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INTRODUCTION: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive. METHODS: Here, we integrated [18F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis. RESULTS: Our results showed that multiple transcriptomic modules are associated with brain [18F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t(223) = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t(223) = 3.90, P value < 0.001). DISCUSSION: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD. HIGHLIGHTS: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [18F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [18F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [18F]FDG-PET metabolism.
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In the pursuit of novel antioxidant therapies for the prevention and treatment of neurodegenerative diseases, three new arylpiperazine derivatives (LQFM181, LQFM276, and LQFM277) were synthesized through a molecular hybridization approach involving piribedil and butylated hydroxytoluene lead compounds. To evaluate the antioxidant and neuroprotective activities of the arylpiperazine derivatives, we employed an integrated approach using both in vitro (SH-SY5Y cells) and in vivo (neurotoxicity induced by 3-nitropropionic acid in Swiss mice) models. In the in vitro tests, LQFM181 showed the most promising antioxidant activity at the neuronal membrane and cytoplasmic levels, and significant neuroprotective activity against the neurotoxicity induced by 3-nitropropionic acid. Hence, this compound was further subjected to in vivo evaluation, which demonstrated remarkable antioxidant capacity such as reduction of MDA and carbonyl protein levels, increased activities of succinate dehydrogenase, catalase, and superoxide dismutase. Interestingly, using the same in vivo model, LQFM181 also reduced locomotor behavior and memory dysfunction through its ability to decrease cholinesterase activity. Consequently, LQFM181 emerges as a promising candidate for further investigation into its neuroprotective potential, positioning it as a new therapeutic agent for neuroprotection.
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Antioxidantes , Fármacos Neuroprotetores , Nitrocompostos , Piperazinas , Propionatos , Animais , Propionatos/toxicidade , Nitrocompostos/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Camundongos , Piperazinas/farmacologia , Piperazinas/química , Humanos , Linhagem Celular Tumoral , Antioxidantes/farmacologia , Masculino , Succinato Desidrogenase/metabolismo , Superóxido Dismutase/metabolismo , Catalase/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
OBJECTIVES: To evaluate whether the glycosylation of chrysin (CHR) enhances its protective effects against aluminum-induced neurotoxicity. METHODS: To compare the antioxidant, anticholinesterase, and behavioral effects of CHR with its glycosylated form (CHR bonded to ß-d-glucose tetraacetate, denoted as LQFM280), we employed an integrated approach using both in vitro (SH-SY5Y cells) and in vivo (aluminum-induced neurotoxicity in Swiss mice) models. KEY FINDINGS: LQFM280 demonstrated higher antioxidant activity than CHR in both models. Specifically, LQFM280 exhibited the ability to exert antioxidant effects in the cytoplasm of SH-SY5Y cells, indicating its competence in traversing neuronal membranes. Remarkably, LQFM280 proved more effective than CHR in recovering memory loss and counteracting neuronal death in the aluminum chloride mice model, suggesting its increased bioavailability at the brain level. CONCLUSIONS: The glycosylation of CHR with ß-d-glucose tetraacetate amplifies its neuroprotective effects, positioning LQFM280 as a promising lead compound for safeguarding against neurodegenerative processes involving oxidative stress.
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Flavonoides , Neuroblastoma , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Camundongos , Animais , Humanos , Alumínio/toxicidade , Glucose/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Antioxidantes/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/prevenção & controle , Linhagem Celular TumoralRESUMO
BACKGROUND: Demographic changes in the world population have resulted in an increasingly aging society, with a progressive increase in the number of people in situations of dependence, who require assistance from family members to meet their basic needs. Caring for older adults involves performing diverse activities, resulting in reduced free time and tiredness, and fulfilling the demands and expectations related to personal, family, physical, and social life, consequently compromising the quality of life of the caregiver. In this context, the informal caregiver of hospitalized older adults emerges as the focus of attention. OBJECTIVE: The aim of this study was to describe the sociodemographic profile, health conditions, and burden of informal caregivers of older adults admitted to a university hospital in Brazil during the COVID-19 pandemic period. METHODS: This is a cross-sectional, descriptive, and analytical study that was conducted with 25 informal caregivers of hospitalized older adults in a university hospital in Brazil between August and September 2022. Three instruments were applied: Caregiver Burden Inventory, sociodemographic questionnaire, and health conditions questionnaire. The data were analyzed using SPSS version 28.0. Descriptive (frequency and percentage) and inferential analyses were performed using 2-sided Student t test with 95% CIs. RESULTS: Of the 25 interviewees, 18 (72%) were females, 17 (46%) were married or in a stable union, 14 (56%) completed secondary education, and 11 (44%) lived with the older adults who needed care. The average age of the participants was 44 (SD 12.8) years. Regarding their health conditions, most caregivers self-reported it as good (12/25, 48%). They provided care to their father or mother older than 70 years (14/25, 56%). The Caregiver Burden Inventory analysis showed that the caregivers were the most negatively impacted in the domains of personal life overload (mean 10.8, SD 3.46; P=.047) and physical overload (mean 10.6, SD 2.32; P=.02). CONCLUSIONS: In recent years, there has been an increase in the burden on informal caregivers of hospitalized older adults in Brazil, thereby impacting their personal and physical lives. The findings of our study show that health care professionals should be trained to promote health guidelines and actions to improve the personal and physical lives of the caregiver population in Brazil.
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Shewanella algae are gram-negative bacteria commonly found in aquatic environments. Infections caused by this agent are rarely documented; however, they are increasingly reported, mainly in countries with warm to temperate climates. Herein, we present a case of a 46-year-old immunocompetent woman with acute cellulitis and S. algae bacteremia (the first isolation culture performed at our hospital). To better understand the epidemiology, clinical outcomes, and treatment possibilities for S. algae bacteremia, we searched literature for similar cases; however, we did not find any cases of infections caused by this microorganism reported in Portugal or the Azores.
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Bacteriemia , Infecções por Bactérias Gram-Negativas , Shewanella , Humanos , Pessoa de Meia-Idade , Celulite (Flegmão)/diagnóstico , Celulite (Flegmão)/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Bacteriemia/diagnóstico , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologiaRESUMO
The γ-aminobutyric acid (GABA)ergic system is the primary inhibitory neurotransmission system in the mammalian brain. Its dysregulation has been shown in multiple brain conditions, but in Alzheimer's disease (AD) studies have provided contradictory results. Here, we conducted a systematic review with meta-analysis to investigate whether the GABAergic system is altered in AD patients compared to healthy controls (HC), following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 18th, 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABAA, GABAB, and GABAC receptors, GABA transporters (GAT) 1-3 and vesicular GAT in the brain, and GABA levels in the cerebrospinal fluid (CSF) and blood. Heterogeneity was estimated using the I2 index, and the risk of bias was assessed with an adapted questionnaire from the Joanna Briggs Institute Critical Appraisal Tools. The search identified 3631 articles, and 48 met the final inclusion criteria (518 HC, mean age 72.2, and 603 AD patients, mean age 75.6). Random-effects meta-analysis [standardized mean difference (SMD)] revealed that AD patients presented lower GABA levels in the brain (SMD = -0.48 [95% CI = -0.7, -0.27], adjusted p value (adj. p) < 0.001) and in the CSF (-0.41 [-0.72, -0.09], adj. p = 0.042), but not in the blood (-0.63 [-1.35, 0.1], adj. p = 0.176). In addition, GAD65/67 (-0.67 [-1.15, -0.2], adj. p = 0.006), GABAA receptor (-0.51 [-0.7, -0.33], adj. p < 0.001), and GABA transporters (-0.51 [-0.92, -0.09], adj. p = 0.016) were lower in the AD brain. Here, we showed a global reduction of GABAergic system components in the brain and lower GABA levels in the CSF of AD patients. Our findings suggest the GABAergic system is vulnerable to AD pathology and should be considered a potential target for developing pharmacological strategies and novel AD biomarkers.
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Resumo A COVID-19 gerou impacto na sociedade com elevados índices de morbidade e mortalidade. A utilização de indicador epidemiológico que estime a carga de doença, agregando em uma medida a mortalidade precoce e os casos não fatais, tem potencial de auxiliar no planejamento de ações adequadas em diferentes níveis de atenção à saúde. O objetivo deste artigo é estimar a carga de doença por COVID-19 em Florianópolis/SC de abril de 2020 a março de 2021. Foi realizado um estudo ecológico com dados de notificação e óbitos por COVID-19 no período de 12 meses. Utilizou-se o indicador de carga denominado Anos de Vida Perdidos Ajustados por Incapacidade (DALY), obtido pela soma dos Anos de Vida Perdidos (YLL) com os Anos Vividos com Incapacidade (YLD). Foram incluídos 78.907 casos de COVID-19 confirmados. Desses, 763 evoluíram a óbito no período estudado. No total, foram estimados 4.496,6 DALYs, taxa de 883,8 DALYs/100.000 habitantes. No sexo masculino, foram 2.693,1 DALYs, taxa de 1.098,0 DALYs/100.000 homens. Em mulheres, foram 1.803,8 DALYs, taxa de 684,4 DALYs/100.000 mulheres. A faixa etária mais acometida em ambos os sexos foi de 60 a 69 anos. Foi alta a carga de COVID-19 na cidade estudada. As maiores taxas foram encontradas no sexo feminino e na faixa-etária de 60-69 anos.
Abstract COVID-19 has had a powerful impact on society with high rates of morbidity and mortality. The use of an epidemiological indicator that estimates the burden of a disease by aggregating early mortality and non-fatal cases in a single measure has the potential to assist in the planning of more appropriate actions at different levels of health care. The scope of this article is to estimate the burden of disease due to COVID-19 in Florianópolis/SC from April 2020 through March 2021. An ecological study was carried out with data from notification and deaths by COVID-19 in the period of 12 months. The burden indicator called Disability-Adjusted Life Years (DALY) was used, obtained by adding the Years of Life Lost (YLL) to the Years of healthy life lost due to disability (YLD). A total of 78,907 confirmed COVID-19 cases were included. Of these, 763 died during the period under study. Overall, 4,496.9 DALYs were estimated, namely a rate of 883.8 DALYs per 100,000 inhabitants. In males, there were 2,693.1 DALYs, a rate of 1,098.0 DALYs per 100,000 males. In women, there were 1,803.8 DALYs, a rate of 684.4 DALYs per100,000 women. The age group most affected in both sexes was 60 to 69 years. The burden of COVID-19 was high in the city studied. The highest rates were in females and in the 60-69 age group.
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COVID-19 has had a powerful impact on society with high rates of morbidity and mortality. The use of an epidemiological indicator that estimates the burden of a disease by aggregating early mortality and non-fatal cases in a single measure has the potential to assist in the planning of more appropriate actions at different levels of health care. The scope of this article is to estimate the burden of disease due to COVID-19 in Florianópolis/SC from April 2020 through March 2021. An ecological study was carried out with data from notification and deaths by COVID-19 in the period of 12 months. The burden indicator called Disability-Adjusted Life Years (DALY) was used, obtained by adding the Years of Life Lost (YLL) to the Years of healthy life lost due to disability (YLD). A total of 78,907 confirmed COVID-19 cases were included. Of these, 763 died during the period under study. Overall, 4,496.9 DALYs were estimated, namely a rate of 883.8 DALYs per 100,000 inhabitants. In males, there were 2,693.1 DALYs, a rate of 1,098.0 DALYs per 100,000 males. In women, there were 1,803.8 DALYs, a rate of 684.4 DALYs per100,000 women. The age group most affected in both sexes was 60 to 69 years. The burden of COVID-19 was high in the city studied. The highest rates were in females and in the 60-69 age group.
A COVID-19 gerou impacto na sociedade com elevados índices de morbidade e mortalidade. A utilização de indicador epidemiológico que estime a carga de doença, agregando em uma medida a mortalidade precoce e os casos não fatais, tem potencial de auxiliar no planejamento de ações adequadas em diferentes níveis de atenção à saúde. O objetivo deste artigo é estimar a carga de doença por COVID-19 em Florianópolis/SC de abril de 2020 a março de 2021. Foi realizado um estudo ecológico com dados de notificação e óbitos por COVID-19 no período de 12 meses. Utilizou-se o indicador de carga denominado Anos de Vida Perdidos Ajustados por Incapacidade (DALY), obtido pela soma dos Anos de Vida Perdidos (YLL) com os Anos Vividos com Incapacidade (YLD). Foram incluídos 78.907 casos de COVID-19 confirmados. Desses, 763 evoluíram a óbito no período estudado. No total, foram estimados 4.496,6 DALYs, taxa de 883,8 DALYs/100.000 habitantes. No sexo masculino, foram 2.693,1 DALYs, taxa de 1.098,0 DALYs/100.000 homens. Em mulheres, foram 1.803,8 DALYs, taxa de 684,4 DALYs/100.000 mulheres. A faixa etária mais acometida em ambos os sexos foi de 60 a 69 anos. Foi alta a carga de COVID-19 na cidade estudada. As maiores taxas foram encontradas no sexo feminino e na faixa-etária de 60-69 anos.
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COVID-19 , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , COVID-19/epidemiologia , Brasil/epidemiologia , Morbidade , Nível de Saúde , Efeitos Psicossociais da Doença , Anos de Vida Ajustados por Qualidade de VidaRESUMO
INTRODUCTION: In Alzheimer's disease clinical research, glial fibrillary acidic protein (GFAP) released/leaked into the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was demonstrated that GFAP levels differ in individuals presenting with amyloid-ß (Aß) or tau pathologies. The molecular underpinnings behind this specificity are little explored. Here we investigated biomarker and transcriptomic associations of hippocampal GFAP-positive astrocytes with Aß and tau pathologies in humans and mouse models. METHODS: We studied 90 individuals with plasma GFAP, Aß- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting Aß (PS2APP) or tau (P301S) pathologies was conducted to explore differentially expressed genes (DEGs), Gene Ontology terms, and protein-protein interaction networks associated with each phenotype. RESULTS: In humans, we found that plasma GFAP associates with Aß but not tau pathology. Unveiling the unique nature of hippocampal GFAP-positive astrocytic responses to Aß or tau pathologies, mouse transcriptomics showed scarce overlap of DEGs between the Aß. and tau mouse models. While Aß GFAP-positive astrocytes were overrepresented with DEGs associated with proteostasis and exocytosis-related processes, tau hippocampal GFAP-positive astrocytes presented greater abnormalities in functions related to DNA/RNA processing and cytoskeleton dynamics. CONCLUSION: Our results offer insights into Aß- and tau-driven specific signatures in hippocampal GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte biomarkers and suggests the need to develop context-specific astrocyte targets to study AD. FUNDING: This study was supported by Instituto Serrapilheira, Alzheimer's Association, CAPES, CNPq and FAPERGS.
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Doença de Alzheimer , Astrócitos , Humanos , Camundongos , Animais , Astrócitos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Hipocampo/metabolismo , Proteínas tau/metabolismoRESUMO
Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD. Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features. Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.