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The large volume expansion effect and unstable solid electrolyte interface films of SiOx-based anode materials have hindered their commercial development. It has been shown that composite doping is a general strategy to solve critical problems. In this study, TiO2-doped core-shell SiOx/TiO2@C composites were created using the sol-gel method. On the one hand, the uniformly dispersed TiO2nanoparticles can alleviate the volume expansion of the SiOxactive material during the lithiation process. On the other hand, they can react with Li+to form LixTiO2, thereby increasing the ion diffusion rate in the composite material. The outer carbon shell acts as a protective layer that not only alleviates the volume expansion of the composite, but also improve the electron migration rate of the composite. The prepared SiOx/TiO2@C composite has a reversible capacity of 828.2 mA h g-1(0.2 A g-1100 cycles). After 500 cycles, it still maintains a reversible capacity of 500 mA h g-1even at a high current density of 2 A g-1. These findings suggest that SiOx/TiO2@C composites have a bright future in applications.
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Mitoxantrone (MTO) is clinically utilized for treating hormone-refractory prostate cancer (PCa), however, the therapeutic outcome is far from optimal due to the lack of proper drug carrier as well as the inherent MTO detoxification mechanisms of DNA lesion repair and anti-oxidation. Herein, a bombesin-installed nanoplatform combining the chemotherapeutic MTO and the chemotherapeutic sensitizer of nitric oxide (NO) is developed based on MTO-loaded macromolecular NO-donor-containing polymeric micelles (BN-NMMTO ) for targeted NO-sensitized chemotherapy against PCa. BN-NMMTO actively target and accumulates in PCa sites and are internalized into the tumor cells. The macromolecular NO-donor of BN-NMMTO undergoes a reductive reaction to unleash NO upon intracellular glutathione (GSH), accompanying by micelle swelling and MTO release. The targeted intracellular MTO release induces DNA lesion and reactive oxygen species (ROS) generation in tumor cells without damage to the normal cells, and MTO's cytotoxicity is further augmented by NO release via the inhibition of both DNA repair and anti-oxidation pathways as compared with traditional MTO therapies.
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Antineoplásicos , Neoplasias de la Próstata , Masculino , Humanos , Micelas , Antineoplásicos/uso terapéutico , Donantes de Óxido Nítrico/uso terapéutico , Mitoxantrona/farmacología , Mitoxantrona/uso terapéutico , Glutatión , Neoplasias de la Próstata/tratamiento farmacológico , Línea Celular TumoralRESUMEN
OBJECTIVE: It has been identified that the smoking rate is higher in schizophrenic patients than general population. This study aimed to explore the association between schizophrenia and tobacco use, and provide rational recommendations for clinical care of schizophrenia. METHODS: We recruited 244 patients with schizophrenia and 225 healthy controls. Of schizophrenia patients, 54 patients were untreated with any antipsychotics over the previous 6 months or first-episode and drug-naïve. These patients (nonmedication subgroup) were followed up for 8 weeks. The associations between tobacco use and susceptibility to schizophrenia and psychotic symptoms were analyzed. RESULTS: Although there was no significant difference between schizophrenia patients and healthy controls in the entire sample, stratification analysis showed the rate of smoking was higher in male patients versus healthy controls and that male smokers exhibited higher odds ratios for schizophrenia than nonsmokers. Next, when we repeated analyses in first-episode patients and healthy controls, significant differences were not observed, indicating tobacco use is an outcome rather than a cause of schizophrenia. Furthermore, among nonmedication subgroup, smokers presented with more severe psychotic symptoms at baseline, and better improvement after medication than nonsmokers, suggesting patients with worse symptoms tend to smoke to relieve symptoms. CONCLUSION: This study supports the self-medication hypothesis. Nonetheless, considering the serious health hazard associated with tobacco use, we should encourage patients to stop smoking. Further investigations are warranted to determine the tobacco constituents that are beneficial or harmful to schizophrenia.
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Trastornos Psicóticos/epidemiología , Esquizofrenia/epidemiología , Psicología del Esquizofrénico , Fumar Tabaco/epidemiología , Adulto , Antipsicóticos/uso terapéutico , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/psicología , Esquizofrenia/tratamiento farmacológico , Automedicación , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Background: Cerebral small vessel disease (SVD) is a common cause of cognitive dysfunction. However, little is known whether the altered reconfiguration pattern of brain modular architecture regulates cognitive dysfunction in SVD. Methods: We recruited 25 cases of SVD without cognitive impairment (SVD-NCI) and 24 cases of SVD with mild cognitive impairment (SVD-MCI). According to the Framingham Stroke Risk Profile, healthy controls (HC) were divided into 17 subjects (HC-low risk) and 19 subjects (HC-high risk). All individuals underwent resting-state functional magnetic resonance imaging and cognitive assessments. Graph-theoretical analysis was used to explore alterations in the modular organization of functional brain networks. Multiple regression and mediation analyses were performed to investigate the relationship between MRI markers, network metrics and cognitive performance. Results: We identified four modules corresponding to the default mode network (DMN), executive control network (ECN), sensorimotor network and visual network. With increasing vascular risk factors, the inter- and intranetwork compensation of the ECN and a relatively reserved DMN itself were observed in individuals at high risk for SVD. With declining cognitive ability, SVD-MCI showed a disrupted ECN intranetwork and increased DMN connection. Furthermore, the intermodule connectivity of the right inferior frontal gyrus of the ECN mediated the relationship between periventricular white matter hyperintensities and visuospatial processing in SVD-MCI. Conclusions: The reconfiguration pattern of the modular architecture within/between the DMN and ECN advances our understanding of the neural underpinning in response to vascular risk and SVD burden. These observations may provide novel insight into the underlying neural mechanism of SVD-related cognitive impairment and may serve as a potential non-invasive biomarker to predict and monitor disease progression.
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OBJECTIVE: To explore the within- and between-network patterns of the default mode network (DMN), the frontoparietal control network (FPCN), and the dorsal attention network (DAN) in cerebral small vessel disease (CSVD) with and without cognitive impairment (CI). METHODS: Twenty CSVD with CI subjects, 21 CSVD without CI subjects, and 25 healthy elderly controls were recruited. The within- and between-network patterns of the networks were identified based on resting-state functional magnetic resonance imaging data. RESULTS: Compared with the control group, both the CSVD with CI group and the CSVD without CI group displayed decreased within-network function of the DMN and lower negative connectivity between the DMN and other networks (i.e., DMN and DAN, DMN and FPCN), whereas the CSVD with CI group additionally showed within- and between-network alterations of the FPCN (i.e., increased within-network function of the FPCN and lower negative connectivity between the FPCN and the DMN). Furthermore, these alterations of the FPCN were correlated with the cognitive function of CSVD subjects. Interestingly, the between-network connectivity of the FPCN and the DMN was negatively correlated with deep white matter hyperintensities (DWMH) volume in CSVD subjects. CONCLUSION: These findings suggest that cognitive alterations of CSVD subjects may be mainly regulated by the FPCN that correlates with DWMH burden, and shed light on the investigation of surrogate markers of CSVD.
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Encéfalo , Enfermedades de los Pequeños Vasos Cerebrales , Cognición/fisiología , Disfunción Cognitiva , Conectoma/métodos , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico , Enfermedades de los Pequeños Vasos Cerebrales/psicología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Correlación de Datos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , MasculinoRESUMEN
Hypertension has a close affinity to brain degeneration and cognitive decline during the aging process. The default mode network (DMN) is usually affected in various diseases related to cognitive impairment (CI). The present research aimed to explore the alterations in the DMN and its subcomponents in hypertensive patients with and without CI and to investigate the associations between cognitive performance and network abnormalities. Resting-state functional magnetic resonance imaging and neuropsychological tests were performed in 74 subjects, namely, 30 hypertensive patients with normal cognition (HTN-NC), 25 hypertensive patients with CI (HTN-CI), and 19 healthy controls. Seed-based functional connectivity (FC) analysis was performed to identify the DMN patterns. The group differences in the DMN were mainly shown in brain regions related to the core subsystem and the dorsal medial subsystem of the DMN. Post hoc analysis revealed a trend of dissociation among the DMN subsystems in the HTN-NC group. In contrast, the HTN-CI group displayed extensively increased FC in both subsystems. Importantly, increased FC of the dorsal medial subsystem in the HTN-CI patients was associated with poor cognitive performance, such as scores on Mini-Mental State Examination (ρ = -0.438, P = 0.029) and Montreal Cognitive Assessment (ρ = -0.449, P = 0.025). The findings suggest that extensively increased connectivities in the core subsystem and the dorsal media subsystem of the DMN may distinguish hypertension with CI from hypertension with normal cognition. The characteristic change in the dorsal medial subsystem may become an early imaging biomarker for the diagnosis and treatment of cognitive impairment associated with hypertension.
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Encéfalo/diagnóstico por imagen , Cognición/fisiología , Disfunción Cognitiva/diagnóstico por imagen , Hipertensión/diagnóstico por imagen , Red Nerviosa/diagnóstico por imagen , Anciano , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/psicología , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/psicología , Imagen por Resonancia Magnética , Masculino , Memoria/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Sustancia Blanca/diagnóstico por imagenRESUMEN
Dracocephalum heterophyllum (DH) is a Chinese herbal medicine used in treating hepatitis. However, the protective effects and pharmacological mechanisms of DH in hepatitis are unknown. In this study, we found that pretreatment with DH extract significantly ameliorated liver injury and suppressed the production of inflammatory cytokines, including tumor necrosis factor (TNF-α) and interferon-γ (IFN-γ) in Concanavalin A- (ConA-) induced hepatitis (CIH). DH recruited more CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs) to the liver and suppressed infiltration of macrophages (Kupffer cells) in the liver. The present work explores DH as an effective hepatoprotective medicine to inhibit inflammation and liver injury caused by hepatitis.
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Concanavalina A/toxicidad , Hepatitis/tratamiento farmacológico , Lamiaceae/química , Extractos Vegetales/farmacología , Enfermedad Aguda , Animales , Femenino , Citometría de Flujo , Hepatitis/etiología , Etiquetado Corte-Fin in Situ , Interferón gamma/metabolismo , Hígado/citología , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Extractos Vegetales/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question. To address this issue, we utilized a transgenic mouse strain in which adult neurogenesis was specifically and conditionally impaired by Nestin-CreER-driven, inducible knockout (icKO) of erk5 MAP kinase in Nestin-expressing neural progenitors of the adult mouse brain upon tamoxifen administration. Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal's susceptibility to depression after chronic unpredictable stress treatment. Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression.
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Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury.
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Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Neurogénesis , Neuronas/metabolismo , Bulbo Olfatorio/metabolismo , Olfato , Animales , Células Cultivadas , Memoria , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 7 Activada por Mitógenos/genética , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/fisiología , Neuronas/citología , Neuronas/fisiología , Bulbo Olfatorio/citología , Bulbo Olfatorio/crecimiento & desarrollo , Bulbo Olfatorio/fisiología , Transducción de SeñalRESUMEN
Mice rely on the sense of olfaction to detect food sources, recognize social and mating partners, and avoid predators. Many behaviors of mice, including learning and memory, social interaction, fear, and anxiety are closely associated with their function of olfaction, and behavior tasks designed to evaluate those brain functions may use odors as cues. Accurate assessment of olfaction is not only essential for the study of olfactory system but also critical for proper interpretation of various mouse behaviors, especially learning and memory, emotionality and affect, and sociality. Here we describe a series of behavior experiments that offer multidimensional and quantitative assessments for mouse olfactory function, including olfactory habituation, discrimination, odor preference, odor detection sensitivity, and olfactory memory, with respect to both social and nonsocial odors.
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Conducta Animal , Odorantes , Percepción Olfatoria , Olfato , Animales , Señales (Psicología) , Discriminación en Psicología , Habituación Psicofisiológica , Vivienda para Animales , Memoria , Ratones , Modelos Animales , Flujo de TrabajoRESUMEN
Recent studies have shown that inhibition of adult neurogenesis impairs the formation of hippocampus-dependent memory. However, it is not known whether increasing adult neurogenesis affects the persistence of hippocampus-dependent long-term memory. Furthermore, signaling mechanisms that regulate adult neurogenesis are not fully defined. We recently reported that the conditional and targeted knock-out of ERK5 MAP kinase in adult neurogenic regions of the mouse brain attenuates adult neurogenesis in the hippocampus and disrupts several forms of hippocampus-dependent memory. Here, we developed a gain-of-function knock-in mouse model to specifically activate endogenous ERK5 in the neurogenic regions of the adult brain. We report that the selective and targeted activation of ERK5 increases adult neurogenesis in the dentate gyrus by enhancing cell survival, neuronal differentiation, and dendritic complexity. Conditional ERK5 activation also improves the performance of challenging forms of spatial learning and memory and extends hippocampus-dependent long-term memory. We conclude that enhancing signal transduction of a single signaling pathway within adult neural stem/progenitor cells is sufficient to increase adult neurogenesis and improve the persistence of hippocampus-dependent memory. Furthermore, activation of ERK5 may provide a novel therapeutic target to improve long-term memory.
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Hipocampo/enzimología , Memoria a Largo Plazo/fisiología , Proteína Quinasa 7 Activada por Mitógenos/genética , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Neurogénesis/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Diferenciación Celular/fisiología , Activación Enzimática/fisiología , Técnicas de Sustitución del Gen , Hipocampo/citología , Aprendizaje por Laberinto/fisiología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
ERK5 MAP kinase is highly expressed in the developing nervous system but absent in most regions of the adult brain. It has been implicated in regulating the development of the main olfactory bulb and in odor discrimination. However, whether it plays an essential role in pheromone-based behavior has not been established. Here we report that conditional deletion of the Mapk7 gene which encodes ERK5 in mice in neural stem cells impairs several pheromone-mediated behaviors including aggression and mating in male mice. These deficits were not caused by a reduction in the level of testosterone, by physical immobility, by heightened fear or anxiety, or by depression. Using mouse urine as a natural pheromone-containing solution, we provide evidence that the behavior impairment was associated with defects in the detection of closely related pheromones as well as with changes in their innate preference for pheromones related to sexual and reproductive activities. We conclude that expression of ERK5 during development is critical for pheromone response and associated animal behavior in adult mice.
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Conducta Animal/efectos de los fármacos , Eliminación de Gen , Proteína Quinasa 7 Activada por Mitógenos/deficiencia , Proteína Quinasa 7 Activada por Mitógenos/genética , Sistema Nervioso/enzimología , Feromonas/farmacología , Agresión/efectos de los fármacos , Animales , Femenino , Técnicas de Inactivación de Genes , Masculino , Ratones , Sistema Nervioso/crecimiento & desarrollo , Células-Madre Neurales/enzimología , Bulbo Olfatorio/anatomía & histología , Tamaño de los Órganos , Conducta Sexual Animal/efectos de los fármacosRESUMEN
The exact molecular mechanisms governing articular chondrocytes remain unknown in skeletal biology. In this study, we have found that ESET (an ERG-associated protein with a SET domain, also called SETDB1) histone methyltransferase is expressed in articular cartilage. To test whether ESET regulates articular chondrocytes, we carried out mesenchyme-specific deletion of the ESET gene in mice. ESET knock-out did not affect generation of articular chondrocytes during embryonic development. Two weeks after birth, there was minimal qualitative difference at the knee joints between wild-type and ESET knock-out animals. At 1 month, ectopic hypertrophy, proliferation, and apoptosis of articular chondrocytes were seen in the articular cartilage of ESET-null animals. At 3 months, additional signs of terminal differentiation such as increased alkaline phosphatase activity and an elevated level of matrix metalloproteinase (MMP)-13 were found in ESET-null cartilage. Staining for type II collagen and proteoglycan revealed that cartilage degeneration became progressively worse from 2 weeks to 12 months at the knee joints of ESET knock-out mutants. Analysis of over 14 pairs of age- and sex-matched wild-type and knock-out mice indicated that the articular chondrocyte phenotype in ESET-null mutants is 100% penetrant. Our results demonstrate that expression of ESET plays an essential role in the maintenance of articular cartilage by preventing articular chondrocytes from terminal differentiation and may have implications in joint diseases such as osteoarthritis.
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Cartílago Articular/enzimología , Diferenciación Celular , Condrocitos/enzimología , N-Metiltransferasa de Histona-Lisina/metabolismo , Articulación de la Rodilla/enzimología , Osteoartritis de la Rodilla/enzimología , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Cartílago Articular/patología , Condrocitos/patología , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Hipertrofia/enzimología , Hipertrofia/genética , Hipertrofia/patología , Articulación de la Rodilla/patología , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , Ratones Noqueados , Especificidad de Órganos/genética , Osteoartritis de la Rodilla/genética , Osteoartritis de la Rodilla/patologíaRESUMEN
The ESET (also called SETDB1) protein contains an N-terminal tudor domain that mediates protein-protein interactions and a C-terminal SET domain that catalyzes methylation of histone H3 at lysine 9. We report here that ESET protein is transiently upregulated in prehypertrophic chondrocytes in newborn mice. To investigate the in vivo effects of ESET on chondrocyte differentiation, we generated conditional knockout mice to specifically eliminate the catalytic SET domain of ESET protein only in mesenchymal cells. Such deletion of the ESET gene caused acceleration of chondrocyte hypertrophy in both embryos and young animals, depleting chondrocytes that are otherwise available to form epiphyseal plates for endochondral bone growth. ESET-deficient mice are thus characterized by defective long bone growth and trabecular bone formation. To understand the underlying mechanism for ESET regulation of chondrocytes, we carried out co-expression experiments and found that ESET associates with histone deacetylase 4 to bind and inhibit the activity of Runx2, a hypertrophy-promoting transcription factor. Repression of Runx2-mediated gene transactivation by ESET is dependent on its H3-K9 methyltransferase activity as well as its associated histone deacetylase activity. In addition, knockout of ESET is associated with repression of Indian hedgehog gene in pre- and early hypertrophic chondrocytes. Together, these results provide clear evidence that ESET controls hypertrophic differentiation of growth plate chondrocytes and endochondral ossification during embryogenesis and postnatal development.
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Condrocitos/citología , Regulación del Desarrollo de la Expresión Génica , Placa de Crecimiento/metabolismo , N-Metiltransferasa de Histona-Lisina/fisiología , Alelos , Animales , Huesos/embriología , Huesos/metabolismo , Cartílago/embriología , Diferenciación Celular , Epigénesis Genética , Proteínas Hedgehog/metabolismo , Histona Desacetilasas/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Mesodermo/citología , Ratones , Ratones Noqueados , Estructura Terciaria de ProteínaRESUMEN
Recent studies have led to the exciting idea that adult-born neurons in the olfactory bulb (OB) may be critical for complex forms of olfactory behavior in mice. However, signaling mechanisms regulating adult OB neurogenesis are not well defined. We recently reported that extracellular signal-regulated kinase (ERK) 5, a MAP kinase, is specifically expressed in neurogenic regions within the adult brain. This pattern of expression suggests a role for ERK5 in the regulation of adult OB neurogenesis. Indeed, we previously reported that conditional deletion of erk5 in adult neurogenic regions impairs several forms of olfactory behavior in mice. Thus, it is important to understand how ERK5 regulates adult neurogenesis in the OB. Here we present evidence that shRNA suppression of ERK5 in adult neural stem/progenitor cells isolated from the subventricular zone (SVZ) reduces neurogenesis in culture. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, stimulates neurogenesis. Furthermore, inducible and conditional deletion of erk5 specifically in the neurogenic regions of the adult mouse brain interferes with cell cycle exit of neuroblasts, impairs chain migration along the rostral migratory stream and radial migration into the OB. It also inhibits neuronal differentiation and survival. These data suggest that ERK5 regulates multiple aspects of adult OB neurogenesis and provide new insights concerning signaling mechanisms governing adult neurogenesis in the SVZ-OB axis.
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Movimiento Celular , Supervivencia Celular , Proteína Quinasa 7 Activada por Mitógenos/genética , Neurogénesis , Neuronas/fisiología , Bulbo Olfatorio/citología , Animales , Ciclo Celular , Células Cultivadas , Ventrículos Cerebrales/citología , Ventrículos Cerebrales/enzimología , Técnicas de Inactivación de Genes , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Quinasa 7 Activada por Mitógenos/deficiencia , Células-Madre Neurales/fisiología , Cultivo Primario de CélulasRESUMEN
Prolactin-stimulated adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) mediates several reproductive behaviors including mating/pregnancy, dominant male pheromone preference in females, and paternal recognition of offspring. However, downstream signaling mechanisms underlying prolactin-induced adult neurogenesis are completely unknown. We report here for the first time that prolactin activates extracellular signal-regulated kinase 5 (ERK5), a MAP kinase that is specifically expressed in the neurogenic regions of the adult mouse brain. Knockdown of ERK5 by retroviral infection of shRNA attenuates prolactin-stimulated neurogenesis in SVZ-derived adult neural stem/progenitor cells (aNPCs). Inducible erk5 deletion in adult neural stem cells of transgenic mice inhibits neurogenesis in the SVZ and OB following prolactin infusion or mating/pregnancy. These results identify ERK5 as a novel and critical signaling mechanism underlying prolactin-induced adult neurogenesis.
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Encéfalo/metabolismo , Proteína Quinasa 7 Activada por Mitógenos/fisiología , Bulbo Olfatorio/metabolismo , Prolactina/metabolismo , Animales , Mapeo Encefálico/métodos , Femenino , Eliminación de Gen , Genotipo , Ratones , Ratones Noqueados , Microscopía Confocal/métodos , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Neurogénesis , Proteínas Recombinantes/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal , Tamoxifeno/farmacologíaRESUMEN
An immunochromatographic assay (ICA) using gold nanoparticles coated with monoclonal antibody (McAb) for the detection of chromium ions (Cr) in water and serum samples was developed, optimized and validated. Gold nanoparticles coated with affinity-purified monoclonal antibodies against isothiocyanobenzyl-EDTA (iEDTA)-chelated Cr(3+) were used as the detecting reagent in this completive immunoassay-based one-step test strip. The ICA was investigated to measure chromium speciation (Cr(3+) and Cr(6+) ions) in water samples. Chromium standard samples of 0-80 ng mL(-1) in water were determined by the test strips. The results showed that the visual lowest detection limit (LDL) of the test strip was 50.0 ng mL(-1). A portable colorimetric lateral flow reader was used for the quantification of Cr. The results indicated that the linear range of the ICA with colorimetric detection was 5-80 ng mL(-1). The ICA was also validated for the detection of chromium ions in serum samples. The test trips showed high stability in that they could be stored at 37°C for at least 12 weeks without significant loss of activity. The test strip also showed good selectivity for Cr detection with negligible interference from other heavy metals. Because of its low cost and short testing time (within 5 min), the test strip is especially suitable for on-site large-scale screening of Cr-polluted water samples, biomonitoring of Cr exposure, and many other field applications.
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Cromatografía de Afinidad , Cromo/análisis , Oro Coloide/química , Nanopartículas del Metal/química , Suero/química , Contaminantes Químicos del Agua/análisis , Agua/química , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Unión Competitiva , Quelantes , Cromo/sangre , Ácido Edético/análogos & derivados , Ácido Edético/química , Ácido Edético/inmunología , Humanos , Iones/análisis , Isotiocianatos/química , Isotiocianatos/inmunología , Límite de Detección , Tiras Reactivas , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Recent studies have led to the exciting idea that adult-born neurons in the dentate gyrus of the hippocampus may play a role in hippocampus-dependent memory formation. However, signaling mechanisms that regulate adult hippocampal neurogenesis are not well defined. Here we report that extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, is selectively expressed in the neurogenic regions of the adult mouse brain. We present evidence that shRNA suppression of ERK5 in adult hippocampal neural stem/progenitor cells (aNPCs) reduces the number of neurons while increasing the number of cells expressing markers for stem/progenitor cells or proliferation. Furthermore, shERK5 attenuates both transcription and neuronal differentiation mediated by Neurogenin 2, a transcription factor expressed in adult hippocampal neural progenitor cells. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, promotes neurogenesis in cultured aNPCs and in the dentate gyrus of the mouse brain. Moreover, neurotrophins including NT3 activate ERK5 and stimulate neuronal differentiation in aNPCs in an ERK5-dependent manner. Finally, inducible and conditional deletion of ERK5 specifically in the neurogenic regions of the adult mouse brain delays the normal progression of neuronal differentiation and attenuates adult neurogenesis in vivo. These data suggest ERK5 signaling as a critical regulator of adult hippocampal neurogenesis.
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Hipocampo/metabolismo , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis , Animales , Antineoplásicos Hormonales/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Western Blotting , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Giro Dentado/citología , Giro Dentado/crecimiento & desarrollo , Giro Dentado/metabolismo , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , MAP Quinasa Quinasa 5/genética , MAP Quinasa Quinasa 5/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Proteína Quinasa 7 Activada por Mitógenos/genética , Células 3T3 NIH , Factores de Crecimiento Nervioso/farmacología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Interferencia de ARN , Tamoxifeno/farmacologíaRESUMEN
ERK5 MAP kinase is highly expressed in the developing nervous system and has been implicated in promoting the survival of immature neurons in culture. However, its role in the development and function of the mammalian nervous system has not been established in vivo. Here, we report that conditional deletion of the erk5 gene in mouse neural stem cells during development reduces the number of GABAergic interneurons in the main olfactory bulb (OB). Our data suggest that this is due to a decrease in proliferation and an increase in apoptosis in the subventricular zone and rostral migratory stream of ERK5 mutant mice. Interestingly, ERK5 mutant mice have smaller OB and are impaired in odor discrimination between structurally similar odorants. We conclude that ERK5 is a novel signaling pathway regulating developmental OB neurogenesis and olfactory behavior.
Asunto(s)
Neuronas GABAérgicas/fisiología , Proteína Quinasa 7 Activada por Mitógenos/deficiencia , Odorantes , Bulbo Olfatorio , Trastornos de la Percepción/genética , Trastornos de la Percepción/patología , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Apoptosis/genética , Bromodesoxiuridina/metabolismo , Movimiento Celular , Modelos Animales de Enfermedad , Electrooculografía/métodos , Embrión de Mamíferos , Regulación del Desarrollo de la Expresión Génica/genética , Glutamato Descarboxilasa/metabolismo , Etiquetado Corte-Fin in Situ , Ventrículos Laterales/embriología , Ventrículos Laterales/crecimiento & desarrollo , Ventrículos Laterales/patología , Ratones , Ratones Transgénicos , Proteína Quinasa 7 Activada por Mitógenos/genética , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Células-Madre Neurales/fisiología , Neurogénesis/genética , Bulbo Olfatorio/embriología , Bulbo Olfatorio/crecimiento & desarrollo , Bulbo Olfatorio/patología , Fosfopiruvato Hidratasa/metabolismo , Factores de Transcripción SOXB1/metabolismo , Ácidos Siálicos/metabolismo , Transducción de Señal , Olfato/genéticaRESUMEN
The commitment of multi-potent cortical progenitors to a neuronal fate depends on the transient induction of the basic-helix-loop-helix (bHLH) family of transcription factors including Neurogenin 1 (Neurog1). Previous studies have focused on mechanisms that control the expression of these proteins while little is known about whether their pro-neural activities can be regulated by kinase signaling pathways. Using primary cultures and ex vivo slice cultures, here we report that both the transcriptional and pro-neural activities of Neurog1 are regulated by extracellular signal-regulated kinase (ERK) 5 signaling in cortical progenitors. Activation of ERK5 potentiated, while blocking ERK5 inhibited Neurog1-induced neurogenesis. Furthermore, endogenous ERK5 activity was required for Neurog1-initiated transcription. Interestingly, ERK5 activation was sufficient to induce Neurog1 phosphorylation and ERK5 directly phosphorylated Neurog1 in vitro. We identified S179/S208 as putative ERK5 phosphorylation sites in Neurog1. Mutations of S179/S208 to alanines inhibited the transcriptional and pro-neural activities of Neurog1. Our data identify ERK5 phosphorylation of Neurog1 as a novel mechanism regulating neuronal fate commitment of cortical progenitors.