RESUMEN
Women with gestational diabetes (GDM) are a high risk group for early type 2 diabetes (T2D). Depression is a risk factor for T2D in the general population. We investigated in women after a recent pregnancy with GDM and without a clinical diagnosis of depression, whether mild to moderate depressive symptoms associate with pathologic glucose metabolism. In a cross-sectional analysis, we examined 173 women, 9 ± 3 months after delivery with several psychopathological assessments, 5-point oral glucose tolerance test with insulin, anthropometrics, and laboratory chemistry. In a subgroup of 101 women, abdominal visceral fat was quantified by magnetic resonance imaging (MRI). A total of 22 women (13%) showed mild to moderate depressive symptoms, and the proportion of women with pathologic glucose metabolism (impaired fasting glucose, impaired glucose tolerance, or T2D) was higher in this group than in the women without depressive symptoms (59.1% vs. 33.1%, p = 0.018). Women with depressive symptoms also had higher body mass index (BMI), systolic blood pressure, plasma leptin, plasma resistin, and abdominal visceral fat volume. Pathologic glucose metabolism (OR = 2.594, 95% CI: 1.021-6.592), systolic blood pressure (OR = 1.076, 95% CI: 1.027-1.128), and abdominal visceral fat volume (OR = 2.491, 95% CI: 1.142-5.433) remained, even after adjustment for BMI, associated with the presence of depressive symptoms. Taken together, we found depressive symptoms at a level not generally diagnosed in clinical practice in a subgroup of women with recent GDM. This subgroup also showed an unfavorable metabolic profile. Mild to moderate depressive symptoms may therefore help to identify this special subgroup.
Asunto(s)
Presión Sanguínea/fisiología , Depresión/metabolismo , Depresión/fisiopatología , Diabetes Gestacional/metabolismo , Intolerancia a la Glucosa/metabolismo , Grasa Intraabdominal/metabolismo , Adulto , Biomarcadores/metabolismo , Estudios Transversales , Depresión/sangre , Femenino , Intolerancia a la Glucosa/sangre , Prueba de Tolerancia a la Glucosa , Humanos , Leptina/sangre , Embarazo , Resistina/sangreRESUMEN
AIMS/HYPOTHESIS: Low physical fitness (PF) is a risk factor for type 2 diabetes mellitus (T2D). Women with a history of gestational diabetes (GDM) are at risk for T2D at a young age, but the role of PF in this population is not clear. PF has also been found to correlate inversely with plasma leptin in previous studies. Here, we examine whether women who had GDM have lower PF than women after a normoglycemic pregnancy and, second, whether PF is associated with plasma leptin, independently of body fat mass. METHODS: Cross-sectional analysis of 236 participants in the PPSDiab Study (cohort study of women 3-16 months after delivery, 152 after gestational diabetes (pGDM), 84 after normoglycemic pregnancy (control subjects); consecutively recruited 2011-16); medical history, physical examination with bioelectrical impedance analysis (BIA), whole body magnetic resonance imaging (MRI) (n = 154), 5-point oral glucose tolerance test, cardiopulmonary exercise testing, clinical chemistry including fasting plasma leptin; statistical analysis with Mann-Whitney U and t -test, Spearman correlation coefficient, multiple linear regression. RESULTS: Women pGDM had lower maximally achieved oxygen uptake (VO2peak/kg: 25.7(21.3-29.9) vs. 30.0(26.6-34.1)ml/min/kg; total VO2peak: 1733(1552-2005) vs. 1970(1767-2238)ml/min; p<0.0001 for both), and maximum workload (122.5(105.5-136.5) vs. 141.0(128.5-159.5)W; p<0.0001). Fasting plasma leptin correlated inversely with PF (VO2peak/kg ρ = -0.72 p<0.0001; VO2peak ρ = -0.16 p = 0.015; max. load ρ = -0.35 p<0.0001). These associations remained significant with adjustment for body mass index, or for body fat mass (BIA and MRI). CONCLUSIONS/INTERPRETATION: Women with a recent history of GDM were less fit than control subjects. Low PF may therefore contribute to the risk for T2D after GDM. This should be tested in intervention studies. Low PF also associated with increased leptin levels-independently of body fat. PF may therefore influence leptin levels and signaling. This hypothesis requires further investigation.
Asunto(s)
Diabetes Gestacional/sangre , Diabetes Gestacional/fisiopatología , Leptina/sangre , Aptitud Física/fisiología , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Estudios Transversales , Diabetes Mellitus Tipo 2/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Modelos Lineales , Consumo de Oxígeno , Embarazo , Estudios Prospectivos , Factores de RiesgoRESUMEN
In the mammalian cochlea, sound is encoded at synapses between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs). Each SGN receives input from a single IHC ribbon-type active zone (AZ) and yet SGNs indefatigably spike up to hundreds of Hz to encode acoustic stimuli with submillisecond precision. Accumulating evidence indicates a highly specialized molecular composition and structure of the presynapse, adapted to suit these high functional demands. However, we are only beginning to understand key features such as stimulus-secretion coupling, exocytosis mechanisms, exo-endocytosis coupling, modes of endocytosis and vesicle reformation, as well as replenishment of the readily releasable pool. Relating structure and function has become an important avenue in addressing these points and has been applied to normal and genetically manipulated hair cell synapses. Here, we review some of the exciting new insights gained from recent studies of the molecular anatomy and physiology of IHC ribbon synapses.
Asunto(s)
Células Ciliadas Auditivas Internas/metabolismo , Animales , Cóclea/metabolismo , Células Ciliadas Auditivas Internas/citología , Ganglio Espiral de la Cóclea/metabolismo , Sinapsis/metabolismoRESUMEN
RUNX1/ETO (RE), the t(8;21)-derived leukemic transcription factor associated with acute myeloid leukemia (AML) development, deregulates genes involved in differentiation, self-renewal and proliferation. In addition, these cells show differences in cellular adhesion behavior whose molecular basis is not well understood. Here, we demonstrate that RE epigenetically silences the gene encoding P-Selectin Glycoprotein Ligand-1 (PSGL-1) and downregulates PSGL-1 expression in human CD34+ and murine lin- hematopoietic progenitor cells. Levels of PSGL-1 inversely and dose-dependently correlate with RE oncogene levels. However, a DNA-binding defective mutant fails to downregulate PSGL-1. We show by ChIP experiments that the PSGL-1 promoter is a direct target of RE and binding is accompanied by high levels of the repressive chromatin mark histone H3K27me3. In t(8;21)+ Kasumi-1 cells, PSGL-1 expression is completely restored at both the mRNA and cell surface protein levels following RE downregulation with short hairpin RNA (shRNA) or RE inhibition with tetramerization-blocking peptides, and at the promoter H3K27me3 is replaced by the activating chromatin mark H3K9ac as well as by RNA polymerase II. Upregulation of PSGL-1 restores the binding of cells to P- and E-selectin and re-establishes myeloid-specific cellular adhesion while it fails to bind to lymphocyte-specific L-selectin. Overall, our data suggest that the RE oncoprotein epigenetically represses PSGL-1 via binding to its promoter region and thus affects the adhesive behavior of t(8;21)+ AML cells.
RESUMEN
BACKGROUND: Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARα. METHODS: Immunoblot, flow cytometry, and May-Grünwald-Giemsa staining were used to analyze differentiation and induction of apoptosis. RESULTS: A PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)É and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPÉ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPÉ are newly identified molecular markers for the efficacy of HDACi against APL cells. CONCLUSIONS: Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Granulocitos/fisiología , Inhibidores de Histona Desacetilasas/farmacología , Tretinoina/farmacología , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica , Humanos , Ácidos Hidroxámicos/farmacología , Indoles/farmacología , Leucemia Promielocítica Aguda , Panobinostat , Proteína bcl-X/metabolismoRESUMEN
The RUNX1/ETO (RE) fusion protein, which originates from the t(8;21) chromosomal rearrangement, is one of the most frequent translocation products found in de novo acute myeloid leukemia (AML). In RE leukemias, activated forms of the c-KIT tyrosine kinase receptor are frequently found, thereby suggesting oncogenic cooperativity between these oncoproteins in the development and maintenance of t(8;21) malignancies. In this report, we show that activated c-KIT cooperates with a C-terminal truncated variant of RE, REtr, to expand human CD34+ hematopoietic progenitors ex vivo. CD34+ cells expressing both oncogenes resemble the AML-M2 myeloblastic cell phenotype, in contrast to REtr-expressing cells which largely undergo granulocytic differentiation. Oncogenic c-KIT amplifies REtr-depended clonogenic growth and protects cells from exhaustion. Activated c-KIT reverts REtr-induced DNA damage and apoptosis. In the presence of activated c-KIT, REtr-downregulated DNA-repair genes are re-expressed leading to an enhancement of DNA-repair efficiency via homologous recombination. Together, our results provide new mechanistic insight into REtr and c-KIT oncogenic cooperativity and suggest that augmented DNA repair accounts for the increased chemoresistance observed in t(8;21)-positive AML patients with activated c-KIT mutations. This cell-protective mechanism might represent a new therapeutic target, as REtr cells with activated c-KIT are highly sensitive to pharmacological inhibitors of DNA repair.
Asunto(s)
Apoptosis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Daño del ADN , Células Madre Hematopoyéticas/citología , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Antígenos CD34/metabolismo , Benzamidas/administración & dosificación , Ciclo Celular , Separación Celular , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Clonación Molecular , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Reparación del ADN , Regulación hacia Abajo , Inhibidores Enzimáticos/química , Citometría de Flujo , Células HEK293 , Humanos , Mesilato de Imatinib , Mutación , Proteínas de Fusión Oncogénica/genética , Fenotipo , Piperazinas/administración & dosificación , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/administración & dosificación , Proteína 1 Compañera de Translocación de RUNX1 , Translocación Genética , Células U937RESUMEN
Neurotransmitter release at chemical synapses occurs when synaptic vesicles fuse to the presynaptic membrane at a specialized site termed the active zone. The depolarization-induced fusion is highly dependent on calcium ions, and, correspondingly, the transmission characteristics of synapses are thought to be influenced by the spatial arrangement of voltage-gated calcium channels with respect to vesicle release sites. Here, we review the involvement of the Drosophila Bruchpilot (BRP) protein in active zone assembly, a process that is required for the clustering of presynaptic calcium channels to ensure efficient vesicle release.
Asunto(s)
Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , Calcio/fisiología , Proteínas de Drosophila/fisiología , Drosophila melanogaster , Cinética , Unión Neuromuscular/fisiología , ProbabilidadRESUMEN
Modular systems for protein coupling have been applied for anchoring enzyme molecules on liposome surfaces. Two cytoplasmic model enzymes, alpha-amylase from Escherichia coli (EC. 3.2.1.1) and guanylate kinase from Saccharomyces cerevisiae (EC. 2.7.4.8), were directly coupled by a histidine-tag or indirectly via strep-tag and streptavidin or streptactin linker to a liposome membrane. Though the catalytic properties of the enzymes are generally maintained, stability and specific activity of the enzymes are modified after coupling and are especially influenced by the lipid used for the liposome assembly.
Asunto(s)
Nucleósido-Fosfato Quinasa/metabolismo , alfa-Amilasas/metabolismo , Secuencia de Bases , Catálisis , Cartilla de ADN , Guanilato-Quinasas , Liposomas , Microscopía Electrónica , Nucleósido-Fosfato Quinasa/ultraestructura , alfa-Amilasas/ultraestructuraRESUMEN
The goal of the present study was to examine the relations between different forms of children's nonsocial play behaviors and adjustment in kindergarten. The participants in this study were 77 kindergarten children (38 boys, 39 girls; mean age = 66.16 months, SD = 4.11 months). Mothers completed ratings of child shyness and emotion dysregulation. Children's nonsocial play behaviors (reticent, solitary-passive. solitary active) were observed during free play. In addition, teachers rated child behavior problems (internalizing and externalizing) and social competence; academic achievement was assessed through child interviews. Results from regression analyses revealed that different types of nonsocial play were differentially associated with child characteristics and indices of adjustment. For some forms of nonsocial play, the nature of these associations differed significantly for boys and girls.
Asunto(s)
Guarderías Infantiles , Juego e Implementos de Juego , Ajuste Social , Conducta Social , Logro , Afecto , Niño , Conducta Infantil/psicología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Factores Sexuales , TemperamentoRESUMEN
Pneumocandin B0 (6) and six related lipopeptides are antifungal and anti-Pneumocystis carinii agents from mutants of Zalerion arboricola, whose structures were determined mainly on the basis of spectroscopic analysis. They belong, along with pneumocandin A0 (L-671,329) previously isolated from these laboratories, to the echinocandin class of antifungal agents. The product from base-catalyzed ring opening involving the hemiaminal position of the dihydroxyornithine residue of B0, has been clearly defined as 6b. Modifications were limited to the 3-hydroxy-4-methylproline, 3,4-dihydroxyhomotyrosine and 4,5-dihydroxyornithine residues of pneumocandin A0.
Asunto(s)
Antibacterianos , Antifúngicos/química , Hongos Mitospóricos/química , Péptidos , Antifúngicos/farmacología , Antivirales/química , Candida albicans/efectos de los fármacos , Cristalografía , Equinocandinas , Espectroscopía de Resonancia Magnética , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Pneumocystis/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel inositol mono-phosphatase inhibitor, L-671,776 (1), was discovered from a culture of the hyphomycete, Memnoniella echinata (ATCC 20928). 1 has a molecular weight of 388 and a molecular formula of C23H32O5. The mode of inhibition is non-competitive, with a Ki of 450 microM. It shows no inhibition of myo-inositol 1,4-bisphosphate 1-phosphatase or myo-inositol 1,4,5-triphosphate 5-phosphatase, although it weakly inhibits myo-inositol 1,4,5-triphosphate 3-kinase (IC50 = 3 mM). It elevates inositol monophosphates in rat parotid slices (EC50 approximately 3 mM), but abolishes agonist effects. It also produces short-lived contraction of guinea pig trachea at 300 microM.
Asunto(s)
Benzofuranos/aislamiento & purificación , Inhibidores Enzimáticos/aislamiento & purificación , Hongos Mitospóricos/química , Monoéster Fosfórico Hidrolasas/antagonistas & inhibidores , Sesquiterpenos/aislamiento & purificación , Compuestos de Espiro/aislamiento & purificación , Animales , Benzofuranos/química , Benzofuranos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Cobayas , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Glándula Parótida/efectos de los fármacos , Monoéster Fosfórico Hidrolasas/metabolismo , Ratas , Sesquiterpenos/química , Sesquiterpenos/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacologíaRESUMEN
Paraherquamides B (2, C27H33N3O4), C (3, C28H33N3O4), D (4, C28H33N3O5), E (5, C28H35N3O4), F (6, C28H35N3O3), and G (7, C28H35N3O4) are novel metabolites of Penicillium charlesii. The structures of these compounds have been determined by NMR and MS analysis.
Asunto(s)
Antihelmínticos/química , Antinematodos/química , Indolizinas/química , Penicillium/metabolismo , Compuestos de Espiro/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura MolecularRESUMEN
An increased tendency of the blood to clot in patients with arterial hypertension is not desirable, since cardiovascular and cerebrovascular sequelae may be aggravated. Recently, activation of coagulation under ACE inhibition with captopril has been described. In an open, randomized study, we compared the influence of enalapril on various coagulation parameters with that of hydrochlorothiazide. In contrast to the latter, we detected no unfavorable influence of enalapril on the coagulation factors investigated. A transient increase in fibrin monomeres was observed in one patient each on enalapril and hydrochlorothiazide.
Asunto(s)
Pruebas de Coagulación Sanguínea , Enalapril/efectos adversos , Hidroclorotiazida/efectos adversos , Hipertensión/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Enalapril/uso terapéutico , Humanos , Hidroclorotiazida/uso terapéutico , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Based on spectroscopic data L-671,329, isolated from a filamentous fungus ATCC 20868, has been assigned the structure 1. The compound is a lipopeptide antifungal agent and a structural analog of echinocandin B.
Asunto(s)
Antibacterianos , Antifúngicos , Proteínas Fúngicas , Secuencia de Aminoácidos , Aminoácidos/análisis , Equinocandinas , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Péptidos , Péptidos Cíclicos , Espectrofotometría UltravioletaRESUMEN
The actions of the 12 alpha-saxitoxinol, 12 beta-saxitoxinol and a C-12 ethylene thioketal derivative of saxitoxin, as well as those of 11 alpha-(OSO3)-saxitoxin, 11 beta-(OSO3)-saxitoxin and 11 alpha-(OH)-saxitoxin, have been examined on the isolated squid giant axon. Each of these analogues acted similarly to saxitoxin in blocking specifically the sodium channel. The relative potencies are: STX (1); 11 beta-(OSO3)-STX (gonyautoxin III) (0.42); 11 alpha-(OSO3)-STX (gonyautoxin II) (0.20); 11 alpha-(OH)-STX (0.10); 12 alpha-saxitoxinol (0.0021); 12 beta-saxitoxinol (0.0005). Thus, the presence of a bulky and negatively charged sulphate group on C-11 does not materially affect the biological activity of STX. Hydrogen bonding at the C-12 position is probably an important means of binding of STX to the membrane receptor site. The difference between the epimers of saxitoxinol suggests that the H in one of them may be geometrically better aligned than that in the other, with the hydrogen acceptor group in the receptor.