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1.
J Enzyme Inhib Med Chem ; 35(1): 227-234, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752563

RESUMO

A novel series of thieno[3,2-d]pyrimidine derivatives were synthesised and their inhibitory effects against diacylglycerol acyltransferase 1 (DGAT-1) were assessed. cis-Isomer 17a showed potent and selective inhibitory activity against DGAT-1 in SF9 cells. In addition, 17a had an acceptable pharmacokinetic profile and accumulated mainly in the small intestine and liver. Oral administration of 17a led to a significant reduction in plasma triacylglycerol level during an oral lipid tolerance test (OLTT) in murine and canine models. Taken together, 17a is a high-quality candidate that deserves further investigation.


Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Animais , Diacilglicerol O-Aciltransferase/metabolismo , Cães , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
2.
PLoS One ; 14(8): e0221042, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31442245

RESUMO

BACKGROUND: Recent nutrition guidelines for extremely-low-birth-weight infants (ELBWIs) recommend implementation of high initial amino acid (AA) supplementation in parenteral nutrition. OBJECTIVE: We sought to evaluate the influence of AA intake on refeeding syndrome-like electrolyte disturbances including hypophosphatemia in ELBWIs. STUDY DESIGN: Medical records of 142 ELBWIs were reviewed. Demographic, nutritional, outcome, and electrolyte data were compared between ELBWIs with initial low (1.5 g/kg/day) and high (3 g/kg/day) AA intake. Multivariate analysis was conducted to determine the odds ratio of hypophosphatemia with high AA intake and small-for-gestational-age (SGA) ELBWIs. RESULTS: The incidence of hypophosphatemia and severe hypophosphatemia increased from 51% and 8% in period I to 59% and 20% in period II, respectively (p = 0.36 and < 0.01). Specifically, SGA ELBWIs showed higher incidence of hypophosphatemia than appropriate-for-gestational age (AGA) ELBWIs in period II, whereas there was no difference in period I. For severe hypophosphatemia, SGA ELBWIs presented a 27% incidence versus a 2% incidence in AGA ELBWIs, even with low initial AA intake. Despite no difference in phosphate intake between infants with and without hypophosphatemia, serum phosphate level reached a nadir at the sixth postnatal day and gradually recovered over the second week in infants with hypophosphatemia. In multivariate analyses, the odds ratios for severe hypophosphatemia were 3.6 and 6.6 with high AA intake and SGA status, respectively, with the highest being 18.0 with combined high AA intake and SGA status. CONCLUSIONS: In summary, high initial AA intake significantly increased the risk of refeeding syndrome-like electrolyte dysregulations including severe hypophosphatemia in ELBWIs. In SGA ELBWIs, the risk of electrolyte disturbance was significantly higher, even with low initial AA intake. Therefore, new tailored parenteral nutrition protocols starting with lower energy intake and a gradual increase over the first week may be warranted for application in high-risk SGA ELBWIs.

3.
PLoS One ; 14(2): e0212256, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30759169

RESUMO

This study aimed to determine the natural course of patent ductus arteriosus (PDA) with noninterventional conservative management and whether the presence and/or prolonged duration of hemodynamically significant (HS) PDA increased the risk of mortality and morbidities in extremely preterm (EPT) infants. We retrospectively reviewed the medical records of EPT infants born at 23-28 weeks of gestation (n = 195) from January 2011 to June 2014, when PDA was managed with noninterventional conservative treatment. We stratified infants into three subgroups of 23-24, 25-26, and 27-28 weeks and analyzed the prevalence and natural evolution of HS PDA, defined as ventilator dependency and PDA size ≥2 mm. Multivariate regression analyses determined if the presence and/or prolonged duration of HS PDA increased the risk for mortality and/or morbidities. The overall incidence of HS PDA was 57% (111/195) at the end of the first postnatal week. In subgroup analyses, infants with 23-24 weeks of gestation had the highest incidence (93%, 50/54), with 64% (47/74) for 25-26 weeks and 21% (14/67) for 27-28 weeks. Six (5%) of 111 infants with HS PDA were discharged without ductus closure, 4 had spontaneous PDA closure on follow up, and device closure was performed for 2 infants. In the multivariate analyses, the presence or prolonged duration (per week) of HS PDA was not associated with the risk of mortality and/or morbidities. Spontaneous closure of HS PDA was mostly achieved, even in EPT infants, with a noninterventional conservative approach. In conclusion, our data showed the incidence and natural course of HS PDA in EPT infants and suggested that the presence or prolonged duration of HS PDA might not increase the rate of mortality or morbidities.


Assuntos
Permeabilidade do Canal Arterial , Canal Arterial/fisiopatologia , Mortalidade Infantil , Lactente Extremamente Prematuro , Tratamento Conservador , Permeabilidade do Canal Arterial/mortalidade , Permeabilidade do Canal Arterial/fisiopatologia , Permeabilidade do Canal Arterial/terapia , Feminino , Seguimentos , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco
4.
Bioorg Chem ; 85: 386-398, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30665033

RESUMO

Protein misfolding can facilitate a protein damaging process and makes it susceptible to a series of events such as unfolding, adduct formation, oligomerization, or aggregation. Loss of a protein's native structure may result in its biological malfunction and/or cellular toxicity that could cause associated diseases. Several factors were identified for causing structural changes of a protein, however quinone-induced protein modifications received very little attention whether for amyloidal or non-amyloidal proteins. In this paper, we report our investigation on lysozyme modifications upon treatment with selected benzoquinones (BQs), utilizing fluorescence spectroscopy including anisotropy determination, UV-Vis spectroscopy, and SDS-PAGE. Lysozyme was reacted with substituted BQs in order to examine substituent effects on protein modifications. In addition, we evaluated lysozyme modifications induced by 1,4-benzoquinone in concentration-, pH-, temperature-, and time-dependent studies. Our study shows that all BQs can readily modify lysozyme in a complex manner through adduct formation, oligomerization, polymeric aggregation, and/or fibrilization. Electrochemical properties of selected BQs were monitored using cyclic voltammetry in phosphate buffered aqueous solution, and it was found that quinone reduction potentials correlate well with their reactivity trend toward lysozyme.


Assuntos
Benzoquinonas/química , Muramidase/química , Animais , Galinhas , Concentração de Íons de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Temperatura Ambiente
5.
Bioorg Chem ; 75: 265-273, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29054071

RESUMO

In this paper, we report the inactivation of copper containing bovine plasma amine oxidase (BPAO) by a series of saturated alkylamines containing halogen atoms at γ-position, which are 1,1,1-trihalo-3-aminopropane, 1,1,1-trifluoro-2-hydroxy-3-aminopropane, 1,1,1-trichloro-2-hydroxy-3-aminopropane, and 1,1,1-trichloro-2-(2-phenethyloxy)-3-aminopropane. The trihalo-2-hydroxypropylamine analogs exhibited a time-dependent inactivation behavior of BPAO, with 1,1,1-trifluoro-2-hydroxy-3-aminopropane as the most efficient inactivator. The incorporation of a OH group at ß-position increased inactivation efficiency by 10-fold within the trifluoro analogs, and the incorporation of a phenethyloxy group at ß-position exhibited a higher efficiency by 3-fold within the trichloro analogs based on I75 values. All four compounds were found to be irreversible inactivators for BPAO.


Assuntos
Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Inibidores Enzimáticos/química , Propano/química , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Domínio Catalítico , Bovinos , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Cinética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Propano/metabolismo
6.
J Korean Med Sci ; 32(8): 1288-1294, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28665065

RESUMO

Prophylactic surfactant is known to be effective to reduce chronic lung disease in preterm infants compared with rescue surfactant treatment. In Korea, early prophylactic surfactant therapy was introduced in 2011. However, recently, the increased utilization of antenatal steroids and early stabilization through continuous positive airway pressure (CPAP) in the delivery room may have changed the risks and benefits of prophylactic surfactant therapy of infants at high risk of respiratory distress syndrome (RDS). We compared the effects and safety of prophylactic surfactant therapy (within 30 minutes after birth) and early selective surfactant therapy (within 3 hours after birth) in preterm infants born at < 30 weeks gestation or with birth weight ≤ 1,250 g. The clinical data of 193 infants in period 1 (from 2008 to 2010, early selective surfactant therapy group) were collected retrospectively; those of 191 infants in period 2 (from 2012 to 2014, prophylactic surfactant therapy group) were collected prospectively. Compared to period 1, the rate of intubation and surfactant use were significantly increased in period 2. The use of multiple doses of surfactant in period 2 was significantly increased compared with period 1. Despite more invasive and aggressive management in period 2, there was no difference in the duration of mechanical ventilation, the incidence of bronchopulmonary dysplasia (BPD) or death, and the risk of other adverse neonatal outcomes between the 2 groups. In conclusion, the benefit of prophylactic surfactant therapy in infants treated under current practices is no longer clear compared to early selective surfactant therapy.


Assuntos
Surfactantes Pulmonares/administração & dosagem , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Displasia Broncopulmonar/epidemiologia , Idade Gestacional , Humanos , Incidência , Lactente , Mortalidade Infantil/tendências , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Unidades de Terapia Intensiva Neonatal , Razão de Chances , República da Coreia , Respiração Artificial , Estudos Retrospectivos
7.
J Anat ; 230(1): 117-127, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27484046

RESUMO

We showed previously that caffeine adversely affects longitudinal bone growth and disrupts the histomorphometry of the growth plate during the pubertal growth spurt. However, little attention has been paid to the direct effects of caffeine on chondrocytes. Here, we investigated the direct effects of caffeine on chondrocytes of the growth plate in vivo and in vitro using a rapidly growing young rat model, and determined whether they were related to the adenosine receptor signaling pathway. A total of 15 male rats (21 days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180 mg kg-1  day-1 for 4 weeks. After sacrifice, the tibia processed for the analysis of the long bone growth and proliferation of chondrocytes using tetracycline and BrdU incorporation, respectively. Caffeine-fed animals showed decreases in matrix mineralization and proliferation rate of growth plate chondrocytes compared with the control. To evaluate whether caffeine directly affects chondrocyte proliferation and chondrogenic differentiation, primary rat chondrocytes were isolated from the growth plates and cultured in either the presence or absence of caffeine at concentrations of 0.1-1 mm, followed by determination of the cellular proliferation or expression profiles of cellular differentiation markers. Caffeine caused significant decreases in extracellular matrix production, mineralization, and alkaline phosphatase activity, accompanied with decreases in gene expression of the cartilage-specific matrix proteins such as aggrecan, type II collagen and type X. Our results clearly demonstrate that caffeine is capable of interfering with cartilage induction by directly inhibiting the synthetic activity and orderly expression of marker genes relevant to chondrocyte maturation. In addition, we found that the adenosine type 1 receptor signaling pathway may be partly involved in the detrimental effects of caffeine on chondrogenic differentiation, specifically matrix production and mineralization, as evidenced by attenuation of the inhibitory effects of caffeine by blockade of this receptor. Thus, our study provides novel information on the integration of caffeine and adenosine receptor signaling during chondrocyte maturation, extending our understanding of the effect of caffeine at a cellular level on chondrocytes of the growth plate.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Cafeína/toxicidade , Diferenciação Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Lâmina de Crescimento/efeitos dos fármacos , Tíbia/efeitos dos fármacos , Animais , Desenvolvimento Ósseo/fisiologia , Diferenciação Celular/fisiologia , Células Cultivadas , Condrócitos/fisiologia , Lâmina de Crescimento/citologia , Lâmina de Crescimento/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor A1 de Adenosina/fisiologia , Tíbia/citologia , Tíbia/fisiologia
8.
J Med Food ; 19(1): 73-84, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26495862

RESUMO

This study investigated the dose- and time-dependent effects of caffeine consumption throughout puberty in peripubertal rats. A total of 85 male SD rats were randomly divided into four groups: control and caffeine-fed groups with 20, 60, or 120 mg/kg/day through oral gavage for 10, 20, 30, or 40 days. Caffeine decreased body weight gain and food consumption in a dose- and time-dependent manner, accompanied by a reduction in muscle and body fat. In addition, it caused a shortening and lightening of leg bones and spinal column. The total height of the growth plate decreased sharply at 40 days in the controls, but not in the caffeine-fed groups, and the height of hypertrophic zone in the caffeine-fed groups was lower than in the control. Caffeine increased the height of the secondary spongiosa, whereas parameters related to bone formation, such as bone area ratio, thickness and number of trabeculae, and bone perimeter, were significantly reduced. Furthermore, serum levels of IGF-1, estradiol, and testosterone were also reduced by the dose of caffeine exposure. Our results demonstrate that caffeine consumption can dose- and time-dependently inhibit longitudinal bone growth in immature male rats, possibly by blocking the physiologic changes in body composition and hormones relevant to bone growth.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Cafeína/efeitos adversos , Puberdade/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Puberdade/fisiologia , Ratos , Ratos Sprague-Dawley , Testosterona/metabolismo
9.
J Anat ; 227(1): 10-20, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26041429

RESUMO

Caffeine adversely affects endochondral ossification during fetal skeletal growth, and results in increased incidence of delayed and abnormal fetal skeletal development. Chronic caffeine intake also decreases growth hormone secretion. Thus, it is conceivable that caffeine may disrupt bone growth during the peripubertal period. This study aimed to investigate the impact of high-caffeine consumption on bone growth throughout puberty. A total of 51 male rats (21 days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180 mg kg(-1)  day(-1) for 4 weeks. After death, the final length and weight of leg bones were measured, and the tibia processed for histomorphometric analysis. Caffeine caused a significant decrease in body mass gain. This was accompanied with proportional decreases in lean body mass and body fat. In addition, bone mass and osteogenic activity in vivo were assessed using dual-energy X-ray absorptiometry and (18) F-NaF positron emission tomography. The results showed significant decreases of bone mass and in vivo osteogenic activity in the caffeine-fed groups. Rats fed with caffeine showed a significantly shorter and lighter tibia and femur and the vertebral column compared with controls. In addition, caffeine does not increase the width of the growth plates (GPs), it slows the rate at which the GP closes due to a slower rate of growth. These results demonstrated that caffeine altered osteogenic activity, leading to delayed peripubertal longitudinal bone growth and maturation. Given that osteogenic cells undergo dynamic changes in metabolic activity and that the pubertal growth spurt is mainly stimulated by growth hormone/insulin-like growth factor-1 and sex steroids during pubertal development, caffeine could suppress ossification by interfering with both physiological changes in hormonal secretion and osteogenic activity during this critical period. Further study will be needed to investigate the cellular/molecular mechanism by which caffeine affects osteogenesis using in vitro experimental models.


Assuntos
Desenvolvimento Ósseo/efeitos dos fármacos , Cafeína/efeitos adversos , Estimulantes do Sistema Nervoso Central/efeitos adversos , Absorciometria de Fóton , Animais , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Cafeína/administração & dosagem , Estimulantes do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Fêmur/efeitos dos fármacos , Lâmina de Crescimento/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Osteogênese/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tíbia/efeitos dos fármacos
10.
Bioorg Chem ; 59: 106-16, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25734950

RESUMO

In this paper, we present our investigation on ribonuclease A (RNase) modifications induced by 1,4-benzoquinone (PBQ), 2-methyl-1,4-benzoquinone (MBQ), and 2-chloro-1,4-benzoquinone (CBQ). The goal of the study was to evaluate quinone-induced protein modifications as well as substituent effects, utilizing several techniques such as SDS-PAGE, fluorescence spectroscopy, microscopy, and LC-ESI(+)-QTOF-MS. SDS-PAGE experiments revealed that all quinones modify RNase through oligomerization as well as polymeric aggregation; with CBQ functioning as the most efficient quinone while MBQ was least efficient. The fluorescence emission was found to be less intense and the anisotropy values were found to be slightly higher for the modified RNase compared to the unmodified RNase. UV-Vis spectroscopy indicated that all three quinones formed adducts in which they were covalently linked to RNase. Confocal imaging analysis showed that the presence of CBQ resulted in massive RNase aggregation, while PBQ-treated RNase formed much smaller aggregates. MBQ-treated RNase exhibited micrographic features that closely resembled those of the unmodified RNase. LC-ESI(+)-QTOF-MS studies indicated the nature of PBQ- and CBQ-induced RNase modifications are complex mainly due to simultaneously occurrence of both adduct formation and oligomerization. Kinetic studies on quinone reactivity toward lysine revealed the rank order of CBQ>PBQ≫MBQ, based on the second-order rate constants. We also utilized scanning electron microscopy in order to investigate the effect of modified RNase on the biomineralization of salts.


Assuntos
Benzoquinonas/farmacologia , Ribonuclease Pancreático/química , Animais , Bovinos , Agregados Proteicos/efeitos dos fármacos , Ribonuclease Pancreático/metabolismo
11.
Bioorg Med Chem Lett ; 24(17): 4271-5, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25082126

RESUMO

Takeda G-protein-coupled receptor 5 (TGR5) is a promising molecular target for metabolic diseases. A series of 4-(2,5-dichlorophenoxy)pyrimidine and cyclopropylmalonamide derivatives were synthesized as potent agonists of TGR5 based on a bioisosteric replacement strategy. Several compounds exhibited improved potency, compared to a reference compound with a pyridine scaffold. The pharmacokinetic profile of the representative compound 18 was considered moderate.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas , Malonatos/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Disponibilidade Biológica , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Malonatos/administração & dosagem , Malonatos/química , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirimidinas/administração & dosagem , Pirimidinas/química , Relação Estrutura-Atividade
12.
Neuropsychologia ; 51(7): 1177-86, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23566889

RESUMO

Cultures vary in the extent to which they emphasize group members to habitually attend to the needs, perspectives, and internal experiences of others compared to the self. Here we examined the influence that collectivistic and individualistic cultural environments may play on the engagement of the neurobiological processes that underlie the perception and processing of emotional pain. Using cross-cultural fMRI, Korean and Caucasian-American participants passively viewed scenes of others in situations of emotional pain and distress. Regression analyses revealed that the value of other-focusedness was associated with heightened neural response within the affective pain matrix (i.e. anterior cingulate cortex and insula) to a greater extent for Korean relative to Caucasian-American participants. These findings suggest that mindsets promoting attunement to the subjective experience of others may be especially critical for pain-related and potentially empathic processing within collectivistic relative to individualistic cultural environments.


Assuntos
Mapeamento Encefálico , Encéfalo/fisiologia , Comparação Transcultural , Emoções/fisiologia , Meio Ambiente , Percepção da Dor/fisiologia , Adolescente , Adulto , Encéfalo/irrigação sanguínea , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Oxigênio/sangue , Estimulação Luminosa , Análise de Regressão , Adulto Jovem
13.
Bioorg Chem ; 40(1): 92-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22138305

RESUMO

The nature of ribonuclease A (RNase) modifications induced by p-benzoquinone (pBQ) was investigated using several analysis methods. SDS-PAGE experiments revealed that pBQ was efficient in producing oligomers and polymeric aggregates when RNase was incubated with pBQ. The fluorescence behavior and anisotropy changes of the modified RNase were monitored for a series of incubation reactions where RNase (0.050 mM) was incubated with pBQ (0.050, 0.25, 0.50, 1.50 mM) at 37 °C in phosphate buffer (pH 7.0, 50 mM). The modified RNase exhibited less intense fluorescence and slightly higher anisotropy than the unmodified RNase. UV-Vis spectroscopy indicated that pBQ formed covalent bonds to the modified RNase. Confocal imaging analysis confirmed the formation of the polymeric RNase aggregates with different sizes upon exposure of RNase to high concentrations of pBQ. The interaction between the modified RNase and salts affecting biomineralization of salts was also investigated by scanning electron microscopy. Overall, our results show that pBQ can induce formation of both RNase adducts and aggregates thus providing a better understanding of its biological activity.


Assuntos
Benzoquinonas/química , Ribonuclease Pancreático/química , Eletroforese em Gel de Poliacrilamida , Polarização de Fluorescência , Microscopia Confocal , Microscopia Eletrônica de Varredura , Ribonuclease Pancreático/metabolismo , Espectrofotometria Ultravioleta
14.
Neuroimage ; 57(2): 642-50, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21549201

RESUMO

Cultures vary in the extent to which people prefer social hierarchical or egalitarian relations between individuals and groups. Here we examined the effect of cultural variation in preference for social hierarchy on the neural basis of intergroup empathy. Using cross-cultural neuroimaging, we measured neural responses while Korean and American participants observed scenes of racial ingroup and outgroup members in emotional pain. Compared to Caucasian-American participants, Korean participants reported experiencing greater empathy and elicited stronger activity in the left temporo-parietal junction (L-TPJ), a region previously associated with mental state inference, for ingroup compared to outgroup members. Furthermore, preferential reactivity within this region to the pain of ingroup relative to outgroup members was associated with greater preference for social hierarchy and ingroup biases in empathy. Together, these results suggest that cultural variation in preference for social hierarchy leads to cultural variation in ingroup-preferences in empathy, due to increased engagement of brain regions associated with representing and inferring the mental states of others.


Assuntos
Mapeamento Encefálico , Córtex Cerebral/fisiologia , Cultura , Emoções/fisiologia , Empatia/fisiologia , Identificação Social , Adulto , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/psicologia , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/psicologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Processamento de Sinais Assistido por Computador , Adulto Jovem
15.
Bioorg Med Chem ; 14(5): 1444-53, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16266805

RESUMO

Various 2- and 3-haloallylamines were synthesized and evaluated as inhibitors of the quinone-dependent bovine plasma amine oxidase (BPAO). 3-Haloallylamines, which were previously found to be good inhibitors of the flavin-dependent mitochondrial monoamine oxidase (MAO), exhibited a time-dependent inactivation of BPAO, with the 2-phenyl analogs being more potent than the 2-methyl analogs. No plateau of enzyme activity loss was observed, suggestive of a lack of competitive partitioning to normal turnover. The (E)- and (Z)-2-phenyl-3-fluoro analogs were the most potent (low microM IC(50)s), with the corresponding 3-bromo and 3-chloro analogs being >10-fold less potent. In each case, the Z-isomers were more potent than the E-isomers, the reverse of the configurational inhibitory preference observed with MAO. In contrast to the 2-phenyl analogs, 3-phenyl-2(or 3)-chloroallylamines displayed a partitioning behavior, consistent with these being both substrates and inactivators of BPAO.


Assuntos
Alilamina/farmacologia , Amina Oxidase (contendo Cobre)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Alilamina/análogos & derivados , Alilamina/síntese química , Amina Oxidase (contendo Cobre)/sangue , Animais , Benzoquinonas/química , Bovinos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Halogênios/química , Concentração Inibidora 50 , Cinética , Modelos Químicos
16.
Mol Pharm ; 2(3): 233-41, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15934784

RESUMO

A methodology has been developed for the analysis of the intracellular metabolism of 3'-azido-3'-deoxythymidine (AZT) amino acid phosphoramidates utilizing reverse-phase high-performance liquid chromatography interfaced with negative ion electrospray ionization mass spectrometry (LC/ESI(-) -MS). The presented work demonstrates the potential of capillary LC/MS and LC/MS/MS to identify and quantitate the cellular uptake and metabolism of nucleoside phosphoramidate. Significant intracellular amounts of D- and L-phenylalanine methyl ester or D- and L-tryptophan methyl ester AZT phosphoramidates were observed for human T-lymphoblastoid leukemia (CEM) cells incubated for 2 and 4 h with the prodrugs. AZT-MP was the primary metabolite observed for human T-lymphoblastoid leukemia (CEM) cells. In this paper, the details of using LC/MS to analyze AZT amino acid phosphoramidates in biological samples are discussed. LC/MS is an efficient method for analyzing multiple samples containing several analytes in a short period of time. The method also provides high selectivity and sensitivity, and requires minimal sample preparation. This approach should be broadly applicable for the analysis of the intracellular metabolism of nucleoside prodrugs and pronucleotides.


Assuntos
Amidas/metabolismo , Fármacos Anti-HIV/metabolismo , Leucemia de Células T/metabolismo , Ácidos Fosfóricos/metabolismo , Pró-Fármacos/metabolismo , Nucleotídeos de Timina/metabolismo , Zidovudina/análogos & derivados , Zidovudina/metabolismo , Aminoácidos/metabolismo , Cromatografia Líquida de Alta Pressão , Didesoxinucleotídeos , Humanos , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray , Nucleotídeos de Timina/administração & dosagem , Células Tumorais Cultivadas , Zidovudina/administração & dosagem
17.
Artigo em Inglês | MEDLINE | ID: mdl-15043168

RESUMO

The intracellular metabolism of 3'-azido-3'-deoxythymidine (AZT)-(L)-tryptophan methyl ester phosphoramidate (L-ATO) and AZT-(L)-phenylalanine methyl ester phosphoramidate (L-APO) by the human T-lymphoblastoid cell line CCRF-CEM (CEM-1.3) and peripheral blood mononuclear cell line (PBMC) was investigated with high field 31P NMR spectroscopy. The AZT amino acid phosphoramidates were shown to accumulate intracellularly and to be readily converted into AZT-MP by both tissues types. Thus, the efficient delivery of nucleoside monophosphates to cells can be facilitated by nucleoside phosphoramidate pronucleotides.


Assuntos
Amidas/metabolismo , Ácidos Fosfóricos/metabolismo , Zidovudina/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Isótopos de Fósforo
18.
Mol Pharm ; 1(2): 102-11, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15832506

RESUMO

Amino acid phosphoramidates of nucleosides have been shown to be potent antiviral and anticancer agents with the potential to act as nucleoside monophosphate prodrugs. To access their ability to deliver 3'-azido-3'-deoxythymidine (AZT) 5'-monophosphate to cells, the decomposition pathway of an 18O-labeled AZT amino acid phosphoramidate was investigated by capillary reverse-phase high-performance liquid chromatography interfaced with negative ion electrospray ionization mass spectrometry (LC-ESI(-)-MS/MS). 18O-labeled L-AZT tryptophan phosphoramidate methyl ester ([18O]2) was synthesized with an 18O/16O relative ratio of 1.22 +/- 0.18. For CEM cells, a human T-lymphoblast leukemia cell line, incubated with [18O]2, values of 1.55 +/- 0.37, 0.34, and 0.13 were found for the 18O/16O relative ratio of intracellular AZT-MP for time intervals of 0.5, 4, and 20 h, respectively. The decrease in the level of labeled AZT-MP in CEM cells corresponded to a rapid increase in the amount of intracellular AZT presumably by dephosphorylation of AZT-MP. In contrast, for peripheral blood mononuclear cells (PBMCs), the 18O/16O relative ratio values of intracellular AZT-MP were 1.43, 1.06, and 0.61 for time intervals of 0.5, 4, and 20 h, respectively. Intracellular AZT in PBMCs was nearly undetectable for each time interval. Taken together, these results are consistent with the detection of direct P-N bond cleavage by CEM cells and PBMCs. However, AZT phosphoramidates are able to more effectively deliver AZT-MP to PBMCs than to CEM cells. Differential expression of 5'-nucleotidase in CEM cells relative to PBMCs is likely the reason for this discrepancy. Although applied to a phosphoramidate pronucleotide, the judicious use of 18O labeling and LC-MS is a general approach that could be applied to the investigation of the intracellular fate of other pronucleotides.


Assuntos
Ribonucleotídeos/farmacocinética , Nucleotídeos de Timina/farmacocinética , Zidovudina/análogos & derivados , Zidovudina/farmacocinética , Amidas , Transporte Biológico , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Didesoxinucleotídeos , Portadores de Fármacos , Humanos , Marcação por Isótopo/métodos , Oxigênio/farmacocinética , Isótopos de Oxigênio , Ácidos Fosfóricos , Espectrometria de Massas por Ionização por Electrospray
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