RESUMEN

Electrical field stimulation (EFS) induces contractions of both snake aorta and human umbilical cord vessels (HUCV) which were dependent on the presence of the endothelium. This study aimed to establish the nature of the mediator(s) responsible for EFS-induced contractions in HUCV. Rings with or without endothelium from human umbilical artery (HUA) or vein (HUV) were mounted in organ bath chambers containing oxygenated, heated Krebs-Henseleit's solution. Basal release of dopamine (DA), noradrenaline, and adrenaline was measured by LC-MS-MS. Cumulative concentration-response curves were performed with dopamine in the absence and in the presence of L-NAME or of dopamine antagonists. EFS studies were performed in the presence and absence of L-NAME, the α-adrenergic blockers prazosin and idazoxan, and the dopamine antagonists SCH-23390 and haloperidol. Tyrosine hydroxylase (TH) and dopa-decarboxylase (DDC) were studied by immunohistochemistry and fluorescence in situ hybridizations. Basal release of dopamine requires an intact endothelium in both HUA and HUV. TH and DDC are present only in the endothelium of both HUA and HUV as determined by immunohistochemistry. Dopamine induced contractions in HUA only in the presence of L-NAME. Dopamine-induced contractions in HUV were strongly potentiated by L-NAME. The EFS-induced contractions in both HUA and HUV were potentiated by L-NAME and inhibited by the D2-like receptor antagonist haloperidol. The α-adrenergic antagonists prazosin and idazoxan and the D1-like receptor antagonist SCH-23390 had no effect on the EFS-induced contractions of HUA and HUV. Endothelium-derived dopamine is a major modulator of HUCV reactivity in vitro.

Asunto(s)

Dopamina/metabolismo , Estimulación Eléctrica , Arterias Umbilicales/metabolismo , Venas Umbilicales/metabolismo , Adolescente , Antagonistas Adrenérgicos alfa/farmacología , Adulto , Cromatografía Liquida , Antagonistas de Dopamina/farmacología , Endotelio Vascular/fisiología , Epinefrina/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Norepinefrina/metabolismo , Espectrometría de Masas en Tándem , Adulto Joven

RESUMEN

Cryptococcus neoformans/Cryptococcus gattii complex species are etiological agents of cryptococcosis, a systemic mycosis that cause respiratory infection and meningoencephalitis. To establish the infection, these yeasts produce virulence factors, such as melanin, which contribute to pathogenicity and antifungal tolerance. The aim of this study was to investigate melanin production by the C. neoformans/C. gattii complex in the presence of different precursors of melanogenesis and evaluate the effect of melanization on the antifungal susceptibility of these species to fluconazole, flucytosine and amphotericin B. Epinephrine, norepinephrine, dopamine and caffeic acid were used as substrates for melanin production, and l-dopa was used as positive control. The susceptibility of melanized strains (n = 6), after exposure to epinephrine or l-dopa, was evaluated by broth microdilution assay, and non-melanized strains were used as control. The antifungal activity of amphotericin B against melanized strains was also investigated by time kill assay. All Cryptococcus spp. strains produced melanin after exposure to the tested substrates. After exposure to epinephrine, minimum inhibitory concentration (MIC) ranges were 1-8 µg/mL for fluconazole, 2-8 µg/mL for flucytosine and 0.125-1 µg/mL for amphotericin B, while, after exposure to l-dopa, MIC ranges were 2-8 µg/mL for fluconazole, 4-8 µg/mL for flucytosine, and 0.125-0.5 µg/mL for amphotericin B. Similar results were observed for non-melanized strains. The production of melanin after exposure to epinephrine was higher than that induced by l-dopa. Melanized cells of both species were more tolerant to amphotericin B than the non-melanized control, emphasizing the importance of melanin production for fungal virulence.

Asunto(s)

Anfotericina B/farmacología , Antifúngicos/farmacología , Cryptococcus gattii/metabolismo , Cryptococcus neoformans/metabolismo , Epinefrina/farmacología , Melaninas/metabolismo , Animales , Antibacterianos , Ácidos Cafeicos/metabolismo , Ácidos Cafeicos/farmacología , Cryptococcus gattii/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Dopamina/metabolismo , Dopamina/farmacología , Epinefrina/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Norepinefrina/metabolismo , Norepinefrina/farmacología

RESUMEN

Salmonella spp. are the main pathogens responsible for foodborne disease worldwide. Bacterial communities use the quorum sensing system to control biofilm formation. These systems function through the secretion of substances, called auto-inducers (AI), into the environment. AI-3 is structurally similar to epinephrine (EPI) and norepinephrine (NOR) -catecholamines secreted by eukaryotic cells to communicate with each other. In this context, this work aimed to evaluate the effect of EPI and NOR on biofilm formation by S. Enteritidis at 12 °C and 25 °C. Also, we detected the presence of the csgD, adrA, and fimA genes in these strains. Biofilm formation was investigated at two temperatures (12 °C and 25 °C) using a microtiter plate assay, under four different treatments (50 mM EPI, 100 mM EPI, 50 mM NOR; 100 mM NOR) and a control group. PCR was used to detect the virulence genes associated with biofilm production. A greater number of biofilm producer isolates were observed at 25 °C than at 12 °C, regardless of the treatment. The number of biofilms forming strains at 12 °C was significantly higher in the treatment with norepinephrine at 100 µM. The proportion of non-producer and biofilm producer strains at 25 °C did not differ significantly among the treatments. All strains presented the three genes (csgD, adrA, and fimA). The approach carried out in this work is a precursor in veterinary medicine, focusing on both public and poultry health, and evaluates the influence of catecholamines on the formation of biofilms with S. Enteritidis, an important pathogen with zoonotic potential. Norepinephrine seems to be more efficient at stimulating biofilm formation by S. Enteritidis strains at 12 °C. csgD, fimA, and adrA were detected in all strains.

Asunto(s)

Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Catecolaminas/metabolismo , Salmonella enteritidis/efectos de los fármacos , Salmonella enteritidis/crecimiento & desarrollo , Epinefrina/metabolismo , Perfilación de la Expresión Génica , Norepinefrina/metabolismo , Reacción en Cadena de la Polimerasa , Percepción de Quorum/efectos de los fármacos , Temperatura , Factores de Virulencia/biosíntesis , Factores de Virulencia/genética

RESUMEN

Steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to control inflammatory pain, but there is a risk of gastrointestinal bleeding and increased heart failure risk. The search for new drugs remains ongoing, and natural products are a source for potential new compounds. Mangiferin, a natural xanthone C-glucoside, has demonstrated biological activity, including anti-inflammatory and analgesic properties, but it's mechanisms are poorly understood. In this study, we investigated the mechanisms underlying the anti-inflammatory and analgesic effects of local administration of mangiferin. We employed an electronic von Frey apparatus to evaluate mechanical hyperalgesia induced by carrageenan in rats. Mangiferin (150-1200 µg/paw), administered locally into the hindpaw, prevented hyperalgesia in a dose-dependent - 150 µg (- 9%), 300 µg (- 27%, P < 0.01), 600 µg (- 77%, P < 0.001) and 1000 µg (- 93%, P < 0.001) - and local manner. Mangiferin showed decreased levels of TNF-α (P < 0.001) and CINC-1 (P < 0.001), but not IL-1ß; it also prevented neutrophil migration (P < 0.01), but not the increased COX-2 expression in peripheral tissue challenged with carrageenan. To further explore the mechanisms of mangiferin actions, rats were injected with modulators of inflammation and nociception; mangiferin prevented hyperalgesia induced by IL-1ß (P < 0.01), CINC-1 (P < 0.01), epinephrine (P < 0.01), 8-Br-cAMP (P < 0.01) or capsaicin (P < 0.01), but not that induced by PGE2 or α,ß-MeATP. Our study shows that mangiferin has anti-inflammatory and analgesic properties when locally administrated. The control of the inflammatory response and mechanical hyperalgesia by mangiferin depends on the inhibition of TNF-α production/release and the CINC1/epinephrine/PKA pathway, supporting its marked inhibition of inflammatory mechanical hyperalgesia.

Asunto(s)

Analgésicos , Antiinflamatorios , Hiperalgesia , Xantonas , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Carragenina , Quimiocina CXCL1/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Epinefrina/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inmunología , Hiperalgesia/metabolismo , Interleucina-1beta/metabolismo , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Xantonas/farmacología , Xantonas/uso terapéutico

RESUMEN

Previous studies have shown that catecholamines in vivo and in vitro inhibit the activity of Ca2+-dependent proteolysis in skeletal muscles under basal conditions. In the present study we sought to investigate the role of catecholamines in regulating the Ca2+-dependent proteolysis in soleus and extensor digitorum longus (EDL) muscles from rats acutely exposed to cold. Overall proteolysis, the activity of proteolytic systems, protein levels and gene expression of different components of the calpain system were investigated in rats submitted to adrenodemedullation (ADMX) and exposed to cold for 24 h. ADMX drastically reduced plasma epinephrine and promoted an additional increase in the overall proteolysis, which was already increased by cold exposure. The rise in the rate of protein degradation in soleus muscles from adrenodemedullated cold-exposed rats was caused by the high activity of the Ca2+-dependent proteolysis, which was associated with the generation of a 145-kDa cleaved α-fodrin fragment, a typical calpain substrate, and lower protein levels and mRNA expression of calpastatin, the endogenous calpain inhibitor. Unlike that observed for soleus muscles, the cold-induced muscle proteolysis in EDL was not affected by ADMX. In isolated soleus muscle, clenbuterol, a selective ß2-adrenoceptor agonist, reduced the basal Ca2+-dependent proteolysis and completely abolished the activation of this pathway by the cholinergic agonist carbachol. These data suggest that catecholamines released from the adrenal medulla inhibit cold-induced protein breakdown in soleus, and this antiproteolytic effect on the Ca2+-dependent proteolytic system is apparently mediated through expression of calpastatin, which leads to suppression of calpain activation.NEW & NOTEWORTHY Although many effects of the sympathetic nervous system on muscle physiology are known, the role of catecholamines in skeletal muscle protein metabolism has been scarcely studied. We suggest that catecholamines released from adrenal medulla may be of particular importance for restraining the activation of the Ca2+-dependent proteolysis in soleus muscles during acute cold exposure. This finding helps us to understand the adaptive changes that occur in skeletal muscle protein metabolism during cold stress.

Asunto(s)

Médula Suprarrenal/metabolismo , Médula Suprarrenal/fisiología , Calcio/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Animales , Proteínas de Unión al Calcio/metabolismo , Calpaína/metabolismo , Proteínas Portadoras/metabolismo , Catecolaminas/metabolismo , Frío , Epinefrina/metabolismo , Masculino , Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Proteolisis , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/fisiología

RESUMEN

UNLABELLED: Enteric pathogens such as enterohemorrhagic Escherichia coli (EHEC) and Citrobacter rodentium, which is largely used as a surrogate EHEC model for murine infections, are exposed to several host neurotransmitters in the gut. An important chemical exchange within the gut involves the neurotransmitters epinephrine and/or norepinephrine, extensively reported to increase virulence gene expression in EHEC, acting through two bacterial adrenergic sensors: QseC and QseE. However, EHEC is unable to establish itself and cause its hallmark lesions, attaching and effacing (AE) lesions, on murine enterocytes. To address the role of these neurotransmitters during enteric infection, we employed C. rodentium Both EHEC and C. rodentium harbor the locus of enterocyte effacement (LEE) that is necessary for AE lesion formation. Here we show that expression of the LEE, as well as that of other virulence genes in C. rodentium, is also activated by epinephrine and/or norepinephrine. Both QseC and QseE are required for LEE gene activation in C. rodentium, and the qseC and qseE mutants are attenuated for murine infection. C. rodentium has a decreased ability to colonize dopamine ß-hydroxylase knockout (Dbh(-/-)) mice, which do not produce epinephrine and norepinephrine. Both adrenergic sensors are required for C. rodentium to sense these neurotransmitters and activate the LEE genes during infection. These data indicate that epinephrine and norepinephrine are sensed by bacterial adrenergic receptors during enteric infection to promote activation of their virulence repertoire. This is the first report of the role of these neurotransmitters during mammalian gastrointestinal (GI) infection by a noninvasive pathogen. IMPORTANCE: The epinephrine and norepinephrine neurotransmitters play important roles in gut physiology and motility. Of note, epinephrine and norepinephrine play a central role in stress responses in mammals, and stress has profound effects on GI function. Bacterial enteric pathogens exploit these neurotransmitters as signals to coordinate the regulation of their virulence genes. The bacterial QseC and QseE adrenergic sensors are at the center of this regulatory cascade. C. rodentium is a noninvasive murine pathogen with a colonization mechanism similar to that of EHEC, enabling the investigation of host signals in mice. The presence of these neurotransmitters in the gut is necessary for C. rodentium to fully activate its virulence program, in a QseC/QseE-dependent manner, to successfully colonize its murine host. Our study data provide the first example of epinephrine and norepinephrine signaling within the gut to stimulate infection by a bacterial pathogen in a natural animal infection.

Asunto(s)

Citrobacter rodentium/patogenicidad , Infecciones por Enterobacteriaceae/microbiología , Escherichia coli Enterohemorrágica/patogenicidad , Tracto Gastrointestinal/microbiología , Regulación Bacteriana de la Expresión Génica , Fosfoproteínas/genética , Receptores Adrenérgicos/genética , Animales , Citrobacter rodentium/genética , Dopamina beta-Hidroxilasa/genética , Enterocitos/microbiología , Escherichia coli Enterohemorrágica/genética , Epinefrina/genética , Epinefrina/metabolismo , Infecciones por Escherichia coli , Proteínas de Escherichia coli/genética , Genes Bacterianos , Interacciones Huésped-Patógeno , Ratones , Ratones Noqueados , Norepinefrina/genética , Norepinefrina/metabolismo , Vasoconstrictores , Virulencia/genética

RESUMEN

We have recently shown that chronic fluoxetine treatment acted significantly increasing plasma norepinephrine and epinephrine concentrations both in control and chronically stressed adult male rats. However, possible effects of fluoxetine on catecholamine synthesis and re-uptake in adrenal medulla have been largely unknown. In the present study the effects of chronic fluoxetine treatment on tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis, as well as a norepinephrine transporter and vesicular monoamine transporter 2 gene expressions in adrenal medulla of animals exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, were investigated. Gene expression analyses were performed using a real-time quantitative reverse transcription-PCR. Chronically stressed animals had increased tyrosine hydroxylase mRNA levels and decreased expression of both transporters. Fluoxetine increased tyrosine hydroxylase and decreased norepinephrine transporter gene expression in both unstressed and CUMS rats. These findings suggest that chronic fluoxetine treatment increased plasma catecholamine levels by affecting opposing changes in catecholamine synthesis and uptake.

Asunto(s)

Médula Suprarrenal/metabolismo , Antidepresivos de Segunda Generación/farmacología , Proteínas de Transporte de Catecolaminas en la Membrana Plasmática/metabolismo , Catecolaminas/biosíntesis , Fluoxetina/farmacología , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Animales , Epinefrina/metabolismo , Masculino , Norepinefrina/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estrés Psicológico , Tirosina 3-Monooxigenasa/metabolismo

RESUMEN

Sedentary lifestyle leads to the accumulation of visceral fat. This is accompanied by the infiltration of immune cells with pro-inflammatory characteristics in adipose tissue, causing an increased release of cytokines and generating a low-grade inflammatory state. It has been associated with the development of insulin resistance, atherosclerosis, neurodegeneration, and development of tumors. Exercise can be used as a treatment to improve symptoms of many of these conditions because it promotes an anti-inflammatory effect. In this review we analyze the pro-inflammatory factors present in obesity and the induction of antiinflammatory factors that occur with exercise.

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La vida sedentaria induce la acumulación de grasa visceral, que se acompaña de la infiltración de células inmunitarias con características proinflamatorias en el tejido adiposo, que ocasiona mayor liberación de citocinas y genera un estado inflamatorio de bajo grado, éste se ha asociado con resistencia a la insulina, aterosclerosis, neurodegeneración y tumores. El ejercicio físico puede indicarse como tratamiento para disminuir los síntomas de muchas afecciones porque promueve un estado antiinflamatorio. En esta revisión se analizarán los factores proinflamatorios que coexisten en la obesidad, y la inducción de factores antiinflamatorios que se originan con el ejercicio físico.

Asunto(s)

Ejercicio Físico , Inflamación/etiología , Obesidad/complicaciones , Conducta Sedentaria , Adipoquinas/metabolismo , Aterosclerosis/etiología , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/metabolismo , Ejercicio Físico/fisiología , Terapia por Ejercicio , Humanos , Hidrocortisona/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/prevención & control , Resistencia a la Insulina , Interleucina-6/metabolismo , Grasa Intraabdominal/metabolismo , Macrófagos/metabolismo , Contracción Muscular , Neoplasias/etiología , Neoplasias/inmunología , Neoplasias/metabolismo , Degeneración Nerviosa/etiología , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Estrés Oxidativo , Linfocitos T Reguladores/inmunología , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine.

Asunto(s)

Epinefrina/farmacología , Paro Cardíaco/tratamiento farmacológico , Lipresina/análogos & derivados , Modelos Animales , Naloxona/farmacología , Vasoconstrictores/farmacología , Animales , Presión Arterial/efectos de los fármacos , Asfixia/complicaciones , Reanimación Cardiopulmonar , Epinefrina/metabolismo , Paro Cardíaco/etiología , Paro Cardíaco/fisiopatología , Hemodinámica/efectos de los fármacos , Lipresina/metabolismo , Lipresina/farmacología , Masculino , Naloxona/metabolismo , Distribución Aleatoria , Ratas , Ratas Wistar , Valores de Referencia , Reproducibilidad de los Resultados , Terlipresina , Factores de Tiempo , Vasoconstrictores/metabolismo

RESUMEN

Animals living in nontropical climates modify their physiology and behavior to adapt to seasonal environmental changes. Part of this adaptation involves the release of catecholamine from sympathetic nerve endings and the adrenal medulla, which play a major role in regulating energy balance. The aim of this work was to investigate whether adult male viscachas in their natural habitat exhibits structural changes in the adrenal medulla during the annual seasonal cycle. In August-September, chromaffin granules revealed ultrastructural changes suggestive of piecemeal degranulation. Quantitative morphometric analysis by transmission electron microscopy showed a significantly lower percentage of resting chromaffin granules and a higher percentage of altered granules and empty containers in August-September (late winter) compared to February-March (late summer), suggesting an increased secretory process of catecholamines in August-September. The mechanism of piecemeal degranulation might amplify this process, encouraging the adaptive response to winter environmental conditions. Tissue levels of epinephrine, norepinephrine, and dopamine (analyzed by high-performance liquid chromatography) changed throughout the year, reaching maximum values in February-March and minimum values in August-September. These results demonstrate morphological and biochemical seasonal variations of the adrenal medulla, suggesting that epinephrine might promote energy mobilization, which allow the Lagostomus to cope with adverse environmental conditions and thus to survive during winter season.

Asunto(s)

Médula Suprarrenal/metabolismo , Catecolaminas/metabolismo , Gránulos Cromafines/metabolismo , Roedores/metabolismo , Estaciones del Año , Adaptación Fisiológica , Médula Suprarrenal/ultraestructura , Animales , Degranulación de la Célula , Gránulos Cromafines/ultraestructura , Cromatografía Líquida de Alta Presión , Dopamina/metabolismo , Metabolismo Energético , Epinefrina/metabolismo , Masculino , Microscopía Electrónica de Transmisión , Norepinefrina/metabolismo , Lluvia , Luz Solar , Temperatura , Factores de Tiempo

RESUMEN

OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine. .

Asunto(s)

Animales , Masculino , Ratas , Epinefrina/farmacología , Paro Cardíaco/tratamiento farmacológico , Lipresina/análogos & derivados , Modelos Animales , Naloxona/farmacología , Vasoconstrictores/farmacología , Presión Arterial/efectos de los fármacos , Asfixia/complicaciones , Reanimación Cardiopulmonar , Epinefrina/metabolismo , Paro Cardíaco/etiología , Paro Cardíaco/fisiopatología , Hemodinámica/efectos de los fármacos , Lipresina/metabolismo , Lipresina/farmacología , Naloxona/metabolismo , Distribución Aleatoria , Ratas Wistar , Valores de Referencia , Reproducibilidad de los Resultados , Factores de Tiempo , Vasoconstrictores/metabolismo

RESUMEN

We examined the underlying neural-endocrine mechanisms of asthma associated with respiratory syncytial virus infection. Thirty Sprague-Dawley rats were randomly divided into control group, respiratory syncytial virus (RSV) group, and anti-nerve growth factor (NGF) IgG group. An RSV infection model was established by nasal drip once a week. In the anti-NGF antibody intervention group, each rat was given an intraperitoneal injection of anti-NGF IgG 3 h before RSV infection. Optical microscopy and transmission electron microscopy were used to observe the structural changes in adrenal medulla cells. Changes in adrenaline and norepinephrine in serum were detected by ELISA. NGF expression was assayed by immunohistochemistry. Expression differences in synaptophysin mRNA were detected by RT-PCR. Transmission electron microscopy displayed widened adrenal medulla intercellular spaces, reduced chromaffin particle concentration, and increased mitochondria in the RSV infection group. At the same time, NGF expression was increased in the RSV infection group significantly. In addition, the adrenaline concentration was significantly decreased compared with the control and anti-NGF antibody groups. Synaptophysin mRNA expression was significantly increased in the RSV infection and anti-NGF antibody groups. However, compared with the RSV infection group, synaptophysin mRNA expression was significantly decreased in the anti-NGF antibody group. We conclude that RSV infection could induce adrenal medulla cell differentiation to nerve cells by over-expression of NGF, resulting in the decreased endocrine function found in asthma progression.

Asunto(s)

Asma/complicaciones , Asma/virología , Sistema Endocrino/metabolismo , Sistema Nervioso/metabolismo , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitiales Respiratorios/fisiología , Médula Suprarrenal/patología , Médula Suprarrenal/ultraestructura , Animales , Asma/fisiopatología , Hiperreactividad Bronquial/complicaciones , Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/virología , Modelos Animales de Enfermedad , Epinefrina/metabolismo , Regulación de la Expresión Génica , Células HeLa , Humanos , Inmunohistoquímica , Hibridación in Situ , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Factor de Crecimiento Nervioso/metabolismo , Norepinefrina/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Infecciones por Virus Sincitial Respiratorio/fisiopatología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sinaptofisina/genética , Sinaptofisina/metabolismo

RESUMEN

Maternal nutritional status affects the future development of offspring. Both undernutrition and overnutrition in critical periods of life (gestation or lactation) may cause several hormonal changes in the pups and programme obesity in the adult offspring. We have shown that hyperleptinaemia during lactation results in central leptin resistance, higher adrenal catecholamine secretion, hyperthyroidism, and higher blood pressure and heart rate in the adult rats. Here, we evaluated the effect of a maternal isocaloric high-fat diet on breast milk composition and its impact on leptinaemia, energy metabolism, and adrenal and thyroid function of the offspring at weaning. We hypothesised that the altered source of fat in the maternal diet even under normal calorie intake would disturb the metabolism of the offspring. Female Wistar rats were fed a normal (9% fat; C group) or high-fat diet (29% fat as lard; HF group) for 8 weeks before mating and during pregnancy and lactation. HF mothers presented increased total body fat content after 8 weeks (+27%, P < 0.05) and a similar fat content at the end of lactation. In consequence, the breast milk from the HF group had higher concentration of protein (+18%, P < 0.05), cholesterol (+52%, P < 0.05) and triglycerides (+86%, P < 0.05). At weaning, HF offspring had increased body weight (+53%, P < 0.05) and adiposity (2 fold, P < 0.05), which was associated with lower ß3-adrenoreceptor content in adipose tissue (-40%, P < 0.05). The offspring also presented hyperglycaemia (+30%, P < 0.05) and hyperleptinaemia (+62%, P < 0.05). In the leptin signalling pathway in the hypothalamus, we found lower p-STAT3/STAT3 (-40%, P < 0.05) and SOCS3 (-55%, P < 0.05) content in the arcuate nucleus, suggesting leptin resistance. HF offspring also had higher adrenal catecholamine content (+17%, P < 0.05), liver glycogen content (+50%, P < 0.05) and hyperactivity of the thyroid axis at weaning. Our results suggest that a high fat diet increases maternal body fat and this additional energy is transferred to the offspring during lactation, since at weaning the dams had normal fat and the pups were obese. The higher fat and protein concentrations in the breast milk seemed to induce early overnutrition in the HF offspring. In addition to storing energy as fat, the HF offspring had a larger reserve of glycogen and hyperglycaemia that may have resulted from increased gluconeogenesis. Hyperleptinaemia may stimulate both adrenal medullary and thyroid function, which may contribute to the development of cardiovascular diseases. These early changes induced by the maternal high-fat diet may contribute to development of metabolic syndrome.

Asunto(s)

Enfermedades de las Glándulas Suprarrenales/etiología , Dieta Alta en Grasa/efectos adversos , Fenómenos Fisiologicos Nutricionales Maternos , Leche Humana/química , Obesidad/etiología , Enfermedades de la Tiroides/etiología , Adiponectina/sangre , Adiposidad , Enfermedades de las Glándulas Suprarrenales/metabolismo , Animales , Epinefrina/metabolismo , Ácidos Grasos no Esterificados/sangre , Femenino , Glucosa/metabolismo , Lactancia , Leptina/metabolismo , Masculino , Norepinefrina/metabolismo , Obesidad/metabolismo , Ratas , Ratas Wistar , Enfermedades de la Tiroides/metabolismo , Hormonas Tiroideas/metabolismo , Destete

RESUMEN

We have recently shown that the ethanol extract of the leaves of Hedyosmum brasiliense exhibits an antidepressant-like effect in the tail suspension and forced swimming tests in mice. The present study investigates the mechanisms involved in the antidepressant-like effect of H. brasiliense extract, together with the antidepressant potential of podoandin, an isolated sesquiterpenoid. H. brasiliense (50mg/kg, i.p.) and podoandin (10mg/kg, i.p.) decreased the immobility time in the forced swimming test, without any accompanying changes in ambulation in the open-field test. The anti-immobility effect of the H. brasiliense extract was prevented by pre-treating the mice with ondansetron, NAN 190, pindolol, prazosin, yohimbine, haloperidol, SCH23390, and sulpiride. On the other hand, pre-treating the mice with: p-chlorophenylalanine (4 consecutive days), ketanserin, naloxone, naltrindole, bicuculline, phaclofen, or l-arginine did not block the antidepressant-like effect of H. brasiliense. In addition, pre-treatment of the animals with methylene blue, NG-nitro-l-arginine or 7-nitroindazole, at subeffective doses, did not cause a synergistic effect with H. brasiliense extract at an effective dose in the forced swimming test. The anti-immobility effect of podoandin was also prevented by pre-treating the mice with NAN-190, ondansetron, prazosin, yohimbine, sulpiride and haloperidol. The results indicate that the antidepressant-like effect of H. brasiliense (and podoandin) is dependent on the serotonergic, noradrenergic and dopaminergic systems, but not on the GABAergic, opioid and oxidonitrergic systems.

Asunto(s)

4-Butirolactona/análogos & derivados , Antidepresivos/farmacología , Cicloheptanos/farmacología , Helechos/química , Lactonas/farmacología , Neurotransmisores/metabolismo , Extractos Vegetales/farmacología , Sesquiterpenos/farmacología , 4-Butirolactona/aislamiento & purificación , 4-Butirolactona/farmacología , Analgésicos Opioides/metabolismo , Animales , Antidepresivos/aislamiento & purificación , Arginina/metabolismo , GMP Cíclico/metabolismo , Cicloheptanos/aislamiento & purificación , Dopamina/metabolismo , Interacciones Farmacológicas , Epinefrina/metabolismo , Fluoxetina/farmacología , Lactonas/aislamiento & purificación , Locomoción/efectos de los fármacos , Masculino , Ratones , Óxido Nítrico/metabolismo , Norepinefrina/metabolismo , Extractos Vegetales/aislamiento & purificación , Serotonina/metabolismo , Sesquiterpenos/aislamiento & purificación , Natación

RESUMEN

Cohabitation for 14 days with Ehrlich tumor-bearing mice was shown to increase locomotor activity, to decrease hypothalamic noradrenaline (NA) levels, to increase NA turnover and to decrease innate immune responses and decrease the animals' resistance to tumor growth. Cage mates of a B16F10 melanoma-bearer mice were also reported to show neuroimmune changes. Chemosignals released by Ehrlich tumor-bearing mice have been reported to be relevant for the neutrophil activity changes induced by cohabitation. The present experiment was designed to further analyze the effects of odor cues on neuroimmune changes induced by cohabitation with a sick cage mate. Specifically, the relevance of chemosignals released by an Ehrlich tumor-bearing mouse was assessed on the following: behavior (open-field and plus maze); hypothalamic NA levels and turnover; adrenaline (A) and NA plasmatic levels; and host resistance induced by tumor growth. To comply with such objectives, devices specifically constructed to analyze the influence of chemosignals released from tumor-bearing mice were employed. The results show that deprivation of odor cues released by Ehrlich tumor-bearing mice reversed the behavioral, neurochemical and immune changes induced by cohabitation. Mice use scents for intraspecies communication in many social contexts. Tumors produce volatile organic compounds released into the atmosphere through breath, sweat, and urine. Our results strongly suggest that volatile compounds released by Ehrlich tumor-injected mice are perceived by their conspecifics, inducing the neuroimmune changes reported for cohabitation with a sick companion.

Asunto(s)

Carcinoma de Ehrlich/inmunología , Carcinoma de Ehrlich/psicología , Señales (Psicología) , Neuroinmunomodulación/fisiología , Olfato/fisiología , Animales , Ansiedad/psicología , Conducta Animal/fisiología , Carcinoma de Ehrlich/patología , Epinefrina/sangre , Epinefrina/metabolismo , Femenino , Hipotálamo/metabolismo , Conducta de Enfermedad/fisiología , Ratones , Actividad Motora/fisiología , Activación Neutrófila/fisiología , Norepinefrina/sangre , Norepinefrina/metabolismo , Odorantes , Conducta Social

RESUMEN

FUNDAMENTO: Mecanismos subjacentes a anormalidades vasculares na obesidade ainda não estão completamente esclarecidos. OBJETIVO: Foi avaliada a via do óxido nítrico/L-arginina na resposta vascular de ratos obesos por dieta rica em gordura, enfocando as células endoteliais e do músculo liso. MÉTODOS: Ratos com 30 dias de vida foram divididos em 2 grupos: controle (C) e obeso (OB, ratos sob dieta rica em gordura por 30 semanas). Após 30 semanas, foram registrados o peso corporal, índice de adiposidade, pressão arterial e perfis metabólicos e endócrinos dos animais. Foram obtidas curvas para noradrelanina na ausência e presença de inibidor de óxido nítrico sintase (L-NAME, 3x10-4M) em aorta torácica intacta e com desnudamento em ratos C e OB. RESULTADOS: As medidas de peso corporal, índice de adiposidade, leptina e insulina aumentaram nos ratos OB, enquanto a pressão arterial permaneceu inalterada. A obesidade também produziu tolerância à glicose e resistência à insulina. A reatividade à noradrenalina da aorta intacta foi similar em ratos C e OB. A presença de L-NAME produziu um aumento similar nas respostas máximas, mas um desvio maior à esquerda das respostas nas aortas intactas dos ratos C em relação aos ratos OB [EC50 (x10-7M): C = 1,84 (0,83-4,07), O = 2,49 (1,41-4,38); presença de L-NAME C = 0,02 (0,01-0,04)*, O = 0,21 (0,11-0,40)*†,*p < 0,05 vs controle respectivo,†p < 0,05 vs controle mais L-NAME, n = 6-7]. Nenhum dos protocolos alterou a reatividade à noradrenalina de aortas com desnudamento. CONCLUSÃO: A obesidade induzida por dieta rica em gordura promove alterações metabólicas e vasculares. A alteração vascular envolveu uma melhora da via endotelial L-arginina/NO provavelmente relacionada à hiperinsulinemia e hiperleptinemia induzidas por dieta. A maior resistência aos efeitos do L-NAME na aorta de ratos obesos diz respeito a menor vulnerabilidade de indivíduos obesos na presença de patologias associadas que causam danos à atividade do sistema NO.

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BACKGROUND: Mechanisms underlying vascular abnormalities in obesity remain to be completely clarified. OBJECTIVE: L-arginine/nitric oxide pathway was evaluated on vascular response of high-fat diet-obese rats, focusing on endothelial and smooth muscle cells. METHODS: 30-day-old rats were divided in two groups: control (C) and obese (OB, high-fat diet for 30 weeks). After 30 weeks, body weight, adiposity index, blood pressure, and metabolic and endocrine profiles of the animals were recorded. Curves to noradrenaline were obtained in absence and presence of nitric oxide synthase inhibitor (L-NAME, 3x10-4M) on intact and denuded thoracic aorta from C and OB rats. RESULTS: Body weight, adiposity index, leptin and insulin levels were increased in OB, while blood pressure was unchanged. Obesity also produced glucose tolerance and insulin resistance. Reactivity to noradrenaline of intact aorta was similar in C and OB rats. L-NAME presence produced a similar increase in maximal responses, but a higher leftward shift of noradrenaline responses in intact aorta from C than in OB rats [EC50 (x10-7M): C = 1.84 (0.83-4.07), O = 2.49 (1.41-4.38); L-NAME presence C = 0.02 (0.01-0.04)*, O = 0.21 (0.11-0.40)*†,*p < 0.05 vs respective control, †p < 0.05 vs control plus L-NAME, n = 6-7]. None of the protocols altered the reactivity to noradrenaline of denuded aortas. CONCLUSION: High-fat diet-induced obesity promotes metabolic and vascular alterations. The vascular alteration involved an endothelial L-arginine/NO pathway improvement was probably correlated to diet-induced hyperinsulinemia and hyperleptinemia. The greater resistance to L-NAME effects in aorta of obese rats raises concerns about the lower cardiovascular vulnerability of obese individuals in the presence of associated pathologies that impair NO-system activity.

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FUNDAMENTO: Los mecanismos subyacentes a las anormalidades vasculares en la obesidad todavía no están completamente aclarados. OBJETIVO: Se evaluó la vía del óxido nítrico/L-arginina en la respuesta vascular de ratones obesos por dieta rica en grasa, concentrándonos en las células endoteliales y en el músculo liso. MÉTODOS: Ratones con 30 días de vida que fueron divididos en 2 grupos: control (C) y obeso (OB, ratones bajo dieta rica en grasa durante 30 semanas). Después de 30 semanas, fueron registrados el peso corporal, el índice de adiposidad, la presión arterial y los perfiles metabólicos y endocrinos de los animales. Fueron obtenidas las curvas para noradrelanina en ausencia y en presencia del inhibidor de óxido nítrico sintasa (L-NAME, 3x10-4M), en la aorta torácica intacta y con denudación de los ratones C y OB. RESULTADOS: Las medidas de peso corporal, índice de adiposidad, leptina e insulina aumentaron en los ratones OB, mientras que la presión arterial permaneció inalterada. La obesidad también produjo una tolerancia a la glucosa y una resistencia a la insulina. La reactividad a la noradrenalina de la aorta intacta fue similar en los ratones C y OB. La presencia de L-NAME generó un aumento similar en las respuestas máximas, pero una desviación mayor a la izquierda de las respuestas en las aortas intactas de los ratones C con relación a los ratones OB [EC50 (x10-7M): C = 1,84 (0,83-4,07), O = 2,49 (1,41-4,38); presencia de L-NAME C = 0,02 (0,01-0,04)*, O = 0,21 (0,11-0,40)*†,*p < 0,05 vs control respectivo, †p < 0,05 vs control más L-NAME, n = 6-7]. Ninguno de los protocolos alteró la reactividad a la noradrenalina de las aortas con denudación. CONCLUSIÓN: La obesidad inducida por dieta rica en grasa genera alteraciones metabólicas y vasculares. La alteración vascular conllevó a una mejoría de la vía endotelial L-arginina/NO tal vez relacionada con la hiperinsulinemia e hiperleptinemia inducidas por dieta. La mayor resistencia a los efectos del L-NAME en la aorta de ratones obesos, se refiere a una menor vulnerabilidad de individuos obesos en presencia de patologías asociadas que causan daños a la actividad del sistema NO.

Asunto(s)

Animales , Masculino , Ratas , Aorta Torácica/metabolismo , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/metabolismo , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico/metabolismo , Obesidad/metabolismo , Adiposidad , Aorta Torácica/fisiopatología , Presión Sanguínea , Peso Corporal , Glucemia/análisis , Endotelio Vascular/fisiopatología , Epinefrina/metabolismo , Miocitos del Músculo Liso/metabolismo , Obesidad/fisiopatología , Ratas Wistar , Factores de Tiempo

RESUMEN

BACKGROUND: Mechanisms underlying vascular abnormalities in obesity remain to be completely clarified. OBJECTIVE: L-arginine/nitric oxide pathway was evaluated on vascular response of high-fat diet-obese rats, focusing on endothelial and smooth muscle cells. METHODS: 30-day-old rats were divided in two groups: control (C) and obese (OB, high-fat diet for 30 weeks). After 30 weeks, body weight, adiposity index, blood pressure, and metabolic and endocrine profiles of the animals were recorded. Curves to noradrenaline were obtained in absence and presence of nitric oxide synthase inhibitor (L-NAME, 3x10-4M) on intact and denuded thoracic aorta from C and OB rats. RESULTS: Body weight, adiposity index, leptin and insulin levels were increased in OB, while blood pressure was unchanged. Obesity also produced glucose tolerance and insulin resistance. Reactivity to noradrenaline of intact aorta was similar in C and OB rats. L-NAME presence produced a similar increase in maximal responses, but a higher leftward shift of noradrenaline responses in intact aorta from C than in OB rats [EC50 (x10-7M): C = 1.84 (0.83-4.07), O = 2.49 (1.41-4.38); L-NAME presence C = 0.02 (0.01-0.04)*, O = 0.21 (0.11-0.40)**p < 0.05 vs respective control, p < 0.05 vs control plus L-NAME, n = 6-7]. None of the protocols altered the reactivity to noradrenaline of denuded aortas. CONCLUSION: High-fat diet-induced obesity promotes metabolic and vascular alterations. The vascular alteration involved an endothelial L-arginine/NO pathway improvement was probably correlated to diet-induced hyperinsulinemia and hyperleptinemia. The greater resistance to L-NAME effects in aorta of obese rats raises concerns about the lower cardiovascular vulnerability of obese individuals in the presence of associated pathologies that impair NO-system activity.

Asunto(s)

Aorta Torácica/metabolismo , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/metabolismo , NG-Nitroarginina Metil Éster/metabolismo , Óxido Nítrico/metabolismo , Obesidad/metabolismo , Adiposidad , Animales , Aorta Torácica/fisiopatología , Glucemia/análisis , Presión Sanguínea , Peso Corporal , Endotelio Vascular/fisiopatología , Epinefrina/metabolismo , Masculino , Miocitos del Músculo Liso/metabolismo , Obesidad/fisiopatología , Ratas , Ratas Wistar , Factores de Tiempo

RESUMEN

By combining the chick embryo model with incubation at high altitude, this study tested the hypothesis that development at high altitude is related to a fetal origin of adrenocortical but not adrenomedullary suppression and that hypoxia is the mechanism underlying the relationship. Fertilized eggs from sea-level or high altitude hens were incubated at sea level or high altitude. Fertilized eggs from sea-level hens were also incubated at altitude with oxygen supplementation. At day 20 of incubation, embryonic blood was taken for measurement of plasma corticotropin, corticosterone, and Po(2). Following biometry, the adrenal glands were collected and frozen for measurement of catecholamine content. Development of chick embryos at high altitude led to pronounced adrenocortical blunting, but an increase in adrenal catecholamine content. These effects were similar whether the fertilized eggs were laid by sea-level or high altitude hens. The effects of high altitude on the stress axes were completely prevented by incubation at high altitude with oxygen supplementation. When chick embryos from high altitude hens were incubated at sea level, plasma hormones and adrenal catecholamine content were partially restored toward levels measured in sea-level chick embryos. There was a significant correlation between adrenocortical blunting and elevated adrenal catecholamine content with both asymmetric growth restriction and fetal hypoxia. The data support the hypothesis tested and provide evidence to isolate the direct contribution of developmental hypoxia to alterations in the stress system.

Asunto(s)

Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/sangre , Altitud , Hipoxia/metabolismo , Animales , Embrión de Pollo , Corticosterona/sangre , Epinefrina/metabolismo , Hipoxia/sangre , Norepinefrina/metabolismo , Oxígeno/sangre

RESUMEN

Stress-induced catecholamine impairs the formation of granulation tissue acting directly in fibroblast activity; however, the mechanism by which high levels of catecholamines alter the granulation tissue formation is still unclear. Thus, the aim of this study was to investigate how high levels of epinephrine compromise the activity of murine dermal fibroblasts. Dermal fibroblasts isolated from the skin of neonatal Swiss mice were preincubated with α- or ß-adrenoceptor antagonists. Thereafter, cells were exposed to physiologically elevated levels of epinephrine or epinephrine plus α- or ß-adrenoceptor antagonists, and fibroblast activity was evaluated. The blockade of ß1- and ß2-adrenoceptors reversed the increase in fibroblast proliferation, ERK 1/2 phosphorylation, myofibroblastic differentiation and the reduction of collagen deposition induced by epinephrine. In addition, the blockade of ß3-adrenoceptors reversed the increase in fibroblast proliferation and nitric oxide synthesis as well as the reduction of fibroblast migration, AKT phosphorylation and active matrix metalloproteinase-2 expression induced by epinephrine. However, the blockade of α1- and α2-adrenoceptors did not alter the effects of epinephrine on the activity of murine dermal fibroblasts. In conclusion, high levels of epinephrine directly compromise the activity of neonatal mouse skin fibroblasts through the activation of ß1-, ß2- and ß3-adrenoceptors, but not through α1- and α2-adrenoceptors.

Asunto(s)

Dermis/citología , Epinefrina/farmacología , Fibroblastos/metabolismo , Receptores Adrenérgicos beta/metabolismo , Estrés Psicológico/metabolismo , Actinas/metabolismo , Antagonistas de Receptores Adrenérgicos beta 3 , Antagonistas Adrenérgicos beta , Animales , Animales Recién Nacidos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cromonas/farmacología , Epinefrina/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Hidroxiprolina/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos , Morfolinas/farmacología , NG-Nitroarginina Metil Éster/farmacología , Nitritos/metabolismo , Fentolamina/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Propanolaminas/farmacología , Propranolol/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo

RESUMEN

BACKGROUND: Biological systems are commonly described as networks of entity interactions. Some interactions are already known and integrate the current knowledge in life sciences. Others remain unknown for long periods of time and are frequently discovered by chance. In this work we present a model to predict these unknown interactions from a textual collection using the vector space model (VSM), a well known and established information retrieval model. We have extended the VSM ability to retrieve information using a transitive closure approach. Our objective is to use the VSM to identify the known interactions from the literature and construct a network. Based on interactions established in the network our model applies the transitive closure in order to predict and rank new interactions. RESULTS: We have tested and validated our model using a collection of patent claims issued from 1976 to 2005. From 266,528 possible interactions in our network, the model identified 1,027 known interactions and predicted 3,195 new interactions. Iterating the model according to patent issue dates, interactions found in a given past year were often confirmed by patent claims not in the collection and issued in more recent years. Most confirmation patent claims were found at the top 100 new interactions obtained from each subnetwork. We have also found papers on the Web which confirm new inferred interactions. For instance, the best new interaction inferred by our model relates the interaction between the adrenaline neurotransmitter and the androgen receptor gene. We have found a paper that reports the partial dependence of the antiapoptotic effect of adrenaline on androgen receptor. CONCLUSIONS: The VSM extended with a transitive closure approach provides a good way to identify biological interactions from textual collections. Specifically for the context of literature-based discovery, the extended VSM contributes to identify and rank relevant new interactions even if these interactions occur in only a few documents in the collection. Consequently, we have developed an efficient method for extracting and restricting the best potential results to consider as new advances in life sciences, even when indications of these results are not easily observed from a mass of documents.

Asunto(s)

Algoritmos , Modelos Teóricos , Bases de Datos Factuales , Epinefrina/metabolismo , Humanos , Internet , Redes Neurales de la Computación , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Interfaz Usuario-Computador