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1.
Plant J ; 103(2): 814-823, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32314445

RESUMEN

C4 plants can fix CO2 efficiently using CO2 -concentrating mechanisms (CCMs), but they require additional ATP. To supply the additional ATP, C4 plants operate at higher rates of cyclic electron transport around photosystem I (PSI), in which electrons are transferred from ferredoxin to plastoquinone. Recently, it has been reported that the NAD(P)H dehydrogenase-like complex (NDH) accumulated in the thylakoid membrane in leaves of C4 plants, making it a candidate for the additional synthesis of ATP used in the CCM. In addition, C4 plants have higher levels of PROTON GRADIENT REGULATION 5 (PGR5) expression, but it has been unknown how PGR5 functions in C4 photosynthesis. In this study, PGR5 was overexpressed in a C4 dicot, Flaveria bidentis. In PGR5-overproducing (OP) lines, PGR5 levels were 2.3- to 3.0-fold greater compared with wild-type plants. PGR5-like PHOTOSYNTHETIC PHENOTYPE 1 (PGRL1), which cooperates with PGR5, increased with PGR5. A spectroscopic analysis indicated that in the PGR5-OP lines, the acceptor side limitation of PSI was reduced in response to a rapid increase in photon flux density. Although it did not affect CO2 assimilation, the overproduction of PGR5 contributed to an enhanced electron sink downstream of PSI.


Asunto(s)
Flaveria/metabolismo , Proteínas del Complejo del Centro de Reacción Fotosintética/metabolismo , Complejo de Proteína del Fotosistema I/metabolismo , Dióxido de Carbono/metabolismo , Clorofila/metabolismo , Transporte de Electrón , Regulación de la Expresión Génica de las Plantas , NADP/metabolismo , Oxidación-Reducción , Ribulosa-Bifosfato Carboxilasa/metabolismo
2.
Plant Cell Physiol ; 61(7): 1252-1261, 2020 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-32333781

RESUMEN

Angiosperms have three PsbQ-like (PQL) proteins in addition to the PsbQ subunit of the oxygen-evolving complex of photosystem II. Previous studies have shown that two PQL proteins, PnsL2 and PnsL3, are subunits of the chloroplast NADH dehydrogenase-like (NDH) complex involved in the photosystem I (PSI) cyclic electron flow. In addition, another PsbQ homolog, PQL3, is required for the NDH activity; however, the molecular function of PQL3 has not been elucidated. Here, we show that PQL3 is an assembly factor, particularly for the accumulation of subcomplex B (SubB) of the chloroplast NDH. In the pql3 mutant of Arabidopsis thaliana, the amounts of NDH subunits in SubB, PnsB1 and PsnB4, were decreased, causing a severe reduction in the NDH-PSI supercomplex. Analysis using blue native polyacrylamide gel electrophoresis suggested that the incorporation of PnsL3 into SubB was affected in the pql3 mutant. Unlike other PsbQ homologs, PQL3 was weakly associated with thylakoid membranes and was only partially protected from thermolysin digestion. Consistent with the function as an assembly factor, PQL3 accumulated independently in other NDH mutants, such as pnsl1-3. Furthermore, PQL3 accumulated in young leaves in a manner similar to the accumulation of CRR3, an assembly factor for SubB. These results suggest that PQL3 has developed a distinct function as an assembly factor for the NDH complex during evolution of the PsbQ protein family in angiosperms.


Asunto(s)
Proteínas de Arabidopsis/fisiología , Arabidopsis/metabolismo , Cloroplastos/enzimología , NADH Deshidrogenasa/metabolismo , Complejo de Proteína del Fotosistema II/fisiología , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cloroplastos/metabolismo , Complejo de Proteína del Fotosistema I/metabolismo , Complejo de Proteína del Fotosistema II/genética , Complejo de Proteína del Fotosistema II/metabolismo , Filogenia , Hojas de la Planta/metabolismo , Tilacoides/metabolismo
3.
Theor Appl Genet ; 133(4): 1291-1301, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31980835

RESUMEN

KEY MESSAGE: Novel drought tolerance genes were identified by screening thousands of random genomic fragments from grass species in transgenic rice. Identification of agronomically important genes is a critical step for crop breeding through biotechnology. Multiple approaches have been employed to identify new gene targets, including comprehensive screening platforms for gene discovery such as the over-expression of libraries of cDNA clones. In this study, random genomic fragments from plants were introduced into rice and screened for drought tolerance in a high-throughput manner with the aim of finding novel genetic elements not exclusively limited to coding sequences. To illustrate the power of this approach, genomic libraries were constructed from four grass species, and screening a total of 50,825 transgenic rice lines for drought tolerance resulted in the identification of 12 reproducibly efficacious fragments. Of the twelve, two were from the mitochondrial genome of signal grass and ten were from the nuclear genome of buffalo grass. Subsequent sequencing and analyses revealed that the ten fragments from buffalo grass carried a similar genetic element with no significant homology to any previously characterized gene. The deduced protein sequence was rich in acidic amino acid residues in the C-terminal half, and two of the glutamic acid residues in the C-terminal half were shown to play an important role in drought tolerance. The results demonstrate that an open-ended screening approach using random genomic fragments could discover trait genes distinct from gene discovery based on known pathways or biased toward coding sequence over-expression.


Asunto(s)
Adaptación Fisiológica/genética , Sequías , Genes de Plantas , Ensayos Analíticos de Alto Rendimiento , Oryza/genética , Oryza/fisiología , Secuencia de Aminoácidos , Biblioteca de Genes , Péptidos/química , Fenotipo , Plantas Modificadas Genéticamente , Reproducibilidad de los Resultados , Transcripción Genética
4.
Plant Cell Physiol ; 57(10): 2020-2028, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27497446

RESUMEN

C4 photosynthesis exhibits efficient CO2 assimilation in ambient air by concentrating CO2 around ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) through a metabolic pathway called the C4 cycle. It has been suggested that cyclic electron flow (CEF) around PSI mediated by chloroplast NADH dehydrogenase-like complex (NDH), an alternative pathway of photosynthetic electron transport (PET), plays a crucial role in C4 photosynthesis, although the contribution of NDH-mediated CEF is small in C3 photosynthesis. Here, we generated NDH-suppressed transformants of a C4 plant, Flaveria bidentis, and showed that the NDH-suppressed plants grow poorly, especially under low-light conditions. CO2 assimilation rates were consistently decreased in the NDH-suppressed plants under low and medium light intensities. Measurements of non-photochemical quenching (NPQ) of Chl fluorescence, the oxidation state of the reaction center of PSI (P700) and the electrochromic shift (ECS) of pigment absorbance indicated that proton translocation across the thylakoid membrane is impaired in the NDH-suppressed plants. Since proton translocation across the thylakoid membrane induces ATP production, these results suggest that NDH-mediated CEF plays a role in the supply of ATP which is required for C4 photosynthesis. Such a role is more crucial when the light that is available for photosynthesis is limited and the energy production by PET becomes rate-determining for C4 photosynthesis. Our results demonstrate that the physiological contribution of NDH-mediated CEF is greater in C4 photosynthesis than in C3 photosynthesis, suggesting that the mechanism of PET in C4 photosynthesis has changed from that in C3 photosynthesis accompanying the changes in the mechanism of CO2 assimilation.


Asunto(s)
Carbono/metabolismo , Flaveria/enzimología , NADH Deshidrogenasa/metabolismo , Fotosíntesis , Complejo de Proteína del Fotosistema I/metabolismo , Proteínas de Plantas/metabolismo , Dióxido de Carbono/metabolismo , Transporte de Electrón/efectos de la radiación , Flaveria/crecimiento & desarrollo , Flaveria/efectos de la radiación , Luz , Fotosíntesis/efectos de la radiación , Hojas de la Planta/metabolismo , Hojas de la Planta/efectos de la radiación , Interferencia de ARN , Análisis Espectral , Supresión Genética/efectos de la radiación , Transformación Genética/efectos de la radiación
5.
Photosynth Res ; 129(3): 261-77, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27017612

RESUMEN

By concentrating CO2, C4 photosynthesis can suppress photorespiration and achieve high photosynthetic efficiency, especially under conditions of high light, high temperature, and drought. To concentrate CO2, extra ATP is required, which would also require a change in photosynthetic electron transport in C4 photosynthesis from that in C3 photosynthesis. Several analyses have shown that the accumulation of the components of cyclic electron flow (CEF) around photosystem I, which generates the proton gradient across thylakoid membranes (ΔpH) and functions in ATP production without producing NADPH, is increased in various NAD-malic enzyme and NADP-malic enzyme C4 plants, suggesting that CEF may be enhanced to satisfy the increased need for ATP in C4 photosynthesis. However, in C4 plants, the accumulation patterns of the components of two partially redundant pathways of CEF, NAD(P)H dehydrogenase-like complex and PROTON GRADIENT REGULATION5-PGR5-like1 complex, are not identical, suggesting that these pathways may play different roles in C4 photosynthesis. Accompanying the increase in the amount of NDH, the expression of some genes which encode proteins involved in the assembly of NDH is also increased at the mRNA level in various C4 plants, suggesting that this increase is needed to increase the accumulation of NDH. To better understand the relation between CEF and C4 photosynthesis, a reverse genetic approach to generate C4 transformants with respect to CEF will be necessary.


Asunto(s)
Adenosina Trifosfato/metabolismo , Arabidopsis/metabolismo , Malato Deshidrogenasa/metabolismo , Complejo de Proteína del Fotosistema I/metabolismo , Arabidopsis/genética , Arabidopsis/efectos de la radiación , Proteínas de Arabidopsis/metabolismo , Dióxido de Carbono/metabolismo , Transporte de Electrón , Electrones , Fotosíntesis , Tilacoides/metabolismo
6.
Mol Plant Microbe Interact ; 25(1): 18-27, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21916556

RESUMEN

Mixed infection of Cucumber mosaic virus (CMV) and Turnip mosaic virus (TuMV) induced more severe symptoms on Nicotiana benthamiana than single infection. To dissect the relationships between spatial infection patterns and the 2b protein (2b) of CMV in single or mixed infections, the CMV vectors expressing enhanced green fluorescent or Discosoma sp. red fluorescent proteins (EGFP [EG] or DsRed2 [Ds], respectively were constructed from the same wild-type CMV-Y and used for inoculation onto N. benthamiana. CMV2-A1 vector (C2-A1 [A1]) has a functional 2b while CMV-H1 vector (C2-H1 [H1]) is 2b deficient. As we expected from the 2b function as an RNA silencing suppressor (RSS), in a single infection, A1Ds retained a high level of accumulation at initial infection sites and showed extensive fluorescence in upper, noninoculated leaves, whereas H1Ds disappeared rapidly at initial infection sites and could not spread efficiently in upper, noninoculated leaf tissues. In various mixed infections, we found two phenomena providing novel insights into the relationships among RSS, viral synergism, and interference. First, H1Ds could not spread efficiently from vasculature into nonvascular tissues with or without TuMV, suggesting that RNA silencing was not involved in CMV unloading from vasculature. These results indicated that 2b could promote CMV to unload from vasculature into nonvascular tissues, and that this 2b function might be independent of its RSS activity. Second, we detected spatial interference (local interference) between A1Ds and A1EG in mixed infection with TuMV, between A1Ds (or H1Ds) and TuMV, and between H1Ds and H1EG. This observation suggested that local interference between two viruses was established even in the synergism between CMV and TuMV and, again, RNA silencing did not seem to contribute greatly to this phenomenon.


Asunto(s)
Cucumovirus/patogenicidad , Nicotiana/virología , Enfermedades de las Plantas/virología , Potyvirus/patogenicidad , ARN Viral/genética , Proteínas Virales/metabolismo , Coinfección , Cucumovirus/genética , Cucumovirus/fisiología , ADN Complementario/genética , Expresión Génica , Proteínas Fluorescentes Verdes , Proteínas Luminiscentes , Interacciones Microbianas , Hojas de la Planta/virología , Plantas Modificadas Genéticamente , Potyvirus/genética , Potyvirus/fisiología , Protoplastos , Interferencia de ARN , ARN Mensajero/genética , Análisis de Secuencia de ADN , Temperatura , Nicotiana/fisiología , Proteínas Virales/genética , Proteína Fluorescente Roja
7.
Plant J ; 57(2): 207-19, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18785996

RESUMEN

Chloroplastic NAD(P)H dehydrogenase (NDH) plays a role in cyclic electron flow around photosystem I to produce ATP, especially in adaptation to environmental changes. Although the NDH complex contains 11 subunits that are homologous to NADH:ubiquinone oxidoreductase (complex I; EC 1.6.5.3), recent genetic and biological studies have indicated that NDH also comprises unique subunits. We describe here an in silico approach based on co-expression analysis and phylogenetic profiling that was used to identify 65 genes as potential candidates for NDH subunits. Characterization of 21 Arabidopsis T-DNA insertion mutants among these ndh gene candidates indicated that three novel ndf (NDH-dependent cyclic electron flow) mutants (ndf1, ndf2 and ndf4) had impaired NDH activity as determined by measurement of chlorophyll fluorescence. The amount of NdhH subunit was greatly decreased in these mutants, suggesting that the loss of NDH activity was caused by a defect in accumulation of the NDH complex. In addition, NDF1, NDF2 and NDF4 proteins co-migrated with the NdhH subunit, as shown by blue native electrophoresis. These results strongly suggest that NDF proteins are novel subunits of the NDH complex. Further analysis revealed that the NDF1 and NDF2 proteins were unstable in the mutants lacking hydrophobic subunits of the NDH complex, but were stable in mutants lacking the hydrophilic subunits, suggesting that NDF1 and NDF2 interact with a hydrophobic sub-complex. NDF4 protein was predicted to possess a redox-active iron-sulfur cluster domain that may be involved in the electron transfer.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , NADPH Deshidrogenasa/metabolismo , Tilacoides/enzimología , Secuencia de Aminoácidos , Arabidopsis/enzimología , Proteínas de Arabidopsis/genética , Biología Computacional , ADN Bacteriano/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Datos de Secuencia Molecular , Mutagénesis Insercional , NADPH Deshidrogenasa/genética , Filogenia , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , ARN de Planta/genética , Alineación de Secuencia , Tilacoides/genética
8.
Plant Cell Physiol ; 51(6): 866-76, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20430763

RESUMEN

Arabidopsis has three PsbQ-like (PQL) proteins in addition to the PsbQ subunit of the oxygen-evolving complex of PSII. Recent bioinformatic and proteomic studies suggested that the two PQL proteins, PQL1 (At1g14150) and PQL2 (At3g01440), might function in the chloroplast NAD(P)H dehydrogenase (NDH) complex; however, their molecular function has not been characterized. In this study, we examined the function of the chloroplast NDH in the Arabidopsis pql1 and pql2 mutants. Post-illumination increases in Chl fluorescence, which are caused by an NDH-dependent cyclic electron flow, were absent in both mutants, indicating that PQL1 and PQL2 are required for NDH activity. In the thylakoid membranes of wild-type plants, PQL1 and PQL2 were tightly associated with the NDH-PSI supercomplex and protected from protease treatments, while unassembled PQLs were not stably accumulated in mutants lacking known NDH subunits. Subunit stability of the NDH complex was affected differently in the thylakoid membranes of the pql1 and pql2 mutants. These data indicate that PQL1 and PQL2 are novel NDH subunits and differ in their functional roles and in their binding sites in the NDH complex. Furthermore, functional analysis on PQL3 (At2g01918) using the pql3 mutant suggests that PQL3 is also required for NDH activity. Proteins homologous to each PQL protein are found in various plant species, but not in cyanobacteria, algae, mosses or ferns. These results suggest that seed plants that have NDH activity in chloroplasts specifically developed three PQL proteins for the function of the chloroplast NDH complex.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimología , Cloroplastos/enzimología , NADPH Deshidrogenasa/metabolismo , Secuencia de Aminoácidos , Arabidopsis/genética , Proteínas de Arabidopsis/genética , ADN Bacteriano/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Datos de Secuencia Molecular , Mutagénesis Insercional , Mutación , NADPH Deshidrogenasa/genética , Complejo de Proteína del Fotosistema I/metabolismo , Alineación de Secuencia
9.
Plant Cell Physiol ; 50(2): 383-93, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19122188

RESUMEN

The chloroplast NAD(P)H dehydrogenase (NDH) complex, which reduces plastoquinones in thylakoid membranes, is involved in PSI cyclic electron flow and chlororespiration. In addition to land plants, the NDH complex is conserved in cyanobacteria. In this study, we identified a novel NDH-related gene of Arabidopsis, NDH-dependent cyclic electron flow 5 (NDF5, At1g55370). Post-illumination increases in chlorophyll fluorescence were absent in ndf5 mutant plants, which indicated that NDF5 is essential for NDH activity. Sequence analysis did not reveal any known functional motifs in NDF5, but there was some homology in amino acid sequence between NDF5 and NDF2, a known NDH subunit. NDF5 and NDF2 homologs were present in higher plants, but not cyanobacteria. A single homolog, which had similarity to both NDF5 and NDF2, was identified in the moss Physcomitrella patens. Immunoblot analysis showed that NDF5 localizes to membrane fractions of chloroplasts. The stability of NdhH, a subunit of the NDH complex, as well as NDF5 and NDF2, was decreased in ndf5, ndf2 and double ndf2/ndf5 mutants, resulting in a loss of NDH activity in these mutants. These results indicated that both NDF5 and NDF2 have essential functions in the stabilization of the NDH complex. We propose that NDF5 and NDF2 were acquired by land plants during evolution, and that in higher plants both NDF5 and NDF2 are critical to regulate NDH activity and each other's protein stability, as well as the stability of additional NDH subunits.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Cloroplastos/metabolismo , NADPH Deshidrogenasa/metabolismo , Secuencia de Aminoácidos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Clorofila/metabolismo , ADN Bacteriano/genética , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Prueba de Complementación Genética , Datos de Secuencia Molecular , Mutagénesis Insercional , Mutación , Fotosíntesis , Filogenia , ARN de Planta/genética , Alineación de Secuencia
10.
Bioorg Med Chem ; 17(1): 64-73, 2009 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19081254

RESUMEN

Starting with a series of CC chemokine receptor-4 (CCR4) antagonists developed in a previous study, the potency was improved by replacing the pyrrolidine moiety of N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 2 with a 3-(hydroxymethyl)piperidine. The resulting compound (1'-{4-[(4-chlorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}-1,4'-bipiperidin-3-yl)methanol 8ic was a strong inhibitor of human/mouse chemotaxis. Oral administration of 8ic showed anti-inflammatory activity in a murine model of acute dermatitis (oxazolone-induced contact hypersensitivity test) in a dose-dependent manner.


Asunto(s)
Antiinflamatorios/síntesis química , Quinazolinas/farmacocinética , Receptores CCR4/antagonistas & inhibidores , Administración Oral , Aminas , Animales , Antiinflamatorios/farmacocinética , Quimiotaxis/efectos de los fármacos , Dermatitis/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Ratones , Piperidinas , Quinazolinas/farmacología , Relación Estructura-Actividad
11.
Plant Cell Physiol ; 49(7): 1066-73, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18535009

RESUMEN

NAD(P)H dehydrogenase (NDH) is a homolog of respiratory complex I and mediates one of the two pathways of cyclic electron flow around PSI (CEF I). Although 15 ndh subunits have been identified in the chloroplastic and nuclear genomes of higher plants, no electron accepter subunits have been identified to date. To identify the missing chloroplastic NDH subunits, we undertook an in silico approach based on co-expression analysis. In this report, we characterized the novel gene NDF6 (NDH-dependent flow 6; At1g18730) which encodes a protein that is essential for NDH activity. NDF6 has one transmembrane domain and is localized in the thylakoid membrane fraction. Homologous proteins of NDF6 were identified in the genomes of terrestrial plants; however, no homologs have been found in cyanobacteria, which are thought to be the origin of chloroplasts and have a minimal NDH complex unit. NDF6 is unstable in ndhB-impaired or disrupted mutants of higher plants in which the chloroplastic NDH complex is thought to be degraded. These results suggest that NDF6 is a novel subunit of chloroplastic NDH that was added to terrestrial plants during evolution.


Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimología , Proteínas de la Membrana/metabolismo , NADPH Deshidrogenasa/metabolismo , Tilacoides/enzimología , Secuencia de Aminoácidos , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/aislamiento & purificación , ADN Bacteriano , Estabilidad de Enzimas , Genes de Plantas , Proteínas de la Membrana/química , Proteínas de la Membrana/aislamiento & purificación , Datos de Secuencia Molecular , Mutagénesis Insercional , Proteínas Mutantes/aislamiento & purificación , Proteínas Mutantes/metabolismo , Mutación/genética , NADPH Deshidrogenasa/química , Fotosíntesis , Transporte de Proteínas , Alineación de Secuencia , Homología de Secuencia de Aminoácido
12.
Mol Cells ; 25(2): 158-62, 2008 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-18414017

RESUMEN

Recent molecular genetics studies have revealed that cyclic electron transport around photosystem I is essential for normal photosynthesis and growth of plants. Chloroplastic NAD(P)H dehydorgenase (NDH) complex, a homologue of the complex I in respiratory electron transport, is involved in one of two cyclic pathways. Recent studies on the function and structure of the NDH complex are reviewed.


Asunto(s)
Cloroplastos/enzimología , NADPH Deshidrogenasa/metabolismo , Complejo de Proteína del Fotosistema I/metabolismo , Cianobacterias/enzimología , Transporte de Electrón , NADPH Deshidrogenasa/química , Plantas/enzimología
13.
Bioorg Med Chem ; 16(14): 7021-32, 2008 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-18539035

RESUMEN

A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure-activity relationships and led the identification of 2-(1,4'-bipiperidine-1'-yl)-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine 14a, which showed potent inhibition in the [(35)S]GTPgammaS-binding assay (IC(50)=18nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC(50)=140nM, 39nM).


Asunto(s)
Quinazolinas/síntesis química , Quinazolinas/farmacología , Receptores CCR4/antagonistas & inhibidores , Animales , Quimiotaxis/efectos de los fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Ratones , Relación Estructura-Actividad
14.
Bioorg Med Chem ; 16(17): 7968-74, 2008 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-18694645

RESUMEN

A series of CC chemokine receptor-4 (CCR4) antagonists were examined in a previous report in an attempt to improve metabolic stability in human liver microsomes. In this study, the cycloheptylamine moiety of N-cycloheptyl-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 1 was replaced with the p-chloroaniline moiety, and the resulting compound, N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine (8c), retained its potency ([(35)S]GTPgammaS-binding inhibition and CCL22-induced chemotaxis in humans/mice). Based on the structure-activity relationships (SAR), a homology model was constructed for CCR4 to explain the binding mode of 8c. Overall, there was good agreement between the docking pose of the CCR4 homology model and the human [(35)S]GTPgammaS assay results. Administration of 8c in a murine model of acute dermatitis showed anti-inflammatory activity (oxazolone-induced contact hypersensitivity test).


Asunto(s)
Simulación por Computador , Modelos Químicos , Quinazolinas/química , Quinazolinas/farmacología , Receptores CCR4/antagonistas & inhibidores , Animales , Sitios de Unión , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Inyecciones Subcutáneas , Ratones , Modelos Moleculares , Estructura Molecular , Oxazolona , Quinazolinas/síntesis química , Receptores CCR4/química , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/patología , Estereoisomerismo , Relación Estructura-Actividad
15.
Bioorg Med Chem ; 16(21): 9457-66, 2008 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-18835179

RESUMEN

From a series of 4'-[(trifluoromethyl)pyrazol-1-yl]carboxanilides derived from 4-methyl-4'-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]-1,2,3-thiadiazole-5-carboxanilide, one inhibited thapsigargin-induced Ca2+ influx in Jurkat T cells (IC(50)=77 nM) and exhibited high selectivity for the CRAC channel over the VOC channel (index: >130). Another acted as an inhibitor for both T lymphocyte activation-induced diseases and ovalbumin-induced airway eosinophilia in rats (ED(50)=1.3 mg/kg) p.o.


Asunto(s)
Anilidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Calcio/metabolismo , Pirazoles/farmacología , Anilidas/síntesis química , Anilidas/química , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Señalización del Calcio/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Hipersensibilidad/tratamiento farmacológico , Interleucina-2/metabolismo , Células Jurkat , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Eosinofilia Pulmonar/inducido químicamente , Eosinofilia Pulmonar/tratamiento farmacológico , Pirazoles/síntesis química , Pirazoles/química , Ratas , Ratas Endogámicas BN , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Tapsigargina/farmacología
16.
Nihon Koshu Eisei Zasshi ; 52(11): 987-93, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16408484

RESUMEN

OBJECTIVE: It is well established that job stress is a leading cause of cardiovascular disease. The relationship with the metabolic syndrome, however, has received only limited attention. The present study was designed to investigate associations between change of the type of job and the prevalence of metabolic syndrome components from the aspect of on-the-job stress and alteration in life style. METHODS: Thirty-six male workers of the manufacturing department were transferred to the carsales department at the same automobile company in 1992 to 1993. These same workers were transferred back to the manufacturing department after two years. We compared the first health-check data before the transfer in 1992 (Term A), a second set of data two years after transfer in 1994-95 (Term B) and a third set of data two years following transfer back to the manufacturing department in 1996-1998 (Term C). The workers were requested to provide information about drinking and smoking habits, and answer Karasek's questionnaire and a simple stress questionnaire in order to clarify the possibility of job stress in occurrence of the metabolic syndrome, defined in terms of obesity, hypertension, dyslipidemia, and impaired glucose tolerance as components. RESULTS: Five workers had two or more components of the metabolic syndrome before the transfer to the car-sales department (Group I). One demonstrated improvement, three no change, and one increase in symptoms from A to B. Seven workers had more than two components after the transfer to car-sales department (Group II), and six of them exhibited decrease two years following transfer back to the manufacturing department. Five of them also showed elevated liver enzymes in serum with the appearance of the components, and three of them demonstrated recover. Three workers had two components of the metabolic syndrome only at time point C (Group III), while the remaining 21 workers had 0 to one component throughout the observation period (Group IV). Amount of drinking and smoking increased significantly when working in the sales department but these items returned to the previous values after rejoining manufacturing, though differences were not observed between workers with (Group II) and without (Group IV) components of the metabolic syndrome. Body mass index (BMI) and alanine aminotransferase (ALT) increased significantly when workers moved to the sales department and that was significant in Group II as compared to Group IV. Three components of Karasek's JCQ changed significantly during job transfer, though differences were not observed between the workers with (Group II) and without (Group IV) components of the metabolic syndrome. Logistic regression analysis with age, lifestyle, Karasek's JCQ, and ALT revealed that elevation of ALT value was associated with having two or more components of metabolic syndrome, while hours of sleep demonstrated an inverse association. CONCLUSION: Elevated ALT and reduction of sleep hours may be associated with development of the metabolic syndrome in workers who change their type of job.


Asunto(s)
Síndrome Metabólico/etiología , Salud Laboral , Estrés Psicológico/complicaciones , Trabajo/psicología , Adulto , Factores de Edad , Índice de Masa Corporal , Antígenos CD13/sangre , Humanos , Estilo de Vida , Modelos Logísticos , Masculino , Síndrome Metabólico/epidemiología , Prevalencia , Privación de Sueño/complicaciones , Estrés Psicológico/epidemiología , Encuestas y Cuestionarios , Lugar de Trabajo
17.
Nihon Koshu Eisei Zasshi ; 52(11): 979-86, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16408483

RESUMEN

We previously reported that the prevalence of elevated alanine aminotransferase (ALT) increases with accumulation of metabolic syndrome components, and a greater degree of involvement of aldehyde dehydrogenase 2 (ALDH2) than beta3-adrenergic receptor gene (beta3-AR) polymorphisms. The present study was designed to clarify the effect of aging, lifestyle and the two gene polymorphisms on the relationship between 4 components of the metabolic syndrome (obesity, hypertension, dyslipidemia and impaired glucose tolerance) and elevated ALT values in a subset of 73 out of 148 male workers who were 35 years of age in the baseline study and 40 years old in the present study. Study subjects completed questionnaires about drinking and smoking habits, and underwent urinalysis, physical examination and peripheral blood tests, blood chemistry, electrocardiogram and chest X-rays each year as required by Japanese law. Information from the questionnaires and physical examinations, including liver function tests, were compared with previously reported ALDH2 and beta3-AR genotypes for the 73 workers. Of the 73 workers studied, 14 (19%) demonstrated decrease in metabolic syndrome components, 39 (53%) demonstrated no change, and 20 (27%) demonstrated an increase. Ten workers (14%) showed liver dysfunction at age 35 and 20 workers (27%) at age 40. Fourteen workers were newly diagnosed as having liver dysfunction at their 40-year checkup, thus being associated with the BMI and an active ALDH2 genotype. Accumulation of components of the metabolic syndrome were associated with the presence of liver dysfunction at 35 years. In conclusion, these findings indicate that ALDH2 genotyping as well as lifestyle habits may be important factors in causing metabolic syndrome with liver dysfunction.


Asunto(s)
Alanina Transaminasa/sangre , Aldehído Deshidrogenasa/genética , Estilo de Vida , Hígado/enzimología , Síndrome Metabólico/etiología , Salud Laboral , Examen Físico , Polimorfismo Genético , Receptores Adrenérgicos beta 3/genética , Adulto , Factores de Edad , Envejecimiento/fisiología , Aldehído Deshidrogenasa Mitocondrial , Humanos , Masculino , Síndrome Metabólico/epidemiología , Prevalencia , Encuestas y Cuestionarios , Factores de Tiempo
18.
Nihon Koshu Eisei Zasshi ; 51(11): 975-85, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15678990

RESUMEN

OBJECTIVE: Although education for smoking cessation is being conducted in Asian countries, the prevalence of smoking is still high. The present study was designed to clarify differences in the socio-cultural background in Japan and Thailand. METHODS: Cross-sectional study. The Japan survey was conducted in Kanagawa and the Thailand survey in Suphanburi. Questionnaires written in English were translated into each language. The subjects were out-patients of community hospitals (331 males and 353 females in Japan and 293 males and 288 females in Thailand). RESULTS: The prevalence of smoking was found to be higher in Thailand than in Japan for males but almost the same for females. A higher percentage of the subjects quit smoking in Japan than in Thailand. The motive for quitting smoking was "awareness of the harmful effects of smoking" in both countries, but "told by others to quit smoking" was also often encountered in Thailand. The method of quitting was most frequently "suppress the urge to smoke by will power" in both countries. Nicotine replacement therapy is not well known yet in either country. CONCLUSION: Smoking behavior was different although the difficulty of quitting smoking was common to both countries. The prevalence of smoking in younger males and females was established to be higher in Japan, and social and environmental regulations for quitting smoking were effective in Thailand. It suggests that such regulations should be made stricter in Japan. Enlightenment by providing knowledge may be particularly useful in Thailand.


Asunto(s)
Cese del Hábito de Fumar/psicología , Fumar/psicología , Adulto , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Medio Social , Tailandia
19.
Health Econ Rev ; 2(1): 10, 2012 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-22827922

RESUMEN

We propose simple modifications for the Kakwani tax progressivity measure that make it suitable for evaluating access inequality for medical services. Our modification is to measure inequality using the ratio of the concentration index to the Gini coefficient instead of the difference between them. We also propose a measure using the Gini coefficient or concentration index of consumption expenditure as the denominator in the modified measure as an alternative type of modified measure. This measure can also be interpreted as the income/consumption expenditure elasticity evaluated at the mean. Additionally, we propose a decomposition method using expenditure components and provide an empirical example with Japanese data.

20.
J Plant Res ; 121(5): 521-6, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18683022

RESUMEN

The activities of electron transport are compared between wild-type Arabidopsis and two Arabidopsis mutants deficient for the chloroplastic NAD(P)H dehydrogenase (NDH) which catalyzes cyclic electron transport around photosystem I. The quantum yield of photosystem II and the degree of non-photochemical quenching of chlorophyll fluorescence were of similar levels in the two NDH-deficient mutants and the wild type under non-stressed standard growth conditions. Stromal over-reduction was induced in Arabidopsis NDH mutants with high light treatment, as is the case in tobacco NDH mutants. However, unlike tobacco mutants, photoinhibition was not observed in the Arabidopsis NDH mutants.


Asunto(s)
Arabidopsis/enzimología , Cloroplastos/enzimología , Transporte de Electrón , Luz , NADPH Deshidrogenasa/metabolismo , Arabidopsis/genética , Mutación , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Oxidación-Reducción
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