ABSTRACT
Metabolic syndrome (MetS), a cluster of metabolic conditions that include obesity, hyperlipidemia, and insulin resistance, increases the risk of several aging-related brain diseases, including Alzheimer's disease (AD). However, the underlying mechanism explaining the link between MetS and brain function is poorly understood. Among the possible mediators are several adipose-derived secreted molecules called adipokines, including adiponectin (ApN) and resistin, which have been shown to regulate brain function by modulating several metabolic processes. To investigate the impact of adipokines on MetS, we employed a diet-induced model to induce the various complications associated with MetS. For this purpose, we administered a high-fat diet (HFD) to both WT and APP/PSN1 mice at a pre-symptomatic disease stage. Our data showed that MetS causes a fast decline in cognitive performance and stimulates Aß42 production in the brain. Interestingly, ApN treatment restored glucose metabolism and improved cognitive functions by 50% while decreasing the Aß42/40 ratio by approximately 65%. In contrast, resistin exacerbated Aß pathology, increased oxidative stress, and strongly reduced glucose metabolism. Together, our data demonstrate that ApN and resistin alterations could further contribute to AD pathology.
Subject(s)
Alzheimer Disease , Metabolic Syndrome , Animals , Mice , Adiponectin , Resistin , Alzheimer Disease/etiology , Adipokines , Obesity , GlucoseABSTRACT
Obese individuals exhibit altered circulating levels of adipokines, the proteins secreted by adipose tissue to mediate tissue cross-talk and regulate appetite and energy expenditure. The effect of adipokines on neuronal glucose metabolism, however, remains largely unknown. Two adipokines produced in adipose tissue, adiponectin and resistin, can gain access to the central nervous system (CNS), and their levels in the cerebrospinal fluid (CSF) are altered in obesity. We hypothesized that dysregulated adipokines in the CNS may underlie the reported link between obesity and higher risk of neurological disorders like Alzheimer's disease (AD), by affecting glucose metabolism in hippocampal neurons. Using cultured primary rat hippocampal neurons and mouse hippocampus slices, we show that recombinant adiponectin and resistin, at a concentration found in the CSF, have opposing effects on glucose metabolism. Adiponectin enhanced glucose uptake, glycolytic rate, and ATP production through an AMP-activated protein kinase (AMPK)-dependent mechanism; inhibiting AMPK abrogated the effects of adiponectin on glucose uptake and utilization. In contrast, resistin reduced glucose uptake, glycolytic rate, and ATP production, in part, by inhibiting hexokinase (HK) activity in hippocampal neurons. These data suggest that altered CNS levels of adipokines in the context of obesity may impact glucose metabolism in hippocampal neurons, brain region involved in learning and memory functions.
Subject(s)
Adiponectin/pharmacology , Glucose/metabolism , Hippocampus/cytology , Hippocampus/metabolism , Neurons/metabolism , Resistin/pharmacology , Animals , Cells, Cultured , Glycolysis/drug effects , Male , Mice, Inbred C57BL , Models, Biological , Neurons/drug effects , Rats, Sprague-DawleyABSTRACT
Selective estrogen receptor (ER) modulators are used as a therapy for ER+ clinical breast cancer, but they exhibit adverse effects. Herbal medicines may provide an alternative or complementary approach. Taheebo, extracted from the inner bark of the Tabebuia avellandae tree found in the Brazilian Amazon, exhibits selective anti-proliferative effects in carcinoma cell lines. The present study identifies the mechanistic leads for the inhibitory effects of Taheebo. Human breast carcinoma derived ER+MCF-7 cells were used as the model. Aqueous extract of Taheebo was the test compound. Cell cycle analysis, clonogenic assay, and global gene expression profiles were the quantitative parameters. Taheebo treatment resulted in a dose/time-dependent growth inhibition (S phase arrest, reduced clonogeneticity) and initiation of apoptosis (chromatin condensation). A 6-h treatment with 1.5 mg/ml Taheebo modulated the gene expression of G2 specific cyclin B1 (-2.0-fold); S phase specific PCNA (-2.0-fold) and OKL38 (+11.0-fold); apoptosis specific GADD-45 family (+1.9-5.4-fold), Caspases (+1.6-1.7-fold), BCL-2 family (-1.5-2.5-fold), estrogen responsive ESR1 (-1.5-fold), and xeno-biotic metabolism specific CYP 1A1 (+19.8 fold) and CYP 1B1 (+7.9-fold). The anti-proliferative effects of Taheebo correlate with down-regulated cell cycle regulatory and estrogen responsive genes, and up-regulated apoptosis specific and xeno-biotic metabolism specific genes. These data validate a rapid mechanistic approach to prioritize efficacious herbal medicines, thereby complementing the existing endocrine therapy for breast cancer.
Subject(s)
Cell Proliferation/drug effects , Plant Bark/chemistry , Plant Extracts/pharmacology , Plant Preparations/pharmacology , Receptors, Estrogen/metabolism , Tabebuia/chemistry , Apoptosis/drug effects , Brazil , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/ultrastructure , Cell Cycle/drug effects , Cell Line, Tumor , Cyclin B/genetics , Cyclin B1 , Cytochrome P-450 CYP1A1/genetics , Dose-Response Relationship, Drug , Female , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Microscopy, Electron, Transmission , Necrosis , Oligonucleotide Array Sequence Analysis , Reverse Transcriptase Polymerase Chain Reaction , Time FactorsABSTRACT
BACKGROUND: Common polymorphisms have been identified in genes suspected to play a role in asthma. We investigated their associations with wheeze and allergy in a case-control sample from Phase 2 of the International Study of Asthma and Allergies in Childhood. METHODS: We compared 1105 wheezing and 3137 non-wheezing children aged 8-12 years from 17 study centres in 13 countries. Genotyping of 55 candidate single nucleotide polymorphisms (SNPs) in 14 genes was performed using the Sequenom System. Logistic regression models were fitted separately for each centre and each SNP. A combined per allele odds ratio and measures of heterogeneity between centres were derived by random effects meta-analysis. RESULTS: Significant associations with wheeze in the past year were detected in only four genes (IL4R, TLR4, MS4A2, TLR9, P<0.05), with per allele odds ratios generally <1.3. Variants in IL4R and TLR4 were also related to allergen-specific IgE, while polymorphisms in FCER1B (MS4A2) and TLR9 were not. There were also highly significant associations (P<0.001) between SPINK5 variants and visible eczema (but not IgE levels) and between IL13 variants and total IgE. Heterogeneity of effects across centres was rare, despite differences in allele frequencies. CONCLUSIONS: Despite the biological plausibility of IgE-related mechanisms in asthma, very few of the tested candidates showed evidence of association with both wheeze and increased IgE levels. We were unable to confirm associations of the positional candidates DPP10 and PHF11 with wheeze, although our study had ample power to detect the expected associations of IL13 variants with IgE and SPINK5 variants with eczema.
Subject(s)
Genetic Association Studies , Hypersensitivity/genetics , Respiratory Sounds/genetics , Allergens/immunology , Asia , Asthma/genetics , Child , DNA-Binding Proteins/genetics , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Ecuador , Eczema/genetics , Europe , Gene Frequency/genetics , Guanine Nucleotide Exchange Factors/genetics , Humans , Hypersensitivity/blood , Hypersensitivity/immunology , Immunoglobulin E/blood , Immunoglobulin E/immunology , Interleukin-13/genetics , Interleukin-4 Receptor alpha Subunit/genetics , Linkage Disequilibrium/genetics , Lipopolysaccharide Receptors/genetics , New Zealand , Polymorphism, Single Nucleotide/genetics , Proteinase Inhibitory Proteins, Secretory/genetics , Receptors, IgE/genetics , Respiratory Sounds/immunology , Rhinitis, Allergic, Perennial/genetics , Rhinitis, Allergic, Seasonal/genetics , Serine Peptidase Inhibitor Kazal-Type 5 , Skin Tests , Toll-Like Receptor 2/genetics , Toll-Like Receptor 4/genetics , Toll-Like Receptor 9/genetics , Transcription Factors/genetics , Transforming Growth Factor beta1/genetics , Tumor Necrosis Factor-alpha/geneticsABSTRACT
Raccoon (Procyon lotor) food habits were studied at Manuel Antonio National Park, a tropical rain forest in the Pacific coast of Costa Rica from May to December 1987, from September to December 1989 and from January to April 1990. A 134 feces sample size was used to assess the most important items in raccoon diet: two crab species (Gecarcinus quadratus and Cardisoma crassum) with a relative frequency of 0.94 in the rainy season of 1987, 0.76 in the rainy season of 1989 and 0.65 in the dry season of 1990. Fruits were the second category in importance, with relative frequencies of 0.09 for 1987, 0.32 for 1989 and 0.44 for 1990.
Subject(s)
Feeding Behavior , Raccoons , Trees , Animals , Costa Rica , Humidity , Rain , SeasonsABSTRACT
OBJECTIVES: To determine gestational age (GA)-specific mortality rates; the effects of GA, birth weight, sex, and multiple gestation on mortality rates; short-term morbidity for infants born at 23 to 28 weeks GA; and impairment rates at a corrected chronologic age of 18 months for those born at 23 to 25 weeks GA. METHODS: A data base analysis was performed with a linked obstetric and a neonatal database. GA was determined by obstetric data and confirmed by early ultrasonography (available in 88%) on all births < 30 weeks GA at British Columbia's tertiary perinatal center from 1983 to 1989. RESULTS: Of 1024 births occurring between 23 and 28 weeks GA, 911 were live born. The mortality rate decreased with increasing GA: 84% at 23 weeks; 57% at 24 weeks; 45% at 25 weeks; 37% at 26 weeks; 23% at 27 weeks; and 13% at 28 weeks GA. For each GA, mortality rate versus birth weight plots showed a decreasing mortality rate with increasing birth weight, except for infants who were large for GA. Male infants had a higher mortality rate than female infants (odds ratio, 1.8; confidence interval, 1.4 to 2.5). Twins fared worse than singletons with a decreasing effect from 24 weeks GA (odds ratio, 10.3) to no effect at 28 weeks GA. The median number of days supported by mechanical ventilation and the length of stay in the neonatal intensive care unit decreased markedly with increasing GA. Eighteen-month outcome of survivors between 23 and 25 weeks GA with 93% follow-up rate revealed an overall impairment rate of 36%, but 6 of the 9 surviving 23-week infants had major impairments. CONCLUSIONS: The GA-specific perinatal outcome results of this large cohort provide information to assist in perinatal management decision making and for counseling parents prenatally.
Subject(s)
Databases, Factual/statistics & numerical data , Gestational Age , Infant Mortality , Infant, Premature , Adolescent , Adult , Birth Weight , Cohort Studies , Confidence Intervals , Female , Follow-Up Studies , Humans , Infant , Infant, Newborn , Length of Stay , Male , Middle Aged , Morbidity , Odds Ratio , Respiration, Artificial , Sex Factors , Survival Rate , Twins/statistics & numerical dataABSTRACT
El uso de la cocaína en el Perú ha atravesado por tres etapas. En la época prehispánica mediante la masticación de la hoja y la absorción del alcaloide a través de las mucosas orales. En el comienzo de este siglo por la inhalación intranasal del clorhidrato de cocaína. En los años setenta fumando la pasta de cocaína. Las tres formas de consumo se mantienen hasta hoy, predominando la última entre los sectores populares. La infección por el virus de la inmunodeficiencia humana (VIH-1) hizo su aparición en el Perú hace diez años extendiéndose rápidamente a todas las capas sociales del país, especialmente entre las más pobres. En 163 países infectados con el VIH-1 en el Hospital Dos de Mayo, estudiados mediante un protocolo especial, se ha comprobado que treinta y cuatro (20.8 por ciento) abusaban de la cocaína en forma no parental. Todos los enfermos comenzaron a usar el alcaloide antes de contraer la infección por el VIH-1. Se analiza las caraterísticas demográficas, clínicas y epidemiológicas de estos sujetos. Asimismo, se describe otros factores de riesgo para la diseminación de la infección en este grupo. En conclusión, tanto el abuso de la cocaína como la contaminación con el VIH-1, son hoy graves problemas de salud pública. Se requiere tomar urgentes medidas preventivas y terapéuticas para evitar la extensión de ambas epidemias en nuestro país. Estas acciones correctivas sólo tendrán éxito si se adoptan tanto por las agencias gubernamentales como por los grupos vecinales, particulares y familiares.