Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Clin Sci (Lond) ; 137(2): 163-180, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36598778

RESUMO

Cigarette smoking is a major risk factor for atherosclerosis. We previously reported that DNA damage was accumulated in atherosclerotic plaque, and was increased in human mononuclear cells by smoking. As vascular endothelial cells are known to modulate inflammation, we investigated the mechanism by which smoking activates innate immunity in endothelial cells focusing on DNA damage. Furthermore, we sought to characterize the plasma level of cell-free DNA (cfDNA), a result of mitochondrial and/or genomic DNA damage, as a biomarker for atherosclerosis. Cigarette smoke extract (CSE) increased DNA damage in the nucleus and mitochondria in human endothelial cells. Mitochondrial damage induced minority mitochondrial outer membrane permeabilization, which was insufficient for cell death but instead led to nuclear DNA damage. DNA fragments, derived from the nucleus and mitochondria, were accumulated in the cytosol, and caused a persistent increase in IL-6 mRNA expression via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. cfDNA, quantified with quantitative PCR in culture medium was increased by CSE. Consistent with in vitro results, plasma mitochondrial cfDNA (mt-cfDNA) and nuclear cfDNA (n-cfDNA) were increased in young healthy smokers compared with age-matched nonsmokers. Additionally, both mt-cfDNA and n-cfDNA were significantly increased in patients with atherosclerosis compared with the normal controls. Our multivariate analysis revealed that only mt-cfDNA predicted the risk of atherosclerosis. In conclusion, accumulated cytosolic DNA caused by cigarette smoke and the resultant activation of the cGAS-STING pathway may be a mechanism of atherosclerosis development. The plasma level of mt-cfDNA, possibly as a result of DNA damage, may be a useful biomarker for atherosclerosis.


Assuntos
Aterosclerose , Ácidos Nucleicos Livres , Fumar Cigarros , Humanos , Aterosclerose/metabolismo , Ácidos Nucleicos Livres/metabolismo , DNA Mitocondrial/metabolismo , Células Endoteliais/metabolismo , Mitocôndrias/metabolismo , Nucleotidiltransferases/genética , Dano ao DNA
2.
SAGE Open Med Case Rep ; 10: 2050313X221105829, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35769831

RESUMO

This report presents a case study on giant left atrial myxoma. Transthoracic echocardiography showed a giant mass in the left atrium of a 53-year-old female patient causing functional mitral stenosis. Tumor resection was performed, and the pathological diagnosis confirmed the atrial myxoma. Postoperative echocardiography showed no evidence of any remaining mass and mitral stenosis.

4.
Data Brief ; 29: 105131, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32021887

RESUMO

Vigna nakashimae is one of the closely related species of Vigna angularis (Adzuki bean). Two strain of 'Ukushima' and 'G418' were identified as salt tolerance strains in Vigna nakashimae from gene bank collection. F2 populations from an inter- or intra-specific cross between the sensitive and tolerant strains are useful for the detection of salt tolerance QTL in Vigna nakashimae. Although Vigna angularis reference genome is available and useful for genetic analysis by genotyping-by-sequencing/RADseq in closely related species, it is not enough for isolation of responsible genes. To reveal sequence variation in Vigna nakashimae "Ukushima" and "G418", the whole genome sequencing was performed using Illumina HiSeq X Ten system (411,174,986 and 478,116,282 read). NGS data was deposited in the DNA Data Bank of Japan (DDBJ) under accession number DRA009307.

5.
Mycoses ; 62(12): 1148-1153, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518455

RESUMO

BACKGROUND: The gold standard for diagnosis of cutaneous sporotrichosis involves the isolation of the fungus, Sporothrix, by a culture test. Generally, the sampling for the culture test is performed at the same time as skin biopsy under local anaesthesia. However, the culture test may occasionally return a false negative result. OBJECTIVE: The aim of our study was to investigate the diagnostic value of a molecular method for diagnosing cutaneous sporotrichosis from formalin-fixed and paraffin-embedded (FFPE) tissues. METHODS: Over a 30-year period, we collected 52 cases of cutaneous sporotrichosis from biopsied specimens that had been positively diagnosed by a culture test. A nested PCR specific for Sporothrix detection was applied using FFPE tissue as template. The results were compared with control samples from 79 patients diagnosed with other cutaneous diseases according to histopathological, clinical findings and a cutler test. RESULTS: Of the 52 patients who were tested positive on the culture test, all cutaneous diseases were detected by PCR. Of the 59 patients in the control group, 58 tested negative by PCR. Under our conditions, the calculated sensitivity of this method was 100%, the specificity was 98.7% and the kappa coefficient was 0.984 (95% CI: 0.953-1.000). CONCLUSIONS: The specific PCR assay used appears to be a useful tool for the prompt and accurate diagnosis of sporotrichosis. Using this method, it would be possible to diagnose cutaneous sporotrichosis for patients who were suspected of cutaneous sporotrichosis but tested negative on culturing, and for pathologically suspected cutaneous sporotrichosis patients for whom the culture test was not undertaken.


Assuntos
Técnicas de Diagnóstico Molecular/normas , Reação em Cadeia da Polimerase/normas , Pele/microbiologia , Sporothrix/isolamento & purificação , Esporotricose/diagnóstico , Idoso , Biópsia , DNA Fúngico/isolamento & purificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Sensibilidade e Especificidade
6.
ACS Omega ; 3(5): 4932-4940, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-31458709

RESUMO

Alminoprofen, (RS)-2-{4-[(2-methylprop-2-en-1-yl)amino]phenyl}propanoic acid (ALP) 1, is a racemic drug categorized as a 2-arylpropanoic acid-class nonsteroidal anti-inflammatory drug. Pharmacokinetic studies of 1 in patients have revealed that the corresponding acyl glucuronide 5 is a major urinary metabolite, but little is known about the structure and stereochemistry of 5. The present work describes the synthesis of a diastereomeric mixture of 1-ß-O-acyl glucuronides (2RS)-5 from 1 and methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-α-d-glucopyranuronate 2 using our chemo-enzymatic method that has complete specificity for the ß-configuration. The structure of (2RS)-5 was characterized by 1H and 13C NMR spectroscopy and high-resolution mass spectrometry as well as by complete hydrolysis by ß-glucuronidase. The absolute stereochemistry of (2RS)-5 was determined by comparison with (2R)-5 synthesized alternatively from (2R)-1 and 2. Compound (2R)-1 was prepared in two steps starting from chiral (R)-2-(4-nitrophenyl)propanoic acid (2R)-6. Chiral resolution of (2RS)-1 was achieved using a chiral high-performance liquid chromatography column, and its stereochemistry was determined by comparison with (2R)-1. The intrinsic degradation rate constant of (2R)-5 was 0.405 ± 0.002 h-1, which is approximately twice that of (2S)-5 (the k value was 0.226 ± 0.002 h-1) under physiological conditions (pH 7.40, 37 °C).

7.
Xenobiotica ; 44(9): 804-18, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24650147

RESUMO

We aimed to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model to predict the onset and degree of severe toxic side effects that severely limit the use of many anticancer agents, such as myelosuppression, in rats. Our PK-PD model consisted of a two-compartment PK model, with one compartment representing proliferative cells and some transit compartments consisting of maturing cells, while the other compartment represented circulating blood cells for the PD model. The semi-physiological PK-PD model effectively captured the features of myelosuppression and the degree of the off-target toxicities observed after 5-fluorouracil (5-FU) chemotherapy, and helped simultaneously simulate the whole time course for alterations in leukocyte, neutrophil and lymphocyte counts after 5-FU treatment in rats. Interestingly, by plotting the nadir period of leukocyte, neutrophil and lymphocyte counts as determined by PK-PD analytical simulation curves against the area under the plasma 5-FU concentration-time curve (AUC0-∞) after intravenous administration of 5-FU, a linear relationship was inferred, with r2=0.989, 0.877 and 0.956, respectively. The semi-physiological PK-PD model is a valuable tool for evaluating a variety of novel cancer chemopreventive agents or emerging therapeutic strategies that are difficult to address in humans.


Assuntos
Fluoruracila/farmacocinética , Leucócitos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Cromatografia Líquida , Simulação por Computador , Leucócitos/metabolismo , Contagem de Linfócitos , Masculino , Modelos Biológicos , Neutrófilos/metabolismo , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem
8.
J Org Chem ; 77(4): 1675-84, 2012 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-22283641

RESUMO

An efficient chemoenzymatic synthesis of ß-D-glucopyranosides of N-arylacetohydroxamic acids 3a-c was achieved by the chemoselective O-deacetylation of 1a-c under mild, neutral conditions, with no accompanying N-deacetylation. Lipase AS Amano from Aspergillus niger (LAS) and carboxylesterase from Streptomyces rochei (CSR) played complementary, synergistic roles in the O-deacetylation of 1a and its partially O-deacetylated intermediates. An intramolecular O-acetyl migration, which proceeded simultaneously, also accelerated the overall reaction rate. Under weakly acidic conditions at pH 5.0, where the intramolecular O-acetyl migration is markedly slower, LAS, CSR, and porcine liver esterase (PLE) exhibited different regioselective O-deacetylation activities. LAS and PLE showed regioselective 3-O-deacetylation and 2-O-deacetylation activity, respectively, for 1a and its tri-O-acetyl derivatives (4-7). CSR showed marked preferences for 3-O-deacetylation of 2,3,6-tri-O-acetyl intermediate 5 and 4-O-deacetylation of 2,4,6-tri-O-acetyl intermediate 6. In contrast, CSR showed almost no O-deacetylation activity toward the other tri-O-acetyl intermediates 4 and 7, which were efficiently O-deacetylated by LAS in a complementary manner. Using these enzyme-catalyzed regioselective O-deacetylation as well as chemical methods, we could synthesize all 14 partially O-acetylated intermediates (4-17) derived from 1a.


Assuntos
Carboxilesterase/metabolismo , Glucosídeos/síntese química , Ácidos Hidroxâmicos/síntese química , Lipase/química , Acetilação , Aspergillus niger/enzimologia , Biocatálise , Cromatografia Líquida de Alta Pressão , Concentração de Íons de Hidrogênio , Hidrólise , Cinética , Estereoisomerismo , Streptomyces/enzimologia , Especificidade por Substrato
9.
Chem Res Toxicol ; 22(12): 1998-2008, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19902937

RESUMO

Since 1-beta-O-acyl glucuronides (betaGAs) are thought to be chemically reactive metabolites capable of binding to tissue proteins, possibly leading to adverse drug reactions of the parent carboxylic acid drugs, we have initiated research efforts to derive structure-activity relationships (SARs) of betaGAs, with a focus on finding appropriate descriptors that predict their intrinsic electrophilic reactivity or degradation rate constants (k values). Our previous SAR studies on the k values of betaGAs derived from o-, m-, and p-substituted benzoic acids demonstrated that the diversity and complexity of the k values were controlled by the electronic and/or steric effects of the parent carboxylic acids. In the present study, we performed further SAR studies on the k values of 13 betaGAs derived from aralkyl carboxylic acids, focusing on the substituents and stereochemistry at the alpha-position of the parent carboxylic acids. In single regression analyses, the pKa and (1)H NMR chemical shifts (delta(COOH)) of the parent carboxylic acids correlated well with the log k values of seven betaGAs derived from five arylacetic and two (R)-2-arylpropionic acids, whereas the (13)C NMR chemical shifts [delta(C horizontal lineO) and delta((C horizontal lineO)OH)] correlated with the log k values of another seven betaGAs derived from the five arylacetic and two (S)-2-arylpropionic acids. Excellent correlations were also obtained between the log k values of four betaGAs with a common 4-phenylbenzyl moiety and the partial atomic charges (natural type) of the corresponding carboxylic hydrogen atoms (Hpac), the molar volume (MV), and the molar refractivity (MR). In multiple regression analyses, appropriate combinations of electronic (delta(COOH) or pKa) and steric [Taft's steric constant (Es) or delta((C horizontal lineO)OH)] descriptors could predict the log k values of betaGAs; electron-withdrawing 1-beta-O-acyl groups increased the k values, while increasing steric hindrance around the linkages decreased them. The standard partial regression coefficients indicated that the steric effects of the 1-beta-O-acyl groups of betaGAs affected the k values as strongly as the electronic effects. External validation of the derived SAR models is also discussed.


Assuntos
Glucuronídeos/química , Glucuronídeos/metabolismo , Glucuronídeos/toxicidade , Isomerismo , Cinética , Ligação Proteica , Proteínas/química , Análise de Regressão , Estereoisomerismo , Relação Estrutura-Atividade
10.
Acta Otolaryngol Suppl ; (562): 46-9, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19848239

RESUMO

CONCLUSION: The subjective visual vertical (SVV) test can detect abnormality of the otolithic organs and the graviceptive pathways present in a considerable number of patients having dizziness but presenting no abnormal findings in conventional vestibular function tests. OBJECTIVE: To evaluate whether the SVV test can detect dysfunction of the otolithic organs and perception of gravity in patients with dizziness having no abnormal finding on routine tests for the vestibular system. PATIENTS AND METHODS: Forty-four patients who complained of chronic dizziness but had no abnormal finding on routine tests for vestibular system and on brain MRI studies were selected between 2004 and 2006. SVV tests were performed on these patients. Patients with chronic dizziness caused by apparent psychogenic disorders, such as depression, were excluded. RESULTS: Among the 44 patients, 3 showed abnormal tilts of SVV. The latter three patients had deep white matter hyperintensities on their MRI, probably due to aging.


Assuntos
Tontura/fisiopatologia , Orientação/fisiologia , Propriocepção/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes de Função Vestibular
11.
Acta Otolaryngol Suppl ; (562): 53-6, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19848241

RESUMO

A 58-year-old Japanese man suddenly suffered from vertigo. On physical examination, left-beating horizontal torsional spontaneous nystagmus was observed; the direction did not change with gaze. Other neurotological examinations revealed findings within normal limits except the left side sensorineural hearing loss of approximately 32 dB on average. Diffusion-weighted MRI revealed no infarction in the brain, but demonstrated an epidermoid cyst in the left cerebello-pontine cistern region. Using free digital imaging and communications in medicine (DICOM) image viewing and processing software, it was found that the epidermoid cyst clearly compressed the left anterior inferior cerebellar artery (AICA). Therefore, we speculated that insufficiency of the left AICA caused his audiovestibular symptoms. This new technique used in the present study was considered useful when the site responsible for vertigo is suspected in the cerebello-pontine angle, where anatomic relationships between the nerves and the vessels are complicated.


Assuntos
Encefalopatias/diagnóstico , Transtornos Cerebrovasculares/etiologia , Cisto Epidérmico/diagnóstico , Perda Auditiva Neurossensorial/etiologia , Vertigem/etiologia , Cerebelo/irrigação sanguínea , Imagem de Difusão por Ressonância Magnética , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Nistagmo Patológico/etiologia , Software
12.
Chem Res Toxicol ; 22(9): 1559-69, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19670844

RESUMO

Glucuronidation of carboxylic acid drugs has been found to be a metabolic activation pathway, possibly leading to covalent binding of the resultant 1-beta-O-acyl glucuronides (beta GAs) to proteins. Previous studies on the structure-activity relationships (SARs) of the degradation rate constants (k values) of beta GAs have revealed that the electrophilicity of and steric hindrance around the 1-beta-O-acyl linkages cause the diversity and complexity of the observed k values. To evaluate these effects and ultimately predict the k values of structurally diverse beta GAs, we derived further SARs for k values of 18 1-beta-O-benzoyl glucuronides with o-, m-, and p-substituents (BAGAs). In single regression analyses of 10 m- and p-substituted BAGAs, the log k values were well-predicted using an electronic parameter of Hammett's sigma constant, pK(a), (1)H NMR chemical shift (delta(COOH)), computed delta(COOH), or computed partial atomic charge (H(PAC) or O(PAC)) of the parent benzoic acids. The log k values of eight o-substituted BAGAs, although showing a correlation with the (13)C NMR chemical shift of the parent benzoic acids [delta(C=O)OH)], were well-predicted using multiple regression analyses; some combinations of electronic (delta(COOH), H(PAC), or calculated pK(a)) and steric [delta(C=O)OH) or Es] descriptors predicted the 18 observed k values with a high degree of certainty. The standard partial regression coefficients indicate that steric effects affected the k values as strongly as electronic effects, indicating that the k values increase as the acidity of the parent acids increases and as the steric bulkiness around the 1-beta-O-acyl linkages decreases. These single and multiple regression equations, using different electronic and/or steric descriptors of the parent benzoic acids, are expected to be useful for predicting the k values of BAGAs. The applicability domain and mechanistic interpretation of the derived SAR models are also discussed together with the relevant toxicology of beta GAs.


Assuntos
Benzoatos/química , Glucuronídeos/química , Benzoatos/metabolismo , Glucuronídeos/metabolismo , Glucuronídeos/toxicidade , Isomerismo , Cinética , Análise de Regressão , Relação Estrutura-Atividade
13.
FEBS Lett ; 583(12): 1951-6, 2009 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-19465021

RESUMO

We report here the functional analysis of human Regulator of Ribosome Synthesis 1 (RRS1) protein during mitosis. We demonstrate that RRS1 localizes in the nucleolus during interphase and is distributed at the chromosome periphery during mitosis. RNA interference experiments revealed that RRS1-depleted cells show abnormalities in chromosome alignment and spindle organization, which result in mitotic delay. RRS1 knockdown also perturbs the centromeric localization of Shugoshin 1 and results in premature separation of sister chromatids. Our results suggest that a nucleolar protein RRS1 contributes to chromosome congression.


Assuntos
Cromossomos Humanos/metabolismo , Proteínas Nucleares/metabolismo , Sequência de Bases , Proteínas de Ciclo Celular/metabolismo , Nucléolo Celular/metabolismo , Nucléolo Celular/ultraestrutura , Pareamento Cromossômico , Segregação de Cromossomos , Cromossomos Humanos/ultraestrutura , Células HeLa , Humanos , Microscopia de Fluorescência , Mitose , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fuso Acromático/metabolismo , Fuso Acromático/ultraestrutura
14.
Acta Otolaryngol ; 129(1): 25-9, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19003588

RESUMO

CONCLUSIONS: Our results suggest that summating potential/action potential (SP/AP) area ratio may not necessarily have higher sensitivity in the diagnosis of endolymphatic hydrops of Meniere's disease (MD) than SP/AP amplitude ratio in transtympanic electrocochleography (ECochG). OBJECTIVE: Recent studies suggested that SP/AP area curve ratio was more sensitive to endolymphatic hydrops in comparison with SP/AP amplitude ratio in extratympanic ECochG. The purpose of the present study was to evaluate the utility of the SP/AP area curve ratio in transtympanic ECochG for the diagnosis of MD. PATIENTS AND METHODS: A retrospective chart review of 198 patients (209 ears) was conducted in cases of MD. RESULTS: With regard to SP/AP amplitude ratio, 57.1% in definite cases of MD (group 1), 39.6% in probable cases of MD (group 2), and 50.0% in the cases who had transformed from probable MD to definite MD (group 3) showed abnormally high values, respectively. Abnormally high values were observed in 43.9%, 27.7%, and 30.0% in SP/AP area ratio in groups 1, 2, and 3, respectively, indicating that abnormal values were observed more frequently in the amplitude ratio than in the area ratio in all three groups.


Assuntos
Potenciais de Ação/fisiologia , Audiometria de Resposta Evocada , Hidropisia Endolinfática/fisiopatologia , Doença de Meniere/fisiopatologia , Processamento de Sinais Assistido por Computador , Hidropisia Endolinfática/diagnóstico , Feminino , Humanos , Masculino , Doença de Meniere/diagnóstico , Valores de Referência , Estudos Retrospectivos
15.
Nephrology (Carlton) ; 14(1): 80-5, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19054333

RESUMO

AIM: Uroguanylin, isolated from human and opossum urine, is a candidate intestinal natriuretic hormone that controls the sodium and water balance between the intestine and the kidneys. Levels of immunoreactive (ir)-uroguanylin in the plasma and urine are increased in rats and humans with nephrotic syndrome, which is physiologically characterized by sodium retention with massive proteinuria. The present study evaluates the effect of natriuresis induced by uroguanylin on nephrotic rats. METHODS: Normal rats and rats rendered nephrotic by injections of puromycin aminonucleoside (PAN) were treated with uroguanylin (0.5 nmol/h, delivered by an osmotic pump) or with vehicle during the sodium retention phase. All rats consumed the same quantity of sodium. RESULTS: Uroguanylin did not increase urinary excretion of sodium and water in normal rats, but significantly increased urinary sodium excretion during the sodium retention phase in nephrotic rats (untreated vs uroguanylin-treated nephrotic rats in mmol/mmol creatinine; 2.92 +/- 0.65 vs 8.93 +/- 2.53 on day 6, P < 0.05; 3.55 +/- 0.47 vs 10.37 +/- 1.73 on day 7, P < 0.01; 14.88 +/- 2.32 vs 24.47 +/- 2.86 on day 8, P < 0.05). Plasma levels of ir-uroguanylin in uroguanylin-treated nephrotic rats on day 6 were significantly increased compared with those in uroguanylin-treated control and untreated nephrotic rats. CONCLUSION: Uroguanylin increased urinary sodium excretion in rats with PAN-induced nephrosis, and might be useful for treating sodium retention in patients with nephrotic syndrome.


Assuntos
Natriurese/efeitos dos fármacos , Peptídeos Natriuréticos/farmacologia , Síndrome Nefrótica/urina , Animais , Guanilato Ciclase/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley
16.
Otol Neurotol ; 30(2): 206-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19092712

RESUMO

OBJECTIVES: To investigate whether or not and how often there is otolith dysfunction in an acute attack of Ménière's disease. PATIENTS: Twenty-two definite cases of unilateral Ménière's disease diagnosed in accordance with the 1995 criteria of the American Academy of Otolaryngology-Head and Neck Surgery for Ménière's disease. INTERVENTION: Subjective visual vertical (SVV) test was performed before, at, and after acute attacks on 22 patients with unilateral Ménière's disease who showed normal tilts of SVV before acute attacks. MAIN OUTCOME MEASURE: Abnormal tilts of SVV. RESULTS: Of 22 cases, 14 (63.6%) with unilateral Ménière's disease showed abnormal tilts of SVV in acute attacks. The tilts were toward the side of the affected ear in 13 (92.9%) of them. Abnormal tilts returned to normal within a few weeks after the acute attacks in 12 (85.7%) of the 14 cases with unilateral Ménière's disease. CONCLUSION: Otolith dysfunction occurred in acute attacks in a considerable number of patients with Ménière's disease. Subjective visual vertical can be used as a good tool for the evaluation of otolith dysfunction at acute attacks in patients with Ménière's disease.


Assuntos
Doença de Meniere/psicologia , Percepção Visual/fisiologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Ataxia/complicações , Testes Calóricos , Feminino , Humanos , Masculino , Doença de Meniere/fisiopatologia , Pessoa de Meia-Idade , Nistagmo Patológico/complicações , Membrana dos Otólitos/fisiopatologia , Testes de Função Vestibular , Adulto Jovem
17.
Chem Res Toxicol ; 22(1): 158-72, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19105593

RESUMO

1-beta-O-Acyl glucuronides (betaGAs) are potentially reactive metabolites capable of binding to proteins, and they have been implicated in adverse drug reactions of the carboxylic acid drugs. To explore their electrophilic reactivity, we studied structure-activity relationships (SARs) to characterize the factors affecting the degradation rate constants (k values) of betaGAs and ultimately to predict k values of structurally diverse betaGAs. Twenty-seven betaGAs and four related compounds were synthesized, and their k values were determined under physiological conditions (pH 7.4 and 37 degrees C). 1-beta-O-Benzoyl glucuronide (BAGA) and glucopyranoside (BAG) showed almost the same k values, whereas their 1-alpha-O-benzoyl isomers degraded approximately 40-fold faster than BAGA and BAG. BAGA methyl ester showed almost the same rate constant as BAGA in the cleavage of their 1-beta-O-benzoyl linkages. A pH-log k profile obtained indicated kinetics catalyzed by both specific and general bases. The log k of betaGAs derived from m- and p-substituted benzoic acids correlated with Hammett's sigma constants. A similar correlation was observed with delta(COOH), (1)H NMR chemical shifts of the parent benzoic acids including ones with less sterically bulky o-substituents. Alternative descriptors of delta(CO) and delta((CO)OH), (13)C chemical shifts for ester carbonyl carbons of betaGAs and for carbonyl carbons of the parent benzoic acids, respectively, correlated well with the log k of all 16 betaGAs derived from benzoic acids including ones with bulkier o-substituents. Of the betaGA isomers derived from (2R)- and (2S)-alpha-methyl-4-biphenylylacetic acid, the (2R)-isomer degraded approximately 2-fold faster than the (2S)-isomer. The alpha-methyl group in the (2S)-isomer would encumber the intramolecular acyl migration. The log k of betaGAs derived from n-aralkyl carboxylic acids and of the (2R)-isomer correlated with their delta(COOH). However, the log k of betaGAs derived from alpha,alpha-dimethyl- and alpha,alpha-diethyl-4-biphenylylacetic acids deviated downward from the regression line, probably due to a steric effect. The diversity and complexity of k values were discussed with respect to the electrophilicity of the ester carbonyl carbons of betaGAs and the steric hindrance around them.


Assuntos
Glucuronídeos/química , Glucuronídeos/síntese química , Glucuronídeos/toxicidade , Cinética , Proteínas/química , Estereoisomerismo , Relação Estrutura-Atividade
18.
J Org Chem ; 72(25): 9541-9, 2007 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-17985922

RESUMO

An improved and widely applicable chemo-enzymatic method for the synthesis of a series of 1-beta-O-acyl glucuronides 5a-f has been developed from the corresponding methyl acetyl derivatives 3a-f, which were stereospecifically synthesized from cesium salts of carboxylic acids 1a-f and methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranuronate (2). Chemoselectivity of lipase AS Amano (LAS) in the hydrolytic removal of O-acetyl groups of 3a-f to provide methyl esters 4a-f was influenced by the nature of their 1-beta-O-acyl groups; high selectivity was evident only for 3b and 3f. Carboxylesterase from Streptomyces rochei (CSR), newly screened as an alternative to LAS, showed much greater chemoselectivity toward the O-acetyl groups than LAS; 3a, 3d, and 3e were chemoselectively hydrolyzed only by CSR. The combination of CSR with LAS yielded better results in the hydrolysis of 3c and 3f than did single usage of CSR. Final deprotection of the methyl ester groups of 4a-f to provide 5a-f was chemoselectively achieved by using lipase from Candida antarctica type B (CAL-B) as well as esterase from porcine liver (PLE), although CAL-B possessed higher chemoselectivity and catalytic efficiency than did PLE. CSR also exhibited high chemoselectivity in the synthesis of (S)-naproxen 1-beta-O-acyl glucopyranoside (7) from its 2,3,4,6-tetra-O-acetyl derivative 6.


Assuntos
Carboxilesterase/química , Esterases/química , Glucuronídeos/síntese química , Lipase/química , Animais , Candida/enzimologia , Catálise , Glucuronídeos/química , Hidrólise , Fígado/enzimologia , Estrutura Molecular , Estereoisomerismo , Streptomyces/enzimologia , Suínos , Fatores de Tempo
19.
Org Biomol Chem ; 4(17): 3303-10, 2006 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-17036119

RESUMO

Using a straightforward chemo-enzymatic procedure, 1-beta-O-acyl glucuronides of three non-steroidal anti-inflammatory drugs, diclofenac (DF) 5, mefenamic acid (MF) 6 and (S)-naproxen (NP) 7, were prepared. Caesium salts of these carboxylic acid drugs reacted with commercially available methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranuronate 4 to give exclusively the corresponding 1-beta-O-acyl glucuronides 8-10 in moderate yields. The protecting acetyl (for -OH group) and methyl ester (for -CO2H group) groups of each sugar moiety were easily removed to provide the corresponding free 1-beta-O-acyl glucuronides 1-3 in high yields. Deprotection was achieved through effective enzyme-catalysed chemo-selective hydrolyses of the acetyl groups using lipase AS Amano (LAS), and of the methyl ester group using esterase from porcine liver (PLE).


Assuntos
Diclofenaco , Glucuronídeos/síntese química , Ácido Mefenâmico , Naproxeno , Acilação , Configuração de Carboidratos , Cromatografia Líquida de Alta Pressão , Glucuronídeos/química , Hidrólise , Cinética , Metilação , Modelos Moleculares
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...