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1.
Sci Rep ; 7(1): 3777, 2017 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-28630440

RESUMEN

The spread of multidrug-resistant Staphylococcus aureus strains, including methicillin-resistant S. aureus (MRSA), has shortened the useful life of anti-staphylococcal drugs enormously. Two approaches can be followed to address this problem: screening various sources for new leads for antibiotics or finding ways to disable the resistance mechanisms to existing antibiotics. Plants are resistant to most microorganisms, but despite extensive efforts to identify metabolites that are responsible for this resistance, no substantial progress has been made. Plants possibly use multiple strategies to deal with microorganisms that evolved over time. For this reason, we searched for plants that could potentiate the effects of known antibiotics. From 29 plant species tested, Cytisus striatus clearly showed such an activity and an NMR-based metabolomics study allowed the identification of compounds from the plant extracts that could act as antibiotic adjuvants. Isoflavonoids were found to potentiate the effect of ciprofloxacin and erythromycin against MRSA strains. For the structure-activity relationship (SAR), 22 isoflavonoids were assessed as antibiotic adjuvants. This study reveals a clear synergy between isoflavonoids and the tested antibiotics, showing their great potential for applications in the clinical therapy of infections with antibiotic-resistant microorganisms such as MRSA.


Asunto(s)
Antibacterianos/farmacología , Ciprofloxacina/farmacología , Cytisus/química , Eritromicina/farmacología , Isoflavonas/farmacología , Staphylococcus aureus Resistente a Meticilina/crecimiento & desarrollo , Hojas de la Planta/química , Antibacterianos/química , Ciprofloxacina/agonistas , Sinergismo Farmacológico , Eritromicina/agonistas , Isoflavonas/agonistas , Isoflavonas/química
2.
Mol Psychiatry ; 14(4): 398-415, 347, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19030002

RESUMEN

Schizophrenia is a widespread psychiatric disorder, affecting 1% of people. Despite this high prevalence, schizophrenia is not well treated because of its enigmatic developmental origin. We explore here the developmental etiology of endophenotypes associated with schizophrenia using a regulated transgenic approach in mice. Recently, a polymorphism that increases mRNA levels of the G-protein subunit Galphas was genetically linked to schizophrenia. Here we show that regulated overexpression of Galphas mRNA in forebrain neurons of mice is sufficient to cause a number of schizophrenia-related phenotypes, as measured in adult mice, including sensorimotor gating deficits (prepulse inhibition of acoustic startle, PPI) that are reversed by haloperidol or the phosphodiesterase inhibitor rolipram, psychomotor agitation (hyperlocomotion), hippocampus-dependent learning and memory retrieval impairments (hidden water maze, contextual fear conditioning), and enlarged ventricles. Interestingly, overexpression of Galphas during development plays a significant role in some (PPI, spatial learning and memory and neuroanatomical deficits) but not all of these adulthood phenotypes. Pharmacological and biochemical studies suggest the Galphas-induced behavioral deficits correlate with compensatory decreases in hippocampal and cortical cyclic AMP (cAMP) levels. These decreases in cAMP may lead to reduced activation of the guanine exchange factor Epac (also known as RapGEF 3/4) as stimulation of Epac with the select agonist 8-pCPT-2'-O-Me-cAMP increases PPI and improves memory in C57BL/6J mice. Thus, we suggest that the developmental impact of a given biochemical insult, such as increased Galphas expression, is phenotype specific and that Epac may prove to be a novel therapeutic target for the treatment of both developmentally regulated and non-developmentally regulated symptoms associated with schizophrenia.


Asunto(s)
Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Regulación del Desarrollo de la Expresión Génica/genética , Acetilcisteína/agonistas , Acetilcisteína/análogos & derivados , Acetilcisteína/antagonistas & inhibidores , Estimulación Acústica , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Antipsicóticos/uso terapéutico , Conducta Animal , Encéfalo/metabolismo , Encéfalo/patología , Trastornos del Conocimiento/tratamiento farmacológico , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , AMP Cíclico/análogos & derivados , AMP Cíclico/metabolismo , AMP Cíclico/farmacología , Modelos Animales de Enfermedad , Eritromicina/agonistas , Eritromicina/análogos & derivados , Eritromicina/antagonistas & inhibidores , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Miedo/efectos de los fármacos , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Haloperidol/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de Fosfodiesterasa/farmacología , Psicofísica , Reflejo de Sobresalto/genética , Rolipram/farmacología , Factores de Tiempo
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