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1.
Cell Death Dis ; 5: e1435, 2014 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-25275596

RESUMEN

Glioblastoma multiforme is resistant to conventional anti-tumoral treatments due to its infiltrative nature and capability of relapse; therefore, research efforts focus on characterizing gliomagenesis and identifying molecular targets useful on therapy. New therapeutic strategies are being tested in patients, such as Histone deacetylase inhibitors (HDACi) either alone or in combination with other therapies. Here two HDACi included in clinical trials have been tested, suberanilohydroxamic acid (SAHA) and valproic acid (VPA), to characterize their effects on glioma cell growth in vitro and to determine the molecular changes that promote cancer cell death. We found that both HDACi reduce glioma cell viability, proliferation and clonogenicity. They have multiple effects, such as inducing the production of reactive oxygen species (ROS) and activating the mitochondrial apoptotic pathway, nevertheless cell death is not prevented by the pan-caspase inhibitor Q-VD-OPh. Importantly, we found that HDACi alter cell cycle progression by decreasing the expression of G2 checkpoint kinases Wee1 and checkpoint kinase 1 (Chk1). In addition, HDACi reduce the expression of proteins involved in DNA repair (Rad51), mitotic spindle formation (TPX2) and chromosome segregation (Survivin) in glioma cells and in human glioblastoma multiforme primary cultures. Therefore, HDACi treatment causes glioma cell entry into mitosis before DNA damage could be repaired and to the formation of an aberrant mitotic spindle that results in glioma cell death through mitotic catastrophe-induced apoptosis.


Asunto(s)
Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Glioma/fisiopatología , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Mitosis/efectos de los fármacos , Ácido Valproico/farmacología , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Glioma/tratamiento farmacológico , Humanos , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Vorinostat
2.
Cell Death Differ ; 16(11): 1460-8, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19590510

RESUMEN

Cardiac morphologic abnormalities in mice deficient for key regulators of the caspase-dependent signaling underscored its role in heart development. However, the mechanisms regulating apoptotic gene expression in the developing heart are unknown. As polypyrimidine tract binding proteins (PTB) determine gene isoform expression during myoblast differentiation and contribute to Apaf-1 translation in cell lines, we investigated whether PTB regulate apoptotic gene expression in differentiating cardiomyocytes. Our results show that PTB are expressed in the embryonic heart and are silenced during development, coinciding with a reduction in the expression of apoptotic genes. Overexpression of PTB in postnatal cardiomyocytes, which express low levels of PTB and apoptotic genes, induced an increase in the amount of pro-apoptotic proteins without affecting abundance of their respective transcripts. Translation of the reporter gene Firefly Luciferase preceded by the 5'-untranslated region of Apaf-1 or Caspase-3 was enhanced by PTB in cardiomyocytes. PTB silencing in fibroblasts induced a decrease of apoptotic protein levels. PTB overexpression in cardiomyocytes induced caspase activity and caspase-dependent DNA fragmentation during ischemia, which is otherwise caspase-independent in differentiated cardiomyocytes. Our results show that PTB contribute to apoptotic gene expression and modulate the susceptibility to caspase activation in differentiating rat cardiomyocytes.


Asunto(s)
Apoptosis , Caspasa 3/metabolismo , Miocitos Cardíacos/citología , Proteína de Unión al Tracto de Polipirimidina/metabolismo , Regiones no Traducidas 5' , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Factor Apoptótico 1 Activador de Proteasas/metabolismo , Caspasa 3/genética , Diferenciación Celular , Fragmentación del ADN , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Proteína de Unión al Tracto de Polipirimidina/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratas , Transducción de Señal
3.
Endocrinology ; 142(9): 3950-63, 2001 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11517174

RESUMEN

For many years, our group has been involved in the development of human PRL antagonists. In two recent publications, S179D-human PRL, a human PRL analog designed to mimic a putative S179-phosphorylated human PRL, was reported to be a highly potent antagonist of human PRL-induced proliferation and signaling in rat Nb2 cells. We prepared this analog with the aim of testing it in various bioassays involving the homologous, human PRL receptor. In our hands, S179D- human PRL was able to stimulate 1) the proliferation of rat Nb2 cells and of human mammary tumor epithelial cells (T-47D), 2) transcriptional activation of the lactogenic hormone response element-luciferase reporter gene, and 3) activation of the Janus kinase/signal transducer and activator of transcription and MAPK pathways. Using the previously characterized antagonist G129R-human PRL as a control, we failed to observe any evidence for antagonism of S179D-human PRL toward any of the human PRL-induced effects analyzed, including cell proliferation, transcriptional activation, and signaling. In conclusion, our data argue that S179D-human PRL is an agonist displaying slightly reduced affinity and activity due to local alteration of receptor binding site 1, and that the antagonistic properties previously attributed to S179D-human PRL cannot be confirmed in any of the assays analyzed in this study.


Asunto(s)
Proteínas de la Leche , Prolactina/análogos & derivados , Prolactina/agonistas , Prolactina/farmacología , Proteínas Proto-Oncogénicas , Animales , Sitios de Unión/fisiología , Unión Competitiva , División Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular , Proteínas de Unión al ADN/genética , Humanos , Janus Quinasa 2 , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosforilación , Prolactina/química , Prolactina/metabolismo , Proteínas Tirosina Quinasas/genética , Ratas , Receptores de Prolactina/metabolismo , Factor de Transcripción STAT5 , Transactivadores/genética , Activación Transcripcional/efectos de los fármacos , Células Tumorales Cultivadas/metabolismo , Células Tumorales Cultivadas/patología
4.
Biochem Biophys Res Commun ; 284(4): 1031-8, 2001 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-11409898

RESUMEN

Previous reports have shown a direct effect of erythropoietin (Epo) on vascular smooth muscle cells (VSMCs). Our aim was to assess expression of the Epo receptor (EpoR) on VSMCs and to study the activation of two major signaling cascades activated by Epo, namely JAK2/STAT5 and MAPK pathways. All experiments were performed in parallel using the Epo-responsive UT7 cell line. From semiquantitative RT-PCR experiments, VSMCs were estimated to express approximately 30-fold less EpoR mRNA than UT7 cells. Epo-induced phosphorylation of proteins involved in the EpoR/JAK2/STAT5 cascade could not be detected in VSMCs, even using pharmacological doses of Epo (250 IU/ml). In contrast, a strong activation of MAP kinase pathway was detected with as low as 10 IU/ml Epo. We suggest that MAPK activation reflects a physiologically relevant effect of Epo on VSMCs that may be correlated to cell proliferation.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Eritropoyetina/farmacología , Proteínas de la Leche , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso Vascular/fisiología , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas , Receptores de Eritropoyetina/genética , Transactivadores/metabolismo , Transcripción Genética , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Janus Quinasa 2 , Leucemia Eritroblástica Aguda , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/enzimología , Ratas , Ratas Endogámicas SHR , Receptores de Eritropoyetina/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT5 , Células Tumorales Cultivadas
5.
Br J Pharmacol ; 132(2): 419-26, 2001 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-11159690

RESUMEN

1. Inducible NO synthase (iNOS) expression and activity were measured in the mouse macrophage cell line J774 after exposure to bacterial lipopolysaccharide (LPS) with or without interferon-gamma (IFN-gamma). 2. Inhibition of NOS activity by concomitant N(G)-monomethyl-L-arginine (L-NMMA) treatment further increased iNOS protein levels, with a substantial increase in iNOS half-life. 3. Western blotting and ELISA demonstrated that several cell proteins were tyrosine-nitrated when iNOS activity was high. 4. Rapid IFN-gamma-induced phosphorylation of STAT1 was reduced by about 40% when cells were pretreated to induce iNOS, unless L-NMMA was present during the pretreatment period. 2D gel electrophoresis demonstrated the presence of nitrotyrosine in STAT1 after iNOS induction, and confirmed the reduction in phospho-STAT1 on subsequent stimulation with IFN-gamma for 15 min and its partial restoration when L-NMMA was present during the pretreatment period. 5. We did not detect tyrosine nitration of the upstream kinase JAK2 in LPS+IFN-gamma pretreated cells, but JAK2 activity was also impaired, and was partially restored by concomitant L-NMMA pretreatment. 6. We conclude that endogenous production of NO induces feedback inhibition of signalling pathways activated by IFN-gamma, at least in part by nitrating tyrosine residues in STAT1 which prevents phosphorylation.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Interferón gamma/farmacología , Macrófagos/fisiología , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogénicas , Transactivadores/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Animales , Western Blotting , Línea Celular , Densitometría , Electroforesis en Gel Bidimensional , Janus Quinasa 1 , Janus Quinasa 2 , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Metionina/metabolismo , Ratones , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo II , Fosforilación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Factor de Transcripción STAT1
6.
Oncogene ; 19(41): 4695-705, 2000 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-11032019

RESUMEN

The involvement of human prolactin (hPRL) in breast cancer has been recently reconsidered based on its autocrine/paracrine proliferative effect described in human mammary tumor epithelial cells. Therefore, there is growing interest in the development of potent hPRL antagonists that may inhibit this effect. We previously designed hPRL analogs displaying antagonistic properties in a human transcriptional bioassay. We now report that the most potent of those analogs, G129R-hPRL, antagonizes all hPRL-induced effects analysed in various breast cancer cell lines, including cell proliferation. The analog per se lacks intrinsic agonistic activity on PRL receptor-activated signaling cascades, cell proliferation and apoptosis, indicating that its mode of action only occurs through competitive inhibition of hPRL. We provide some molecular basis of this antagonistic effect by demonstrating that G129R-hPRL competitively inhibits hPRL-activation of the JAK-STAT and MAPK pathways, two signaling cascades involved in the mitogenic effect of hPRL in mammary epithelial cells. This competitive inhibition persists for at least 48 h, as evidenced by long term analysis of STAT5b activation or of progression through cell cycle. These results are the first demonstration at the molecular level that hPRL antagonists interfering with receptor dimerization disrupt signaling events in breast cancer cells, which prevents hPRL-induced cell proliferation.


Asunto(s)
Comunicación Autocrina/efectos de los fármacos , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antagonistas de Hormonas/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas de la Leche , Neoplasias Hormono-Dependientes/patología , Prolactina/antagonistas & inhibidores , Prolactina/farmacología , Proteínas Proto-Oncogénicas , Unión Competitiva , Neoplasias de la Mama/genética , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Dimerización , Femenino , Antagonistas de Hormonas/metabolismo , Humanos , Janus Quinasa 2 , Neoplasias Hormono-Dependientes/genética , Prolactina/metabolismo , Prolactina/fisiología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Receptores de Prolactina/agonistas , Receptores de Prolactina/antagonistas & inhibidores , Receptores de Prolactina/química , Receptores de Prolactina/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Factor de Transcripción STAT1 , Factor de Transcripción STAT3 , Factor de Transcripción STAT5 , Transactivadores/antagonistas & inhibidores , Transactivadores/metabolismo , Células Tumorales Cultivadas/efectos de los fármacos
7.
J Cell Physiol ; 184(3): 380-4, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10911370

RESUMEN

Incubation of isolated rat soleus and EDL muscles in the presence of 10 mM leucine resulted in a decreased proteolytic rate as measured by the release of tyrosine into the incubation medium. The effect of this branched-chain amino acid (BCAA) is associated with a decreased activity of the lysosomal proteases and a decreased expression of the genes of the ATP-ubiquitin-dependent proteolysis (ubiquitin and C8). Incubation of muscles in the presence of actinomycin D revealed that the effects of the amino acid can be accounted for by an inhibition of the transcription rate. The presence of leucine did not influence the gene expression of other nonlysosomal (m-calpain) and lysosomal (cathepsin B) proteolytic systems. It is concluded that the well-known effect of BCAA on muscle proteolysis is mediated, in the short term, by the inhibition of lysosomal proteolysis. In a longer period, based on the inhibition of gene transcription observed, an involvement of the ATP-dependent proteolytic system is also likely to occur.


Asunto(s)
Aminoácidos de Cadena Ramificada/farmacología , Endopeptidasas/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/enzimología , Adenosina Trifosfato/metabolismo , Animales , Endopeptidasas/genética , Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Masculino , Músculo Esquelético/metabolismo , Fosfocreatina/metabolismo , Inhibidores de Proteasas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Ubiquitinas/genética , Ubiquitinas/metabolismo
8.
Exp Gerontol ; 35(1): 41-51, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10705038

RESUMEN

The mammary gland is the major target tissue of prolactin (PRL) in mammals. Although this pituitary hormone has been long suspected to be involved in the progression of human breast cancer, the failure of clinical improvement by treatment with dopamine agonists (which lower circulating levels of PRL) rapidly reduced the interest of oncologists concerning a potential role of PRL in the development of breast cancer. Within the last few years, however, several studies reported first, that PRL is also synthesized by mammary epithelial cells, and second that it may exert a proliferative action in an autocrine/paracrine manner. In agreement with a recent epidemiological study, these observations have led to a reconsideration of the role of PRL as an active participant in breast cancer, and are an impetus to redefine the molecular targets of anti-prolactin strategies since dopamine analogs are assumed to be inefficient on extrapituitary PRL synthesis. In this review, we briefly summarize the current knowledge of PRL effects on both normal and tumor mammary cells, and we discuss the most relevant articles supporting the autocrine-paracrine action of PRL in the breast. With the aim of defining putative new molecular targets, we propose an overview of the main PRL receptor signaling cascades known to be triggered by PRL in mammary epithelial cells or, when not available, in other cell types. Finally, because proteolytic fragments of rat PRL have been shown to inhibit the angiogenic process, which may be relevant for preventing the progression of solid tumors such as breast tumors, we discuss the hypothesis that the enzymatic cleavage of human PRL could also represent a new molecular target in the search for alternative strategies in the treatment of breast cancer.


Asunto(s)
Neoplasias de la Mama/fisiopatología , Prolactina/fisiología , Animales , Femenino , Humanos , Glándulas Mamarias Animales/crecimiento & desarrollo , Prolactina/metabolismo , Ratas , Transducción de Señal
9.
J Chromatogr A ; 870(1-2): 469-72, 2000 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-10722104

RESUMEN

The effect of several solvent systems on the chromatographic response of fumonisin B1 and B2 derived with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AccQ.Fluor) is described. Naturally contaminated corn samples were extracted and purified by a standard method. Then, samples were dissolved in different solvents, derived with AccQ.Fluor reagent and analysed using HPLC. Results were solvent dependent, methanol being the best one among all assayed solvents for both fumonisins studied and acetonitrile the poorest. o-Phthaldialdehyde (OPA) reagent was used as a reference method.


Asunto(s)
Aminoquinolinas/química , Carbamatos/química , Ácidos Carboxílicos/análisis , Cromatografía Líquida de Alta Presión/métodos , Fumonisinas , Indicadores y Reactivos/química , Estándares de Referencia , Solventes , Espectrometría de Fluorescencia
10.
Food Addit Contam ; 16(3): 125-8, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10492705

RESUMEN

Fumonisins are produced by several fungal species that are common contaminants of maize. The most abundant naturally occurring fumonisin, fumonisin B1 (FB1), has been shown to induce several animal disease syndromes. The development of analytical methods is therefore important. A new method is described that integrates extraction and purification of maize samples in one step. It efficiency is compared against well-known methods, and shows similar results for naturally contaminated maize. It is concluded that the proposed method can be applied to fumonisin B1 and fumonisin B2 (FB2) analysis in maize at least within the concentration range found.


Asunto(s)
Ácidos Carboxílicos/aislamiento & purificación , Carcinógenos Ambientales/aislamiento & purificación , Contaminación de Alimentos , Fumonisinas , Zea mays/química , Cromatografía Líquida de Alta Presión , Humanos
11.
Neurochem Int ; 34(2): 137-40, 1999 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10213072

RESUMEN

Histological features of neurogenic muscle involvement included type grouping, muscle fiber atrophy, and target fibers. In muscles with myofiber atrophy and target fibers, we found an increased expression of the genes encoding for the ubiquitin-ATP-dependent proteolytic system. Thus, in patients with target fibers, a 5.2- and a 3.9-fold increase were observed for the 2.4 and 1.2 kb transcripts, respectively, while in those with atrophic angulated hyperoxidative fibers, a 3.9- and a 4.4-fold increase were observed for the 2.4 and 1.2 kb transcripts, respectively. It is suggested that the activation of this proteolytic system may be responsible for the skeletal muscle alterations that often accompany human muscle neurogenic involvement.


Asunto(s)
Regulación de la Expresión Génica , Músculo Esquelético/metabolismo , Ubiquitinas/genética , Northern Blotting , Humanos , Técnicas para Inmunoenzimas , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/inervación , ARN Mensajero/genética , ARN Mensajero/metabolismo
12.
J Food Prot ; 62(2): 202-5, 1999 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10030643

RESUMEN

An alternative approach based on the use of gas chromatography-mass spectrometry (GC-MS) is used to confirm the presence of patulin in apple juice. In the gas chromatography (GC) methods previously described, derivatization of patulin was always necessary in order to achieve good chromatographic detection. The use of electronic pressure control (EPC) and on-column injection avoids the need for patulin derivatization and allows a sensitive analysis of patulin. A detection limit of 4 microg/liter in apple juice can be attributed to the method.


Asunto(s)
Bebidas/análisis , Carcinógenos/análisis , Cromatografía de Gases y Espectrometría de Masas , Patulina/análisis , Rosales , Cromatografía Líquida de Alta Presión
13.
Int J Mol Med ; 2(1): 69-73, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9854146

RESUMEN

Human biopsies obtained from skeletal muscle of cachectic AIDS patients clearly showed an increased expression (in relation to that of healthy subjects) of the genes encoding for the ubiquitin-ATP-dependent proteolytic system. Increases of 120% and 42% were observed for the 2.4 and 1.2 kb ubiquitin transcripts, respectively. The expression of the C8 proteasome subunit was also increased by 60% in the cachectic AIDS patients in relation to the healthy control subjects. It is suggested that the activation of this proteolytic system (possibly via changes in circulating cytokines, such as TNF) may be responsible for the skeletal muscle waste that often accompanies AIDS.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/genética , Cisteína Endopeptidasas/genética , Síndrome de Emaciación por VIH/genética , Complejos Multienzimáticos/genética , Músculo Esquelético/metabolismo , Ubiquitinas/genética , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/metabolismo , Regulación de la Expresión Génica , Humanos , Complejo de la Endopetidasa Proteasomal , Factor de Necrosis Tumoral alfa/fisiología
14.
Mol Cell Endocrinol ; 142(1-2): 183-9, 1998 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-9783914

RESUMEN

The implantation of the Lewis lung carcinoma (a fast-growing mouse tumour that induces cachexia) to both wild-type and gene-deficient mice for the TNF-alpha receptor type I protein (Tnfr1 degree/Tnfr1 degree), resulted in a considerable loss of carcass weight in both groups. However, while in the wild-type mice there was a loss of both fat and muscle, in the gene-knockout mice muscle wastage was not affected to the same extent. In both groups, tumour burden resulted in significant increases in circulating TNF-alpha, a cytokine which, as we have previously demonstrated, can induce protein breakdown in skeletal muscle. Muscle wastage in wild-type mice was accompanied by an increase in the fractional rate of protein degradation, while no changes were observed in protein synthesis. The result is a decreased rate of protein accumulation that accounts for the muscle weight loss observed as a result of tumour burden. In contrast, gene knockout mice did not have significantly lower rates of protein accumulation as a result of tumour implantation. The increase in protein degradation in the tumour-bearing wild mice was accompanied by an enhanced expression of both ubiquitin and proteasome subunit genes, all of them related to the activation of the ATP-dependent proteolytic system in skeletal muscle. Tumour-bearing gene-deficient mice did not show any increase in gene expression. It is concluded that TNF-alpha (alone or in combination with other cytokines) is responsible for the activation of protein breakdown in skeletal muscle of tumour-bearing mice.


Asunto(s)
Caquexia/metabolismo , Carcinoma Pulmonar de Lewis/complicaciones , Proteínas Musculares/metabolismo , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/fisiología , Animales , Caquexia/etiología , Eliminación de Gen , Proteínas de Homeodominio/genética , Ratones , Ratones Noqueados , Músculo Esquelético/metabolismo , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitinas/genética , Pérdida de Peso
15.
Cancer Lett ; 130(1-2): 19-27, 1998 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-9751252

RESUMEN

The implantation of the Lewis lung carcinoma (a fast-growing mouse tumour that induces cachexia) to both wild-type and transgenic mice for the soluble TNF receptor type I protein (sTNF-R1) resulted in a considerable loss of carcass weight in both groups. However, while in the wild-type mice there was a loss of both fat and muscle, in the transgenic mice muscle waste was not affected to the same extent as in the wild-type group. Muscle waste in wild-type mice was accompanied by an increase in the fractional rate of protein degradation, while no changes were observed in protein synthesis. The result was a decreased rate of protein accumulation which accounted for the muscle weight loss observed as a result of the tumour burden. In contrast, transgenic mice did not have such low rates of protein accumulation after tumour implantation. The increase in protein degradation in the tumour-bearing transgenic mice was accompanied by a similar increase in protein synthesis which compensated for the loss of muscle protein by degradation. Both tumour-bearing groups showed an enhanced expression of ubiquitin and proteasome C8 subunit genes, all of them related to the activation of the ATP-dependent proteolytic system in skeletal muscle. It is suggested that TNF may, in part, be responsible for the loss of protein in skeletal muscle of tumour-bearing mice.


Asunto(s)
Antígenos CD/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Animales , Peso Corporal , Caquexia/etiología , Carcinoma Pulmonar de Lewis/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Músculo Esquelético/patología , Receptores Tipo I de Factores de Necrosis Tumoral
16.
Biofactors ; 8(1-2): 143-7, 1998.
Artículo en Inglés | MEDLINE | ID: mdl-9699023

RESUMEN

Newborns requiring intensive clinical care are susceptible to a wide range of excessive oxygen free radical production-related problems. In utero, fetal organs, particularly lungs, are exposed to relatively hypoxic tensions which rise abruptly after birth and this transition may cause oxidative injury in the neonate. The aims of this study were to determine oxygen free radical activity in neonates at the first 24 h, examine the role of immaturity and infection risk and compare the degree of oxidant stress in newborns treated with different oxygen concentrations. Plasma selenium levels in neonates with high infection risk (IR) were significantly lower than in healthy neonates. Comparative study of selenium in preterm, term and young infants showed age-related increases and differences were significant. Plasma selenium values were lower when oxygen therapy was administered. Vitamin E levels were significantly decreased in IR compared with healthy newborns. The results suggest that selenium and vitamin E deficiencies predispose to neonatal infection and that supplementary oxygen contributes significantly to decreasing the antioxidant defence system.


Asunto(s)
Antioxidantes/análisis , Enfermedades Transmisibles/epidemiología , Recién Nacido/sangre , Recien Nacido Prematuro/sangre , Terapia por Inhalación de Oxígeno , Selenio/sangre , Radicales Libres/sangre , Humanos , Lactante , Valores de Referencia , Factores de Riesgo , España/epidemiología
17.
Cancer Lett ; 133(1): 83-7, 1998 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-9929164

RESUMEN

Intravenous administration of different cytokines caused important changes in the expression of ubiquitin genes in skeletal muscle. Tumour necrosis factor-alpha caused a 2.2- and 1.9-fold increase in the expression of the 2.4 and 1.2 kb transcripts, respectively. Administration of interferon-gamma also caused a 2.2- and 1.8-fold increase in the 2.4 and 1.2 kb transcripts, respectively. While administration of leukaemia inhibitory factor and interleukin-6 resulted in no changes in ubiquitin gene expression, interleukin-1 administration also caused an increase in both ubiquitin gene transcripts (2.8- and 1.9-fold for the 2.4 and 1.2 kb transcripts, respectively). The results suggest that some of the cytokine effects on the ubiquitin system gene expression could be related to the enhanced skeletal muscle proteolysis found during cancer cachexia and other pathological states.


Asunto(s)
Citocinas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Músculo Esquelético/metabolismo , Ubiquitinas/genética , Animales , Caquexia/metabolismo , Interferón gamma/farmacología , Interleucina-1/farmacología , Interleucina-6/farmacología , Masculino , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/farmacología
18.
Mol Cell Endocrinol ; 132(1-2): 93-9, 1997 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-9324050

RESUMEN

The implantation of the Lewis lung carcinoma (a fast-growing mouse tumour that induces cachexia) to both wild-type and gene-deficient mice for the tumour necrosis factor (TNF) receptor type I protein (Tnfr1(0)/Tnfr1(0)), resulted in a considerable loss of carcass (26%) and white (77%) and brown adipose (37%) tissue weights in the wild-type mice, while it induced much less marked effects in the gene-deficient mice. Tumour burden also inflicted an important decrease in total lipoprotein lipase (LPL) activity in epididymal white adipose tissue (50%) in the wild-type mice while no changes were observed in the knockout mice. In addition, all tumour-bearing animals were clearly hypertriglyceridaemic (80% increase in circulating triacylglycerols in wild-type and 36% in knockout mice). It is concluded that although TNF seems to be to some extent responsible for adipose waste, LPL changes and hyperlipaemia (via receptor I), the role of other cytokines (alone or in combination with TNF) in promoting changes in lipid metabolism during cancer cachexia cannot be discarded.


Asunto(s)
Tejido Adiposo/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Metabolismo de los Lípidos , Neoplasias Pulmonares/metabolismo , Receptores del Factor de Necrosis Tumoral/genética , Tejido Adiposo/patología , Animales , Peso Corporal , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Noqueados , Trasplante de Neoplasias , Receptores del Factor de Necrosis Tumoral/deficiencia
19.
Cancer Lett ; 115(1): 113-8, 1997 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-9097986

RESUMEN

The implantation of the Yoshida AH-130 ascites hepatoma (a fast growing tumour) to rats resulted in a dramatic loss of both white adipose tissue and muscle (skeletal and cardiac) mass. Administration of beta2-adrenergic agonists to tumour-bearing rats resulted in a partial recovery of skeletal muscle and heart mass. Treatment of the tumour-bearing animals with the different drugs (salbutamol, salmeterol and clenbuterol) did not influence tumour growth or food intake so it can be suggested that the effects were solely due to metabolic changes. In addition, while the three drugs had clear effects on gastrocnemius muscles, clenbuterol and salbutamol had also an effect on soleus, and salbutamol had a clear effect on cardiac muscle. It is suggested that any of the studied beta2-adrenergic agonists (but perhaps, particularly salmeterol) could be used clinically in the treatment of cancer cachexia.


Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Neoplasias Hepáticas Experimentales/complicaciones , Proteínas Musculares/efectos de los fármacos , Atrofia Muscular/tratamiento farmacológico , Tejido Adiposo/efectos de los fármacos , Albuterol/análogos & derivados , Albuterol/farmacología , Animales , Peso Corporal/efectos de los fármacos , Caquexia/etiología , Clenbuterol/farmacología , Ingestión de Alimentos/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Xinafoato de Salmeterol
20.
Biochem Biophys Res Commun ; 230(2): 238-41, 1997 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-9016756

RESUMEN

Incubation of isolated rat soleus muscles in the presence of human recombinant TNF-alpha (10,000 U/ml) resulted in an important increase in ubiquitin gene expression (over 50%). Although previous studies involving cytokine administration in vivo (1) have demonstrated an action on ubiquitin-dependent proteolysis, this is the first report demonstrating a direct action of the cytokine on protein breakdown in incubated rat skeletal muscle.


Asunto(s)
Cisteína Endopeptidasas/biosíntesis , Complejos Multienzimáticos/biosíntesis , Músculo Esquelético/metabolismo , Proteínas/metabolismo , Transcripción Genética/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Ubiquitinas/metabolismo , Animales , Humanos , Músculo Esquelético/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Proteínas Recombinantes/farmacología , Ubiquitinas/biosíntesis
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