RESUMEN
The Nrf2 signaling pathway prevents cancer initiation, but genetic mutations that activate this pathway are found in various types of cancer. The molecular mechanisms underlying this Janus-headed character are still not understood. Here, we show that sustained Nrf2 activation induces proliferation and dedifferentiation of a Wnt-responsive perivenular hepatic progenitor cell population, transforming them into metastatic cancer cells. The neoplastic lesions display many histological features known from human hepatoblastoma. We describe an Nrf2-induced upregulation of ß-catenin expression and its activation as the underlying mechanism for the observed malignant transformation. Thus, we have identified the Nrf2-ß-catenin axis promoting proliferation of hepatic stem cells and triggering tumorigenesis. These findings support the concept that different functional levels of Nrf2 control both the protection against various toxins as well as liver regeneration by activating hepatic stem cells. Activation of the hepatic stem cell compartment confers the observation that unbridled Nrf2 activation may trigger tumorigenesis.
Asunto(s)
Neoplasias Hepáticas , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Células Madre/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Neoplasias Hepáticas/metabolismo , Proliferación CelularRESUMEN
The major histopathological hallmarks of Alzheimer's disease (AD) include ß-amyloid (Aß) plaques, neurofibrillary tangles, and neuronal loss. Aß 1-42 (Aß1-42) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aß1-42 were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2). The present study investigated the impact of a new FPR2 agonist, MR-39, on the neuroinflammatory response in ex vivo and in vivo models of AD. To address this question, organotypic hippocampal cultures from wild-type (WT) and FPR2-deficient mice (knockout, KO, FPR2-/-) were treated with fibrillary Aß1-42, and the effect of the new FPR2 agonist MR-39 on the release of pro- and anti-inflammatory cytokines was assessed. Similarly, APP/PS1 double-transgenic AD mice were treated for 20 weeks with MR-39, and immunohistological staining was performed to assess neuronal loss, gliosis, and Aß load in the hippocampus and cortex. The data indicated that MR-39 was able to reduce the Aß1-42-induced release of proinflammatory cytokines and to improve the release of anti-inflammatory cytokines in mouse hippocampal organotypic cultures. The observed effect was apparently related to the inhibition of the MyD88/TRAF6/NFкB signaling pathway and a decrease in NLRP3 inflammasome activation. Administration of MR-39 to APP/PS1 mice improved neuronal survival and decreased microglial cell density and plaque load.These results suggest that FPR2 may be a promising target for alleviating the inflammatory process associated with AD and that MR-39 may be a useful therapeutic agent for AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/farmacología , Antiinflamatorios/uso terapéutico , Hipocampo/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Fragmentos de Péptidos/farmacología , Receptores de Formil Péptido/agonistas , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Antiinflamatorios/farmacología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Ratones , Ratones Transgénicos , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patologíaRESUMEN
BACKGROUND: Bacterial meningitis is still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein-coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands, including pro- and anti-inflammatory ones. Here, we investigated the effects of the annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis. METHODS: Wildtype (WT) and Fpr1- and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8, and 24 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection. RESULTS: Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in Fpr2-deficient compared to Fpr1-deficient mice. CONCLUSIONS: In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for Streptococcus pneumoniae-induced meningitis.
Asunto(s)
Anexina A1/uso terapéutico , Antiinflamatorios/uso terapéutico , Encefalitis/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Meningitis Neumocócica/tratamiento farmacológico , Infiltración Neutrófila/efectos de los fármacos , Péptidos/uso terapéutico , Animales , Anexina A1/farmacología , Antiinflamatorios/farmacología , Ratones , Ratones Noqueados , Neutrófilos/efectos de los fármacos , Péptidos/farmacología , Receptores de Formil Péptido/genética , Resultado del TratamientoRESUMEN
BACKGROUND: An important hallmark of Alzheimer's disease (AD) is the increase of Aß1-42 burden and its accumulation to senile plaques, leading the reactive gliosis and neurodegeneration. The modulation of glia cell function represents an attractive therapeutic strategy, but is currently limited by an incomplete understanding of its relevance for AD. The chemotactic G-protein coupled formyl peptide receptor (FPR), which is known to modulate Aß1-42 uptake and signal transduction, might be one candidate molecule regulating glia function in AD. Here, we investigate whether the modulation of FPR exerts beneficial effects in an AD preclinical model. METHODS: To address this question, APP/PS1 double-transgenic AD mice were treated for 20 weeks with either the pro-inflammatory FPR agonist fMLF, the FPR1/2 antagonist Boc2 or the anti-inflammatory FPR2 agonist Ac2-26. Spatial learning and memory were evaluated using a Morris water maze test. Immunohistological staining, gene expression studies, and flow cytometry analyses were performed to study neuronal loss, gliosis, and Aß-load in the hippocampus and cortex, respectively. RESULTS: FPR antagonism by Boc2-treatment significantly improved spatial memory performance, reduced neuronal pathology, induced the expression of homeostatic growth factors, and ameliorated microglia, but not astrocyte, reactivity. Furthermore, the elevated levels of amyloid plaques in the hippocampus were reduced by Boc2-treatment, presumably by an induction of amyloid degradation. CONCLUSIONS: We suggest that the modulation of FPR signaling cascades might be considered as a promising therapeutic approach for alleviating the cognitive deficits associated with early AD. Additional studies are now needed to address the downstream effectors as well as the safety profile of Boc2.
Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/efectos de los fármacos , Oligopéptidos/farmacología , Receptores de Formil Péptido/antagonistas & inhibidores , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones TransgénicosRESUMEN
Pneumococcal meningitis, caused by Streptococcus pneumoniae, is the most common type of bacterial meningitis. The clinical management of this disease has been challenged by the emergence of multidrug-resistant Streptococcus pneumoniae, requiring the urgent development of new therapeutic alternatives. Over the course of bacterial meningitis, pathogen invasion is accompanied by a massive recruitment of peripheral immune cells, especially neutrophil granulocytes, which are recruited under the coordination of several cytokines and chemokines. Here, we used chemokine (C-C motif) ligand 3 (Ccl3)-deficient mice to investigate the functional role of CCL3 in a mouse model of pneumococcal meningitis. Following intrathecal infection with Streptococcus pneumoniae Ccl3-deficient mice presented a significantly shorter survival and higher bacterial load than wildtype mice, paralleled by an ameliorated infiltration of neutrophil granulocytes into the CNS. Blood sample analysis revealed that infected Ccl3-deficient mice showed a significant decrease in erythrocytes, hemoglobin and hematocrit as well as in the number of banded neutrophils. Moreover, infected Ccl3-deficient mice showed an altered cytokine expression profile. Glial cell activation remained unchanged in both genotypes. In summary, this study demonstrates that CCL3 is beneficial in Streptococcus pneumoniae-induced meningitis. Pharmacological modulation of the CCL3 pathways might, therefore, represent a future therapeutic option to manage Streptococcus pneumoniae meningitis.
Asunto(s)
Quimiocina CCL3/inmunología , Meningitis Bacterianas/inmunología , Meningitis Neumocócica/inmunología , Animales , Quimiocinas/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Inmunidad Innata/inmunología , Meningitis Bacterianas/microbiología , Meningitis Neumocócica/microbiología , Ratones , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Streptococcus pneumoniae/inmunologíaRESUMEN
OBJECTIVES: Reducing or eliminating seclusion from mental health care settings has been a national priority for Australia since 2005. This paper describes Australia's national seclusion data collection, and summarises changes in seclusion rates in Australian public mental health services. METHODS: Seclusion events per 1000 patient days were calculated from 2009-2010 to 2014-2015 utilising state and territory administrative data sources. Combined national data were used to calculate results for a number of service characteristics, such as target population and location of the service. RESULTS: The rate of seclusion events decreased by 43% over the 6 years. Child and adolescent services reported consistently higher rates of seclusion, but a shorter duration of seclusion episodes, compared with other service types. There is high variation in seclusion rates between individual services (range 0.0-53.0 seclusion events per 1000 bed days in 2014-2015). CONCLUSIONS: Seclusion event rates in Australia's specialised public acute mental health hospital services are declining. The use of existing administrative data was instrumental in establishing a national data source to facilitate the monitoring and reporting of progress of seclusion reduction strategies.
Asunto(s)
Servicios de Salud del Adolescente/estadística & datos numéricos , Servicios de Salud del Niño/estadística & datos numéricos , Hospitales/estadística & datos numéricos , Trastornos Mentales/terapia , Servicios de Salud Mental/estadística & datos numéricos , Programas Nacionales de Salud/estadística & datos numéricos , Aislamiento de Pacientes/estadística & datos numéricos , Adolescente , Adulto , Australia , Niño , HumanosRESUMEN
In the course of our ongoing studies several substituted benzyloxyphenylacetic acids were prepared. Comparison of their aldose reductase inhibition with the biological activity obtained for recently evaluated benzoic acid analogues revealed the critical role of a methylene spacer between the aromatic core and the acidic function. Starting from the most potent derivative (i.e. 5d, IC50 = 20.9 microM) further structural modifications were performed and their influence on the inhibitory effect was established.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hidrocarburos Halogenados/síntesis química , Fenilacetatos/síntesis química , Aldehído Reductasa/aislamiento & purificación , Aldehído Reductasa/metabolismo , Animales , Benzoatos/química , Bovinos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Hidrocarburos Halogenados/farmacología , Fenilacetatos/farmacología , Relación Estructura-ActividadRESUMEN
In continuation of our attempts to develop novel aldose reductase inhibitors (ARIs), a number of compounds characterized by bioisosteric replacement of pharmacophors were prepared. On the one hand, the acidic function was formally replaced by an oxime or a nitro group and on the other hand the lipophilic substituent was modified. The results of the biological evaluation of these derivatives enabled us to gain insight into structural features critical for the aldose reductase inhibition.