RESUMEN
Cultures of Shewanella putrefaciens grown in medium containing 10mM 1,4-diamino-2-butanone (DBO) as an inhibitor of ornithine decarboxylase and 10mM 1,5-diaminopentane (cadaverine) showed the simultaneous biosynthesis of the macrocyclic dihydroxamic acids: putrebactin (pbH2), avaroferrin (avH2) and bisucaberin (bsH2). The level of DBO did not completely repress the production of endogenous 1,4-diaminobutane (putrescine) as the native diamine substrate of pbH2. The relative concentration of pbH2:avH2:bsH2 was 1:2:1, which correlated with the substrate selection of putrescine:cadaverine in a ratio of 1:1. The macrocycles were characterised using LC-MS as free ligands and as 1:1 complexes with Fe(III) of the form [Fe(pb)]+, [Fe(av)]+ or [Fe(bs)]+, with labile ancillary ligands in six-coordinate complexes displaced during ESI-MS acquisition; or with Mo(VI) of the form [Mo(O)2(pb)], [Mo(O)2(av)] or [Mo(O)2(bs)]. Chromium(V) complexes of the form [CrO(pb)]+ were detected from solutions of Cr(VI) and pbH2 in DMF using X-band EPR spectroscopy. Supplementation of S. putrefaciens medium with DBO and 1,3-diaminopropane, 1,6-diaminohexane or 1,4-diamino-2(Z)-butene (Z-DBE) resulted only in the biosynthesis of pbH2. The work has identified a native system for the simultaneous biosynthesis of a suite of three macrocyclic dihydroxamic acid siderophores and highlights both the utility of precursor-directed biosynthesis for expanding the structural diversity of siderophores, and the breadth of their coordination chemistry.
Asunto(s)
Cromo/química , Hierro/química , Molibdeno/química , Péptidos Cíclicos/biosíntesis , Putrescina/análogos & derivados , Shewanella putrefaciens/metabolismo , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Cadaverina/metabolismo , Complejos de Coordinación/química , Diaminas/farmacología , Espectroscopía de Resonancia por Spin del Electrón , Expresión Génica , Ácidos Hidroxámicos/antagonistas & inhibidores , Ornitina Descarboxilasa/genética , Ornitina Descarboxilasa/metabolismo , Inhibidores de la Ornitina Descarboxilasa/farmacología , Péptidos Cíclicos/antagonistas & inhibidores , Putrescina/antagonistas & inhibidores , Putrescina/biosíntesis , Putrescina/farmacología , Shewanella putrefaciens/efectos de los fármacos , Shewanella putrefaciens/genética , Succinatos/antagonistas & inhibidoresRESUMEN
A randomised controlled trial (RCT) of high-dose v. low-dose fish oil in recent-onset rheumatoid arthritis (RA) demonstrated that the group allocated to high-dose fish oil had increased remission and decreased failure of disease-modifying anti-rheumatic drug (DMARD) therapy. This study examines the relationships between plasma phospholipid levels of the n-3 fatty acids in fish oil, EPA and DHA, and remission and DMARD use in recent-onset RA. EPA and DHA were measured in blood samples from both groups of the RCT. The data were analysed as a single cohort, and Cox proportional hazards models were used to examine relationships between plasma phospholipid (PL) EPA and DHA and various outcome measures. When analysed as a single cohort, plasma PL EPA was related to time to remission, with a one unit increase in EPA (1% total fatty acids) associated with a 12% increase in the probability of remission at any time during the study period (hazard ratio (HR)=1.12; 95% CI 1.02, 1.23; P=0.02). Adjustment for smoking, anti-cyclic citrullinated peptide antibodies and 'shared epitope' HLA-DR allele status did not change the HR. Plasma PL EPA, adjusted for the same variables, was negatively related to time to DMARD failure (HR=0.85; 95% CI 0.72, 0.99; P=0.047). The HR for DHA and time to remission or DMARD failure were similar in magnitude to those for EPA, but not statistically significant. Biomarkers of n-3 status, such as plasma PL EPA, have the potential to predict clinical outcomes relevant to standard drug treatment of RA patients.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/dietoterapia , Suplementos Dietéticos , Ácidos Docosahexaenoicos/sangre , Ácido Eicosapentaenoico/sangre , Aceites de Pescado/uso terapéutico , Fosfolípidos/sangre , Adulto , Anciano , Antirreumáticos/administración & dosificación , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Autoanticuerpos/análisis , Biomarcadores/sangre , Estudios de Cohortes , Terapia Combinada , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/análisis , Ácidos Docosahexaenoicos/uso terapéutico , Método Doble Ciego , Resistencia a Medicamentos , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/análisis , Ácido Eicosapentaenoico/uso terapéutico , Femenino , Aceites de Pescado/administración & dosificación , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/antagonistas & inhibidores , Fosfolípidos/química , Modelos de Riesgos Proporcionales , Inducción de RemisiónRESUMEN
Toxin-producing cyanobacteria pose a worldwide health threat to humans and animals due to their increasing presence in both drinking and recreational waters. Little work has, however, been done on a preventative therapy for anyone at risk of exposure to cyanobacterial toxins. The potential benefits of dietary supplementation of selenium, an antioxidant, to protect against the mouse liver injury induced by the toxin, microcystin-LR, has been investigated. BALB/c mice were pretreated for two weeks with sodium selenite (1.5 microg/mouse/day) before an intraperitoneal injection of microcystin-LR. Selenium-supplementation was found to provide some protection to the action of the toxin. In addition selenium pretreatment reduced the liver damage caused by lethal and sub-lethal toxin doses as reflected in liver pathology, decreased serum ALT and lipid peroxidation levels as well as prevention of glycogen loss compared to non-selenium supplemented toxin treated mice. The increased level of liver glutathione peroxidase activity following selenium-supplementation may indicate the possible route of selenium protection in the mice.
Asunto(s)
Toxinas Bacterianas/antagonistas & inhibidores , Hepatopatías/prevención & control , Hígado/efectos de los fármacos , Péptidos Cíclicos/antagonistas & inhibidores , Selenito de Sodio/farmacología , Alanina Transaminasa/metabolismo , Animales , Toxinas Bacterianas/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas , Cianobacterias , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Dosificación Letal Mediana , Hígado/enzimología , Hígado/patología , Toxinas Marinas , Ratones , Ratones Endogámicos BALB C , Microcistinas , Péptidos Cíclicos/toxicidadRESUMEN
Central administration of exogenous cyclo(His-Pro) (CHP) is known to produce hypothermia in rodents. In the present study, we examined the role of endogenous CHP in cold-induced hypothermia in the desert rat, Mastomys natalensis. The results of these studies show that a rise in hypothalamic CHP content accompanied a decrease in rectal temperature during cold exposure. Immunoneutralization of endogenous CHP resulted in a significant decline in cold-induced hypothermia. In addition, central administration of cyclo(Ala-Gly), a structural analogue of CHP, also led to a decrease in cold-induced hypothermia. The results of these studies show that changes in endogenous CHP levels may affect body temperature regulation.
Asunto(s)
Regulación de la Temperatura Corporal , Ventrículos Cerebrales/fisiología , Hipotálamo/fisiología , Hipotermia Inducida , Muridae/fisiología , Péptidos Cíclicos/fisiología , Análisis de Varianza , Animales , Anticuerpos/administración & dosificación , Anticuerpos/farmacología , Temperatura Corporal/efectos de los fármacos , Ventrículos Cerebrales/efectos de los fármacos , Frío , Clima Desértico , Dicetopiperazinas , Hipotálamo/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/análisis , Péptidos Cíclicos/antagonistas & inhibidores , Péptidos Cíclicos/farmacología , Piperazinas/administración & dosificación , Piperazinas/análisis , Piperazinas/antagonistas & inhibidores , Piperazinas/farmacología , Ratas , Especificidad de la EspecieRESUMEN
Recent studies on a group of fungal metabolites, collectively called the destruxins, have suggested that these compounds activate calcium influx in insect skeletal muscle. In this study, we have investigated the sensitivity of destruxin B to the voltage-dependent calcium channel antagonists; omega-conotoxin GVIA, nifedipine, diltiazem and methoxyverapamil on skeletal muscle from the lepidopteran insect pest, tobacco budworm (Heliothis virescens). At a concentration of 1.7 microM, destruxin B caused a rapid decrease in the transmembrane resting potential. The effect of destruxin B on insect muscle was blocked by micromolar concentrations of omega-conotoxin GVIA and nifedipine but not by methoxyverapamil or diltiazem. The inhibitory activity of omega-conotoxin GVIA on invertebrate muscle tissue was surprising since this compound was previously thought to be selective to vertebrate nervous tissue. The sensitivity of the destruxin-stimulated depolarization to the two antagonists suggested that destruxin B activated a voltage-dependent calcium channel. Neuromuscular transmission was monitored in the presence of omega-conotoxin GVIA and nifedipine to investigate the physiological role of the destruxin-activated channel. Neither antagonist altered the waveform of graded action potentials produced by synaptic activation. The lack of effect of omega-conotoxin GVIA and a high dose of nifedipine could be explained by the existence of two populations of pharmacologically distinct voltage-dependent calcium channels on the muscle membrane. One population which is involved with the production of graded action potentials is insensitive to omega-conotoxin GVIA and nifedipine. The other population is activated by destruxin B and inhibited by omega-conotoxin GIVA and nifedipine.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Depsipéptidos , Micotoxinas/antagonistas & inhibidores , Nifedipino/farmacología , Péptidos Cíclicos/antagonistas & inhibidores , Péptidos Cíclicos/farmacología , Animales , Canales de Calcio/efectos de los fármacos , Diltiazem/farmacología , Galopamilo/farmacología , Larva/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Venenos de Moluscos/farmacología , Mariposas Nocturnas , Músculos/efectos de los fármacos , omega-Conotoxina GVIARESUMEN
The antinociceptive effect of the cyclic dipeptide cyclo[Tyr(Et)- homoarginine] (C.TEHA) was examined utilizing the tail flick test and the digitus pinching test in rats in comparison with the linear dipeptide Boc-Tyr(Et)-homoarginine-OMe (B.TEHM). Though both dipeptides administered into the lateral, 3rd and 4th cerebroventricles produced antinociceptive effects equipotent to morphine, except for the 4th cerebroventricular administration of B.TEHM, the administration into the spinal subarachnoid space was without effect. The effect of B.TEHM was completely antagonized by the pretreatment of naloxone (i.p.) when administered into the 3rd cerebroventricle where its effect was demonstrated to be the most potent. However, naloxone had no significant effect on C.TEHA administered into the 3rd cerebroventricle in both tests. It was concluded that both dipeptides act on the upper brain stem, especially around the 3rd cerebroventricle. Moreover, it was also thought that the effect of B.TEHM may be involved in the brain opioid system, and that of C.TEHA can be produced via a naloxone-resistant opioid system or a non-opioid system.