RESUMEN
The nonselective inhibitors of class I/II histone deacetylases (HDACs) including trichostatin A and the clinically used suberoylanilide hydroxamic acid (SAHA, vorinostat) are neuroprotective in several models of neuronal injury. Here, we report that in cultured cortical neurons from newborn rats and in the cerebral cortex of whole neonate rats, these HDAC inhibitors exacerbated cytotoxicity of the DNA double-strand break (DSB)-inducing anticancer drug etoposide by enhancing apoptosis. Similar neurotoxic interactions were also observed in neurons that were treated with other DNA damaging drugs including cisplatin and camptothecin. In addition, in rat neonates, SAHA increased cortical neuron apoptosis that was induced by a single injection of the NMDA receptor antagonist dizocilpine (MK801). In etoposide-treated neurons, the nonselective HDAC inhibition resulted in more DSBs. It also potentiated etoposide-induced accumulation and phosphorylation of the pro-apoptotic transcription factor p53. Moreover, nonselective HDAC inhibition exacerbated neuronal apoptosis that was induced by the overexpressed p53. Importantly, such effects cannot be fully explained by inhibition of HDAC1, which is known to play a role in DSB repair and regulation of p53. The specific HDAC1 inhibitor MS275 only moderately enhanced etoposide-induced neuronal death. Although in etoposide-treated neurons MS275 increased DSBs, it did not affect activation of p53. Our findings suggest that besides HDAC1, there are other class I/II HDACs that participate in neuronal DNA damage response attenuating neurotoxic consequences of genotoxic insults to the developing brain.
Asunto(s)
Roturas del ADN de Doble Cadena/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Animales , Animales Recién Nacidos , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Camptotecina/toxicidad , Células Cultivadas , Corteza Cerebral/citología , Cisplatino/toxicidad , Maleato de Dizocilpina/toxicidad , Etopósido/administración & dosificación , Etopósido/toxicidad , Genes p53 , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/fisiología , Ácidos Hidroxámicos/farmacología , Inyecciones Intraventriculares , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Mutación Puntual , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Proteína p53 Supresora de Tumor/metabolismo , VorinostatAsunto(s)
Migración de Cuerpo Extraño/complicaciones , Absceso Piógeno Hepático/etiología , Agujas , Adolescente , Drenaje , Femenino , Migración de Cuerpo Extraño/diagnóstico por imagen , Migración de Cuerpo Extraño/cirugía , Humanos , Absceso Piógeno Hepático/diagnóstico por imagen , Absceso Piógeno Hepático/cirugía , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
For the past ten years, our research has been focused on elucidating the mechanism by which procathepsin D (pCD) impacts cancer development. Various studies have shown that pCD is overexpressed and secreted by numerous cancer cell lines. After secretion, it exhibits "growth hormone-like" activity on cancerous cells but the exact mechanism of this mitogenic activity is not yet understood. The activation peptide of pCD (APpCD) (which is cleaved off upon activation of the zymogen) is responsible for the mitogenic function of pCD. Various in vitro and in vivo studies support our theory that the APpCD interacts with both parent and neighborhood cancer cells and thus functions as an autocrine mitogen. We propose a model of pCD mitogenic function and also some possible approaches for treatment and prevention of certain types of cancer.
Asunto(s)
Catepsina D/metabolismo , Precursores Enzimáticos/metabolismo , Neoplasias/enzimología , Biomarcadores de Tumor , Catepsina D/inmunología , Precursores Enzimáticos/inmunología , Humanos , Neoplasias/prevención & controlRESUMEN
We present a case of hypoparathyroidism, demonstrating extensive intracranial calcification, not only in basal ganglia, but also outside the extrapyramidal system. The patient presented with an unexplained epileptifors disorder, accompanied by extrapyramidal dysfunction in the form of choreoathetosis and hemiballismus. Hemiballismus is reported for the first time to our knowledge in association with hypoparathyroidism.
Asunto(s)
Encefalopatías/patología , Calcinosis/patología , Hipoparatiroidismo/patología , Adolescente , Ganglios Basales/patología , Encefalopatías/complicaciones , Calcinosis/complicaciones , Cerebelo/patología , Corteza Cerebral/patología , Humanos , Hipoparatiroidismo/complicaciones , Cristalino/patología , Masculino , Tomografía Computarizada por Rayos XRESUMEN
Sixty five (65) hypertensive, 91 non-insulin dependent diabetes and 50 matched, healthy controls were examined for the presence of microalbuminuria, using the Micral strip test. Microalbuminuria was observed in 25 per cent of diabetics and 21.54 per cent of hypertensive subjects. None of the controls demonstrated microalbuminuria. Diabetics with microalbuminuria were poorly controlled and demonstrated significantly higher systolic pressure. In hypertensive subjects, microalbuminuria was seen more in patients with severe disease. In both diabetics and hypertensives, presence of microalbuminuria was significantly influenced by the disease duration.
Asunto(s)
Albuminuria , Diabetes Mellitus Tipo 2/orina , Hipertensión/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadAsunto(s)
Diabetes Mellitus/diagnóstico , Glucosuria , Adolescente , Adulto , Niño , Humanos , Persona de Mediana EdadRESUMEN
The kinetics of electron transfer between the Rhodobacter sphaeroides R-26 reaction center and nine soluble c-cytochromes have been analyzed and compared to the patterns of the surface electrostatic potentials for each of the proteins. Characteristic first-order electron-transfer rates for 1:1 complexes formed at low ionic strength between the reaction center and the different c-cytochromes were identified and found to vary by a factor of almost 100, while second-order rates were found to differ by greater than 10(6). A correlation was found between the location of likely electrostatic interaction domains on each cytochrome and its characteristic rate of electron transfer. The interaction domains were identified by mapping electrostatic potentials, calculated from the Poisson-Boltzmann equation, onto simulated "encounter surfaces" for each of the cytochromes and the reaction center. For the reaction center, the c-cytochrome binding domain was found to have almost exclusively net negative potential (< -3 kT) and to be shifted slightly toward the M-subunit side of the reaction center. The location of interaction domains of complementary, positive potential (> 3 kT) differed for each cytochrome. The correspondence between electrostatic, structural, and kinetic properties of 1:1 reaction center-cytochrome complexes leads to a proposed mechanism for formation of reaction center-cytochrome electron-transfer complexes that is primarily driven by the juxtaposition of regions of delocalized complementary potential. In this mechanism the clustering of charged residues is of primary importance and not the location of specific residues. A consequence of this mechanism is that many different sets of charge distributions are predicted to be capable of stabilizing a specific configuration for a reaction center-cytochrome complex. This mechanism for reaction center association with water-soluble c-cytochromes fits molecular recognition mechanisms proposed for c-cytochromes in nonphotosynthetic systems. In general, the kinetic scheme for reaction center driven cytochrome oxidation was found to vary between a simple two-state model, involving cytochrome in free and reaction center bound states, and a three-state model, that includes cytochrome binding in kinetically competent ("proximal") and incompetent ("distal") modes. The kinetically incompetent mode of cytochrome binding is suggested not to be an intrinsic feature of the reaction center-cytochrome association but is likely to be due to variation in the physical state of the reaction center.