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Plant responses to different light and water availability are variable among species and their respective phenotypic plasticity, and the combination between these two abiotic factors can alleviate or intensify stressful effects. This study aimed to evaluate the impacts of exposure time of Cedrela fissilis Vell. seedlings to different water and light availability considering natural radiation variations and the interaction of these factors. Seedlings were submitted to combinations of three shading levels-SH (0, 30 and 70%) and three water regimes based on the water holding capacity (WHC) in the substrate, constituting nine cultivation conditions: T1-0% SH + 40% WHC; T2-0% SH + 70% WHC; T3-0% SH + 100% WHC; T4-30% SH + 40% WHC; T5-30% SH + 70% WHC; T6-30% SH + 100% WHC; T7-70% SH + 40% WHC; T8-70% SH + 70% WHC; T9-70% SH + 100% WHC. C. fissilis seedlings are sensitive to water deficit, here represented by 40% WHC, regardless of exposure time, and when cultivated in full sun even though there are variations in radiation, the stressful effects were enhanced, acting in a synergistic manner. The condition that provided better gas exchange performance and greater total dry mass accumulation for C. fissilis seedlings was 30% shading combined with 100% WHC. C. fissilis seedlings have physiological plasticity and resilience to survive under different water and light conditions.
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Suplementos Nutricionais , Ácidos Graxos Voláteis , Lactação , Prebióticos , Humanos , Gravidez , Feminino , Prebióticos/administração & dosagem , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/fisiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Recém-Nascido , Lactente , Leite Humano/química , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
BACKGROUND: The immunomodulatory oligodeoxynucleotide (ODN) IMT504 might harbor antifibrotic properties within the liver. METHODS: Fibrosis models were induced in mice through thioacetamide (TAA) administration and bile-duct ligation. Cre-loxP mice were utilized to identify GLAST + Wnt1 + bone marrow stromal progenitors (BMSPs) and to examine their contribution with cells in the liver. In vivo and in vitro assays; flow-cytometry, immunohistochemistry, and qPCR were conducted. RESULTS: IMT504 demonstrated significant inhibition of liver fibrogenesis progression and reversal of established fibrosis. Early responses to IMT504 involved the suppression of profibrogenic and proinflammatory markers, coupled with an augmentation of hepatocyte proliferation. Additionally, this ODN stimulated the proliferation and mobilization of GLAST + Wnt1 + BMSPs, likely amplifying their contribution with endothelial- and hepatocytes-like cells. Moreover, IMT504 significantly modulated the expression levels of Wnt ligands and signaling pathway/target genes specifically within GLAST + Wnt1 + BMSPs, with minimal impact on other BMSPs. Intriguingly, both IMT504 and conditioned media from IMT504-pre-treated GLAST + Wnt1 + BMSPs shifted the phenotype of fibrotic macrophages, hepatic stellate cells, and hepatocytes, consistent with the potent antifibrotic effects observed. CONCLUSION: In summary, our findings identify IMT504 as a promising candidate molecule with potent antifibrotic properties, operating through both direct and indirect mechanisms, including the activation of GLAST + Wnt1 + BMSPs.
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Cirrose Hepática , Células-Tronco Mesenquimais , Proteína Wnt1 , Animais , Camundongos , Cirrose Hepática/patologia , Cirrose Hepática/tratamento farmacológico , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Proteína Wnt1/metabolismo , Proteína Wnt1/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , TioacetamidaRESUMO
Individuals considered resilient can overcome adversity, achieving normal physical and psychological development, while those deemed vulnerable may not. Adversity promotes structural and functional alterations in the medial prefrontal cortex (mPFC) and hippocampus. Moreover, activity-dependent synaptic plasticity is intricately linked to neuronal shaping resulting from experiences. We hypothesize that this plasticity plays a crucial role in resilience processes. However, there is a notable absence of studies investigating this plasticity and behavioral changes following social adversity at different life stages. Consequently, we evaluated the impact of social adversity during early postnatal development (maternal separation [MS]), adulthood (social defeat [SD]), and a combined exposure (MS + SD) on behavioral outcomes (anxiety, motivation, anhedonia, and social interaction). We also examined cFos expression induced by social interaction in mPFC and hippocampus of adult male rats. Behavioral analyses revealed that SD-induced anhedonia, whereas MS + SD increased social interaction and mitigated SD-induced anhedonia. cFos evaluation showed that social interaction heightened plasticity in the prelimbic (PrL) and infralimbic (IL) cortices, dentate gyrus (DG), CA3, and CA1. Social interaction-associated plasticity was compromised in IL and PrL cortices of the MS and SD groups. Interestingly, social interaction-induced plasticity was restored in the MS + SD group. Furthermore, plasticity was impaired in DG by all social stressors, and in CA3 was impaired by SD. Our findings suggest in male rats (i) two adverse social experiences during development foster resilience; (ii) activity-dependent plasticity in the mPFC is a foundation for resilience to social adversity; (iii) plasticity in DG is highly susceptible to social adversity.
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Privação Materna , Plasticidade Neuronal , Córtex Pré-Frontal , Resiliência Psicológica , Animais , Plasticidade Neuronal/fisiologia , Masculino , Ratos , Anedonia/fisiologia , Interação Social , Derrota Social , Hipocampo , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Ratos Wistar , Comportamento Animal/fisiologia , Comportamento Social , Ansiedade/fisiopatologiaRESUMO
Understanding how evolution and phenotypic plasticity contribute to variation in heat tolerance is crucial to predict responses to warming. Here we analyze 272 thermal death time curves of 53 fish species acclimated to different temperatures and quantify their relative contributions. Analyses show that evolution and plasticity account, respectively, for 80.5 % and 12.4 % of the variation in elevation across curves, whereas their slope remained invariant. Evolutionary and plastic adaptive responses differ in magnitude, with heat tolerance increasing 0.54 ºC between species and 0.32 ºC within species for every 1 ºC increase in environmental temperatures. After successfully predicting critical temperatures under ramping conditions to validate these estimates, we show that fish populations can only partly ameliorate the impact of warming waters via thermal acclimation and this deficit in plasticity could increase as the warming accelerates.
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Background: In recent years, there has been a growing use of technological advancements to enhance the rehabilitation of individuals who have suffered from cerebrovascular accidents. Virtual reality rehabilitation programs enable patients to engage in a customized therapy program while interacting with a computer-generated environment. Therefore, our goal was to investigate the effectiveness of virtual reality in occupational therapy for people's rehabilitation after a cerebrovascular accident. Methods: We systematically searched databases (Pubmed/Medline, Scopus, Web of Science, and Science Direct) for randomized controlled trials published within the last 10 years. Studies involving adult stroke survivors undergoing virtual reality-based interventions aimed at improving upper-extremity motor function were included. The quality assessment followed PRISMA guidelines, with the risk of bias assessed using the Cochrane tool (version 6.4) and methodological quality evaluated using GRADEpro. Results: We selected sixteen studies that met the main criteria for the implementation of virtual reality technology. The interventions described in the articles focused mainly on the upper extremities and their fine motor skills. Conclusions: When used in conventional treatments to improve people's motor and cognitive functions after a cerebrovascular accident, virtual reality emerges as a beneficial tool. Additionally, virtual reality encourages adherence to the interventional process of rehabilitation through occupational therapy.
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Vespula vulgaris is an invasive social wasp that has become established in many parts of the world. Plastic cognitive systems are expected to be advantageous for invasive species, given that they continuously face dynamic and unpredictable environments. We analyzed foraging behavior associated with undepleted and depleted resources. The wasps were trained to associate a certain location with food and we recorded their behavior after successive displacement of it. We also studied how long wasps continued to search for food that was no longer available and whether it was dependent on experience. We found that when wasps associated a certain location with food, they returned to the same site even though food was no longer available or had been displaced. Handling time remained constant, while relocation time and learning flights decreased with experience. With a food position change, learning flights increased and searching time varied with experience. When food was removed, hovering and landings were greatest in wasps that had the most experience with the resource, although extinction of the searching response was not dependent on experience. Our results illustrate the plasticity of wasp behavior in uncertain foraging contexts, which could have allowed the species to establish successfully in new habitats.
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This integrative review aims to highlight the importance of investigating the functional role of AHCYL1, also known as IRBIT, in cancer cells. It has recently been suggested that AHCYL1 regulates cell survival/death, stemness capacity, and the host adaptive response to the tumor microenvironment. Despite this knowledge, the role of AHCYL1 in cancer is still controversial, probably due to its ability to interact with multiple factors in a tissue-specific manner. Understanding the mechanisms regulating the functional interplay between the tumor and the tumor microenvironment that controls the expression of AHCYL1 could provide a deeper comprehension of the regulation of tumor development. Addressing how AHCYL1 modulates cellular plasticity processes in a tumoral context is potentially relevant to developing translational approaches in cancer biology.
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Adenosil-Homocisteinase , Neoplasias , Microambiente Tumoral , Animais , Humanos , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Adenosil-Homocisteinase/metabolismoRESUMO
OBJECTIVE: Wnt-induced signaling protein 1 (WISP1) and Dickkopf-1 (DKK1) are highly expressed in esophageal squamous cell carcinoma (ESCC), but no direct connection was identified between them. Phenotypic plasticity is a hallmark of ESCC. This research intended to identify the association between WISP1 and DKK1 and their roles in the phenotypic plasticity of ESCC. METHODS: Genes differentially expressed in esophageal carcinoma were analyzed in the GEO database, followed by analyses of GO and KEGG enrichment to screen the hub gene. WISP1 expression and DKK1 secretion was assessed in ESCC tissues and cells. The tumor xenograft and in vivo metastasis models were established by injecting ESCC cells into nude mice. Functional deficiency and rescue experiments were conducted, followed by assays for cell proliferation, migration/invasion, stemness, epithelial-mesenchymal transition (EMT), and apoptosis, as well as tumor volume, weight, proliferation, stemness, and lung metastasis. The binding relationship and co-expression of WISP1 and DKK1 were determined. RESULTS: WISP1 and DKK1 were upregulated in ESCC cells and tissues, and WISP1 was enriched in the cell stemness and Wnt pathways. WISP1 knockdown subdued proliferation, migration/invasion, EMT activity, and stemness but enhanced apoptosis in ESCC cells. WISP1 knockdown restrained ESCC growth, proliferation, stemness, and metastasis in vivo. WISP1 bound to DKK1 in ESCC. DKK1 overexpression abolished the repressive impacts of WISP1 knockdown on the malignant behaviors of ESCC cells in vitro and of ESCC tumor in vivo. CONCLUSION: Knockdown of WISP1/DKK1 restrains the phenotypic plasticity in esophageal squamous cell carcinoma by suppressing epithelial-mesenchymal transition and stemness.
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Medicinal signaling cells (MSC) hold promise for regenerative medicine due to their ability to repair damaged tissues. However, their effectiveness can be affected by how long they are cultured in the lab. This study investigated how passage number influences key properties for regenerative medicine of pig bone marrow MSC. The medicinal signiling cells derived from pig bone marrow (BM-MSC) were cultured in D-MEM High Glucose supplemented with 15% foetal bovine serum until the 25th passage and assessed their growth, viability, ability to differentiate into different cell types (plasticity), and cell cycle activity. Our findings showed that while the cells remained viable until the 25th passage, their ability to grow and differentiate declined after the 5th passage. Additionally, cells in later passages spent more time in a resting phase, suggesting reduced activity. In conclusion, the number of passages is a critical factor for maintaining ideal MSC characteristics. From the 9th passage BM-MSC exhibit decline in proliferation, differentiation potential, and cell cycle activity. Given this, it is possible to suggest that the use of 5th passage cells is the most suitable for therapeutic applications.
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Células da Medula Óssea , Diferenciação Celular , Proliferação de Células , Animais , Suínos , Células da Medula Óssea/citologia , Células Cultivadas , Ciclo Celular/fisiologia , Ciclo Celular/efeitos dos fármacos , Técnicas de Cultura de Células/métodos , Sobrevivência Celular/fisiologia , Fatores de Tempo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Células-Tronco Mesenquimais/metabolismo , Medicina Regenerativa/métodosRESUMO
Major depressive disorder (MDD) has demonstrated its negative impact on various aspects of the lives of those affected. Although several therapies have been developed over the years, it remains a challenge for mental health professionals. Thus, understanding the pathophysiology of MDD is necessary to improve existing treatment options or seek new therapeutic alternatives. Clinical and preclinical studies in animal models of depression have shown the involvement of synaptic plasticity in both the development of MDD and the response to available drugs. However, synaptic plasticity involves a cascade of events, including the action of presynaptic proteins such as synaptophysin and synapsins and postsynaptic proteins such as postsynaptic density-95 (PSD-95). Additionally, several factors can negatively impact the process of spinogenesis/neurogenesis, which are related to many outcomes, including MDD. Thus, this narrative review aims to deepen the understanding of the involvement of synaptic formations and their components in the pathophysiology and treatment of MDD.
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Transtorno Depressivo Maior , Plasticidade Neuronal , Humanos , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Animais , Plasticidade Neuronal/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/efeitos dos fármacosRESUMO
The Rio de Janeiro Marine Aquarium (AquaRio) is the first to successfully maintain and reproduce the spiny butterfly ray (Gymnura altavela), providing unique information about the species' biology. Seven rays were kept in captivity between 2018 and 2023, two captured on the southeastern coast of Brazil and five born in the aquarium. The applied abiotic conditions and nutrition allowed for the survival, growth, and reproduction of these individuals. Growth parameters (asymptotic disk width-DW∞ and growth coefficient-k) were estimated based on the von Bertalanffy model using the Fabens method for males and females separately. The best models estimated DW∞ = 106.47 cm and k = 0.396 for males and DW∞ = 172.2 cm and k = 0.190 for females. Sexual dimorphism was corroborated, with females reaching larger sizes and presenting slower growth rates than males. The estimated k values were higher than those estimated for rays of similar size to G. altavela in the natural environment, probably due to the constant water temperature (around 25.5°C), food abundance, low population density, reduced predation rates, and high water quality in the captive environment. A comparison of the captivity findings with other studies on G. altavela age and growth in the Atlantic and Mediterranean indicates a broad phenotypic plasticity regarding growth. Three G. altavela reproductions were recorded, with size at birth appearing to be a key factor for pup's survival. Behavioral pattern observations associated with reproduction are also described, encompassing chasing and copulation, whereas the species' internal morphology is described through coelomic cavity ultrasound scanning.
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Rajidae , Animais , Feminino , Masculino , Rajidae/fisiologia , Rajidae/crescimento & desenvolvimento , Rajidae/anatomia & histologia , Reprodução , Brasil , Caracteres Sexuais , Características de História de Vida , Tamanho CorporalRESUMO
INTRODUCTION: Impairments in bottom-up perceptual processing have been associated to the age-related cognitive decline. Digital cognitive training focusing on bottom-up and/or top-down processes have been studied as a tool to remediate age-related cognitive decline. However, the most effective training type and order of application remain unclear. METHODS: One hundred and fifteen older adults were randomly assigned to 40 h of bottom-up then top-down or top-down then bottom-up digital cognitive training or an active control group. We evaluated cognition at baseline, after 20 h and 40 h of training and at follow-up using a mixed-model analysis. RESULTS: Global cognition improved, for the top-down group, after 20 h of training (p = 0.04; d = 0.7) and for all three groups after 40 h. The improvement in global cognition remained five months after the bottom-up/ top-down training (p = 0.009; d = 4.0). There were also improvements in the recall cognitive domain, after 20 h of training, for the bottom-up group and, after 40 h, for all three groups. Gains were observed in verbal fluency after 40 h of training for both therapeutic groups. Processing speed was significantly slower, after 20 h of training, for the control and bottom-up groups and, after 40 h, only for the control group. Emotion recognition improved, after 20 h, for the control group as compared to the therapeutic groups. CONCLUSIONS: These results indicate that the bottom-up/top-down training has the most endurable effects, which reveals the importance of the order of application of the exercises for gains in cognition in older adults.
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Cognição , Disfunção Cognitiva , Humanos , Masculino , Feminino , Idoso , Disfunção Cognitiva/terapia , Cognição/fisiologia , Terapia Cognitivo-Comportamental/métodos , Testes Neuropsicológicos , Idoso de 80 Anos ou mais , Treino CognitivoRESUMO
The Brazilian Atlantic Forest, renowned for its exceptional species richness and high endemism, acts as a vital reservoir of terrestrial biodiversity, often referred to as a biodiversity hotspot. Consequently, there is an urgent need to restore this forest to safeguard certain species and to unravel the ecophysiological adaptations of others. This study aims to integrate some physiological parameters, including gas exchange and chlorophyll a fluorescence, with anatomical and metabolic techniques to elucidate how five different native species (Paubrasilia echinata, Chorisia glaziovii, Clusia nemorosa, Licania tomentosa, and Schinus terebinthifolius), each occupying distinct ecological niches, respond to seasonal variations in rainfall and their consequences. Our investigation has revealed that C. nemorosa and P. echinata exhibit robust mechanisms to mitigate the adverse effects of drought. In contrast, others demonstrate greater adaptability (e.g., S. terebinthifolia and C. glaziovii). In this context, exploring metabolic pathways has proven invaluable in comprehending the physiological strategies and their significance in species acclimatization. This study provides a comprehensive overview of the impact of water restrictions and their consequential effects on various species, defining the strategies each species uses to mitigate water privation during the dry season.
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Through enviromics, precision breeding leverages innovative geotechnologies to customize crop varieties to specific environments, potentially improving both crop yield and genetic selection gains. In Brazil's four southernmost states, data from 183 distinct geographic field trials (also accounting for 2017-2021) covered information on 164 genotypes: 79 phenotyped maize hybrid genotypes for grain yield and their 85 nonphenotyped parents. Additionally, 1342 envirotypic covariates from weather, soil, sensor-based, and satellite sources were collected to engineer 10 K synthetic enviromic markers via machine learning. Soil, radiation light, and surface temperature variations remarkably affect differential genotype yield, hinting at ecophysiological adjustments including evapotranspiration and photosynthesis. The enviromic ensemble-based random regression model showcases superior predictive performance and efficiency compared to the baseline and kernel models, matching the best genotypes to specific geographic coordinates. Clustering analysis has identified regions that minimize genotype-environment (G × E) interactions. These findings underscore the potential of enviromics in crafting specific parental combinations to breed new, higher-yielding hybrid crops. The adequate use of envirotypic information can enhance the precision and efficiency of maize breeding by providing important inputs about the environmental factors that affect the average crop performance. Generating enviromic markers associated with grain yield can enable a better selection of hybrids for specific environments.
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OBJECTIVES: The present study aims to evaluate the impact of early exposure to brain injury and malnutrition on episodic memory and behavior. METHODS: For this, a systematic review was carried out in the Medline/Pubmed, Web of Science, Scopus, and LILACS databases with no year or language restrictions. RESULTS: Initially, 1759 studies were detected. After screening, 53 studies remained to be read in full. The meta-analysis demonstrated that exposure to double insults worsens episodic recognition memory but does not affect spatial memory. Early exposure to low-protein diets has been demonstrated to aggravate locomotor and masticatory sequelae. Furthermore, it reduces the weight of the soleus muscle and the muscle fibers of the masseter and digastric muscles. Early exposure to high-fat diets promotes an increase in oxidative stress and inflammation in the brain, increasing anxiety- and depression-like behavior and reducing locomotion. DISCUSSION: Epigenetic modifications were noted in the hippocampus, hypothalamus, and prefrontal cortex depending on the type of dietetic exposure in early life. These findings demonstrate the impact of the double insult on regions involved in cognitive and behavioral processes. Additional studies are essential to understand the real impact of the double insults in the critical period.
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DNA metabarcoding and stable isotope analysis have significantly advanced our understanding of marine trophic ecology, aiding systematic research on foraging habits and species conservation. In this study, we employed these methods to analyse faecal and blood samples, respectively, to compare the trophic ecology of two Red-billed Tropicbird (Phaethonaethereus; Linnaeus, 1758) colonies on Mexican islands in the Pacific. Trophic patterns among different breeding stages were also examined at both colonies. Dietary analysis reveals a preference for epipelagic fish, cephalopods, and small crustaceans, with variations between colonies and breeding stages. Isotopic values (δ15N and δ13C) align with DNA metabarcoding results, with wider niches during incubation stages. Differences in diet are linked to environmental conditions and trophic plasticity among breeding stages, influenced by changing physiological requirements and prey availability. Variations in dietary profiles reflect contrasting environmental conditions affecting local prey availability.
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Código de Barras de DNA Taxonômico , Cadeia Alimentar , Animais , Isótopos de Carbono/análise , Dieta , Isótopos de Nitrogênio/análise , Aves/fisiologia , MéxicoRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-ß, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-ß-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-ß. NFPS pretreatment prevented amyloid-ß-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-ß injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-ß-induced hippocampal damage.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Proteínas da Membrana Plasmática de Transporte de Glicina , Hipocampo , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Camundongos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Modelos Animais de Doenças , Sarcosina/análogos & derivados , Sarcosina/farmacologia , Sarcosina/uso terapêutico , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologiaRESUMO
INTRODUCTION: Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. METHODS: We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. RESULTS: HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-ß oligomers (AßO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. DISCUSSION: Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD. HIGHLIGHTS: The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice.
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Doença de Alzheimer , Modelos Animais de Doenças , Hipocampo , Ketamina , Camundongos Transgênicos , Plasticidade Neuronal , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Ketamina/análogos & derivados , Ketamina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Camundongos , Potenciação de Longa Duração/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , RNA Mensageiro/metabolismo , Memória/efeitos dos fármacos , Masculino , Transtornos da Memória/tratamento farmacológico , Camundongos Endogâmicos C57BL , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , HumanosRESUMO
The adaptive potential of plastic phenotypes relies on combined developmental responses. We investigated how manipulation of developmental conditions related to foraging mode in the fish Megaleporinus macrocephalus induces plastic responses at different levels: (a) functional modularity of skull bones, (b) biomechanical properties of the chondrocranium using finite element models, (c) bmp4 expression levels, used as a proxy for molecular pathways involved in bone responses to mechanical load. We identified new modules in experimental groups, suggesting increased integration in specific head bone elements associated with the development of subterminal and upturned mouths, which are major features of Megaleporinus plastic morphotypes released in the lab. Plastic responses in head shape involved differences in the magnitude of mechanical stress, which seem restricted to certain chondrocranium regions. Three bones represent a "mechanical unit" related to changes in mouth position induced by foraging mode, suggesting that functional modularity might be enhanced by the way specific regions respond to mechanical load. Differences in bmp4 expression levels between plastic morphotypes indicate associations between molecular signaling pathways and biomechanical responses to load. Our results offer a multilevel perspective of epigenetic factors involved in plastic responses, expanding our knowledge about mechanisms of developmental plasticity that originate novel complex phenotypes.