Ito S

References (31)

Title : Development of evolutionary algorithm-based protein redesign method - Ozawa_2024_Cell.Rep.Phys.Sci_5_
Author(s) : Ozawa H , Unno I , Sekine R , Chisuga T , Ito S , Nakano S
Ref : Cell Rep Phys Sci , 5 : , 2024
Abstract : Several enzymes are already used on the industrial scale because of the development of various enzyme engineering approaches. In this study, we developed a protein redesign tool, GAOptimizer, to tackle the challenge. GAOptimizer is a genetic algorithm-based tool for optimizing mutation combinations to engineer diverse enzymes. The tool requires two input parameters influencing the mutation selection: fitness functions and sequence libraries. Both stability-based and non-stability-based scores can serve as fitness functions, and these scores are used to determine if the selected mutations are favorable in the design process. Sequence libraries are crucial in defining the sequence space for selecting mutation candidates. We use GAOptimizer on three distinct native enzymes to validate its utility for screening applicable enzymes. Functional analyses of the designed enzymes show that GAOptimizer can produce enzymes exhibiting superior properties to their native enzymes with a high success rate.
ESTHER : Ozawa_2024_Cell.Rep.Phys.Sci_5_
PubMedSearch : Ozawa_2024_Cell.Rep.Phys.Sci_5_
PubMedID:
Gene_locus related to this paper: manes-hnl

Title : Effect of antibiotic-administration period on hepatic bile acid profile and expression of pharmacokinetic-related proteins in mouse liver, kidney, and brain capillaries - Yagi_2023_Drug.Metab.Pharmacokinet_50_100494
Author(s) : Yagi R , Masuda T , Ito S , Ohtsuki S
Ref : Drug Metab Pharmacokinet , 50 :100494 , 2023
Abstract : Antibiotic administration affects pharmacokinetics through changes in the intestinal microbiota, and bile acids are involved in this regulation. The purpose of the present study was to clarify the effect of different periods of antibiotic administration on the hepatic bile acid profile and expression of pharmacokinetic-related proteins in mouse liver, kidney, and brain capillaries. Vancomycin and polymyxin B were orally administered to mice for either 5- or 25-days. The hepatic bile acid profile of the 25-day treatment group was distinct. In the liver, the protein expression of cytochrome P450 (Cyp)3a11 showed the greatest reduction to 11.4% after the 5-day treatment and further reduced to 7.01% after the 25-day treatment. Similar reductions were observed for sulfotransferase 1d1, Cyp2b10, carboxylesterase 2e, UDP-glucuronosyltransferase (Ugt)1a5, and Ugt1a9. In the kidney and brain capillaries, no drug-metabolizing enzymes or drug transporters were changed with >1.5-fold or <0.66-fold statistical significance in either period. These results suggest that bile acids and metabolizing enzymes in the liver are affected in a period-dependent manner by antibiotic treatment, while the blood-brain barrier and kidneys are less affected. Drug-drug interactions of antibiotics via the intestinal microbiota should be considered by changing drug metabolism in the liver.
ESTHER : Yagi_2023_Drug.Metab.Pharmacokinet_50_100494
PubMedSearch : Yagi_2023_Drug.Metab.Pharmacokinet_50_100494
PubMedID: 37119611

Title : Recent advances in the regulation of root parasitic weed damage by strigolactone-related chemicals - Ito_2023_Biosci.Biotechnol.Biochem_87_247
Author(s) : Ito S
Ref : Biosci Biotechnol Biochem , 87 :247 , 2023
Abstract : Root parasitic weeds such as Striga spp. and Orobanche spp. dramatically reduce the yields of important agricultural crops and cause economic losses of over billions of US dollars worldwide. One reason for the damage by root parasitic weeds is that they germinate after specifically recognizing the host cues, strigolactones (SLs). SLs were identified >50 years ago as germination stimulants for root parasitic weeds, and various studies have been conducted to control parasitic weeds using SLs and related chemicals. Recently, biochemical and molecular biological approaches have revealed the SL biosynthesis and SL receptors; using these findings, various SL-related chemicals have been developed. This review summarizes recent research on SLs and their related chemicals for controlling root parasitic weeds.
ESTHER : Ito_2023_Biosci.Biotechnol.Biochem_87_247
PubMedSearch : Ito_2023_Biosci.Biotechnol.Biochem_87_247
PubMedID: 36610999

Title : Synthesis of Carlactone Derivatives to Develop a Novel Inhibitor of Strigolactone Biosynthesis - Kawada_2023_ACS.Omega_8_13855
Author(s) : Kawada K , Saito T , Onoda S , Inayama T , Takahashi I , Seto Y , Nomura T , Sasaki Y , Asami T , Yajima S , Ito S
Ref : ACS Omega , 8 :13855 , 2023
Abstract : Strigolactones (SLs), phytohormones that inhibit shoot branching in plants, promote the germination of root-parasitic plants, such as Striga spp. and Orobanche spp., which drastically reduces the crop yield. Therefore, reducing SL production via chemical treatment may increase the crop yield. To design specific inhibitors, it is valid to utilize the substrate structure of the target proteins as lead compounds. In this study, we focused on Os900, a rice enzyme that oxidizes the SL precursor carlactone (CL) to 4-deoxyorobanchol (4DO), and synthesized 10 CL derivatives. The effects of the synthesized CL derivatives on SL biosynthesis were evaluated by the Os900 enzyme assay in vitro and by measuring 4DO levels in rice root exudates. We identified some CL derivatives that inhibited SL biosynthesis in vitro and in vivo.
ESTHER : Kawada_2023_ACS.Omega_8_13855
PubMedSearch : Kawada_2023_ACS.Omega_8_13855
PubMedID: 37091382

Title : Functional involvement of endothelial lipase in hepatitis B virus infection - Shirasaki_2023_Hepatol.Commun_7_e0206
Author(s) : Shirasaki T , Murai K , Ishida A , Kuroki K , Kawaguchi K , Wang Y , Yamanaka S , Yasukawa R , Kawasaki N , Li YY , Shimakami T , Sumiyadorj A , Nio K , Sugimoto S , Orita N , Takayama H , Okada H , Thi Bich PD , Iwabuchi S , Hashimoto S , Ide M , Tabata N , Ito S , Matsushima K , Yanagawa H , Yamashita T , Kaneko S , Honda M
Ref : Hepatol Commun , 7 :e0206 , 2023
Abstract : BACKGROUND: HBV infection causes chronic liver disease and leads to the development of HCC. To identify host factors that support the HBV life cycle, we previously established the HC1 cell line that maintains HBV infection and identified host genes required for HBV persistence. METHODS: The present study focused on endothelial lipase (LIPG), which binds to heparan sulfate proteoglycans (HSPGs) in the cell membrane. RESULTS: We found HBV infection was impaired in humanized liver chimeric mouse-derived hepatocytes that were transduced with lentivirus expressing short hairpin RNA against LIPG. Long-term suppression of LIPG combined with entecavir further suppressed HBV replication. LIPG was shown to be involved in HBV attachment to the cell surface by using 2 sodium taurocholate cotransporting peptide (NTCP)-expressing cell lines, and the direct interaction of LIPG and HBV large surface protein was revealed. Heparin and heparinase almost completely suppressed the LIPG-induced increase of HBV attachment, indicating that LIPG accelerated HBV attachment to HSPGs followed by HBV entry through NTCP. Surprisingly, the attachment of a fluorescently labeled NTCP-binding preS1 probe to NTCP-expressing cells was not impaired by heparin, suggesting the HSPG-independent attachment of the preS1 probe to NTCP. Interestingly, attachment of the preS1 probe was severely impaired in LIPG knockdown or knockout cells. Inhibitors of the lipase activity of LIPG similarly impaired the attachment of the preS1 probe to NTCP-expressing cells. CONCLUSIONS: LIPG participates in HBV infection by upregulating HBV attachment to the cell membrane by means of 2 possible mechanisms: increasing HBV attachment to HSPGs or facilitating HSPG-dependent or HSPG-independent HBV attachment to NTCP by its lipase activity.
ESTHER : Shirasaki_2023_Hepatol.Commun_7_e0206
PubMedSearch : Shirasaki_2023_Hepatol.Commun_7_e0206
PubMedID: 37655967
Gene_locus related to this paper: human-LIPG

Title : Canonical strigolactones are not the major determinant of tillering but important rhizospheric signals in rice - Ito_2022_Sci.Adv_8_eadd1278
Author(s) : Ito S , Braguy J , Wang JY , Yoda A , Fiorilli V , Takahashi I , Jamil M , Felemban A , Miyazaki S , Mazzarella T , Chen GE , Shinozawa A , Balakrishna A , Berqdar L , Rajan C , Ali S , Haider I , Sasaki Y , Yajima S , Akiyama K , Lanfranco L , Zurbriggen MD , Nomura T , Asami T , Al-Babili S
Ref : Sci Adv , 8 :eadd1278 , 2022
Abstract : Strigolactones (SLs) are a plant hormone inhibiting shoot branching/tillering and a rhizospheric, chemical signal that triggers seed germination of the noxious root parasitic plant Striga and mediates symbiosis with beneficial arbuscular mycorrhizal fungi. Identifying specific roles of canonical and noncanonical SLs, the two SL subfamilies, is important for developing Striga-resistant cereals and for engineering plant architecture. Here, we report that rice mutants lacking canonical SLs do not show the shoot phenotypes known for SL-deficient plants, exhibiting only a delay in establishing arbuscular mycorrhizal symbiosis, but release exudates with a significantly decreased Striga seed-germinating activity. Blocking the biosynthesis of canonical SLs by TIS108, a specific enzyme inhibitor, significantly lowered Striga infestation without affecting rice growth. These results indicate that canonical SLs are not the determinant of shoot architecture and pave the way for increasing crop resistance by gene editing or chemical treatment.
ESTHER : Ito_2022_Sci.Adv_8_eadd1278
PubMedSearch : Ito_2022_Sci.Adv_8_eadd1278
PubMedID: 36322663

Title : Chemical Synthesis of Triazole-Derived Suppressors of Strigolactone Functions - Ito_2021_Methods.Mol.Biol_2309_25
Author(s) : Ito S , Kikuzato K , Nakamura H , Asami T
Ref : Methods Mol Biol , 2309 :25 , 2021
Abstract : Triazole is a five-membered heteroring consists of two carbon atoms and three nitrogen atoms and exhibits a wide range of biological activities. The basic heterocyclic rings are 1,2,3-triazole and 1,2,4-triazole. Here we describe the chemical synthetic methods for triazole derivatives that can suppress the function of SL by inhibiting SL biosynthesis pathway or SL perception sites such as D14.
ESTHER : Ito_2021_Methods.Mol.Biol_2309_25
PubMedSearch : Ito_2021_Methods.Mol.Biol_2309_25
PubMedID: 34028676

Title : Strigolactone signaling inhibition increases adventitious shoot formation on internodal segments of ipecac - Okazaki_2021_Planta_253_123
Author(s) : Okazaki K , Watanabe S , Koike I , Kawada K , Ito S , Nakamura H , Asami T , Shimomura K , Umehara M
Ref : Planta , 253 :123 , 2021
Abstract : SL inhibited adventitious shoot formation of ipecac, whereas the SL-related inhibitors promoted adventitious shoot formation. SL-related inhibitors might be useful as new plant growth regulators for plant propagation. In most plant species, phytohormones are required to induce adventitious shoots for propagating economically important crops and regenerating transgenic plants. In ipecac (Carapichea ipecacuanha (Brot.) L. Andersson), however, adventitious shoots can be formed without phytohormone treatment. Here we evaluated the effects of GR24 (a synthetic strigolactone, SL), SL biosynthetic inhibitors, and an SL antagonist on adventitious shoot formation during tissue culture of ipecac. We found that exogenously applied GR24 suppressed indole-3-acetic acid transport in internodal segments and decreased the number of adventitious shoots formed; in addition, the distribution of adventitious shoots changed from the apical to middle region of the internodal segments. In contrast, the SL-related inhibitors promoted adventitious shoot formation on both apical and middle regions of the segments. In particular, SL antagonist treatment increased endogenous cytokinin levels and induced multiple shoot development. These results indicate that SL inhibits adventitious shoot formation in ipecac. In ipecac, one of the shoots in each internodal segment becomes dominant and auxin derived from that shoot suppresses the other shoot growth. Here, this dominance was overcome by application of SL-related inhibitors. Therefore, SL-related inhibitors might be useful as new plant growth regulators to improve the efficiency of plant propagation in vitro.
ESTHER : Okazaki_2021_Planta_253_123
PubMedSearch : Okazaki_2021_Planta_253_123
PubMedID: 34014387

Title : Synthesis and Biological Evaluation of Novel Triazole Derivatives as Strigolactone Biosynthesis Inhibitors - Kawada_2019_J.Agric.Food.Chem_67_6143
Author(s) : Kawada K , Takahashi I , Arai M , Sasaki Y , Asami T , Yajima S , Ito S
Ref : Journal of Agricultural and Food Chemistry , 67 :6143 , 2019
Abstract : Strigolactones (SLs) are one of the plant hormones that control several important agronomic traits, such as shoot branching, leaf senescence, and stress tolerance. Manipulation of the SL biosynthesis can increase the crop yield. We previously reported that a triazole derivative, TIS108, inhibits SL biosynthesis. In this study, we synthesized a number of novel TIS108 derivatives. Structure-activity relationship studies revealed that 4-(2-phenoxyethoxy)-1-phenyl-2-(1 H-1,2,4-triazol-1-yl)butan-1-one (KK5) inhibits the level of 4-deoxyorobanchol in roots more strongly than TIS108. We further found that KK5-treated Arabidopsis showed increased branching phenotype with the upregulated gene expression of AtMAX3 and AtMAX4. These results indicate that KK5 is a specific SL biosynthesis inhibitor in rice and Arabidopsis.
ESTHER : Kawada_2019_J.Agric.Food.Chem_67_6143
PubMedSearch : Kawada_2019_J.Agric.Food.Chem_67_6143
PubMedID: 31083983

Title : Altered regulation of serum lysosomal acid hydrolase activities in Parkinson's disease: A potential peripheral biomarker? - Niimi_2019_Parkinsonism.Relat.Disord_61_132
Author(s) : Niimi Y , Ito S , Mizutani Y , Murate K , Shima S , Ueda A , Satake W , Hattori N , Toda T , Mutoh T
Ref : Parkinsonism Relat Disord , 61 :132 , 2019
Abstract : INTRODUCTION: Recent studies have indicated that lysosomal dysfunction contributes to the development of idiopathic Parkinson's disease (PD). It is uncertain whether dysregulation of serum lysosomal acid hydrolase activity exists in sporadic PD patients compared with normal controls (NCs) and parkinsonian syndrome (PS) patients. METHODS: Sporadic PD patients without GBA1 mutations (n=68) were matched with normal controls (n=45), and parkinsonian syndrome patients (n=32) in terms of family history, age, and sex. We measured the activities of lysosomal enzymes, alpha-galactosidase, beta-galactosidase, and beta-hexosaminidase and examined the possible correlations between lysosomal acid hydrolase activities with age in NCs, PD, and PS patients. RESULTS: beta-Galactosidase activity was significantly higher in the PD and PS than in the NC group (P<0.001). The beta-galactosidase to alpha-galactosidase and beta-hexosaminidase to beta-galactosidase activity ratios were more useful for distinguishing PD and PS patients from NCs (P<0.0001). Furthermore, alpha-galactosidase activity was significantly higher in PS patients than both PD and NC groups (p=0.04). beta-Galactosidase and alpha-galactosidase activities exhibited a statistically significant negative correlation with age in NCs, and beta-hexosaminidase activity showed a positive correlation with age in PS. However, PD patients did not show any of these correlations. CONCLUSION: Our results suggest the presence of an unknown regulatory mechanism(s) of serum acid hydrolase activities with aging in the normal population and abnormalities in their regulation in PD and PS patients. However, the pattern of dysregulation in these two groups is different. Thus, serum lysosomal acid hydrolase activity can be used as a peripheral biomarker for PD.
ESTHER : Niimi_2019_Parkinsonism.Relat.Disord_61_132
PubMedSearch : Niimi_2019_Parkinsonism.Relat.Disord_61_132
PubMedID: 30415794

Title : Early use of donepezil against psychosis and cognitive decline in Parkinson's disease: a randomised controlled trial for 2 years - Sawada_2018_J.Neurol.Neurosurg.Psychiatry_89_1332
Author(s) : Sawada H , Oeda T , Kohsaka M , Umemura A , Tomita S , Park K , Mizoguchi K , Matsuo H , Hasegawa K , Fujimura H , Sugiyama H , Nakamura M , Kikuchi S , Yamamoto K , Fukuda T , Ito S , Goto M , Kiyohara K , Kawamura T
Ref : Journal of Neurology Neurosurg Psychiatry , 89 :1332 , 2018
Abstract : OBJECTIVES: Brain acetylcholine is decreased even in patients with cognitively preserved Parkinson's disease (PD). We investigated whether early and long-term use of donepezil prevents psychosis in non-demented PD patients. METHODS: A double-blinded, placebo-controlled trial was conducted. A total of 145 non-demented PD patients were randomly assigned to receive 5 mg/day donepezil (n=72) or placebo (n=73) for 96 weeks. Medications for PD were not restricted, but antipsychotic drugs were not permitted throughout the study. The primary outcome measure was survival time to psychosis that was predefined by Parkinson's Psychosis Questionnaire (PPQ) B score >/=2 or C score >/=2. Secondary outcome measures included psychosis developing within 48 weeks, total PPQ score, Mini-Mental State Examination (MMSE), Wechsler Memory Scale (WMS) and subgroup analysis by apolipoprotein epsilon4 genotyping. RESULTS: Kaplan-Meier curves for psychosis development were very similar between the two groups, and the Cox proportional hazard model revealed an adjusted HR of 0.87 (95%CI 0.48 to 1.60). The changes in MMSE and WMS-1 (auditory memory) were significantly better with donepezil than in placebo. In the subgroup analysis, donepezil provided an HR of 0.31 (0.11-0.86) against psychosis in 48 weeks for apolipoprotein epsilon4 non-carriers. CONCLUSIONS: Although donepezil provided beneficial effects on PPQ, MMSE and auditory WMS score changes in 2 years, it had no prophylactic effect on development of psychosis in PD. Apolipoprotein epsilon4 may suppress the antipsychotic effect of donepezil. TRIAL REGISTRATION NUMBER: UMIN000005403.
ESTHER : Sawada_2018_J.Neurol.Neurosurg.Psychiatry_89_1332
PubMedSearch : Sawada_2018_J.Neurol.Neurosurg.Psychiatry_89_1332
PubMedID: 30076270

Title : Effects of gibberellin and strigolactone on rice tiller bud growth - Ito_2018_J.Pestic.Sci_43_220
Author(s) : Ito S , Yamagami D , Asami T
Ref : J Pestic Sci , 43 :220 , 2018
Abstract : Strigolactones (SLs) regulate diverse developmental phenomena. Rice SL biosynthesis and signaling mutants have an increased number of tillers and a reduced plant height relative to wild-type (WT) rice plants. In this study, we tested the effectiveness of gibberellin (GA) on restoring more tillering phenotype and dwarfism observed in both SL biosynthesis and signaling mutants. The application of GA to these mutants rescued the tiller bud outgrowth; however, the sensitivity to GA was different between the WT and the SL biosynthesis mutant.
ESTHER : Ito_2018_J.Pestic.Sci_43_220
PubMedSearch : Ito_2018_J.Pestic.Sci_43_220
PubMedID: 30363138

Title : Effects of prenatal exposure to triclosan on the liver transcriptome in chicken embryos - Guo_2018_Toxicol.Appl.Pharmacol_347_23
Author(s) : Guo J , Ito S , Nguyen HT , Yamamoto K , Tanoue R , Kunisue T , Iwata H
Ref : Toxicol Appl Pharmacol , 347 :23 , 2018
Abstract : Triclosan (TCS), a commonly used antimicrobial compound, has recently been detected in the eggs of wild avian species. Exposure to TCS in rodents is known to interfere with thyroid hormone (TH), disrupt immune responses and cause liver disease. However, no attempt has been made to clarify the effects of TCS in avian species. The aim of this study is therefore to evaluate the toxic effects of in ovo exposure to TCS and explore the molecular mechanism by transcriptome analysis in the embryonic liver of a model avian species, chicken (Gallus gallus). Embryos were treated with graded concentration of TCS (0.1, 1 and 10mug/g egg) at Hamburger Hamilton Stage (HHS) 1 (1st day), followed by 20days of incubation to HHS 46. At the administration of 10mug TCS/g egg, embryo mortality increased from 20% in control to 37% accompanied with 8% attenuation in tarsus length. While liver somatic index (LSI) in TCS treatments was enhanced, statistical difference was only observed at the treatment of 0.1mug TCS/g egg in females. The up-regulation of several crucial differentially expressed genes (DEGs) in transcriptome analysis suggested that TCS induced xenobiotic metabolism (e.g. CYP2C23a, CYP2C45 and CYP3A37 in males; CYP2C45 in females) and activated the thyroid hormone receptor (THR) - mediated downstream signaling (e.g. THRSPB and DIO2 in males; THRSPB in females). In females, TCS may further activate the lipogenesis signaling (e.g. ACSL5, ELOVL2) and repress the lipolysis signaling (e.g. ABHD5, ACAT2). A battery of enriched transcription factors in relation to these TCS-induced signaling and phenotypes were found, including activated SREBF1, PPARa, LXRa, and LXRb in males and activated GLI2 in females; COUP-TFII was predicted to be suppressed in both genders. Finally, we developed adverse outcome pathways (AOPs) that provide insights into the molecular mechanisms underlying the alteration of phenotypes.
ESTHER : Guo_2018_Toxicol.Appl.Pharmacol_347_23
PubMedSearch : Guo_2018_Toxicol.Appl.Pharmacol_347_23
PubMedID: 29596926

Title : A Taylor-Made Design of Phenoxyfuranone-Type Strigolactone Mimic - Fukui_2017_Front.Plant.Sci_8_936
Author(s) : Fukui K , Yamagami D , Ito S , Asami T
Ref : Front Plant Sci , 8 :936 , 2017
Abstract : Strigolactones are a class of plant hormones that inhibit axillary bud outgrowth and are released from plant roots to act as a rhizosphere communication signal. The Orobanchaceae parasitic plant Striga hermonthica perceives strigolactone as its germination signal, indicating host presence. After germination, the Striga plant parasitises the host plant and suppresses host growth by draining photosynthetic products, water and other essential nutrients. Because of this way of life, this parasite threatens crop production in sub-Saharan Africa with infestation in crop fields and crop devastation. Crop protection in such areas is among the most concerning problems to be dealt with as immediately as possible. With respect to crop protection from Striga, many strigolactone agonists have been developed and used in research to reveal Striga biology, and have contributed to development of crop protection methods. However, an effective method has yet to be found. In a previous study, we reported debranones as a group of strigolactone mimics that inhibit axillary buds outgrowth with moderate stimulation activity for Striga germination. Debranones would be accessible because they are simply synthesized from commercially available phenols and bromo butenolide. Taking this advantage of debranones for Striga research, we tried to find the debranones stimulating Striga seed germination. To modulate functional selectivity and to enhance germination inducing activity of debranones, we studied structure-activity relationships. We investigated effects of substituent position and functional group on debranone activity and selectivity as a strigolactone mimic. As a result, we improved stimulation activity of debranones for Striga seed germination by chemical modification, and demonstrated the pharmacophore of debranones for selective modulation of distinct strigolactone responses.
ESTHER : Fukui_2017_Front.Plant.Sci_8_936
PubMedSearch : Fukui_2017_Front.Plant.Sci_8_936
PubMedID: 28676802

Title : Mechanism of lipid-lowering action of the dipeptidyl peptidase-4 inhibitor, anagliptin, in low-density lipoprotein receptor-deficient mice - Yano_2017_J.Diabetes.Investig_8_155
Author(s) : Yano W , Inoue N , Ito S , Itou T , Yasumura M , Yoshinaka Y , Hagita S , Goto M , Nakagawa T , Inoue K , Tanabe S , Kaku K
Ref : J Diabetes Investig , 8 :155 , 2017
Abstract : AIMS/INTRODUCTION: Dipeptidyl peptidase-4 inhibitors are used for treatment of patients with type 2 diabetes. In addition to glycemic control, these agents showed beneficial effects on lipid metabolism in clinical trials. However, the mechanism underlying the lipid-lowering effect of dipeptidyl peptidase-4 inhibitors remains unclear. Here, we investigated the lipid-lowering efficacy of anagliptin in a hyperlipidemic animal model, and examined the mechanism of action. MATERIALS AND METHODS: Male low-density lipoprotein receptor-deficient mice were administered 0.3% anagliptin in their diet. Plasma lipid levels were assayed and lipoprotein profile was analyzed using high-performance liquid chromatography. Hepatic gene expression was examined by deoxyribonucleic acid microarray and quantitative polymerase chain reaction analyses. Sterol regulatory element-binding protein transactivation assay was carried out in vitro. RESULTS: Anagliptin treatment significantly decreased the plasma total cholesterol (14% reduction, P < 0.01) and triglyceride levels (27% reduction, P < 0.01). Both low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol were also decreased significantly by anagliptin treatment. Sterol regulatory element-binding protein-2 messenger ribonucleic acid expression level was significantly decreased at night in anagliptin-treated mice (15% reduction, P < 0.05). Anagliptin significantly suppressed sterol regulatory element-binding protein activity in HepG2 cells (21% decrease, P < 0.001). CONCLUSIONS: The results presented here showed that the dipeptidyl peptidase-4 inhibitor, anagliptin, exhibited a lipid-lowering effect in a hyperlipidemic animal model, and suggested that the downregulation of hepatic lipid synthesis was involved in the effect. Anagliptin might have beneficial effects on lipid metabolism in addition to a glucose-lowering effect.
ESTHER : Yano_2017_J.Diabetes.Investig_8_155
PubMedSearch : Yano_2017_J.Diabetes.Investig_8_155
PubMedID: 27860391

Title : Analyzing a dipeptide library to identify human dipeptidyl peptidase IV inhibitor - Lan_2015_Food.Chem_175_66
Author(s) : Lan VT , Ito K , Ohno M , Motoyama T , Ito S , Kawarasaki Y
Ref : Food Chem , 175 :66 , 2015
Abstract : Human dipeptidyl peptidase IV (hDPPIV) inhibitors provide an effective strategy for the treatment of type 2 diabetes. Because certain peptides are known to act as hDPPIV inhibitors, a dataset of possible peptides with their inhibition intensities will facilitate the development of functional food for type 2 diabetes. In this study, we examined a total of 337 dipeptides with respect to their hDPPIV inhibitory effects. Amino acid residues at N-termini dominated their inhibition intensities. Particularly highly inhibitory dipeptides discovered included the following novel dipeptides: Thr-His, Asn-His, Val-Leu, Met-Leu, and Met-Met. Using our dataset, prime candidates contributing to the hDPPIV inhibitory effect of soy protein hydrolyzates were successfully identified. Possible dietary proteins potentially able to produce particularly highly hDPPIV inhibitory peptides are also discussed on the basis of the dataset.
ESTHER : Lan_2015_Food.Chem_175_66
PubMedSearch : Lan_2015_Food.Chem_175_66
PubMedID: 25577052

Title : Trp-Arg-Xaa tripeptides act as uncompetitive-type inhibitors of human dipeptidyl peptidase IV - Lan_2014_Peptides_54C_166
Author(s) : Lan VT , Ito K , Ito S , Kawarasaki Y
Ref : Peptides , 54C :166 , 2014
Abstract : Human dipeptidyl peptidase IV (hDPPIV, alternative name: CD26) inhibitors provide an effective strategy for the treatment of type 2 diabetes. Recently, our research group discovered a non substrate-mimic inhibitory dipeptide, Trp-Arg, by the systematic analysis of a dipeptide library. In the present study, a tripeptide library Trp-Arg-Xaa (where Xaa represents any amino acid) was analyzed to investigate the interactions of peptidergic inhibitors with hDPPIV. Trp-Arg-Glu showed the highest inhibitory effect toward hDPPIV (Ki=130muM). All of the tested 19 Trp-Arg-Xaa tripeptides showed unique uncompetitive-type inhibition. The inhibition mechanism of Trp-Arg-Xaa is discussed based on the crystal structure of hDPPIV. The information obtained by this study suggests a novel concept for developing hDPPIV inhibitory peptides and drugs.
ESTHER : Lan_2014_Peptides_54C_166
PubMedSearch : Lan_2014_Peptides_54C_166
PubMedID: 24512990

Title : Molecular mechanism of strigolactone perception by DWARF14 - Nakamura_2013_Nat.Commun_4_2613
Author(s) : Nakamura H , Xue YL , Miyakawa T , Hou F , Qin HM , Fukui K , Shi X , Ito E , Ito S , Park SH , Miyauchi Y , Asano A , Totsuka N , Ueda T , Tanokura M , Asami T
Ref : Nat Commun , 4 :2613 , 2013
Abstract : Strigolactones (SLs) are phytohormones that inhibit shoot branching and function in the rhizospheric communication with symbiotic fungi and parasitic weeds. An alpha/beta-hydrolase protein, DWARF14 (D14), has been recognized to be an essential component of plant SL signalling, although its precise function remains unknown. Here we present the SL-dependent interaction of D14 with a gibberellin signalling repressor SLR1 and a possible mechanism of phytohormone perception in D14-mediated SL signalling. D14 functions as a cleavage enzyme of SLs, and the cleavage reaction induces the interaction with SLR1. The crystal structure of D14 shows that 5-hydroxy-3-methylbutenolide (D-OH), which is a reaction product of SLs, is trapped in the catalytic cavity of D14 to form an altered surface. The D14 residues recognizing D-OH are critical for the SL-dependent D14-SLR1 interaction. These results provide new insight into crosstalk between gibberellin and SL signalling pathways.
ESTHER : Nakamura_2013_Nat.Commun_4_2613
PubMedSearch : Nakamura_2013_Nat.Commun_4_2613
PubMedID: 24131983
Gene_locus related to this paper: orysj-Q10QA5

Title : Confirming stereochemical structures of strigolactones produced by rice and tobacco - Xie_2013_Mol.Plant_6_153
Author(s) : Xie X , Yoneyama K , Kisugi T , Uchida K , Ito S , Akiyama K , Hayashi H , Yokota T , Nomura T
Ref : Mol Plant , 6 :153 , 2013
Abstract : Major strigolactones (SLs) produced by rice (Oryza sativa L. cv. Nipponbare) and tobacco (Nicotiana tabacum L. cv. Michinoku No. 1) were purified and their stereochemical structures were determined by comparing with optically pure synthetic standards for their NMR and CD data and retention times and mass fragmentations in ESI-LC/MS and GC-MS. SLs purified from root exudates of rice plants were orobanchol, orobanchyl acetate, and ent-2'-epi-5-deoxystrigol. In addition to these SLs, 7-oxoorobanchyl acetate and the putative three methoxy-5-deoxystrigol isomers were detected by LC-MS/MS. The production of 7-oxoorobanchyl acetate seemed to occur in the early growth stage, as it was detected only in the root exudates collected during the first week of incubation. The root exudates of tobacco contained at least 11 SLs, including solanacol, solanacyl acetate, orobanchol, ent-2'-epi-orobanchol, orobanchyl acetate, ent-2'-epi-orobanchyl acetate, 5-deoxystrigol, ent-2'-epi-5-deoxystrigol, and three isomers of putative didehydro-orobanchol whose structures remain to be clarified. Furthermore, two sorgolactone isomers but not sorgolactone were detected as minor SLs by LC-MS/MS analysis. It is intriguing to note that rice plants produced only orobanchol-type SLs, derived from ent-2'-epi-5-deoxystrigol, but both orobanchol-type and strigol-type SLs, derived from 5-deoxystrigol were detected in tobacco plants.
ESTHER : Xie_2013_Mol.Plant_6_153
PubMedSearch : Xie_2013_Mol.Plant_6_153
PubMedID: 23204500

Title : D14-SCFD3-dependent degradation of D53 regulates strigolactone signalling - Zhou_2013_Nature_504_406
Author(s) : Zhou F , Lin Q , Zhu L , Ren Y , Zhou K , Shabek N , Wu F , Mao H , Dong W , Gan L , Ma W , Gao H , Chen J , Yang C , Wang D , Tan J , Zhang X , Guo X , Wang J , Jiang L , Liu X , Chen W , Chu J , Yan C , Ueno K , Ito S , Asami T , Cheng Z , Lei C , Zhai H , Wu C , Wang H , Zheng N , Wan J
Ref : Nature , 504 :406 , 2013
Abstract : Strigolactones (SLs), a newly discovered class of carotenoid-derived phytohormones, are essential for developmental processes that shape plant architecture and interactions with parasitic weeds and symbiotic arbuscular mycorrhizal fungi. Despite the rapid progress in elucidating the SL biosynthetic pathway, the perception and signalling mechanisms of SL remain poorly understood. Here we show that DWARF 53 (D53) acts as a repressor of SL signalling and that SLs induce its degradation. We find that the rice (Oryza sativa) d53 mutant, which produces an exaggerated number of tillers compared to wild-type plants, is caused by a gain-of-function mutation and is insensitive to exogenous SL treatment. The D53 gene product shares predicted features with the class I Clp ATPase proteins and can form a complex with the alpha/beta hydrolase protein DWARF 14 (D14) and the F-box protein DWARF 3 (D3), two previously identified signalling components potentially responsible for SL perception. We demonstrate that, in a D14- and D3-dependent manner, SLs induce D53 degradation by the proteasome and abrogate its activity in promoting axillary bud outgrowth. Our combined genetic and biochemical data reveal that D53 acts as a repressor of the SL signalling pathway, whose hormone-induced degradation represents a key molecular link between SL perception and responses.
ESTHER : Zhou_2013_Nature_504_406
PubMedSearch : Zhou_2013_Nature_504_406
PubMedID: 24336215

Title : New branching inhibitors and their potential as strigolactone mimics in rice - Fukui_2011_Bioorg.Med.Chem.Lett_21_4905
Author(s) : Fukui K , Ito S , Ueno K , Yamaguchi S , Kyozuka J , Asami T
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :4905 , 2011
Abstract : Strigolactones (SLs) are rhizosphere communication chemicals. Recent studies of highly branched mutants revealed that SL or its metabolites work as a phytohormone to inhibit shoot branching. When SLs are exogenously applied to the rice d10-1 mutant that has a highly branched phenotype caused by a defect in the SL biosynthesis gene (CCD8), they inhibit tiller bud outgrowth (branching in rice) of the mutant. We focused our attention on the SL function as a phytohormone and tried to find new chemicals mimicking the hormonal action of SL by screening chemicals that inhibit branching of rice d10-1 mutant. Fortunately, we found 5-(4-chlorophenoxy)-3-methylfuran-2(5H)-one (3a) as a new chemical possessing SL-like activity against the rice d10-1 mutant. Then, we prepared several derivatives of 3a (3b-3k) to examine their ability to inhibit shoot branching of rice d10-1. These derivatives were synthesized by a one-pot coupling reaction between phenols and halo butenolide to give 5-phenoxy 3-methylfuran-2(5H)-one (3) derivatives, which possess a common substructure with SLs. Some of the derivatives showed SL-like activity more potently than GR24, a typical SL derivative, in a rice assay. As SLs also show activity by inducing seed germination of root parasitic plants, the induction activity of these derivatives was also evaluated. Here we report the structure-activity relationships of these compounds.
ESTHER : Fukui_2011_Bioorg.Med.Chem.Lett_21_4905
PubMedSearch : Fukui_2011_Bioorg.Med.Chem.Lett_21_4905
PubMedID: 21741836

Title : Effects of triazole derivatives on strigolactone levels and growth retardation in rice - Ito_2011_PLoS.One_6_e21723
Author(s) : Ito S , Umehara M , Hanada A , Kitahata N , Hayase H , Yamaguchi S , Asami T
Ref : PLoS ONE , 6 :e21723 , 2011
Abstract : We previously discovered a lead compound for strigolactone (SL) biosynthesis inhibitors, TIS13 (2,2-dimethyl-7-phenoxy-4-(1H-1,2,4-triazol-1-yl)heptan-3-ol). Here, we carried out a structure-activity relationship study of TIS13 to discover more potent and specific SL biosynthesis inhibitor because TIS13 has a severe side effect at high concentrations, including retardation of the growth of rice seedlings. TIS108, a new TIS13 derivative, was found to be a more specific SL biosynthesis inhibitor than TIS13. Treatment of rice seedlings with TIS108 reduced SL levels in both roots and root exudates in a concentration-dependent manner and did not reduce plant height. In addition, root exudates of TIS108-treated rice seedlings stimulated Striga germination less than those of control plants. These results suggest that TIS108 has a potential to be applied in the control of root parasitic weeds germination.
ESTHER : Ito_2011_PLoS.One_6_e21723
PubMedSearch : Ito_2011_PLoS.One_6_e21723
PubMedID: 21760901

Title : A new lead chemical for strigolactone biosynthesis inhibitors - Ito_2010_Plant.Cell.Physiol_51_1143
Author(s) : Ito S , Kitahata N , Umehara M , Hanada A , Kato A , Ueno K , Mashiguchi K , Kyozuka J , Yoneyama K , Yamaguchi S , Asami T
Ref : Plant Cell Physiol , 51 :1143 , 2010
Abstract : Several triazole-containing chemicals have previously been shown to act as efficient inhibitors of cytochrome P450 monooxygenases. To discover a strigolactone biosynthesis inhibitor, we screened a chemical library of triazole derivatives to find chemicals that induce tiller bud outgrowth of rice seedlings. We discovered a triazole-type chemical, TIS13 [2,2-dimethyl-7-phenoxy-4-(1H-1,2,4-triazol-1-yl)heptan-3-ol], which induced outgrowth of second tiller buds of wild-type seedlings, as observed for non-treated strigolactone-deficient d10 mutant seedlings. TIS13 treatment reduced strigolactone levels in both roots and root exudates in a concentration-dependent manner. Co-application of GR24, a synthetic strigolactone, with TIS13 canceled the TIS13-induced tiller bud outgrowth. Taken together, these results indicate that TIS13 inhibits strigolactone biosynthesis in rice seedlings. We propose that TIS13 is a new lead compound for the development of specific strigolactone biosynthesis inhibitors.
ESTHER : Ito_2010_Plant.Cell.Physiol_51_1143
PubMedSearch : Ito_2010_Plant.Cell.Physiol_51_1143
PubMedID: 20522488

Title : Fabacyl acetate, a germination stimulant for root parasitic plants from Pisum sativum - Xie_2009_Phytochemistry_70_211
Author(s) : Xie X , Yoneyama K , Harada Y , Fusegi N , Yamada Y , Ito S , Yokota T , Takeuchi Y
Ref : Phytochemistry , 70 :211 , 2009
Abstract : A germination stimulant, fabacyl acetate, was purified from root exudates of pea (Pisum sativum L.) and its structure was determined as ent-2'-epi-4a,8a-epoxyorobanchyl acetate [(3aR,4R,4aR,8bS,E)-4a,8a-epoxy-8,8-dimethyl-3-(((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yloxy)methylene)-2-oxo-3,3a,4,5,6,7,8,8b-decahydro-2H-indeno[1,2-b]furan-4-yl acetate], by 1D and 2D NMR spectroscopic, ESI- and EI-MS spectrometric, X-ray crystallographic analyses, and by comparing the (1)H NMR spectroscopic data and relative retention times (RR(t)) in LC-MS and GC-MS with those of synthetic standards prepared from (+)-orobanchol and (+)-2'-epiorobanchol. The (1)H NMR spectroscopic data and RR(t) of fabacyl acetate were identical with those of an isomer prepared from (+)-2'-epiorobanchol except for the opposite sign in CD spectra. This is the first natural ent-strigolactone containing an epoxide group. Fabacyl acetate was previously detected in root exudates of other Fabaceae plants including faba bean (Vicia faba L.) and alfalfa (Medicago sativa L.).
ESTHER : Xie_2009_Phytochemistry_70_211
PubMedSearch : Xie_2009_Phytochemistry_70_211
PubMedID: 19155028

Title : Urinary dysfunction and autonomic control in amyloid neuropathy - Ito_2006_Clin.Auton.Res_16_66
Author(s) : Ito T , Sakakibara R , Yamamoto T , Uchiyama T , Liu Z , Asahina M , Higashi M , Arai K , Ito S , Awa Y , Yamamoto K , Kinou M , Yamanishi T , Hattori T
Ref : Clin Auton Res , 16 :66 , 2006
Abstract : Uro-neurological assessment was performed in four patients with small-fiber neuropathy due to amyloidosis (2 transthyretin-type/2 immunoglobulin light-chain-type). Voiding difficulties were due to detrusor weakness and impaired bladder sensation. In two patients cholinesterase inhibition treatment caused urge incontinence, indicating detrusor denervation supersensitivity. The underlying mechanisms of urinary dysfunction seem to involve postganglionic cholinergic and afferent somatic nerves.
ESTHER : Ito_2006_Clin.Auton.Res_16_66
PubMedSearch : Ito_2006_Clin.Auton.Res_16_66
PubMedID: 16477499

Title : Simultaneous determination of choline and acetylcholine based on a trienzyme chemiluminometric biosensor in a single line flow injection system - Kiba_2003_Anal.Sci_19_1647
Author(s) : Kiba N , Ito S , Tachibana M , Tani K , Koizumi H
Ref : Anal Sci , 19 :1647 , 2003
Abstract : A detector for the simultaneous determination of choline (Ch) and acetylcholine (ACh) based on a sensitive trienzyme chemiluminometric biosensor in a single line flow injection (FI) system is described. Immobilized choline oxidase (ChOx), immobilized peroxidase (POx), immobilized acetylcholinesterase, and coimmobilized ChOx/POx were packed, in turn, in a transparent ETFE tube (1 mm i.d., 75 cm) and the tube was placed in front of a photomultipier tube as a flow cell. Two-peak response was obtained by one injection of the sample solution. The first and second peaks were dependent on the concentrations of Ch and ACh, respectively. The influence of some experimental parameters such as flow rate, amounts of immobilized enzymes on the behavior of the sensor was studied in order to optimize the sensitivity, sample throughput and resolution. Calibration curves were linear at 1 - 1000 nM for Ch and 3 - 3000 nM for ACh. The sample throughput was 25/h without carryover. The FI system was applied to the simultaneous determination of Ch and ACh in rabbit brain tissue homogenates.
ESTHER : Kiba_2003_Anal.Sci_19_1647
PubMedSearch : Kiba_2003_Anal.Sci_19_1647
PubMedID: 14696930

Title : The genome sequence and structure of rice chromosome 1 - Sasaki_2002_Nature_420_312
Author(s) : Sasaki T , Matsumoto T , Yamamoto K , Sakata K , Baba T , Katayose Y , Wu J , Niimura Y , Cheng Z , Nagamura Y , Antonio BA , Kanamori H , Hosokawa S , Masukawa M , Arikawa K , Chiden Y , Hayashi M , Okamoto M , Ando T , Aoki H , Arita K , Hamada M , Harada C , Hijishita S , Honda M , Ichikawa Y , Idonuma A , Iijima M , Ikeda M , Ikeno M , Ito S , Ito T , Ito Y , Iwabuchi A , Kamiya K , Karasawa W , Katagiri S , Kikuta A , Kobayashi N , Kono I , Machita K , Maehara T , Mizuno H , Mizubayashi T , Mukai Y , Nagasaki H , Nakashima M , Nakama Y , Nakamichi Y , Nakamura M , Namiki N , Negishi M , Ohta I , Ono N , Saji S , Sakai K , Shibata M , Shimokawa T , Shomura A , Song J , Takazaki Y , Terasawa K , Tsuji K , Waki K , Yamagata H , Yamane H , Yoshiki S , Yoshihara R , Yukawa K , Zhong H , Iwama H , Endo T , Ito H , Hahn JH , Kim HI , Eun MY , Yano M , Jiang J , Gojobori T
Ref : Nature , 420 :312 , 2002
Abstract : The rice species Oryza sativa is considered to be a model plant because of its small genome size, extensive genetic map, relative ease of transformation and synteny with other cereal crops. Here we report the essentially complete sequence of chromosome 1, the longest chromosome in the rice genome. We summarize characteristics of the chromosome structure and the biological insight gained from the sequence. The analysis of 43.3 megabases (Mb) of non-overlapping sequence reveals 6,756 protein coding genes, of which 3,161 show homology to proteins of Arabidopsis thaliana, another model plant. About 30% (2,073) of the genes have been functionally categorized. Rice chromosome 1 is (G + C)-rich, especially in its coding regions, and is characterized by several gene families that are dispersed or arranged in tandem repeats. Comparison with a draft sequence indicates the importance of a high-quality finished sequence.
ESTHER : Sasaki_2002_Nature_420_312
PubMedSearch : Sasaki_2002_Nature_420_312
PubMedID: 12447438
Gene_locus related to this paper: orysa-Q9S7P1 , orysa-Q9FYP7 , orysa-Q5ZBH3 , orysa-Q5NA74 , orysa-Q5ZA26 , orysa-Q5JLP6 , orysa-Q94D81 , orysa-cbp , orysa-Q5VQE5 , orysa-Q8RZ95 , orysa-Q9AWW1 , orysa-Q9AS70 , orysa-Q0JK71 , orysa-Q8S1D9 , orysa-Q5N8V4 , orysa-Q943F9 , orysa-B9EWJ8 , orysa-Q5N8H1 , orysa-Q5NAI4 , orysa-Q94DP8 , orysa-Q658B2 , orysa-Q5JMQ8 , orysa-Q5QMD9 , orysa-Q5N7L1 , orysa-Q5N7J6 , orysa-Q8RYV9 , orysa-Q5SNH3 , orysa-Q94DD0 , orysa-Q8W0F0 , orysa-pir7a , orysa-pir7b , orysa-Q4VWY7 , orysa-q5jlm9 , orysa-q5na00 , orysa-q5nbu1 , orysa-Q5QLC0 , orysa-q5vnp5 , orysa-Q5VP27 , orysa-Q5ZAM8 , orysa-Q5ZBI5 , orysa-q5zc23 , orysa-Q5ZCR3 , orysa-Q8L562 , orysa-Q8L570 , orysa-Q8LQS5 , orysa-Q8RZ40 , orysa-Q8RZ79 , orysa-Q8S0U8 , orysa-Q8S0V0 , orysa-Q8S125 , orysa-Q9LHX5 , orysa-Q94E46 , orysa-Q656F2 , orysi-a2wn01 , orysi-b8a7e6 , orysi-b8a7e7 , orysj-b9eya5 , orysj-q5jl22 , orysj-q5jlw7 , orysj-q94d71

Title : Cloning and functional expression of rat kidney dipeptidyl peptidase II - Fukasawa_2001_Biochem.J_353_283
Author(s) : Fukasawa KM , Fukasawa K , Higaki K , Shiina N , Ohno M , Ito S , Otogoto J , Ota N
Ref : Biochemical Journal , 353 :283 , 2001
Abstract : Dipeptidyl peptidase II (DPP II; EC 3.4.14.2) from rat kidney was purified to a specific activity of 65.4 micromol/min per mg of protein for Lys-Ala-beta-naphthylamide. The N-terminal and partial amino acid sequences of the enzyme were determined. The peptide sequences were used to identify expressed sequence tag (EST) clones. By using the cDNA fragment of one of the EST clones as a probe, we isolated a cDNA clone with 1710 bp encoding DPP II from a rat kidney cDNA library. The cDNA of rat DPP II contained an open reading frame of 1500 bp, coding for a protein of 500 amino acids. The first 10 residues of the purified enzyme matched the deduced protein sequence starting with residue 37, suggesting the presence of a signal peptide. The mature enzyme (464 residues) had a calculated molecular mass of 51400 Da, which was lower than the value (about 60000 Da) determined by SDS/PAGE; and the deduced amino acid sequence showed six potential N-glycosylation sites. The deduced amino acid sequence of rat DPP II shared high similarity with quiescent-cell proline dipeptidase (78% identity) and prolyl carboxypeptidase (38% identity) and bore the putative catalytic triad (Ser, Asp, His) conserved in serine peptidase families. We transiently transfected COS-7 cells with pcDNA3.1 containing the cloned cDNA and obtained the overexpression of an immunoreactive protein (of about 60000 Da). The transfected cells showed Lys-Ala-methylcoumarinamide-hydrolysing activity that was 50 times higher than the control cells.
ESTHER : Fukasawa_2001_Biochem.J_353_283
PubMedSearch : Fukasawa_2001_Biochem.J_353_283
PubMedID: 11139392
Gene_locus related to this paper: ratno-dpp2

Title : Inhibitory effects of tacrine and physostigmine on catecholamine secretion and membrane currents in guinea-pig adrenal chromaffin cells - Sugawara_1998_Fundam.Clin.Pharmacol_12_279
Author(s) : Sugawara T , Kitamura N , Ohta T , Ito S , Nakazato Y
Ref : Fundamental & Clinical Toxicology , 12 :279 , 1998
Abstract : The effects of tacrine and physostigmine on catecholamine secretion induced by veratridine and high K+, and on voltage-dependent Na+ and Ca2+ currents, were investigated in guinea-pig adrenal chromaffin cells. In perfused adrenal glands, tacrine (100 microM) caused an inhibition of veratridine-induced catecholamine secretion, but physostigmine (100 microM) did not. In dispersed cells, both tacrine (1 microM-1 mM) and physostigmine (1 microM-1 mM) decreased catecholamine secretion induced by veratridine in a dose-dependent manner. The inhibitory effect of tacrine was much greater than that of physostigmine. Tacrine alone at a high concentration (such as 1 mM) caused a substantial increase in catecholamine secretion by itself and completely abolished the veratridine-induced secretory response in dispersed cells. High-concentration physostigmine showed a similar effect, but to a much lesser extent. The high K+ (46.2 mM)-evoked catecholamine secretion from dispersed cells was not affected by tacrine (1-100 microM) or physostigmine (1 microM-1 mM). In fura-2 loaded cells, tacrine (100 microM) almost abolished [Ca2+]i rise induced by veratridine, but only slightly reduced that evoked by high K+. In voltage-clamped cells, tacrine (300 microM) depressed the voltage-dependent Na+ and Ca2+ current by about 93% and 69%, and physostigmine (300 microM) depressed them by about 30% and 17%, respectively. These results suggest that tacrine decreases the veratridine-induced catecholamine secretion primarily by inhibiting the voltage-dependent Na+ channels rather than the Ca2+ channels. Physostigmine acts in a manner similar to tacrine, but its potency is much lower than that of tacrine.
ESTHER : Sugawara_1998_Fundam.Clin.Pharmacol_12_279
PubMedSearch : Sugawara_1998_Fundam.Clin.Pharmacol_12_279
PubMedID: 9646060

Title : Tacrine inhibits nicotinic secretory and current responses in adrenal chromaffin cells - Sugawara_1997_Eur.J.Pharmacol_319_123
Author(s) : Sugawara T , Ohta T , Asano T , Ito S , Nakazato Y
Ref : European Journal of Pharmacology , 319 :123 , 1997
Abstract : Tacrine enhanced acetylcholine-induced catecholamine secretion with a concentration of up to 10 microM, but inhibited it at over 10 microM in perfused adrenal glands. Qualitatively the same result was obtained with physostigmine. Both tacrine and physostigmine only inhibited the secretory responses to carbachol and/or nicotine in perfused glands and dispersed chromaffin cells. Acetylcholinesterase activity of adrenal homogenates was inhibited by tacrine and physostigmine in a concentration-dependent manner. In whole-cell patch-clamp experiments, tacrine and physostigmine caused reversible inhibition of nicotine-evoked inward currents with a dose range similar to that for the inhibitory action on the secretory response. These results suggest that the enhancing effect of tacrine and physostigmine on acetylcholine-induced catecholamine secretion results from the prevention of enzymatic hydrolysis of acetylcholine in adrenal glands and that the inhibitory effect is due to the inhibition of nicotinic receptor-mediated membrane currents in adrenal chromaffin cells.
ESTHER : Sugawara_1997_Eur.J.Pharmacol_319_123
PubMedSearch : Sugawara_1997_Eur.J.Pharmacol_319_123
PubMedID: 9030907

Title : Persistent pulsatile release of glutamate induced by N-methyl-D-aspartate in neonatal rat hippocampal neurones - Cherubini_1991_J.Physiol_436_531
Author(s) : Cherubini E , Ben-Ari Y , Ito S , Krnjevic K
Ref : The Journal of Physiology , 436 :531 , 1991
Abstract : 1. Intracellular recordings were made from CA3 hippocampal neurones in vitro, during the first ten days of postnatal life and in adulthood. 2. Repeated (three to six) applications of N-methyl-D-aspartate (NMDA), in the presence of tetrodotoxin (TTX, 1-3 microM) and K+ channel blockers (tetraethylammonium chloride or bromide (TEA), 10 mM, and Cs+, 2 mM; or 4-aminopyridine (4-AP), 30-50 microM, and Cs+, 2 mM) induced in neonatal but not in adult neurones, periodic inward currents (PICs) which persisted for several hours after the last application of NMDA. 3. PICs which were due to non-specific cation currents had a frequency of 0.10 +/- 0.04 Hz, and an amplitude of 1.1 +/- 0.28 nA at holding potentials between -40 and -50 mV. The amplitude was a linear function of the membrane potential over the range -70 to +20 mV. They reversed polarity at 4.1 +/- 9.8 mV. 4. K+ channel blockers alone failed to induce PICs. Repeated (three to six) brief applications of high (12 mM) K+ medium also induced PICs. The frequency and amplitude of K(+)-induced PICs were however considerably reduced by concomitant applications of the NMDA receptor antagonist D,L-3-[( +/- )-2-carboxypiperazin-4-yl-]propyl-1-phosphonic acid (CPP, 20 microM). PICs could be induced also by caffeine (1 mM) in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX, 200 microM), TTX, TEA and Cs+. 5. Intracellular injection of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) did not prevent the induction of PICs by NMDA. However PICs were blocked by removal of the external calcium and by the calcium antagonists cobalt (2 mM) and cadmium (50 microM). 6. In spite of blockade of propagated synaptic activity by TTX, PICs were synchronous in a pair of intracellularly recorded cells. They were also synchronous with extracellular spikes recorded by electrodes located into stratum pyramidal or stratum radiatum. 7. Once established, PICs were unaffected by NMDA receptor antagonists D(-)2-amino-5-phosphonovaleric acid (AP-5, 50 microM), CPP (20 microM) and the NMDA channel blocker ketamine (10 microM). They were reversibly blocked by the broad spectrum excitatory amino acid antagonist kynurenic acid (1 mM) and by the selective non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). 8. It is concluded that PICs are generated in neonatal neurones by a synchronous, pulsatile release of glutamate from presynaptic nerve terminals, secondary to oscillations in intracellular calcium.
ESTHER : Cherubini_1991_J.Physiol_436_531
PubMedSearch : Cherubini_1991_J.Physiol_436_531
PubMedID: 1676421