RESUMEN
The hematopoietic growth factor, granulocyte colony-stimulating factor (G-CSF), has become one of the few growth factors approved for clinical use. It has therapeutic potential for numerous neurodegenerative diseases; however, at present the cellular effects of G-CSF on the central nervous system remain unclear and in need of investigation. In the present study, we used spinal cord ischemia, a neurodegenerative model, to examine the effects of intrathecal (i.t.) G-CSF on glial cell (microglia and astrocyte) activation and neuroprotective factor expression, including glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor A (VEGF-A) protein expression. Our results indicate that i.t. G-CSF could enhance ischemia-induced microglial activation and inhibit ischemia-induced astrocyte activation. Both GDNF and VEGF-A are upregulated after injury, and i.t. G-CSF could enhance GDNF and VEGF-A expressions after injury. Interestingly, our results indicate that performing i.t. G-CSF alone on normal animals could have the effect of microglial and astrocyte activation and enhanced GDNF and VEGF-A expressions. Furthermore, through laser scanning confocal microscopy, we found that astrocytes may contribute to the majority of GDNF and VEGF-A expressions of G-CSF after spinal cord ischemia. Overall, this G-CSF-induced upregulation suggests that activation of endogenous neuroprotective mechanisms could resist neurodegenerative insults. These observations demonstrate the cellular mechanism of i.t. G-CSF after spinal cord ischemia and confirm the neuroprotective effect of G-CSF after spinal cord ischemia injury.
Asunto(s)
Astrocitos/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/biosíntesis , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/farmacología , Isquemia/metabolismo , Médula Espinal/patología , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Animales , Astrocitos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Inyecciones Espinales , Isquemia/tratamiento farmacológico , Isquemia/patología , Masculino , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Wistar , Recuperación de la Función , Médula Espinal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
WNT signalling plays a central role in mammalian sex determination by promoting ovarian development and repressing aspects of testis development in the early gonad. Dickkopf homolog 1 (DKK1) is a WNT signalling antagonist that plays critical roles in multiple developmental systems by modulating WNT activity. Here, we examined the role of DKK1 in mouse sex determination and early gonadal development. Dkk1 mRNA was upregulated sex-specifically during testis differentiation, suggesting that DKK1 could repress WNT signalling in the developing testis. However, we observed overtly normal testis development in Dkk1-null XY gonads, and found no significant upregulation of Axin2 or Sp5 that would indicate increased canonical WNT signalling. Nor did we find significant differences in expression of key markers of testis and ovarian development. We propose that DKK1 may play a protective role that is not unmasked by loss-of-function in the absence of other stressors.
Asunto(s)
Gónadas/crecimiento & desarrollo , Gónadas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Animales , Femenino , Hibridación in Situ , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Ratones , Ratones Noqueados , Ovario/crecimiento & desarrollo , Ovario/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Procesos de Determinación del Sexo/genética , Procesos de Determinación del Sexo/fisiología , Testículo/crecimiento & desarrollo , Testículo/metabolismoRESUMEN
A CadDX system that confers resistance to Cd(2+) and Zn(2+) was identified in Streptococcus salivarius 57.I. Unlike with other CadDX systems, the expression of the cad promoter was negatively regulated by CadX, and the repression was inducible by Cd(2+) and Zn(2+), similar to what was found for CadCA systems. The lower G+C content of the S. salivarius cadDX genes suggests acquisition by horizontal gene transfer.
Asunto(s)
Proteínas Bacterianas/genética , Cadmio/metabolismo , Farmacorresistencia Bacteriana/genética , Regulación Bacteriana de la Expresión Génica , Operón/genética , Streptococcus/genética , Zinc/metabolismo , Composición de Base , Secuencia de Bases , Cartilla de ADN/genética , Biblioteca de Genes , Datos de Secuencia Molecular , Plásmidos/genética , Análisis de Secuencia de ADNRESUMEN
AIM: To evaluate the clinical significance of endocrine-like tumor cells in human colorectal carcinomas. METHODS: The immunohistochemistry method (ABC) using a rabbit polyclonal antibody against human chromogranin A (CGA) was employed to determine changes in endocrine-like tumor cells from the surgically resected colorectal carcinoma tissues of patients (35 males and 27 females, aged from 19 to 78 years, with a mean age of 50.3 years). Of the 62 specimens, 44 were from rectal carcinomas, 18 from colonic carcinomas, 14 from lymph nodes and 48 from non-involvement. Dukes classification revealed 19 of the cases were in stage A, 29 cases were in stage B and 14 cases were in stage C. All of the specimens were fixed with 10% formalin, embedded with paraffin and cut into 5 µm sections. Additionally, the correlations among CGA-positive tumor cells, as well as the clinicopathologic data, age and sex of the patients, were also investigated. RESULTS: CGA-positive tumor cells were found in 35.5% of the patients with colorectal cancers, representing 20.0% (5 of 25) and 45.9% (17 of 37) of the aged and non-aged, respectively. These differences were significant (χ(2) test, P < 0.05). Nevertheless, no significant correlations were found between the CGA-positive tumor cells and the sex, Dukes stages, tumor location, degree of histological differentiation or presence of lymph node metastasis. CONCLUSION: The low incidence of endocrine-like tumor cells found in the aged patients may be a new pathological feature for colorectal carcinomas, which could explain why the aged patients usually had a better prognosis. The exact significance of these findings requires further characterization.