copyright (c) 2015 John Wiley & Sons, Ltd.
ESTHER : Shimada_2015_Int.J.Geriatr.Psychiatry_30_1105
PubMedSearch : Shimada_2015_Int.J.Geriatr.Psychiatry_30_1105
PubMedID: 26280153

Title : A novel Ca-activated, thermostabilized polyesterase capable of hydrolyzing polyethylene terephthalate from Saccharomonospora viridis AHK190 - Kawai_2014_Appl.Microbiol.Biotechnol_98_10053
Author(s) : Kawai F , Oda M , Tamashiro T , Waku T , Tanaka N , Yamamoto M , Mizushima H , Miyakawa T , Tanokura M
Ref : Applied Microbiology & Biotechnology , 98 :10053 , 2014
Abstract : Only two polyethylene glycol terephthalate (PET)-degrading enzymes have been reported, and their mechanism for the biochemical degradation of PET remains unclear. To identify a novel PET-degrading enzyme, a putative cutinase gene (cut190) was cloned from the thermophile Saccharomonospora viridis AHK190 and expressed in Escherichia coli Rosetta-gami B (DE3). Mutational analysis indicated that substitution of Ser226 with Pro and Arg228 with Ser yielded the highest activity and thermostability. The Ca2+ ion enhanced the enzyme activity and thermostability of the wild-type and mutant Cut190. Circular dichroism suggested that the Ca2+ changes the tertiary structure of the Cut190 (S226P/R228S), which has optimal activity at 65-75 degrees C and pH 6.5-8.0 in the presence of 20 % glycerol. The enzyme was stable over a pH range of 5-9 and at temperatures up to 65 degrees C for 24 h with 40 % activity remaining after incubation for 1 h at 70 degrees C. The Cut190 (S226P/R228S) efficiently hydrolyzed various aliphatic and aliphatic-co-aromatic polyester films. Furthermore, the enzyme degraded the PET film above 60 degrees C. Therefore, Cut190 is the novel-reported PET-degrading enzyme with the potential for industrial applications in polyester degradation, monomer recycling, and PET surface modification. Thus, the Cut190 will be a useful tool to elucidate the molecular mechanisms of the PET degradation, Ca2+ activation, and stabilization.
ESTHER : Kawai_2014_Appl.Microbiol.Biotechnol_98_10053
PubMedSearch : Kawai_2014_Appl.Microbiol.Biotechnol_98_10053
PubMedID: 24929560
Gene_locus related to this paper: sacvd-c7mve8

Title : Role of white adipose lipolysis in the development of NASH induced by methionine- and choline-deficient diet - Tanaka_2014_Biochim.Biophys.Acta_1841_1596
Author(s) : Tanaka N , Takahashi S , Fang ZZ , Matsubara T , Krausz KW , Qu A , Gonzalez FJ
Ref : Biochimica & Biophysica Acta , 1841 :1596 , 2014
Abstract : Methionine- and choline-deficient diet (MCD) is a model for nonalcoholic steatohepatitis (NASH) in rodents. However, the mechanism of NASH development by dietary methionine/choline deficiency remains undetermined. To elucidate the early metabolic changes associated with MCD-NASH, serum metabolomic analysis was performed using mice treated with MCD and control diet for 3 days and 1 week, revealing significant increases in oleic and linoleic acids after MCD treatment. These increases were correlated with reduced body weight and white adipose tissue (WAT) mass, increased phosphorylation of hormone-sensitive lipase, and up-regulation of genes encoding carboxylesterase 3 and beta2-adrenergic receptor in WAT, indicating accelerated lipolysis in adipocytes. The changes in serum fatty acids and WAT by MCD treatment were reversed by methionine supplementation, and similar alterations were detected in mice fed a methionine-deficient diet (MD), thus demonstrating that dietary methionine deficiency enhances lipolysis in WAT. MD treatment decreased glucose and increased fibroblast growth factor 21 in serum, thus exhibiting a similar metabolic phenotype as the fasting response. Comparison between MCD and choline-deficient diet (CD) treatments suggested that the addition of MD-induced metabolic alterations, such as WAT lipolysis, to CD-induced hepatic steatosis promotes liver injury. Collectively, these results demonstrate an important role for dietary methionine deficiency and WAT lipolysis in the development of MCD-NASH.
ESTHER : Tanaka_2014_Biochim.Biophys.Acta_1841_1596
PubMedSearch : Tanaka_2014_Biochim.Biophys.Acta_1841_1596
PubMedID: 25178843

Title : Crystallographic and mutational analyses of tannase from Lactobacillus plantarum - Matoba_2013_Proteins_81_2052
Author(s) : Matoba Y , Tanaka N , Noda M , Higashikawa F , Kumagai T , Sugiyama M
Ref : Proteins , 81 :2052 , 2013
Abstract : Tannin acylhydrolase (EC referred commonly as tannase catalyzes the hydrolysis of the galloyl ester bond of tannins to release gallic acid. Although the enzyme is useful for various industries, the tertiary structure is not yet determined. In this study, we determined the crystal structure of tannase produced by Lactobacillus plantarum. The tannase structure belongs to a member of alpha/beta-hydrolase superfamily with an additional "lid" domain. A glycerol molecule derived from cryoprotectant solution was accommodated into the tannase active site. The binding manner of glycerol to tannase seems to be similar to that of the galloyl moiety in the substrate. Proteins 2013; 81:2052-2058. (c) 2013 Wiley Periodicals, Inc.
ESTHER : Matoba_2013_Proteins_81_2052
PubMedSearch : Matoba_2013_Proteins_81_2052
PubMedID: 23836494
Gene_locus related to this paper: lacpl-tanL

Title : Ethanol- and acetaldehyde-induced cholinergic imbalance in the hippocampus of Aldh2-knockout mice does not affect nerve growth factor or brain-derived neurotrophic factor - Jamal_2013_Brain.Res_1539_41
Author(s) : Jamal M , Ameno K , Ruby M , Miki T , Tanaka N , Nakamura Y , Kinoshita H
Ref : Brain Research , 1539 :41 , 2013
Abstract : Neurotrophins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), play an important role in the maintenance of cholinergic-neuron function. The objective of this study was to investigate whether ethanol (EtOH)- and acetaldehyde (AcH)- induced cholinergic effects would cause neurotrophic alterations in the hippocampus of mice. We used Aldh2 knockout (Aldh2-KO) mice, a model of aldehyde dehydrogenase 2 (ALDH2)-deficiency in humans, to examine the effects of acute administration of EtOH and the role of AcH. Hippocampal slices were collected and the mRNA and protein levels of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), NGF and BDNF were analyzed 30min after the i.p. administration of EtOH (0.5, 1.0, or 2.0g/kg). We show that treatment with 2.0g/kg of EtOH decreased ChAT mRNA and protein levels in Aldh2-KO mice but not in wild-type (WT) mice, which suggests a role for AcH in the mechanism of action of EtOH. The administration of 2.0g/kg of EtOH increased AChE mRNA in both strains of mice. EtOH failed to change the levels of NGF or BDNF at any dose. Aldh2-KO mice exhibited a distinctly lower expression of ChAT and a higher expression of NGF both at mRNA and protein levels in the hippocampus compared with WT mice. Our observations suggest that administration of EtOH and elevated AcH can alter cholinergic markers in the hippocampus of mice, and this effect did not change the levels of NGF or BDNF.
ESTHER : Jamal_2013_Brain.Res_1539_41
PubMedSearch : Jamal_2013_Brain.Res_1539_41
PubMedID: 24096209

Title : Greater responsiveness to donepezil in Alzheimer patients with higher levels of acetylcholinesterase based on attention task scores and a donepezil PET study - Kasuya_2012_Alzheimer.Dis.Assoc.Disord_26_113
Author(s) : Kasuya M , Meguro K , Okamura N , Funaki Y , Ishikawa H , Tanaka N , Iwata R , Yanai K
Ref : Alzheimer Disease & Associated Disorders , 26 :113 , 2012
Abstract : The aim of the study was to predict donepezil responders among patients with Alzheimer disease (AD) based on cognitive tests and positron emission tomography. The Mini-Mental State Examination, Digit Symbol subtest (DigSm) of Wechsler Adult Intelligence Scale Revised, and Trail-Making Test A were administered for 80 patients with AD to assess global function, attention, and executive function, respectively. The same tests and the Clinical Global Impression (CGI) scale were conducted after treatment with oral donepezil (5 mg/d) for 6 months (study 1). [C]-Donepezil positron emission tomography examinations were conducted before and after treatment for 30 randomly selected patients. The distribution volume (DV), which indicates the density of donepezil-binding sites, was calculated using Logan graphical analysis (study 2). In study 1, 35 patients were identified as responders based on the CGI and Mini-Mental State Examination changes. These patients had higher baseline DigSm scores compared with nonresponders. In study 2, 15 patients were responders. DigSm correlated with DV at baseline. DV at baseline and %DV change in responders were higher than in nonresponders, and these variables correlated with DeltaDigSm and CGI scores. Higher baseline attention may predict responsiveness to donepezil in patients with AD, and higher acetylcholinesterase levels result in a greater clinical effect.
ESTHER : Kasuya_2012_Alzheimer.Dis.Assoc.Disord_26_113
PubMedSearch : Kasuya_2012_Alzheimer.Dis.Assoc.Disord_26_113
PubMedID: 21666432

Title : Metabolomics identifies an inflammatory cascade involved in dioxin- and diet-induced steatohepatitis - Matsubara_2012_Cell.Metab_16_634
Author(s) : Matsubara T , Tanaka N , Krausz KW , Manna SK , Kang DW , Anderson ER , Luecke H , Patterson AD , Shah YM , Gonzalez FJ
Ref : Cell Metab , 16 :634 , 2012
Abstract : 2,3,7,8-Tetrachlorodibenzo-p-dioxin TCDD is among the most potent environmentally toxic compounds Serum metabolomics identified azelaic acid monoesters as significantly increased metabolites after TCDD treatment due to downregulation of hepatic carboxylesterase 3 CES3 also known as triglyceride hydrolase expression in an arylhydrocarbon receptor AhR)-dependent manner in mice The decreased CES3 expression was accomplished by TCDD-stimulated TGFbeta-SMAD3 and IL6-STAT3 signaling but not by direct AhR signaling Methionine and choline-deficient MCD diet-treated mice also showed enhanced serum azelaic acid monoester levels after attenuation of hepatic CES3 expression while db/db mice did not thus suggesting an association with steatohepatitis Forced expression of CES3 reversed serum azelaic acid monoester/azelaic acid ratios and hepatic TGFbeta mRNA levels in TCDD and MCD diet-treated mice and ameliorated steatohepatitis induced by MCD diet These results support the view that azelaic acid monoesters are possible indicators of TCDD exposure and steatohepatitis and suggest a link between CES3 TGFbeta and steatohepatitis.
ESTHER : Matsubara_2012_Cell.Metab_16_634
PubMedSearch : Matsubara_2012_Cell.Metab_16_634
PubMedID: 23140643

Title : Effects of systemic nicotine, alcohol or their combination on cholinergic markers in the frontal cortex and hippocampus of rat - Jamal_2010_Neurochem.Res_35_1064
Author(s) : Jamal M , Ameno K , Miki T , Tanaka N , Ohkubo E , Kinoshita H
Ref : Neurochem Res , 35 :1064 , 2010
Abstract : Acute alcohol (Alc) intoxication has been shown to decrease choline acetyltransferase (ChAT) in the rat brain. The present study extends that finding by examining the effects of nicotine (Nic), Alc, and their combination on ChAT and acetylcholinesterase (AChE) in the frontal cortex and hippocampus of rat. The samples were collected at 30 and 120 min after intraperitoneal administration of saline (0.9%, control), Nic (1 mg/kg), Alc (1 g/kg), and Nic + Alc and analyzed by RT-PCR, Western blot and colorimetry. Alc alone considerably reduced ChAT mRNA expression, whereas Nic alone decreased AChE mRNA expression. In contrast, Nic + Alc exposure had resulted in no significant change in the parameters. These findings are consistent with the results of the Western blot and AChE activity analysis. The results, therefore, indicate that Nic and Alc alone may interact with the central cholinergic system. This interactive effect may contribute to a frequent association of tobacco and Alc consumption.
ESTHER : Jamal_2010_Neurochem.Res_35_1064
PubMedSearch : Jamal_2010_Neurochem.Res_35_1064
PubMedID: 20309727

Title : Cholinergic imaging in corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia - Hirano_2010_Brain_133_2058
Author(s) : Hirano S , Shinotoh H , Shimada H , Aotsuka A , Tanaka N , Ota T , Sato K , Ito H , Kuwabara S , Fukushi K , Irie T , Suhara T
Ref : Brain , 133 :2058 , 2010
Abstract : Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [11C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6+/-5.9 years), 12 with progressive supranuclear palsy (68.5+/-4.1 years), eight with frontotemporal dementia (59.8+/-6.9 years) and 16 healthy controls (61.2+/-8.5 years). Two-tissue compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k3 values) in the paracentral region, frontal, parietal and occipital cortices (P<0.05, cluster corrected). The group with progressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P<0.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P<0.001), 9.4% in progressive supranuclear palsy (P<0.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P<0.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy.
ESTHER : Hirano_2010_Brain_133_2058
PubMedSearch : Hirano_2010_Brain_133_2058
PubMedID: 20558417

Title : Estimation of plasma IC50 of donepezil for cerebral acetylcholinesterase inhibition in patients with Alzheimer disease using positron emission tomography - Ota_2010_Clin.Neuropharmacol_33_74
Author(s) : Ota T , Shinotoh H , Fukushi K , Kikuchi T , Sato K , Tanaka N , Shimada H , Hirano S , Miyoshi M , Arai H , Suhara T , Irie T
Ref : Clinical Neuropharmacology , 33 :74 , 2010
Abstract : OBJECTIVES: Estimate the value of in vivo plasma IC50 of donepezil, the concentration of donepezil in plasma that inhibits brain acetylcholinesterase (AChE) activity by 50% at the steady-state conditions of donepezil between the plasma and the brain. METHODS: N-[C] methylpiperidin-4-yl acetate ([C]MP4A) positron emission tomography was performed in 16 patients with probable Alzheimer disease (AD) before and during the treatment of donepezil (5 mg/day) with a mean interval of 5.3 months. The plasma IC50 value of donepezil was estimated from plasma donepezil concentrations and cerebral cortical mean AChE inhibition rates measured by positron emission tomography, using one-parameter model. RESULTS: Donepezil reduced AChE activity uniformly in the cerebral cortex compared with the baseline in each AD patient, and the mean reduction rate in the cerebral cortex was 34.6%. The donepezil concentrations in the plasma ranged from 18.5 to 43.9 ng/mL with a mean of 28.9 +/- 7.3 ng/mL. The plasma IC50 value was estimated to be 53.6 +/- 4.0 ng/mL. CONCLUSIONS: Once the plasma IC50 of donepezil is determined, the brain AChE inhibition rate could be estimated from the plasma concentration of donepezil in each subject based on the plasma IC50. Now that the mean donepezil concentrations in the plasma, when the patients took 5 mg/day, remained 28.9 ng/mL, approximately half of the plasma IC50, higher dose of donepezil might provide further benefits for patients with AD. This technique can be also applied to measure the in vivo plasma IC50 of other cholinesterase inhibitors such as rivastigmine and galantamine.
ESTHER : Ota_2010_Clin.Neuropharmacol_33_74
PubMedSearch : Ota_2010_Clin.Neuropharmacol_33_74
PubMedID: 19935404

Title : Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET - Shimada_2009_Neurology_73_273
Author(s) : Shimada H , Hirano S , Shinotoh H , Aotsuka A , Sato K , Tanaka N , Ota T , Asahina M , Fukushi K , Kuwabara S , Hattori T , Suhara T , Irie T
Ref : Neurology , 73 :273 , 2009
Abstract : OBJECTIVE: To characterize brain cholinergic deficits in Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB). METHODS: Participants included 18 patients with PD, 21 patients with PDD/DLB, and 26 healthy controls. The PD group consisted of nine patients with early PD, each with a disease duration of less than 3 years, five of whom were de novo PD patients, and nine patients with advanced PD, each with a disease duration greater than or equal to 3 years. The PDD/DLB group consisted of 10 patients with PDD and 11 patients with DLB. All subjects underwent PET scans with N-[11C]-methyl-4-piperidyl acetate to measure brain acetylcholinesterase (AChE) activity. Brain AChE activity levels were estimated voxel-by-voxel in a three-compartment analysis using the arterial input function, and compared among our subject groups through both voxel-based analysis using the statistical parametric mapping software SPM5 and volume-of-interest analysis. RESULTS: Among patients with PD, AChE activity was significantly decreased in the cerebral cortex and especially in the medial occipital cortex (% reduction compared with the normal mean = -12%) (false discovery rate-corrected p value <0.01). Patients with PDD/DLB, however, had even lower AChE activity in the cerebral cortex (% reduction = -27%) (p < 0.01). There was no significant difference between early PD and advanced PD groups or between DLB and PDD groups in the amount by which regional AChE activity in the brain was reduced. CONCLUSIONS: Brain cholinergic dysfunction occurs in the cerebral cortex, especially in the medial occipital cortex. It begins in early Parkinson disease, and is more widespread and profound in both Parkinson disease with dementia and dementia with Lewy bodies.
ESTHER : Shimada_2009_Neurology_73_273
PubMedSearch : Shimada_2009_Neurology_73_273
PubMedID: 19474411

Title : Association of serum glycated albumin to haemoglobin A1C ratio with hepatic function tests in patients with chronic liver disease - Bando_2009_Ann.Clin.Biochem_46_368
Author(s) : Bando Y , Kanehara H , Toya D , Tanaka N , Kasayama S , Koga M
Ref : Annals of Clinical Biochemistry , 46 :368 , 2009
Abstract : BACKGROUND: In patients with chronic liver disease (CLD), glycated haemoglobin (HbA(1C)) levels have been shown to be apparently lower than real values, whereas serum glycated albumin (GA) levels are apparently higher. The present study was aimed to examine whether both glycaemic indices are influenced by hepatic function. METHODS: Subjects consisted of 82 patients with CLD. Various indicators for hepatic function as well as HbA(1C) and GA were also measured. Estimated HbA(1C) values were calculated from the mean plasma glucose levels. Two hundred and two type 2 diabetic patients without CLD were studied as controls. RESULTS: Although GA was strongly correlated with HbA(1C) in patients with CLD as well as diabetic patients, GA levels in patients with CLD were relatively higher than those in diabetic patients. In patients with estimated HbA(1C) < or = 5.8%, GA levels significantly increased but HbA(1C) levels decreased as a function of decreasing hepaplastin test (HPT). The ratio of GA/HbA(1C) (G/H ratio) increased as a function of decreasing HPT. In patients with estimated HbA(1C) > 5.8%, in contrast, GA levels were independent of HPT levels. In the patients with CLD, GA and HbA(1C) were associated with mean plasma glucose levels and some indicators for hepatic function. The multivariate analysis revealed a significant association of G/H ratio with HPT, cholinesterase and direct bilirubin. The G/H ratio was not associated with the mean plasma glucose but with HPT and cholinesterase levels. CONCLUSIONS: The G/H ratio correlates with hepatic function but not with plasma glucose levels. Therefore, CLD should be suspected for diabetic patients with an elevated G/H ratio.
ESTHER : Bando_2009_Ann.Clin.Biochem_46_368
PubMedSearch : Bando_2009_Ann.Clin.Biochem_46_368
PubMedID: 19675058

Title : PET study of brain acetylcholinesterase in cerebellar degenerative disorders - Hirano_2008_Mov.Disord_23_1154
Author(s) : Hirano S , Shinotoh H , Arai K , Aotsuka A , Yasuno F , Tanaka N , Ota T , Sato K , Fukushi K , Tanada S , Hattori T , Irie T
Ref : Movement Disordersord , 23 :1154 , 2008
Abstract : To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.
ESTHER : Hirano_2008_Mov.Disord_23_1154
PubMedSearch : Hirano_2008_Mov.Disord_23_1154
PubMedID: 18412283

Title : Molecular mechanism of age-specific hepatic lipid accumulation in PPARalpha (+\/-):LDLR (+\/-) mice, an obese mouse model - Li_2008_Lipids_43_301
Author(s) : Li Y , Sugiyama E , Yokoyama S , Jiang L , Tanaka N , Aoyama T
Ref : Lipids , 43 :301 , 2008
Abstract : This study aimed to clarify the molecular mechanisms of age-specific hepatic lipid accumulation accompanying hyperinsulinemia in a peroxisome proliferator-activated receptor alpha (PPARalpha) (+/-):low-density lipoprotein receptor (LDLR) (+/-) mouse line. The hepatic fat content, protein amounts, and mRNA levels of genes involved in hepatic lipid metabolism were analyzed in 25-, 50-, 75- and 100-week-old mice. Severe fatty liver was confirmed only in 50- and 75-week-old mice. The hepatic expression of proteins that function in lipid transport and catabolism did not differ among the groups. In contrast, the mRNA levels and protein amounts of lipogenic enzymes, including acetyl-coenzyme A carboxylase-1, fatty acid synthase, and glycerol-3-phosphate acyltransferase, enhanced in the mice with fatty liver. Elevated mRNA and protein levels of lipoprotein lipase and fatty acid translocase, which are involved in hepatic lipid uptake, were also detected in mice with fatty liver. Moreover, both protein and mRNA levels of sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor regulating lipid synthesis, had age-specific patterns similar to those of the proteins described above. Therefore, the age-specific fatty liver found in the PPARalpha (+/-):LDLR (+/-) mouse line is probably caused by age-specific expression of SREBP-1 and its downstream lipogenic genes, coordinated by the increased uptake of lipids. All of these factors might be affected by age-specific changes in serum insulin concentration.
ESTHER : Li_2008_Lipids_43_301
PubMedSearch : Li_2008_Lipids_43_301
PubMedID: 18335269

Title : Brain acetylcholinesterase activity in FTDP-17 studied by PET -
Author(s) : Hirano S , Shinotoh H , Kobayashi T , Tsuboi Y , Wszolek ZK , Aotsuka A , Tanaka N , Ota T , Fukushi K , Tanada S , Irie T
Ref : Neurology , 66 :1276 , 2006
PubMedID: 16636254

Title : Crystal structures of RsbQ, a stress-response regulator in Bacillus subtilis - Kaneko_2005_Protein.Sci_14_558
Author(s) : Kaneko T , Tanaka N , Kumasaka T
Ref : Protein Science , 14 :558 , 2005
Abstract : Growth-limiting stresses in bacteria induce the general stress response to protect the cells against future stresses. Energy stress caused by starvation conditions in Bacillus subtilis is transmitted to the sigma(B) transcription factor by stress-response regulators. RsbP, a positive regulator, is a phosphatase containing a PAS (Per-ARNT-Sim) domain and requires catalytic function of a putative alpha/beta hydrolase, RsbQ, to be activated. These two proteins have been found to interact with each other. We determined the crystal structures of RsbQ in native and inhibitor-bound forms to investigate why RsbP requires RsbQ. These structures confirm that RsbQ belongs to the alpha/beta hydrolase superfamily. Since the catalytic triad is buried inside the molecule due to the closed conformation, the active site is constructed as a hydrophobic cavity that is nearly isolated from the solvent. This suggests that RsbQ has specificity for a hydrophobic small compound rather than a macromolecule such as RsbP. Moreover, structural comparison with other alpha/beta hydrolases demonstrates that a unique loop region of RsbQ is a likely candidate for the interaction site with RsbP, and the interaction might be responsible for product release by operating the hydrophobic gate equipped between the cavity and the solvent. Our results support the possibility that RsbQ provides a cofactor molecule for the mature functionality of RsbP.
ESTHER : Kaneko_2005_Protein.Sci_14_558
PubMedSearch : Kaneko_2005_Protein.Sci_14_558
PubMedID: 15632289
Gene_locus related to this paper: bacsu-RsbQ

Title : Estimation of plasma IC50 of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) and PET - Shiraishi_2005_Neuropsychopharmacology_30_2154
Author(s) : Shiraishi T , Kikuchi T , Fukushi K , Shinotoh H , Nagatsuka S , Tanaka N , Ota T , Sato K , Hirano S , Tanada S , Iyo M , Irie T
Ref : Neuropsychopharmacology , 30 :2154 , 2005
Abstract : Donepezil hydrochloride is a potent and selective inhibitor for brain acetylcholinesterase (AChE) and is currently used worldwide for the treatment of Alzheimer's disease. Until now, there is no in vivo study on the relation between the plasma concentration and the brain AChE inhibition. The purpose of this study was to estimate in vivo plasma IC(50) of donepezil in living monkeys by measuring plasma donepezil concentration (LC/MS/MS) and brain AChE activity with positron emission tomography (PET) and N-[(11)C]methylpiperidin-4-yl acetate, which is an acetylcholine analog recently developed by us for quantifying in vivo brain AChE activity. PET scans with donepezil at two doses, 100 microg/kg (donepezil-1; N=5) or 250 microg/kg (donepezil-2; N=5), were performed using the same monkeys at 4-week intervals. Before each PET scan, baseline PET scans (N=10 in total) were performed without donepezil. The plasma donepezil concentrations 14 min after intravenous injection were proportional to the doses, 17.2+/-2.9 ng/ml (donepezil-1) and 44.0+/-5.0 ng/ml (donepezil-2), and the mean AChE inhibitions in four neocortical regions as evaluated by PET were also dose-dependent, 27% (donepezil-1) and 53% (donepezil-2). In IC(50) estimation, measured plasma donepezil concentrations were corrected for the change during PET scan. The IC(50) values (estimate+/-SE) were 42+/-9.0 (ng/ml; donepezil-1), 34+/-3.2 (donepezil-2), and 37+/-4.1 (combined data). The present method may be useful for in vivo evaluation of other AChE inhibitors and novel drugs.
ESTHER : Shiraishi_2005_Neuropsychopharmacology_30_2154
PubMedSearch : Shiraishi_2005_Neuropsychopharmacology_30_2154
PubMedID: 15920507

Title : Acephate in biological fluids of two autopsy cases after ingestion of the chemical - Tanaka_2005_J.Forensic.Sci_50_933
Author(s) : Tanaka T , Tanaka N , Kita T , Kasai K , Sato H
Ref : J Forensic Science , 50 :933 , 2005
Abstract : Two autopsy cases, where the individuals were suspected of having ingested acephate, an organophosphorous insecticide, are reported. Acephate and its active metabolite, methamidophos (MP), were analyzed in the biological fluids by GC/MS, using the salting out method with liquid-liquid extraction columns. The first case was that of a 70-year-old man whose blood acephate was 149 microg/mL, and MP was 3.0 microg/mL. Serum pseudocholinesterase (ChE) activity was inhibited. No remarkable finding of injury or disease was determined as the cause of his death, but acute poisoning by acephate was mostly suspected. The second case was that of a 60-year-old man. A deep gash in the left neck injured the left common carotid artery in addition to the severely ischemic state of the primary organs. His blood acephate was 46 microg/mL, and MP was not detected. ChE activity was in the normal range. Hemorrhage was mainly suspected as the cause of his death. The concentrations of acephate and MP in human blood after oral ingestion are first reported here, and the acute toxic level of acephate is discussed.
ESTHER : Tanaka_2005_J.Forensic.Sci_50_933
PubMedSearch : Tanaka_2005_J.Forensic.Sci_50_933
PubMedID: 16078501

Title : Evaluation of simplified kinetic analyses for measurement of brain acetylcholinesterase activity using N-[11C]Methylpiperidin-4-yl propionate and positron emission tomography - Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
Author(s) : Sato K , Fukushi K , Shinotoh H , Nagatsuka S , Tanaka N , Aotsuka A , Ota T , Shiraishi T , Tanada S , Iyo M , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 24 :600 , 2004
Abstract : The applicability of two reference tissue-based analyses without arterial blood sampling for the measurement of brain regional acetylcholinesterase (AChE) activity using N-[11C]methylpiperidin-4-yl propionate ([11C]MP4P) was evaluated in 12 healthy subjects. One was a linear least squares analysis derived from Blomqvist's equation, and the other was the analysis of the ratio of target-tissue radioactivity relative to reference-tissue radioactivity proposed by Herholz and coworkers. The standard compartment analysis using arterial input function provided reliable quantification of k3 (an index of AChE activity) estimates in regions with low (neocortex and hippocampus), moderate (thalamus), and high (cerebellum) AChE activity with a coefficient of variation (COV) of 12% to 19%. However, the precise k3 value in the striatum, where AChE activity is the highest, was not obtained. The striatum was used as a reference because its time-radioactivity curve was proportional to the time integral of the arterial input function. Reliable k3 estimates were also obtained in regions with low-to-moderate AChE activity with a COV of less than 21% by striatal reference analyses, though not obtained in the cerebellum. Shape analysis, the previous method of direct k3 estimation from the shape of time-radioactivity data, gave k3 estimates in the cortex and thalamus with a somewhat larger COV. In comparison with the standard analysis, a moderate overestimation of k3 by 9% to 18% in the linear analysis and a moderate underestimation by 2% to 13% in the Herholz method were observed, which were appropriately explained by the results of computer simulation. In conclusion, simplified kinetic analyses are practical and useful for the routine analysis of clinical [11C]MP4P studies and are nearly as effective as the standard analysis for detecting regions with abnormal AChE activity.
ESTHER : Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
PubMedSearch : Sato_2004_J.Cereb.Blood.Flow.Metab_24_600
PubMedID: 15181367

Title : A simple method for the detection of abnormal brain regions in Alzheimer's disease patients using [11C]MP4A: comparison with [123I]IMP SPECT - Ota_2004_Ann.Nucl.Med_18_187
Author(s) : Ota T , Shinotoh H , Fukushi K , Nagatsuka S , Namba H , Iyo M , Aotsuka A , Tanaka N , Sato K , Shiraishi T , Tanada S , Arai H , Irie T
Ref : Ann Nucl Med , 18 :187 , 2004
Abstract : We have developed a radiolabeled lipophilic acetylcholine analogue, N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) to measure brain acetylcholinesterase (AChE) activity by positron emission tomography (PET) in vivo. Aiming to develop a new SPECT tracer similar to MP4A, we first proposed a simple method for diagnosing Alzheimer's disease (AD) using [11C]MP4A PET. We performed [11C]MP4A PET and N-isopropyl [123I]iodoamphetamine ([123I]IMP) SPECT in 13 patients with AD and in 17 normal controls (NC). We calculated the ratio of radioactivity of the cortical region of interest (ROI) to that of the cerebellum measured with [11C]MP4A PET (MP4A ratio) and the ratio of regional cerebral blood flow (rCBF) to that of the cerebellum measured with [123I]IMP SPECT (IMP ratio). Eleven cortical ROIs were placed in the frontal, sensorimotor, temporal, parietal, and occipital cortices in both hemispheres and in the posterior cingulate cortex, and z-score was calculated in each ROI in patients with AD compared with NC. When the z-score was 2 or more in a ROI, it was defined as a positive ROI. When a patient had 3 or more positive ROIs, the patient was diagnosed as having AD. The reduction in the MP4A ratio was greater than that in the IMP ratio in all cortical ROIs except for in the right parietal cortex and cingulate cortex in patients with AD. MP4A ratio method showed 92% sensitivity and the IMP ratio method 69% sensitivity for the diagnosis of AD. These results encourage us to develop a new SPECT tracer similar to MP4A for the diagnosis of AD.
ESTHER : Ota_2004_Ann.Nucl.Med_18_187
PubMedSearch : Ota_2004_Ann.Nucl.Med_18_187
PubMedID: 15233279

Title : Synaptic scaffolding molecule interacts with axin - Hirabayashi_2004_J.Neurochem_90_332
Author(s) : Hirabayashi S , Nishimura W , Iida J , Kansaku A , Kishida S , Kikuchi A , Tanaka N , Hata Y
Ref : Journal of Neurochemistry , 90 :332 , 2004
Abstract : Synaptic scaffolding molecule (S-SCAM) is a synaptic protein that consists of PDZ domains, a guanylate kinase domain, and WW domains. It interacts with N-methyl-d-aspartate receptor subunits, neuroligin, and beta-catenin. Here, we identified Axin as a novel binding partner of S-SCAM. Axin was co-immunoprecipitated with S-SCAM from rat brain, detected in the post-synaptic density fraction in rat brain subcellular fractionation, and partially co-localized with S-SCAM in neurons. The guanylate kinase domain of S-SCAM directly bound to the GSK3beta-binding region of Axin. S-SCAM formed a complex with beta-catenin and Axin, but competed with GSK3beta for Axin-binding. Thereby, S-SCAM inhibited the Axin-mediated phosphorylation of beta-catenin by GSK3beta.
ESTHER : Hirabayashi_2004_J.Neurochem_90_332
PubMedSearch : Hirabayashi_2004_J.Neurochem_90_332
PubMedID: 15228590

Title : Novel inhibitor for prolyl aminopeptidase from Serratia marcescens and studies on the mechanism of substrate recognition of the enzyme using the inhibitor - Inoue_2003_Arch.Biochem.Biophys_416_147
Author(s) : Inoue T , Ito K , Tozaka T , Hatakeyama S , Tanaka N , Nakamura KT , Yoshimoto T
Ref : Archives of Biochemistry & Biophysics , 416 :147 , 2003
Abstract : Prolyl aminopeptidase from Serratia marcescens hydrolyzed x-beta-naphthylamides (x=prolyl, alanyl, sarcosinyl, L-alpha-aminobutylyl, and norvalyl), which suggested that the enzyme has a pocket for a five-member ring. Based on the substrate specificity, novel inhibitors of Pro, Ala, and Sar having 2-tert-butyl-[1,3,4]oxadiazole (TBODA) were synthesized. The K(i) value of Pro-TBODA, Ala-TBODA, and Sar-TBODA was 0.5 microM, 1.6 microM, and 12mM, respectively. The crystal structure of enzyme-Pro-TBODA complex was determined. Pro-TBODA was located at the active site. Four electrostatic interactions were located between the enzyme and the amino group of Pro inhibitors (Glu204:0E1-N:Inh, Glu204:0E2-N:Inh, Glu232:0E1-N:Inh, and Gly46:O-N:Inh), and the residue of the inhibitors was inserted into the hydrophobic pocket composed of Phe139, Leu141, Leu146, Tyr149, Tyr150, and Phe236. The roles of Phe139, Tyr149, and Phe236 in the hydrophobic pocket and Glu204 and Glu232 in the electrostatic interactions were confirmed by site-directed mutagenesis, which indicated that the molecular recognition of proline is achieved through four electrostatic interactions and an insertion in the hydrophobic pocket of the enzyme.
ESTHER : Inoue_2003_Arch.Biochem.Biophys_416_147
PubMedSearch : Inoue_2003_Arch.Biochem.Biophys_416_147
PubMedID: 12893291
Gene_locus related to this paper: serma-impep

Title : The amygdala and Alzheimer's disease: positron emission tomographic study of the cholinergic system - Shinotoh_2003_Ann.N.Y.Acad.Sci_985_411
Author(s) : Shinotoh H , Fukushi K , Nagatsuka S , Tanaka N , Aotsuka A , Ota T , Namba H , Tanada S , Irie T
Ref : Annals of the New York Academy of Sciences , 985 :411 , 2003
Abstract : The primary transmitter deficit is cholinergic in Alzheimer's disease (AD), and the amygdala receives a major cholinergic projection from the nucleus basalis of Meynert (Ch4), which may play an important role in the retention of affective conditioning and/or memory consolidation. We measured brain acetylcholinesterase (AChE) activity in 54 patients with AD and in 22 normal controls by positron emission tomography and N-[(11)C]methylpiperidin-4-yl acetate to characterize the cholinergic pathology in AD. The k(3) values were calculated as an index of AChE activity in a three-compartment model analysis using the metabolite-corrected arterial input function. The k(3) values were highly significantly reduced by 20% in the cerebral neocortex (P <0.0001 in the two-tailed t test), 14% in the hippocampus (P <0.001), and 33% in the amygdala (P <0.0001) in AD patients compared with normal controls. The k(3) values were significantly correlated with the Mini-Mental State Examination scores in both the cerebral cortex (P <0.001) and the amygdala (P <0.05) in AD patients, supporting the cholinergic hypothesis of cognitive dysfuncion in AD. Further studies are required, however, to elucidate the specific role of the cholinergic deficit in the amygdala in the emotional and behavioral symptoms in AD.
ESTHER : Shinotoh_2003_Ann.N.Y.Acad.Sci_985_411
PubMedSearch : Shinotoh_2003_Ann.N.Y.Acad.Sci_985_411
PubMedID: 12724174

Title : Interaction of synaptic scaffolding molecule and Beta -catenin - Nishimura_2002_J.Neurosci_22_757
Author(s) : Nishimura W , Yao I , Iida J , Tanaka N , Hata Y
Ref : Journal of Neuroscience , 22 :757 , 2002
Abstract : Synaptic scaffolding molecule (S-SCAM) is a synaptic membrane-associated guanylate kinase with inverted domain organization (MAGI) that interacts with NMDA receptor subunits and neuroligin. In epithelial cells, the non-neuronal isoform of S-SCAM (MAGI-1) is localized at tight or adherens junctions. Recent studies have revealed that the polarized targeting of MAGI-1 to the lateral membrane is mediated by its C-terminal region and that MAGI-1 interacts with beta-catenin in epithelial cells. In this article, we report that S-SCAM interacts with beta-catenin in neurons. beta-Catenin is coimmunoprecipitated with S-SCAM from rat brain. Both S-SCAM and beta-catenin are localized at synapses and are partially colocalized. The C-terminal region of S-SCAM binds to the C-terminal region of beta-catenin. We have tested how the interaction between S-SCAM and beta-catenin plays a role in the synaptic targeting of S-SCAM and beta-catenin. S-SCAM is targeted to synapses via the C-terminal postsynaptic density-95/Dlg-A/ZO-1 (PDZ) domain. beta-Catenin is targeted to synapses with armadillo repeats. The overexpressed C-terminal region of beta-catenin blocks the synaptic targeting of S-SCAM. The overexpressed C-terminal region of S-SCAM is partially targeted to synapses and forms a small number of clusters. In the presence of overexpressed beta-catenin, the C-terminal region of S-SCAM forms more clusters at synapses. These data suggest that the synaptic targeting of S-SCAM is mediated by the interaction with beta-catenin.
ESTHER : Nishimura_2002_J.Neurosci_22_757
PubMedSearch : Nishimura_2002_J.Neurosci_22_757
PubMedID: 11826105

Title : Effect of donepezil on brain acetylcholinesterase activity in patients with AD measured by PET - Shinotoh_2001_Neurology_56_408
Author(s) : Shinotoh H , Aotsuka A , Fukushi K , Nagatsuka S , Tanaka N , Ota T , Tanada S , Irie T
Ref : Neurology , 56 :408 , 2001
Abstract : Acetylcholinesterase (AChE) activities in the brain of three patients with AD were measured once before and once during donepezil treatment (5 mg/d in two patients, 3 mg/d in one patient) using PET and N-[11C]methylpiperidin-4-yl acetate. Donepezil reduced k(3) values, an index of AChE activity, in the cerebral cortex by 39 +/- 5%. All patients showed some degree of symptomatic improvement, and it was concluded that this improvement was likely caused by improved cholinergic activity by inhibition of AChE in the brain.
ESTHER : Shinotoh_2001_Neurology_56_408
PubMedSearch : Shinotoh_2001_Neurology_56_408
PubMedID: 11171913

Title : Positron emission tomographic measurement of brain acetylcholinesterase activity using N-[(11)C]methylpiperidin-4-yl acetate without arterial blood sampling: methodology of shape analysis and its diagnostic power for Alzheimer's disease - Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
Author(s) : Tanaka N , Fukushi K , Shinotoh H , Nagatsuka S , Namba H , Iyo M , Aotsuka A , Ota T , Tanada S , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 21 :295 , 2001
Abstract : N-[11C]methylpiperidin-4-yl acetate ([11C]MP4A) is a radiotracer that has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET) using a standard compartment model analysis and a metabolite-corrected arterial input function. In the current study, the authors evaluated the applicability of a simple kinetic analysis without blood sampling, namely shape analysis. First, the authors used computer simulations to analyze factors that affect the precision and bias of shape analysis, then optimized the shape analysis procedure for [11C]MP4A. Before shape analysis execution, the later part of dynamic PET data except for the initial 3 minutes were smoothed by fitting to a bi-exponential function followed by linear interpolation of 8 data points between each of adjacent scan frames. Simulations showed that shape analysis yielded estimates of regional metabolic rates of [11C]MP4A by AChE (k3) with acceptable precision and bias in brain regions with low k3 values such as neocortex. Estimates in regions with higher k3 values became progressively more inaccurate. The authors then applied the method to [11C]MP4A PET data in 10 healthy subjects and 20 patients with Alzheimer's disease (AD). There was a highly significant linear correlation in regional k3 estimates between shape and compartment analyses (300 neocortical regions, [shape k3] = 0.93 x [NLS k3], r = 0.89, P < 0.001). Significant reductions in k3 estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral cortices in patients with AD as compared with controls were observed when using shape analysis (P < 0.013, two-tailed t-test), although these reductions (17% to 20%) were somewhat less than those obtained by compartment analysis (22% to 27%). The sensitivity of shape analysis for detecting neocortical regions with abnormally low k3 in the 20 patients with AD (92 out of 200 regions, 46%) also was somewhat less than compartment analysis (136 out of 200 regions, 68%). However, taking its simplicity and noninvasiveness into account, the authors conclude that quantitative measurement of neocortical AChE activity with shape analysis and [11C]MP4A PET is practical and useful for clinical diagnosis of AD.
ESTHER : Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
PubMedSearch : Tanaka_2001_J.Cereb.Blood.Flow.Metab_21_295
PubMedID: 11295884

Title : Kinetic analysis of [(11)C]MP4A using a high-radioactivity brain region that represents an integrated input function for measurement of cerebral acetylcholinesterase activity without arterial blood sampling - Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
Author(s) : Nagatsuka Si S , Fukushi K , Shinotoh H , Namba H , Iyo M , Tanaka N , Aotsuka A , Ota T , Tanada S , Irie T
Ref : Journal of Cerebral Blood Flow & Metabolism , 21 :1354 , 2001
Abstract : N -[(11)C]methylpiperidin-4-yl acetate ([(11)C]MP4A) is an acetylcholine analog. It has been used successfully for the quantitative measurement of acetylcholinesterase (AChE) activity in the human brain with positron emission tomography (PET). [(11)C]MP4A is specifically hydrolyzed by AChE in the brain to a hydrophilic metabolite, which is irreversibly trapped locally in the brain. The authors propose a new method of kinetic analysis of brain AChE activity by PET without arterial blood sampling, that is, reference tissue-based linear least squares (RLS) analysis. In this method, cerebellum or striatum is used as a reference tissue. These regions, because of their high AChE activity, act as a biologic integrator of plasma input function during PET scanning, when regional metabolic rates of [(11)C]MP4A through AChE (k(3); an AChE index) are calculated by using Blomqvist's linear least squares analysis. Computer simulation studies showed that RLS analysis yielded k(3) with almost the same accuracy as the standard nonlinear least squares (NLS) analysis in brain regions with low (such as neocortex and hippocampus) and moderately high (thalamus) k(3) values. The authors then applied these methods to [(11) C]MP4A PET data in 12 healthy subjects and 26 patients with Alzheimer disease (AD) using the cerebellum as the reference region. There was a highly significant linear correlation in regional k(3) estimates between RLS and NLS analyses (456 cerebral regions, [RLS k(3) ] = 0.98 x [NLS k(3) ], r = 0.92, P < 0.001). Significant reductions were observed in k(3) estimates of frontal, temporal, parietal, occipital, and sensorimotor cerebral neocortices (P < 0.001, single-tailed t-test), and hippocampus (P = 0.012) in patients with AD as compared with controls when using RLS analysis. Mean reductions (19.6%) in these 6 regions by RLS were almost the same as those by NLS analysis (20.5%). The sensitivity of RLS analysis for detecting cortical regions with abnormally low k 3 in the 26 patients with AD (138 of 312 regions, 44%) was somewhat less than NLS analysis (52%), but was greater than shape analysis (33%), another method of [(11)C]MP4A kinetic analysis without blood sampling. The authors conclude that RLS analysis is practical and useful for routine analysis of clinical [(11)C]MP4A studies.
ESTHER : Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
PubMedSearch : Nagatsuka_2001_J.Cereb.Blood.Flow.Metab_21_1354
PubMedID: 11702050

Title : Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study - Shinotoh_2000_Ann.Neurol_48_194
Author(s) : Shinotoh H , Namba H , Fukushi K , Nagatsuka S , Tanaka N , Aotsuka A , Ota T , Tanada S , Irie T
Ref : Annals of Neurology , 48 :194 , 2000
Abstract : We measured brain acetylcholinesterase activity in 30 patients with Alzheimer's disease (AD) and 14 age-matched controls by positron emission tomography (PET) and using a carbon 11-labeled acetylcholine analogue. Seven AD patients had repeat PET scans. The k3 values were calculated as an index of acetylcholinesterase activity in a three-compartment analysis using the metabolite corrected arterial input function. Twenty-eight of the 30 AD patients (14 each in the early and late onset subgroups) were retained in the study so as to equalize the range and average severity of cognitive impairment within the early and late onset subgroups. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala in the early onset AD patients, although the k3 values were significantly reduced only in the temporoparietal cortex and amygdala in the late onset AD patients. In the longitudinal study, all 7 repeat AD patients showed further reduction of cortical k3 values in the second PET scans, with a mean interval of 2 years, suggesting a progressive loss of the ascending cholinergic system from the nucleus basalis of Meynert in AD. In 37 AD patients, there was a highly significant correlation between the cortical k3 values and Mini-Mental State Examination scores, supporting the cholinergic hypothesis in AD.
ESTHER : Shinotoh_2000_Ann.Neurol_48_194
PubMedSearch : Shinotoh_2000_Ann.Neurol_48_194
PubMedID: 10939570

Title : Brain acetylcholinesterase activity in Alzheimer disease measured by positron emission tomography - Shinotoh_2000_Alzheimer.Dis.Assoc.Disord_14 Suppl 1_S114
Author(s) : Shinotoh H , Namba H , Fukushi K , Nagatsuka S , Tanaka N , Aotsuka A , Tanada S , Irie T
Ref : Alzheimer Disease & Associated Disorders , 14 Suppl 1 :S114 , 2000
Abstract : Brain acetylcholinesterase activity was measured in 14 patients with Alzheimer disease and 14 age-matched control subjects by positron emission tomography with a radioactive acetylcholine analogue. Kinetic analysis was performed to calculate k3, an index of acetylcholinesterase activity. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala of all patients with Alzheimer disease, suggesting a loss of cholinergic innervation from the basal forebrain. Most profound reductions of k3 values were observed in the temporal (-30%) and parietal cortices (-31%), although reductions of k3 values were relatively uniform in the cerebral neocortex. This technique may be a powerful tool for early diagnosis of Alzheimer disease and also for therapeutic monitoring of acetylcholinesterase inhibitors in Alzheimer disease.
ESTHER : Shinotoh_2000_Alzheimer.Dis.Assoc.Disord_14 Suppl 1_S114
PubMedSearch : Shinotoh_2000_Alzheimer.Dis.Assoc.Disord_14 Suppl 1_S114
PubMedID: 10850739

Title : Crystal structure of prolyl aminopeptidase from Serratia marcescens - Yoshimoto_1999_J.Biochem_126_559
Author(s) : Yoshimoto T , Kabashima T , Uchikawa K , Inoue T , Tanaka N , Nakamura KT , Tsuru M , Ito K
Ref : J Biochem , 126 :559 , 1999
Abstract : Prolyl aminopeptidase from Serratia marcescens specifically catalyzes the removal of N-terminal proline residues from peptides. We have solved its three-dimensional structure at 2.3 A resolution by the multiple isomorphous replacement method. The enzyme consists of two contiguous domains. The larger domain shows the general topology of the alpha/beta hydrolase fold, with a central eight-stranded beta-sheet and six helices. The smaller domain consists of six helices. The catalytic triad (Ser113, His296, and Asp268) is located near the large cavity at the interface between the two domains. Cys271, which is sensitive to SH reagents, is located near the catalytic residues, in spite of the fact that the enzyme is a serine peptidase. The specific residues which make up the hydrophobic pocket line the smaller domain, and the specificity of the exo-type enzyme originates from this smaller domain, which blocks the N-terminal of P1 proline.
ESTHER : Yoshimoto_1999_J.Biochem_126_559
PubMedSearch : Yoshimoto_1999_J.Biochem_126_559
PubMedID: 10467172
Gene_locus related to this paper: serma-impep

Title : Relapse and elevation of blood urea nitrogen in acute fenitrothion and malathion poisoning - Futagami_1996_International.Journal.of.Clin.Pharmacol.Therap_34_453
Author(s) : Futagami K , Tanaka N , Nishimura M , Tateishi H , Aoyama T , Oishi R
Ref : International Journal of Clinical Pharmacology & Therapeutics , 34 :453 , 1996
Abstract : We observed 6 patients with severe fenitrothion and/or malathion poisoning necessitating artificial ventilation and intensive care monitoring. Three developed relapse following acute cholinergic crisis. In these patients the blood urea nitrogen (BUN) abnormally elevated before the development of relapse and the initial high concentration of plasma organophosphate (OP) decreased only gradually. However, the patients who did not develop relapse showed no elevation of BUN and a relatively low concentration of plasma OP. This observation was confirmed in a retrospective search of 14 patients. In addition, erythrocyte cholinesterase (EChE) activities were more helpful to diagnose the development of relapse than plasma cholinesterase activities. Therefore, careful monitoring of BUN in addition to plasma OP concentration may be useful to predict the development of relapse.
ESTHER : Futagami_1996_International.Journal.of.Clin.Pharmacol.Therap_34_453
PubMedSearch : Futagami_1996_International.Journal.of.Clin.Pharmacol.Therap_34_453
PubMedID: 8897085