RESUMEN
Viroids are small, proteinless single-stranded circular RNAs. In plants, they can be transmitted via infected pollen and seeds. The effectiveness of viroid transmission through pollen depends on both the viroid and host species. It is, however, unclear whether viroid variant type or infection stage influences seed transmission through pollen. In the present study, we collected pollen from petunia infected with nine different variants of the potato spindle tuber viroid (PSTVd) at various stages after inoculation and used the material to pollinate healthy plants. Five and eight PSTVd variants were transmitted by pollen at 3 and 6 mpi respectively. All variants were pollen-transmissible at 9 mpi. The foregoing results indicated that seed transmission of PSTVd through pollen collected from infected donor plants may depend on the time elapsed since inoculation. For variant no. EU862231, however, the rate of seed transmission via pollen may depend on the pollen viroid titre. Nevertheless, there was no apparent correlation between the transmission rate and the pollen viroid titre in the U23058 or V01465 variant. Hence, the relationship between the viroid transmission rate and the pollen viroid titre may depend on the viroid variant type.
Asunto(s)
Solanum lycopersicum , Solanum tuberosum , Viroides , Enfermedades de las Plantas , Plantas , Polen , ARN Circular , ARN Viral/genética , Semillas , Viroides/genéticaRESUMEN
Potato viral disease has been a major problem in potato production worldwide including Russia. Here, we detected Potato Virus M (PVM), P (PVP), S (PVS), Y (PVY), and X (PVX) and Potato Leaf Roll Virus (PLRV) by RT-PCR on potato leaves and tubers from the Northwestern (NW), Volga (VF), and Far Eastern (FE) federal districts of Russia. Each sample was co-infected with up to five viruses. RT-PCR disclosed all six viruses in NW, three in VF, and five in FE. Phylogenetic analyses of PVM and PVS strains resolved all PVM isolates in Group O (ordinary) and all PVS isolates in Group O. Seven PVY strains were detected, and they included only recombinants. PVY recombinants were thus the dominant potato virus strains in Russia, although they widely varied among the regions. Our research provides insights into the geographical distribution and genetic variability of potato viruses in Russia.
Asunto(s)
Carlavirus/fisiología , Luteoviridae/fisiología , Enfermedades de las Plantas/virología , Virus de Plantas/fisiología , Solanum tuberosum/virología , Filogenia , Hojas de la Planta/virología , Virus de Plantas/genética , Federación de RusiaRESUMEN
The precise role of smooth muscle cell contractility in elastic arteries remains unclear, but accumulating evidence suggests that smooth muscle dysfunction plays an important role in the development of thoracic aortic aneurysms and dissections (TAADs). Given the increasing availability of mouse models of these conditions, there is a special opportunity to study roles of contractility ex vivo in intact vessels subjected to different mechanical loads. In parallel, of course, there is a similar need to study smooth muscle contractility in models that do not predispose to TAADs, particularly in cases where disease might be expected. Multiple mouse models having compromised glycoproteins that normally associate with elastin to form medial elastic fibers present with TAADs, yet those with fibulin-5 deficiency do not. In this paper, we show that deletion of the fibulin-5 gene results in a significantly diminished contractility of the thoracic aorta in response to potassium loading despite otherwise preserved characteristic active behaviors, including axial force generation and rates of contraction and relaxation. Interestingly, this diminished response manifests around an altered passive state that is defined primarily by a reduced in vivo axial stretch. Given this significant coupling between passive and active properties, a lack of significant changes in passive material stiffness may help to offset the diminished contractility and thereby protect the wall from detrimental mechanosensing and its sequelae.
Asunto(s)
Aorta Torácica/fisiología , Proteínas de la Matriz Extracelular/deficiencia , Vasoconstricción , Animales , Genotipo , Masculino , Ratones , Proteínas Recombinantes , Estrés MecánicoRESUMEN
Central artery stiffness has emerged over the past 15 years as a clinically significant indicator of cardiovascular function and initiator of disease. Loss of elastic fiber integrity is one of the primary contributors to increased arterial stiffening in aging, hypertension, and related conditions. Elastic fibers consist of an elastin core and multiple glycoproteins; hence defects in any of these constituents can adversely affect arterial wall mechanics. In this paper, we focus on mechanical consequences of the loss of fibulin-5, an elastin-associated glycoprotein involved in elastogenesis. Specifically, we compared the biaxial mechanical properties of five central arteries-the ascending thoracic aorta, descending thoracic aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and common carotid artery-from male and female wild-type and fibulin-5 deficient mice. Results revealed that, independent of sex, all five regions in the fibulin-5 deficient mice manifested a marked increase in structural stiffness but also a marked decrease in elastic energy storage and typically an increase in energy dissipation, with all differences being most dramatic in the ascending and abdominal aortas. Given that the primary function of large arteries is to store elastic energy during systole and to use this energy during diastole to work on the blood, fibulin-5 deficiency results in a widespread diminishment of central artery function that can have significant effects on hemodynamics and cardiac function.
Asunto(s)
Arterias/fisiología , Elasticidad , Proteínas de la Matriz Extracelular/deficiencia , Rigidez Vascular , Animales , Arterias/citología , Arterias/metabolismo , Arterias/fisiopatología , Femenino , Genotipo , Masculino , Ratones , Fenotipo , Proteínas Recombinantes , Caracteres SexualesRESUMEN
We present time-resolved photoemission experiments from a peculiar bismuth surface, Bi(114). The strong one-dimensional character of this surface is reflected in the Fermi surface, which consists of spin-polarized straight lines. Our results show that the depletion of the surface state and the population of the bulk conduction band after the initial optical excitation persist for very long times. The disequilibrium within the hot electron gas along with strong electron-phonon coupling cause a displacive excitation of coherent phonons, which in turn are reflected in coherent modulations of the electronic states. Beside the well-known A(1g) bulk phonon mode at 2.76 THz, the time-resolved photoelectron spectra reveal a second mode at 0.72 THz which can be attributed to an optical surface phonon mode along the atomic rows of the Bi(114) surface.
RESUMEN
Dentatorubral and pallidoluysian atrophy is associated with expansion of an unstable CAG repeat on chromosome 12p. We have determined the nucleotide sequences of overlapping cDNA clones and deduced the gene structure. The gene is ubiquitously expressed to form a single 4.5 kb transcript and encoded by an open reading frame of 1184 amino acids (aa), in which a polyglutamine track with variable length starts at aa 484. Although the predicted amino acid sequence does not reveal any function, it does contain several interesting motifs consisting of a simple repeated amino acid sequence, a homo-proline track, two stretches of arginine-glutamic acid dipeptides and a stretch of alternative histidine residues. These results provide clues toward understanding neurodegenerative diseases associated with triplet repeat expansion.
Asunto(s)
Repeticiones de Minisatélite , Proteínas del Tejido Nervioso/genética , Degeneraciones Espinocerebelosas/genética , Atrofia , Secuencia de Bases , Clonación Molecular , ADN Complementario/genética , Expresión Génica , Genes , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Homología de SecuenciaRESUMEN
Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by combined systemic degeneration of the dentatofugal and pallidofugal pathways. We investigated a candidate gene and found that DRPLA patients had an expanded CAG trinucleotide repeat in a gene on the short arm of chromosome 12. The repeat size varied from 7-23 in normal individuals. In patients one allele was expanded to between 49-75 repeats or occasionally even more. Expansion was usually associated with paternal transmission and only occasionally with maternal transmission. Repeat size showed a close correlation with age of onset of symptoms and disease severity. We conclude that DRPLA is the seventh genetic disorder known to be associated with expansion of an unstable trinucleotide repeat.
Asunto(s)
Cromosomas Humanos Par 12 , Enfermedades del Sistema Nervioso/genética , Secuencias Repetitivas de Ácidos Nucleicos , Alelos , Secuencia de Aminoácidos , Atrofia , Secuencia de Bases , Encéfalo/patología , Ataxia Cerebelosa/genética , Cartilla de ADN/genética , Femenino , Globo Pálido/patología , Humanos , Masculino , Datos de Secuencia Molecular , Enfermedades del Sistema Nervioso/patología , Oligodesoxirribonucleótidos/genética , LinajeRESUMEN
The synchondrosis in the cranial base is an important growth center for the craniofacial region. Abnormalities in the synchondroses affect the development of adjacent regions, including the craniofacial skeleton. Here, we report that the transcription factor TBX1, the candidate gene for DiGeorge syndrome, is expressed in mesoderm-derived chondrocytes and plays an essential and specific role in spheno-occipital synchondrosis development by inhibiting the expression of genes involved in chondrocyte hypertrophy and osteogenesis. In Tbx1-deficient mice, the spheno-occipital synchondrosis was completely mineralized at birth. TBX1 interacts with RUNX2, a master molecule of osteoblastogenesis and a regulator of chondrocyte maturation, and suppresses its transcriptional activity. Indeed, deleting Tbx1 triggers accelerated mineralization due to accelerated chondrocyte differentiation, which is associated with ectopic expression of downstream targets of RUNX2 in the spheno-occipital synchondrosis. These findings reveal that TBX1 acts as a regulator of chondrocyte maturation and osteogenesis during the spheno-occipital synchondrosis development. Thus, the tight regulation of endochondral ossification by TBX1 is crucial for the normal progression of chondrocyte differentiation in the spheno-occipital synchondrosis.
Asunto(s)
Condrocitos , Condrogénesis , Hueso Occipital , Osteogénesis , Proteínas de Dominio T Box , Animales , Diferenciación Celular , Ratones , Hueso Esfenoides , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/fisiologíaAsunto(s)
Proteínas de Unión al ADN/genética , Fóvea Central/anomalías , Proteínas de Homeodominio , Mutación , Secuencia de Aminoácidos , Secuencia de Bases , Anomalías del Ojo/genética , Proteínas del Ojo , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box , Linaje , Proteínas RepresorasRESUMEN
The intercellular signaling mediated by endothelins and their G protein-coupled receptors has recently been shown to be essential for the normal embryonic development of subsets of neural crest cell derivatives. Endothelin-1 (ET-1) is proteolytically generated from its inactive precursor by endothelin-converting enzyme-1 (ECE-1) and acts on the endothelin-A (ETA) receptor. Genetic disruption of this ET-1/ECE-1/ETA pathway results in defects in branchial arch- derived craniofacial tissues, as well as defects in cardiac outflow and great vessel structures, which are derived from cephalic (cardiac) neural crest. In this study, in situ hybridization of ETA-/- and ECE-1(-)/- embryos with a cardiac neural crest marker, cellular retinoic acid-binding protein-1, shows that the migration of neural crest cells from the neural tube to cardiac outflow tract is not affected in these embryos. Immunostaining of an endothelial marker, platelet endothelial cell adhesion molecule CD-31, shows that the initial formation of the branchial arch arteries is not disturbed in ETA-/- or ECE-1(-)/- embryos. To visualize the subsequent patterning of arch vessels in detail, we generated ETA-/- or ECE-1(-)/- embryos that expressed an SM22alpha-lacZ marker transgene in arterial smooth muscle cells. Wholemount X-gal staining of these mutant embryos reveals that the abnormal regression and persistence of specific arch arteries results in disturbance of asymmetrical remodeling of the arch arteries. These defects include abnormal regression of arch arteries 4 and 6, enlargement of arch artery 3, and abnormal persistence of the bilateral ductus caroticus and right dorsal aorta. These abnormalities eventually lead to various types of great vessel malformations highly similar to those seen in neural crest-ablated chick embryos and human congenital cardiac defects. This study demonstrates that ET-1/ETA-mediated signaling plays an essential role in a complex process of aortic arch patterning by affecting the postmigratory cardiac neural crest cell development.
Asunto(s)
Aorta Torácica/embriología , Región Branquial/fisiología , Endotelina-1/fisiología , Receptores de Endotelina/fisiología , Animales , Ácido Aspártico Endopeptidasas/genética , Endotelina-1/genética , Enzimas Convertidoras de Endotelina , Femenino , Metaloendopeptidasas , Ratones , Ratones Endogámicos C57BL , Cresta Neural/fisiología , Embarazo , ARN Mensajero/análisis , Receptor de Endotelina A , Receptores de Endotelina/genéticaRESUMEN
Endothelin-converting enzyme-1 and -2 (ECE-1 and -2) are membrane-bound metalloproteases that can cleave biologically the inactive endothelin-1 (ET-1) precursor to form active ET-1 in vitro. We previously reported developmental defects in specific subsets of neural crest-derived tissues, including branchial arch-derived craniofacial structures, aortic arch arteries, and the cardiac outflow tract in ECE-1 knockout mice. To examine the role of ECE-2 in cardiovascular development, we have now generated a null mutation in ECE-2 by homologous recombination. ECE-2 null mice develop normally, are healthy into adulthood, are fertile in both sexes, and live a normal life span. However, when they are bred into an ECE-1-null background, defects in cardiac outflow structures become more severe than those in ECE-1 single knockout embryos. In addition, ECE-1(-/-); ECE-2(-/-) double null embryos exhibited abnormal atrioventricular valve formation, a phenotype never seen in ECE-1 single knockout embryos. In the developing mouse heart, ECE-2 mRNA is expressed in the endocardial cushion mesenchyme from embyronic day (E) 12.5, in contrast to the endocardial expression of ECE-1. Levels of mature ET-1 and ET-2 in whole ECE-1(-/-); ECE-2(-/-) embryos at E12.5 do not differ appreciably from those of ECE-1(-/-) embryos. The significant residual ET-1/ET-2 in the ECE-1(-/-); ECE-2(-/-) embryos indicates that proteases distinct from ECE-1 and ECE-2 can carry out ET-1 activation in vivo.
Asunto(s)
Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/fisiología , Corazón Fetal/embriología , Corazón Fetal/enzimología , Metaloendopeptidasas/genética , Metaloendopeptidasas/fisiología , Animales , Secuencia de Bases , Cartilla de ADN/genética , Endotelina-1/metabolismo , Endotelina-2/metabolismo , Enzimas Convertidoras de Endotelina , Femenino , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Cardiopatías Congénitas/enzimología , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Hibridación in Situ , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Distribución TisularRESUMEN
Thoracic aortic aneurysms are life-threatening lesions that afflict young and old individuals alike. They frequently associate with genetic mutations and are characterized by reduced elastic fibre integrity, dysfunctional smooth muscle cells, improperly remodelled collagen and pooled mucoid material. There is a pressing need to understand better the compromised structural integrity of the aorta that results from these genetic mutations and renders the wall vulnerable to dilatation, dissection or rupture. In this paper, we compare the biaxial mechanical properties of the ascending aorta from 10 murine models: wild-type controls, acute elastase-treated, and eight models with genetic mutations affecting extracellular matrix proteins, transmembrane receptors, cytoskeletal proteins, or intracellular signalling molecules. Collectively, our data for these diverse mouse models suggest that reduced mechanical functionality, as indicated by a decreased elastic energy storage capability or reduced distensibility, does not predispose to aneurysms. Rather, despite normal or lower than normal circumferential and axial wall stresses, it appears that intramural cells in the ascending aorta of mice prone to aneurysms are unable to maintain or restore the intrinsic circumferential material stiffness, which may render the wall biomechanically vulnerable to continued dilatation and possible rupture. This finding is consistent with an underlying dysfunctional mechanosensing or mechanoregulation of the extracellular matrix, which normally endows the wall with both appropriate compliance and sufficient strength.
Asunto(s)
Aorta , Aneurisma de la Aorta Torácica , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular , Modelos Cardiovasculares , Mutación , Animales , Aorta/metabolismo , Aorta/patología , Aorta/fisiopatología , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Aneurisma de la Aorta Torácica/fisiopatología , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , RatonesRESUMEN
In the present review, laser fields are so strong that they become part of the electronic potential, and sometimes even dominate the Coulomb contribution. This manipulation of atomic potentials and of the associated states and bands finds fascinating applications in gases and solids, both in the bulk and at the surface. We present some recent spectacular examples obtained within the NCCR MUST in Switzerland.
RESUMEN
In order to investigate the exposure of humans to 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole [(Glu-P-1) Chemical Abstracts Service:67730-11-4] and 2-aminodipyrido[1,2-a:3',2'-d]imidazole [(Glu-P-2) Chemical Abstracts Service:67730-10-3], carcinogenic heterocyclic amines, we developed a high-performance liquid chromatography method to detect Glu-P-1 and Glu-P-2 in biological samples, and compared the plasma levels of the carcinogens in normal subjects with those in uremic patients in which higher incidence of malignancy has been reported. Glu-P-1 and Glu-P-2 levels in plasma of uremic patients before induction of hemodialysis treatment were 12.62 +/- 3.65 (SD) pmol/ml (n = 5) and 14.81 +/- 5.17 pmol/ml (n = 5), respectively, whereas Glu-P-1 and/or Glu-P-2 could be detected in only two of seven normal subjects and the levels were lower than 3.1 pmol/ml. Approximately 10% of these carcinogens in plasma of uremic patients could be removed by the first hemodialysis treatment, and reasonable amounts of these carcinogens could be detected in the dialysate of uremic patients. However, significant amounts of Glu-P-1 and Glu-P-2 were still detected in plasma of all uremic patients even after 1 month-hemodialysis treatments. These results suggest that one of the excretory pathways of these carcinogens is via kidney.
Asunto(s)
Carcinógenos , Imidazoles/sangre , Uremia/sangre , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Imidazoles/aislamiento & purificación , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
Competent elastic fibers endow central arteries with the compliance and resilience that are fundamental to their primary mechanical function in vertebrates. That is, by enabling elastic energy to be stored in the arterial wall during systole and then to be used to work on the blood during diastole, elastic fibers decrease ventricular workload and augment blood flow in pulsatile systems. Indeed, because elastic fibers are formed during development and stretched during somatic growth, their continual tendency to recoil contributes to the undulation of the stiffer collagen fibers, which facilitates further the overall compliance of the wall under physiologic pressures while allowing the collagen to limit over-distension during acute increases in blood pressure. In this paper, we use consistent methods of measurement and quantification to compare the biaxial material stiffness, structural stiffness, and energy storage capacity of murine common carotid arteries having graded degrees of elastic fiber integrity - normal, elastin-deficient, fibrillin-1 deficient, fibulin-5 null, and elastase-treated. The finding that the intrinsic material stiffness tends to be maintained nearly constant suggests that intramural cells seek to maintain a favorable micromechanical environment in which to function. Nevertheless, a loss of elastic energy storage capability due to the loss of elastic fiber integrity severely compromises the primary function of these central arteries.
RESUMEN
A nuclear protooncogene c-myb has been hypothesized to play an important role in hematopoiesis, but little is known about the physiological function of the c-myb gene products. To study the role of c-myb gene expression in monocyte-macrophage differentiation and proliferation, we introduced exogenous c-myb gene into murine myelomonocytic leukemia WEHI-3B(D+) cells which can be induced to differentiate into mature monocytes with granulocyte-colony stimulation factor (G-CSF) and actinomycin D. Expression of the transfected gene was found to result in elevated levels of c-myb transcripts, which were not subject to normal down-regulation by differentiation induction. This constitutive expression of c-myb gene allowed the c-myb transfectants to differentiate into promonocytes with G-CSF and actinomycin D, but blocked further maturation from promonocytes to mature monocytes. It is concluded that normal down-regulation of c-myb gene expression during monocyte-macrophage differentiation is required for the maturation of promonocytes to mature monocytes.
Asunto(s)
Regulación de la Expresión Génica , Macrófagos/citología , Monocitos/citología , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Animales , Diferenciación Celular/efectos de los fármacos , ADN/genética , Dactinomicina/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Ratones , Proteínas Proto-Oncogénicas c-myb , ARN/análisis , Transfección , Células Tumorales CultivadasRESUMEN
The Drosophila spinster (spin) gene product is required for programmed cell death in the nervous and reproductive systems. We have identified a human homologue of the Drosophila spin gene product (HSpin1). HSpin1 bound to Bcl-2 and apoptosis regulator Bcl-X (Bcl-xL), but not to proapoptotic members such as Bcl-2-associated X protein and Bcl-2 homologous antagonist killer, in cells treated with TNF-alpha. Exogenous expression of HSpin1 resulted in the cell death without inducing a release of cytochrome c from mitochondria. Overexpression of Bcl-xL inhibited the HSpin1-induced cell death. Interestingly, a necrosis inhibitor, pyrrolidine dithiocarbomate, but not the pancaspase inhibitors, carbobenzoxy-VAD-fluoromethyl ketone and p35, blocked the HSpin1-induced cell death. HSpin1-induced cell death increases autophagic vacuole and mature form of cathepsin D, suggesting a novel caspase-independent cell death, which is link to autophagy.
Asunto(s)
Autofagia/genética , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Inhibidores de Caspasas , Caspasas/metabolismo , Catepsina D/metabolismo , Proteínas de Ciclo Celular , Muerte Celular/genética , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/aislamiento & purificación , Proteínas de Transporte de Membrana , Proteínas Asociadas a Microtúbulos , Fosfoproteínas , Unión Proteica/fisiología , Estructura Terciaria de Proteína/fisiología , Pirrolidinas/farmacología , Tiocarbamatos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Vacuolas/efectos de los fármacos , Vacuolas/metabolismo , Proteína bcl-XRESUMEN
We prepared a mouse monoclonal antibody (mAb), termed 4C8, to the human C5a receptor (C5aR, CD88) by fusing spleen cells from mice immunized with mouse Ltk- cells transfected with cDNA of human C5aR (Ltk-/C5aR) to the mouse myeloma cell line P3U1. This mAb belonging to the IgM kappa subclass, detected a 43 kDa band on cell lysates of Ltk-/C5aR by immunoblotting analysis. Flow cytometry revealed that 4C8 specifically bound to Ltk-/C5aR, suggesting that this antibody is specific for C5aR. Furthermore, 4C8 was found to partially block both intracellular Ca2+ increase in PMN stimulated by C5a and 125I-C5a binding to C5aR on PMN. When cross-linked by anti-mouse IgM, 4C8 completely inhibited the binding of C5a to C5aR on PMN and Ltk-/C5aR. Therefore, it seems likely that this mAb does not recognize the C5aR active site but sterically inhibits the binding of C5a to its receptor. Using this mAb, we detected a 50 kDa band of C5aR on cell lysates of PMN, monocytes and platelets by immunoblotting. C5aR was expressed on PMN and monocytes as determined by flow cytometry, whereas it was not demonstrated on the surface of platelets. Based on these results, this mAb should be useful for analysis of C5aR expression in various immunological conditions and inflammatory diseases.
Asunto(s)
Anticuerpos Monoclonales , Antígenos CD/análisis , Receptores de Complemento/análisis , Animales , Especificidad de Anticuerpos , Antígenos CD/metabolismo , Plaquetas/metabolismo , Western Blotting , Calcio/metabolismo , Complemento C5a/metabolismo , Citometría de Flujo , Humanos , Hibridomas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Peso Molecular , Monocitos/metabolismo , Neutrófilos/metabolismo , Receptor de Anafilatoxina C5a , Receptores de Complemento/metabolismoRESUMEN
alpha-[6-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-5-oxoperhydro -1,4-thiazepin-4-yl]acetic acids (monoester monoacids) and their dicarboxylic acids having the hydrophobic substituents at the 2- or 3-position of the thiazepinone ring were prepared and assayed for angiotensin-converting enzyme (ACE) inhibitory activity. The dicarboxylic acids having the pseudoequatorial amino groups at the 6-position and the pseudoequatorial hydrophobic substituents at the 2- or 3-position of the chair conformation of the thiazepinone ring had potent in vitro inhibitory activity. The monoester monoacids having the hydrophobic substituents at the 2-position suppressed pressor response to angiotensin I for a longer duration than those having the substituents at the 3-position when administered orally. The structure-activity relationship was studied by conformational energy calculations of the thiazepinone ring.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Tiazepinas/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Masculino , Conformación Molecular , Conejos , Ratas , Ratas Endogámicas , Relación Estructura-Actividad , Tiazepinas/farmacologíaRESUMEN
alpha-[(3S)-3-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-2-oxo-6 or 7-phenylperhydroazepin-1-yl]acetic acids (monoester monoacids) and their dicarboxylic acids were synthesized, and their angiotensin-converting enzyme (ACE) inhibitory activities were evaluated. The dicarboxylic acids having phenyl substituents at the 6R, 6S, and 7S positions on the azepinone ring showed potent inhibition in vitro. The corresponding monoester monoacids, when administered orally, suppressed the pressor response to angiotensin I administered intravenously. The monoester monoacids having the phenyl substituent at the 6-position showed a longer duration of action than one having the substituent at the 7-position. The structure-activity relationship was studied on the basis of the conformational energy calculation.