Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease.

Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of ß-amyloid (Aß) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on Aß generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of Aß(1-40) and Aß(1-42) that is necessary for the formation of neurotoxic oligomeric Aß species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.

Brain-targeted proanthocyanidin metabolites for Alzheimer's disease treatment.

While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-ß-glucuronide (3'-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.

AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism.

Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-beta (Abeta) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Abeta levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Abeta metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-beta. Direct pharmacological and genetic activation of AMPK lowered extracellular Abeta accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Abeta levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Abeta. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease.

Obesity and the COVID-19: Analysis of the clinical and epidemiological profiles of 138 individuals.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is the disease caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the ongoing obesity pandemic, its coexistence with COVID-19 becomes worrying and has a less favorable outcome. OBJECTIVE: This study aimed to describe the clinical and epidemiological profiles of confirmed cases of COVID-19 in individuals with obesity in the state of Alagoas. METHODS: The observational cross-sectional study involving 138 confirmed cases of COVID-19 who had obesity as a comorbidity reported at the time of notification of the disease. The data were collected from the COVID-19 database in the state of Alagoas, and the variables analyzed were sex, age (and age group), race/color, outcome, clinical manifestations, and associated comorbidities. The Kolmogorov-Smirnov, Mann-Whitney U, χ², or Fisher's exact tests were performed as appropriate. The significance was set at 5 and 95% confidence intervals. RESULTS: There was a predominance of females (55.1%; n=76), aged <60 years (70.3%; n=97) and brown race/color (n=76; 55.1%). The most prevalent symptoms were cough (n=84; 60.9%), fever (n=78; 56.5%), headache (n=36; 26.1%), and adynamia (n=28; 20.3%). The median age was 49 years, with no difference between genders (p=0.340). The lethality rate was 17.4% (n=24), being higher in the male population (22.6% in males and 13.2% in females). Of the 24 deaths, 13 (54.2%) were recorded in the elderly people. In addition to obesity, 54.3% (n=75) had systemic arterial hypertension and 30.4% (n=42) had diabetes mellitus. There was no difference in the prevalence of comorbidity between genders. CONCLUSIONS: The profile studied demonstrates that obesity represents a challenge for coping with COVID-19.

Obesity and the COVID-19: Analysis of the clinical and epidemiological profiles of 138 individuals

SUMMARY INTRODUCTION: Coronavirus disease 2019 (COVID-19) is the disease caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the ongoing obesity pandemic, its coexistence with COVID-19 becomes worrying and has a less favorable outcome. OBJECTIVE: This study aimed to describe the clinical and epidemiological profiles of confirmed cases of COVID-19 in individuals with obesity in the state of Alagoas. METHODS: The observational cross-sectional study involving 138 confirmed cases of COVID-19 who had obesity as a comorbidity reported at the time of notification of the disease. The data were collected from the COVID-19 database in the state of Alagoas, and the variables analyzed were sex, age (and age group), race/color, outcome, clinical manifestations, and associated comorbidities. The Kolmogorov-Smirnov, Mann-Whitney U, χ², or Fisher's exact tests were performed as appropriate. The significance was set at 5 and 95% confidence intervals. RESULTS: There was a predominance of females (55.1%; n=76), aged <60 years (70.3%; n=97) and brown race/color (n=76; 55.1%). The most prevalent symptoms were cough (n=84; 60.9%), fever (n=78; 56.5%), headache (n=36; 26.1%), and adynamia (n=28; 20.3%). The median age was 49 years, with no difference between genders (p=0.340). The lethality rate was 17.4% (n=24), being higher in the male population (22.6% in males and 13.2% in females). Of the 24 deaths, 13 (54.2%) were recorded in the elderly people. In addition to obesity, 54.3% (n=75) had systemic arterial hypertension and 30.4% (n=42) had diabetes mellitus. There was no difference in the prevalence of comorbidity between genders. CONCLUSIONS: The profile studied demonstrates that obesity represents a challenge for coping with COVID-19.

Mortalidade por Câncer de Mama Feminino em Alagoas no Período de 2001 a 2016: Análise de Tendência e Distribuição Espacial / Female Breast Cancer Mortality in Alagoas from 2001 to 2016: Trend Analysis and Spatial Distribution / Mortalidad por Cáncer de Mama en Mujeres en Alagoas nel Periodo de 2001 a 2016: Análisis de Tendencias y Distribución Espacial

Introdução: O câncer de mama é a neoplasia que mais causa mortes na população feminina mundial e brasileira. Objetivo: Analisar o perfil epidemiológico, a tendência e a distribuição espacial da mortalidade por câncer de mama feminino em Alagoas no período de 2001 a 2016. Método: Trata-se de um estudo ecológico misto, incluindo os óbitos femininos por câncer de mama registrados em Alagoas durante esse período. Foram utilizadas as variáveis sociodemográficas (faixa etária, cor/raça, estado civil, escolaridade e local de ocorrência) e a taxa de mortalidade por faixa etária e por município do Estado. Os dados foram obtidos do Sistema de Informações sobre Mortalidade e os dados populacionais, do Instituto Brasileiro de Geografia e Estatística (IBGE). A análise de tendência utilizou o modelo de regressão por pontos de inflexão (joinpoint regression model) e a espacial, a estatística de Moran. Resultados: Houve 1.816 óbitos no período, 25,3% entre 50-59 anos, 46,3% de cor parda, 36,1% casadas, 35,5% com menos de oito anos de estudos e 67,2% de óbitos no ambiente hospitalar. As faixas etárias de 40 anos ou mais apresentaram tendências de crescimento, destacando-se 80 anos ou mais (percentual médio de variação anual: 9,2; p<0,001) com o maior crescimento. A distribuição espacial foi aleatória. Conclusão: A taxa de mortalidade por câncer de mama feminino cresceu no período de 2001 a 2016 nas faixas etárias de 40 anos ou mais no Estado e sem padrão espacial definido.

Introduction: Breast cancer is the neoplasm that causes more deaths in the female population worldwide and in Brazil. Objective: To analyze the epidemiological profile, trend and spatial distribution of female breast cancer mortality in Alagoas from 2001 to 2016. Method: Mixed ecological study, including female deaths from breast cancer recorded in Alagoas in the period. Sociodemographic variables (age, color/race, marital status, education and place of occurrence) and the specific mortality rate by age group and municipality were used. Data were obtained from the Mortality Information System and population data from the Brazilian Institute of Geography and Statistics (IBGE). The trend analysis used the Joinpoint regression model and Moran statistics for the spatial distribution. Results: 1,816 deaths in the period, 25.3% between 50-59 years, 46.3%, brown race, 36.1%, married, 35.5%, with less than 8 years of education and 67.2% of deaths within the hospital environment. The age groups of 40 years or older showed a growing trend and the highest growth, for 80 years old or more (average annual percent variation: 9.2; p<0.001). The spatial distribution was random. Conclusion: The mortality rate for female breast cancer increased in the period from 2001 to 2016 in the age group of 40 years and older in the state and without defined spatial pattern.

Introducción: El cáncer de mama es el cáncer que causa más muertes en la población femenina en todo el mundo y en Brasil. Objetivo: Analizar el perfil epidemiológico, la tendencia y la distribución espacial de la mortalidad por cáncer de mama femenino en Alagoas durante el período 2001 a 2016. Método: Este es un estudio ecológico mixto, que incluye muertes femeninas por cáncer de seno registradas en Alagoas durante el período. Se utilizaron variables sociodemográficas (grupo de edad, color/raza, estado civil, educación y lugar de ocurrencia) y tasa de mortalidad por grupo de edad y municipio del estado. Los datos se obtuvieron del Sistema de Información de Mortalidad y los datos de población del Instituto Brasileño de Geografía y Estadística (IBGE). El análisis de tendencias utilizó el modelo de regresión de punto de unión y el espacial con las estadísticas de Moran. Resultados: Hubo 1.816 muertes en el período, 25,3% entre 50-59 años, 46,3% marrón, 36,1% casados, 35,5% con menos de 8 años de educación y 67,2% de muertes en el período. Ambiente hospitalario. Los grupos de edad de 40 años y mayores mostraron una tendencia creciente, con un punto culminante de 80 años y mayores (cambio porcentual anual promedio: 9,2; p<0,001) con el mayor crecimiento. La distribución espacial fue aleatoria. Conclusión: La tasa de mortalidad por cáncer de mama femenino aumentó en el período 2001 a 2016 en el grupo de edad de 40 años y más en el estado y sin un patrón espacial definido.

Infecções de sítio cirúrgico: incidência e perfil de resistência antimicrobiana em unidade de terapia intensiva / Las infecciones del sitio quirúrgico: incidencia y perfil de resistencia antimicrobiana en la unidad de cuidados intensivos / Surgical site infections: incidence and profile of antimicrobial resistance in intensive care unit

Objetivo analisar a incidência das infecções de sítio cirúrgico e seu perfil de resistência microbiana em uma Unidade de Terapia Intensiva. Método trata-se de um estudo transversal, documental, descritivo. Foram incluídos na população de estudo 52 pacientes com infecção de sítio cirúrgico de um hospital universitário de Salvador, Bahia, no período de 2011 a 2013. Resultados a idade, cor/raça e número de dias em UTI demonstraram relação estatisticamente significante para o desfecho. Dentre as cirurgias, a da especialidade cardíaca destacou-se em número de infecções; dentre as bactérias, as do tipo gram-negativas (Enterobacter e Escherichia) estavam em culturas de 75,39% dos casos, sendo mais resistentes às penicilinas; o desfecho mais frequente foi a alta da unidade. Conclusão os estudos sobre essas infecções constituem um padrão importante para as unidades hospitalares que, na atualidade, enfrentam sérios riscos, especialmente relacionados ao uso e ao manejo de antibióticos com impacto no sistema de saúde.

Objetivo analizar la incidencia de infecciones del sitio quirúrgico y su perfil de resistencia microbiana en una unidad de cuidados intensivos. Método Este es un estudio transversal, documental, descriptivo. La populación del estudio incluyó 52 pacientes con infección del sitio quirúrgico de un hospital universitario en Salvador, Bahía, de 2011 a 2013. Resultados edad, color/raza y número de días en la UCI mostraron una relación estadísticamente significativa para el resultado. Entre las cirugías, la especialidad cardíaca se destacó en número de infecciones; Entre las bacterias, las bacterias gramnegativas (Enterobacter y Escherichia) se encontraban en cultivos del 75,39% de los casos, siendo más resistentes a las penicilinas; el resultado más frecuente fue el alta de la unidad. Conclusión Los estudios sobre estas infecciones son un estándar importante para los hospitales que actualmente enfrentan serios riesgos, especialmente relacionados con el uso y manejo de antibióticos con impacto en el sistema de salud.

Objective to analyze the incidence of surgical site infections and their profile of microbial resistance in an Intensive Care Unit. Method this was a cross-sectional, documentary, descriptive study. The study population included 52 patients with surgical site infection in a university hospital in Salvador, Bahia, in the period from 2011 to 2013. Results age, race/color and number of days in the ICU showed a statistically significant relationship with the outcome. Among the surgeries, the cardiac specialty stood out in number of infections; among the bacteria, gram-negative bacteria (Enterobacter and Escherichia) grew in cultures of 75.39% of the cases, being more resistant to penicillin; the most frequent outcome was the discharge from the unit. Conclusion the studies about these infections constitute an important standard for hospital units, which currently face serious risks, especially related to the use and management of antibiotics with impact on the health system.

Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease.

The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 +/-45.9 and 576.7 +/- 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.