RESUMEN
Although Kawasaki disease (KD) is characterized by a marked activation of the immune system with elevations of serum proinflammatory cytokines and chemokines at acute phase, the major sources for these chemical mediators remain controversial. We analysed the activation status of peripheral blood mononuclear cells (PBMCs) by flow cytometry, DNA microarray and quantitative reverse transcription-polymerase chain reaction. The proportions of CD69+ cells in both natural killer cells and gammadeltaT cells at acute-phase KD were significantly higher than those at convalescent-phase KD. Microarray analysis revealed that five genes such as NAIP, IPAF, S100A9, FCGR1A and GCA up-regulated in acute-phase KD and the pathways involved in acute phase KD were related closely to the innate immune system. The relative expression levels of damage-associated molecular pattern molecule (DAMP) (S100A9 and S100A12) genes in PBMCs at acute-phase KD were significantly higher than those at convalescent-phase KD, while those of TNFA, IL1B and IL6 genes were not significantly different between KD patients and healthy controls. Intracellular production of tumour necrosis factor-alpha, interleukin-10 and interferon-gamma in PBMCs was not observed in KD patients. The present data have indicated that PBMCs showed a unique activation status with high expression of DAMP genes but low expression of proinflammatory cytokine genes, and that the innate immune system appears to play a role in the pathogenesis and pathophysiology of KD.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Genes MHC Clase II , Leucocitos Mononucleares/inmunología , Activación de Linfocitos , Síndrome Mucocutáneo Linfonodular/sangre , Enfermedad Aguda , Adulto , Antígenos de Superficie/análisis , Niño , Preescolar , Convalecencia , Citocinas/biosíntesis , Citocinas/genética , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata/genética , Lactante , Péptidos y Proteínas de Señalización Intracelular/genética , Leucocitos Mononucleares/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Masculino , Síndrome Mucocutáneo Linfonodular/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
kaiABC, a gene cluster, encodes KaiA, KaiB and KaiC proteins that are essential to circadian rhythms in the unicellular cyanobacterium Synechococcus sp. strain PCC 7942. Kai proteins can interact with each other in all possible combinations. This study identified two KaiA-binding domains (C(KABD1) and C(KABD2)) in KaiC at corresponding regions of its duplicated structure. Clock mutations on the two domains and kaiA altered the strength of C(KABD)-KaiA interactions assayed by the yeast two-hybrid system. Thus, interaction between KaiA and KaiC through C(KABD1) and C(KABD2) is likely important for circadian timing in the cyanobacterium.
Asunto(s)
Proteínas Bacterianas/química , Adenosina Trifosfato/metabolismo , Proteínas Bacterianas/metabolismo , Ritmo Circadiano , Péptidos y Proteínas de Señalización del Ritmo Circadiano , Glutatión Transferasa/metabolismo , Modelos Biológicos , Modelos Moleculares , Familia de Multigenes , Mutación , Plásmidos/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
A series of N alpha-(arylsulfonyl)-L-arginine amide derivatives having carboxamide N-substituents with a carboxyl group was prepared and tested as inhibitors of the clotting activity of thrombin. The most inhibitory compounds were obtained when a carboxyl group was introduced into the carbon next to the amide nitrogen of N alpha-(arylsulfonyl)-L-arginine amide derivatives, e.g., N alpha-(arylsulfonyl)-L-arginyl-N-butyl-, N-(methoxyethyl)- or N-(tetrahydrofurfuryl)glycine and 4-alkyl-1-[N alpha-(arylsulfonyl)-L-arginyl]-2-piperidinecarboxylic acid, with an I50 of 1-3 X 10(-7) M.
Asunto(s)
Arginina/análogos & derivados , Trombina/antagonistas & inhibidores , Animales , Arginina/síntesis química , Arginina/farmacología , Técnicas In Vitro , Dosificación Letal Mediana , Trombosis/prevención & controlRESUMEN
A series of N alpha-(arylsulfonyl)-L-arginine esters was prepared and tested as inhibitors of the clotting activity of thrombin. N alpha-Dansyl-L-arginine methyl ester was the most inhibitory of the N alpha-(arylsulfonyl)-L-arginine methyl esters. The most potent inhibitors were the n-propyl and n-butyl esters of N alpha-dansyl-L-arginine with an I50 of 2 X 10(-6) M. Esters of unsaturated straight-chain alcohols with a chain length of four carbons were also as inhibitory as the n-butyl ester. The inhibitors were hydrolyzed by thrombin and trypsin more slowly than N alpha-tosyl-L-arginine methyl ester.
Asunto(s)
Arginina/análogos & derivados , Trombina/antagonistas & inhibidores , Animales , Arginina/síntesis química , Arginina/metabolismo , Arginina/farmacología , Coagulación Sanguínea/efectos de los fármacos , Bovinos , Esterificación , Hidrólisis , Técnicas In Vitro , Relación Estructura-Actividad , Trombina/metabolismo , Tripsina/metabolismoRESUMEN
A series of N alpha-(arylsulfonyl)-L-arginine amide derivatives with substituted or unsubstituted naphthalene and heterocyclic compounds as the N alpha-substituent was prepared and tested as inhibitors of the clotting activity of thrombin. N-n-Butyl and N-n-butyl-N-methyl derivatives of N alpha-dansyl-L-arginine amide were the most inhibitory of N-alkyl and N,N-dialkyl derivatives of N alpha-dansyl-L-arginine amide. Their inhibitory effect was as potent as that of N alpha-dansyl-L-arginine-n-butyl ester with an I50 of 2 X 10(-6) M. N alpha-Substituted naphtalenesulfonyl-L-arginine amide derivatives of 4-methyl- and 4-ethylpiperidine also showed a potent inhibition with an I50 of 10(-7) to 10(-6) M. The most potent inhibitior in this study was 1-[N alpha-(4,6-dimethoxynaphthalene-2-sulfonyl)-arginyl]-4-methylpiperidine, with an I50 of 7.5 X 10(-8) M. Arginine amide derivatives of 4-methyl- or 4-ethylpiperidine with tetralin or an oxygen-containing heterocyclic compound as a N alpha-substituent showed an inhibition with an I50 less than 10(-5) M. N-Monosubstituted derivatives of N alpha-dansyl-L-arginine amide were not hydrolyzed at all by thrombin and were hydrolyzed very slowly by trypsin, and N,N-disubstituted derivatives were not hydrolyzed at all by both enzymes.
Asunto(s)
Arginina/análogos & derivados , Trombina/antagonistas & inhibidores , Amidas/síntesis química , Animales , Arginina/síntesis química , Arginina/metabolismo , Arginina/farmacología , Coagulación Sanguínea/efectos de los fármacos , Bovinos , Hidrólisis , Técnicas In Vitro , Relación Estructura-Actividad , Trombina/metabolismo , Tripsina/metabolismoRESUMEN
The synthetic thrombin-inhibitor termed No. 205 (N-alpha-dansyl-L-arginine-4-ethyl-piperidine amide) found in our laboratories was studied kinetically using synthetic peptide substrates. The following results were obtained. 1. No. 205 inhibited thrombin competively with bz-Phe-Val-Arg-pNA and the Ki value obtained was extremely small, 3.7 x 10(-8) M. 2. No. 205 also inhibited trypsin competitively with bz-Phe-Val-Arg-pNA but the Ki value obtained was far larger than that for thrombin, 1.0 x 10(-5) M. 3. No. 205 inhibited F. Xa, plasmin and urokinase only to a small extent when estimated using 2 x 10(-4) M D-Val-Leu-Lys-pNA, bz-Ile-Glu-Gly-Arg-pNA and Glu-Gly-Arg-pNA, respectively. 4. No 205 differed from APPA in its specific inhibitory spectrum for thrombin as compared to trypsin, plasmin and F. Xa. The above results indicate that No. 205 is an extremely potent and highly selective reversible thrombin-inhibitor.
Asunto(s)
Antitrombinas/farmacología , Oligopéptidos/metabolismo , Animales , Arginina/análogos & derivados , Arginina/farmacología , Benzamidinas/farmacología , Bovinos , Compuestos de Dansilo/farmacología , Factor X/antagonistas & inhibidores , Fibrinolisina/antagonistas & inhibidores , Humanos , Cinética , Ácidos Fenilpirúvicos/farmacología , Inhibidores de Tripsina/farmacología , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidoresRESUMEN
The effect of cis-diamminedichloro platinum (II) (CDDP) was evaluated in 14 patients with advanced pancreatic carcinoma. Prior chemotherapy was done in 7 cases and the remaining 7 were fresh cases. The drug was given at a dose of 80 mg/m2 I.V. every 3 weeks, with hydration and mannitol diuresis. Four cases out of 14 showed no change, while the remaining 10 cases showed progressive disease. The response rate was 0%. Most of the patients who showed myelosuppression had received prior chemotherapy. Non-hematologic toxicity occurred in 9 patients (64%) and consisted of nausea in 9, vomiting in 7 and anorexia in 9. Values of serum creatinine and BUN were transiently elevated.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Cisplatino/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anorexia/inducido químicamente , Nitrógeno de la Urea Sanguínea , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Vómitos/inducido químicamenteAsunto(s)
Pierna/irrigación sanguínea , Perfusión , Activadores Plasminogénicos/metabolismo , Trombina/farmacología , Acetilación , Animales , Perros , Relación Dosis-Respuesta a Droga , Femenino , Fibrina/metabolismo , Fibrinógeno/metabolismo , Isoflurofato/farmacología , Masculino , Clorometilcetona Tosilisina/farmacologíaAsunto(s)
Miocardio/análisis , Plasminógeno/análisis , Acrilatos , Adsorción , Aminocaproatos/farmacología , Animales , Antifibrinolíticos/farmacología , Quimotripsina/antagonistas & inhibidores , Ácidos Ciclohexanocarboxílicos/farmacología , Fibrina/metabolismo , Calor , Concentración de Iones de Hidrógeno , Isoflurofato/farmacología , Métodos , Metilaminas , Peso Molecular , Nitrilos , Plasminógeno/antagonistas & inhibidores , Plasminógeno/aislamiento & purificación , Polímeros , Porcinos , Inhibidores de Tripsina/farmacologíaAsunto(s)
Plaquetas/efectos de los fármacos , Dipéptidos/farmacología , Sulfonamidas/farmacología , Trombina/antagonistas & inhibidores , Animales , Tiempo de Sangría , Retracción del Coagulo , Colágeno/farmacología , Cobayas , Técnicas In Vitro , Masculino , Adhesividad Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , ConejosAsunto(s)
Arginina/análogos & derivados , Dipéptidos/farmacología , Piperidinas/farmacología , Sulfonamidas/farmacología , Trombina/antagonistas & inhibidores , Administración Oral , Animales , Arginina/metabolismo , Arginina/farmacología , Dipéptidos/metabolismo , Perros , Infusiones Parenterales , Inyecciones Intravenosas , Hígado/metabolismo , Masculino , Piperidinas/metabolismo , Conejos , Ratas , Sulfonamidas/metabolismoRESUMEN
Cry jI, a major allergenic glycoprotein of Cryptomeria japonica (Japanese cedar, Sugi), is the most common pollen allergen in Japan. Carbohydrate analysis and lectin staining indicated that Cry jI possesses the fucose/xylose-containing N-linked oligosaccharide which previously has been found in some plant glycoproteins. Rabbit polyclonal anti-Cry jI IgG antibodies were found to be highly cross-reactive with two other plant glycoproteins which have the same type of oligosaccharides, and the cross-reactivities were completely abolished on chemical deglycosylation of the glycoproteins. Enzyme-linked immunosorbent assay inhibition showed that the majority (up to 70%) of the anti-Cry jI rabbit IgG antibodies recognized the oligosaccharide moiety of Cry jI. The carbohydrate epitopes were found to be only partially involved in the binding of specific IgE antibodies from a pool of human patient sera.